TECHNICAL FIELD

The present disclosure relates to novel compounds capable of modulating NLRP3 activity. Such activity may be inhibited by the compounds described herein. The present invention further describes the synthesis of the compounds and their uses as medicaments in diseases or disorders where modulation of NLRP3 may be beneficial.

BACKGROUND

NLR family pyrin domain containing 3 (NLRP3) (also known as NACHT, LRR and PYD domains- containing protein 3 [NALP3] and cryopyrin), is a protein that in humans is encoded by the NLRP3 gene.

NLRP3 is expressed predominantly in cells involved in innate immunity, such as macrophages and astrocytes and microglia in the CNS and is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome (Tao J.H., et al., (2013). "P2X7R: a potential key regulator of acute gouty arthritis", review. Seminars in Arthritis and Rheumatism. 43 (3), 376-80; Lu A., et al. (2015). "Structural mechanisms of inflammasome assembly", review. The FEBS Journal. 282 (3), 435-44).

Assembly of the NLRP3 inflammasome leads to caspase 1 -dependent release of the pro-inflammatory cytokines IL-1 β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death.

The NLRP3 inflammasome detects products of damaged cells such as extracellular ATP and crystalline uric acid. Activated NLRP3 in turn triggers an immune response. Mutations in the NLRP3 gene are associated with a number of autoimmune and other diseases.

At present, to treat NLRP3-associated diseases, drugs are available that block IL-1 p, such as canakinumab® (anti-IL-1 β antibody), anakinra® (IL-1 receptor antagonist), and rilonacept® (decoy IL- 1 receptor). These biological agents are being used to treat Cryopyrin-associated periodic syndrome (CAPS) and other diseases associated with IL-1 β (Dinarello C.A., et al. Treating inflammation by blocking interleukin-1 in humans; Semin Immunol. (2013) 25, 469-84). However, activated NLRP3 inflammasome does not produce only IL-1 p, there are other cytokines such as IL-18 which may also contribute to the NLRP3-associated disorders (Nowarski R, et al. Epithelial IL-18 equilibrium controls barrier function in colitis. Cell. (2015) 163, 1444-56; Lu B, et al. Novel role of PKR in inflammasome activation and HMGB1 release; Nature. (2012) 488, 670-4). Moreover, IL-1 β production can be mediated by other inflammasomes or by inflammasome-independent pathways; so inhibitors aimed at IL-1 β may result in unintentional immunosuppressive effects. Therefore, pharmacological inhibitors which specifically target NLRP3 or the NLRP3 inflammasome only could be a better option for treatment of NLRP3-associated diseases.

Examples of NLRP3-related diseases, or diseases associated with the NLRP3 inflammasome. Such diseases are detailed in WO2022/063876, in the section entitled “Pharmacology” on pages 25-34, which is incorporated herein by reference, and the main categories are diseases associated with: inflammation, inflammatory disease, immune diseases, cancer, infections, central nervous system diseases, metabolic diseases, cardiovascular diseases, respiratory diseases, liver diseases, renal diseases, ocular diseases, skin diseases, lymphatic conditions, psychological disorders, graft versus host diseases, bone diseases, blood diseases, allodynia, any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

Specific examples of NLRP3-related diseases, or diseases associated with the NLRP3 inflammasome include: autoimmune disorder, inflammatory disease, cancer and/or oncologic disease (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis) and/or HIV infection and replication, inflammatory conditions such as rheumatoid arthritis, multiple sclerosis, psoriasis, asthma, atopic dermatitis, Crohn’s disease, autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, non-alcoholic steatohepatitis NASH, neuroinflammation-related disorders (e.g. brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, and wound healing and scar formation.

The present invention has been devised with the above observations in mind.

SUMMARY OF THE INVENTION

In one aspect of the invention there is provided a compound of structural Formula I: wherein

Ring A is a 6-membered heteroaryl ring containing 1-3 N atoms;

Ring B is a 6-membered heteroaryl ring containing 1-3 N atoms; wherein Ring A and Ring B may be independently optionally substituted with a further 1-2 substituents selected from the group consisting of: OR ^1a , N(R ^ia ) ₂ , CN, halogen, -C=OOH, - C(R ^1a ) ₂ C=OOH, -C=ON(R ^1a ) ₂ ; -CR ^ia ₂ C=ON(R ^1a ) ₂ ; -CR ^ia ₂ N(R ^1a ) ₂ ; -SO ₂ R ^1a , C1-C4 alkyl, C3-C6 cycloalkyi and C4-C6 heterocycioalkyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl groups are optionally substituted with -OH, C1-C2 alkyl, or halogen; wherein:

R ¹ is C3-C10 monocyclic, bicyclic, spirocyclic or bridged cycloalkyl, optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen, CN, .N(R ^1a )2, ~(CH ₂ )mOH, (CH ₂ ) _m COOH, -OR ^,a . -(C=O)R ^1s , .(00)N(R ^1s ) ₂ . (C=O)OR ^1a , -SR ^1a , SOR ¹³ , -SO ₂ R ^1a , -SON(R ^1a ) ₂ , -SO ₂ N(R ^1a ) ₂ , C1-C4 alkyl, C3-C6 cycloalkyi and C4-C6 heterocycloalkyl wherein the C1-C4 alkyl, C3- C6 cycloalkyl or C4-C6 heterocycloalkyl group can be further substituted with 1 -3 substituents selected from R ^1S ; or

R ¹ is a C3-C10 monocyclic, bicyclic, spirocyclic or bridged heteroalkyl, or heteroalkenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, -CN. -OR ^1a , -N(R ^!a ) ₂ , -O(C=O)N(R ^1a ) ₂ , -NR ^1a (C=O)N(R ^!a ) _2! -NR ^1a (C=O)OR ^1a , -SR’ ^a . -SOR ^1a , - SOzR ^1a , .SON(R ^1a ) ₂ , SO ₂ N(R ^1a ) ₂ , -N=SO(R ^1a ) ₂ , -SO(=NR ^1a )(R ^1a ), -(C=O)N(R ^1a ) ₂ , -CO ₂ R ^1a , and C1-C4 alkyl, C3-C6 cycloalkyl and C4-C6 heterocycloalkyl wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4- C6 heterocycloalkyl group can be further substituted with 1-3 substituents selected from R ^1b ; or

R ¹ is a C2-C6 alkyl, optionally substituted with 1 or more substituents independently selected from: F, -CN, -N(R ^1a ) _2s -OR ^1a , -SR ^1a , -SOR ^1a , -SO ₂ R ^1a , -SON(R ^1a ) ₂ , -SO ₂ N(R ^1a ) ₂ , -SO(=NR ^1a )(R ^1a ), - N=SO(R ^1a ) ₂ , C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl group can be further substituted with 1-3 substituents selected from R ^1b ; or

R ¹ is an aryl or heteroaryl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, CN, -N(R ^1a ) ₂ , -OR ¹³ , (C=O)R ^1a ,

(C=O)N(R ¹³ ) ₂ , (C=O)OR ^1a , -SR ¹³ , -SOR ^1a , -SO ₂ R ^ia , -SON(R ^1a ) ₂ , -SO ₂ N(R ^{1 a} ) ₂ , C1-C4 alkyl, C3-C6 cycloalkyi and C4-C6 heterocycioalkyl wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl group can be further substituted with 1-3 substituents selected from R ^1b ; and wherein:

R ^1a is selected from the group consisting of: H, C1-C4 alkyl, C3-C6 cycloalkyi and C4-C6 heterocycioalkyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyi or C4-C6 heterocycioalkyl groups are optionally substituted with -OH or halogen;

R ^1b is selected from the group consisting of: halogen, C1-C4 alkyl, -N(R ^1a ) ₂ and OR ¹³ ;

R ² is C5-C10 monocyclic or bicyclic aryl or heteroaryl, optionally substituted with one or more substituents selected from R ^2a ;

R ^2a is selected from the group consisting of: -OR ^1a , -N(R ^1a ) ₂ , halogen, -CN, -SR ^ia , -SOR ^ia , - SO ₂ R ^1a , -SON(R ^1a ) ₂ , -SO ₂ N(R ^1a ) ₂ , -N=SO(R ^1a ) ₂ , -SO(=NR ^1a )(R ^1a ), -CO ₂ .NR’ ^a , -CO ₂ R ¹⁵ , or C1-C4 alkyl, C3-C6 cycloalkyi or C4-C6 heterocycioalkyl wherein the C1-C4 alkyl, C3-C6 cycloalkyi or C4-C6 heterocycioalkyl group can be further substituted with 1-3 substituents selected from R ^1b , R® and R ⁷ ; wherein R ⁸ and R ⁷ are independently selected from the group consisting of: H, -N(R ^1a ) ₂ . -OR ^1a , C1-C4 alkyl, C3-C6 cycloalkyi and C4-C6 heterocycioalkyl wherein the C1-C4 aikyi, C3-C6 cycloalkyi or C4-C6 heterocycioalkyl group can be optionally substituted with 1-3 substituents selected from R1 ^b . In embodiments of Formula I, there is provided a compound of structural Formula la: wherein R ¹ and R ² are as defined for Formula I, and:

D is independently selected from N, CR ³ and -N(R ^1a )-C(=O)- or -N=C(OR ^ia )-, wherein R ^1a is as defined in Formula I;

R ³ is selected from the group consisting of: H, C1-C2 alkyl, CN, or halogen;

E is N or C n is 2.

In embodiments of Formulae I and la, there is provided a compound of structural Formula Ila or lib: wherein Ring A or Ring B, E, R ¹ , R ² , Xa and Xb are as defined for Formula I (including subformulae);

Xa and Xb are each independently selected from N and CR ³ ; or

Xa and Xb taken together are -N(R ^1a )-C(=O)- or -N=C(OR ^,a )-;

R ³ is selected from the group consisting of: H, C1-C2 alkyl, CN, or halogen; and wherein is an aromatic bond (i.e. a bond in an aromatic system between two sp2 hybridised atoms).

In embodiments of Formula I and/or Formula II (including subformulae), there is provided a compound of structural Formula Illa or lllb: wherein Ring A or Ring B, E, Xa, Xb, R ¹ and R ² are as defined for Formula I, Formula Ila and Formula lib (or sub-formulae thereof); wherein is an aromatic bond. In embodiments of Formula I, Formula II and/or Formula III (or sub-formulae thereof), there is provided a compound of structural Formula V: wherein E, Xa, Xb, R ¹ and R ² are as defined for Formula II and III (including subformulae).

In embodiments of Formula V, there is provided a compound having a structural formula as follows: wherein each of the above structures may be substituted with 1 to 4 further substituents dependent on the number of ring atoms available with suitable valency, wherein the further substituents are independently selected from the group consisting of: OR ^1a , N(R ^1a )2, -SO ₂ ^R1a , CN, halogen, C1-C4 alkyl, C1-C4 amido, C1-C4 ester, C1-C4 alkoxy, C3-C6 cycloalkyl and C4-C6 heterocycloalkyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl groups are optionally substituted with -OH or OR ^1a , or halogen.

In some embodiments of Formula V, there is provided a compound having a structural formula as follows: wherein each of the above structures may be substituted with 1 to 4 further substituents dependent on the number of ring atoms available with suitable valency, wherein the further substituents are independently selected from the group consisting of: OR ^1a , N(R' ^ia )2, -SO ₂ ^R1a , CN, halogen, C1-C4 alkyl, C1-C4 amido, C1-C4 ester, C1-C4 alkoxy, C3-C6 cycloalkyl and C4-C6 heterocycloalkyl, wherein the

C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl groups are optionally substituted with -OH or OR ^1a , or halogen.

In embodiments, the further substituents on Formulae VI, V or VI are selected from:

Suitably further substitution on the bicyclic core as defined by Formula V, is on one or more, suitably, one, of the carbon atoms adjacent (alpha to) the ring junction atom.

In embodiments, R ² has the general Form wherein: denotes the attachment point to the bicyclic core;

W is a C5-C10 monocyclic aryl or heteroaryl; x is 1 , 2, 3 or 4 wherein R ^2a is defined as in Formula I, wherein at least one R ^2a is independently selected from the group consisting of: -OH, -[(CR ^1a )2]nOH, wherein n is 1 to 3, OR ^1a , -NHR ^1a , -NHCOR ^1a , - NHCON(R ^ia )2, -NHSO _n R ^1a -NHSO,iN(R ^1a )2, wherein n is 1 or 2, C1-C3 alkyl optionally substituted by R ^s and/or R ⁷ , halogen and C1-C3 haloalkyl (e.g. -CHFa, -CHF2CH3, CH2CHF2); and wherein R ^ia is defined as in Formula I. In embodiments, R ² has the general Formula VII and at least one R ^2a is OH or OMe. Suitably, R ^2a is positioned ortho to the attachment point to Ring A. Suitably, R ^2a is OH and positioned ortho to the attachment point to Ring A. in embodiments, R ² has the general formula Vila, Vllb, Vile or VI Id : denotes the attachment point to the bicyclic core;

R ^2a and x are as for Formula VII.

In embodiments, R ² is: wherein: denotes the attachment point to the bicyclic core.

In embodiments, R ¹ is selected from the following:

wherein:

R ^1c is selected from the group consisting of: halogen. -CN, -OR ^1a , -N(R ^1a )?„ (CH2)mOH, (CH ₂ )mCOOH, -O(C=O)N(R ^1a ) ₂ . -NR ^!a (C=O)N(R ^1a ) ₂ . -NR ^1a (C=O)OR ^1a -. -SR ^1a , -SOR ^1a , -SO?.R ^1a , - SON(R ^:a ) ₂ , SO;:N(R ^ia ) ₂ , -N=SO(R ^ia ) ₂ , -SO(=NR ^1a )(R ^1a ), -(£>O)N(R ^1a ) ₂ , -CO ₂ R ^1a , and C1-C4 alkyl, C3- C6 cycloalkyl and C4-C6 heterocycloalkyl wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl group can be further substituted with 1-3 substituents selected from R ^1b . wherein R ^{1 b} is as for Formula I; or wherein two R ^ic groups are attached to the same atom, the two R ^1c groups combine to form an optionally substituted 3-7-membered ring, wherein the 3-7 membered ring may optionally contain 1-2 heteroatoms selected from N or O;

R ^1d is selected from H, C1-C4 alkyl, -C(=O)C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, (CH ₂ )mOH, (CH ₂ ) _m COOH, optionally substituted (CH^-CWW COOH and (CH ₂ )m-CWW ¹ ’ CONHR ^1a , wherein W ¹ and W are each independently selected from optionally substituted C1-C4 alkyl, or W ¹ and W are joined to form an optionally substituted C3-C7 cycloalkyl;

G is O or CH ₂ ; m is 0, 1 , 2 or 3.

In specific embodiments, compounds of the present invention have a structure as defined in Table 1 (i.e. compounds 1-32, 33-36, 38-45, 52-55, 62, 69, 76-81 , 83-84, 87-92, 94-102, 104-107, 109, 111- 112, 114-117, 120, 122, 125-127, 130, 134-139, 141-158, 160-168, 170, 172-175, 177-178, 180-233).

Suitably, compounds of the present invention have the structure of compound nos. 1-32, 33-34, 38-45, 62, 69, 76-77, 80-81 , 83-84, 87-92, 94-102, 104-107, 109, 1 11-112, 114-117, 120, 122, 125-127, 130, 134-139, 141-158, 160-168, 170, 172-175, 177-178, 180-233.

Suitably compounds of the present invention have the structure of compound nos. 4, 193, 222, 209, 156, 220, 6, 164, 29, 155, 134, 221 , 227, 148, 22, 151 , 198, 155, and 189. In a second aspect, the invention provides a pharmaceutical composition comprising one or more compound of the first aspect of the invention or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form, or pharmaceutically active metabolite thereof, or combinations thereof, and one or more pharmaceutically acceptable carrier.

In a third aspect the invention provides the compound of the first aspect or the pharmaceutical composition of the second aspect for use in the treatment of a disorder or disease. In embodiments the disease or disorder is selected from the group consisting of: autoimmune disorder, inflammatory disease, cancer and/or oncologic disease (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis) and/or HIV infection and replication, inflammatory conditions such as rheumatoid arthritis, multiple sclerosis, psoriasis, asthma, atopic dermatitis, Crohn’s disease, autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g. brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, and wound healing and scar formation; hepatic encephalopathy, chronic insomnia, stroke, migraine, atherosclerosis / coronary artery disease, glioma and CNS diseases.

Examples of CNS diseases or disorders that may be treated by the compounds of the present invention include, but are not limited to: Parkinson’s disease, Alzheimer’s disease, dementia, motor neuron disease, Huntington’s disease, cerebral malaria, brain injury from pneumococcal meningitis, intracranial aneurysms, traumatic brain injury, multiple sclerosis, and amyotrophic lateral sclerosis (see: W02002/063876: (1) page 32 lines 11 , and (2) page 25 line 34 to page 26 line 3, supported with literature references; which are each incorporated herein by reference); see also Song et al, Frontiers Cellular Neurosci. 2017; 11 ; 63: Table 1 page 6 “Neurological disorders that involve the NLRP3 inflammasome”, with references therein which are each incorporated herein by reference: brain infection: S. pneumoniae meningitis, Japanese encephalitis, Influenza virus infection, HIV/AIDS,

Acute injury: cerebral ischemia, traumatic brain injury, spinal cord injury, subarachnoid haemorrhage, intracerebral haemorrhage

Neurodegenerative diseases: Alzheimer’s disease, Multiple sclerosis, Amyotprohic lateral sclerosis (with prion diseases as remains controversial)

Furthermore, additional CNS disorders not listed above are: Age-related cognitive function (Wang T, et al. Neurochem Int. 2022; 152: 105220); Epilepsy (Zhang H, et al. Neurochem Res. 2022; 47(3): 713- 722); Perioperative neurocognitive disorder (Chen K, et al. Adv Sci.; 2022 : e2104106); Autism (Zhao P, et al.. J Neuropathol Exp Neurol. 2022; ;81 (2): 127-134); Autoimmune encephalomyelitis (Li C, et al. Front Cell Dev Biol.; 2022; 16; 10: 822236); Neuropathic pain (Derangula K, et al. Int immunopharmacol. 2022; 102: 108397); spinal cord injury (Zhao H, el al; BMC Neurosci.; 2022; 23(1): 16); sepsis associated encephalopathy (Xiong Y, et al.; Psychogeriatrics; 2022; 22(2): 167-179); alcohol-induced cognitive impairment (Mohamed DI, et al; Pharmaceutics; 2022; 14(3): 529); and depression (Bian H, et al.; Int Immunopharmacol; 2022; 107: 108723). in embodiments, the compound is an inhibitor of NLRP3.

In embodiments, the use comprises administering the compound orally; topically; by inhalation; by intranasal administration; or systemically by intravenous, intraperitoneal, subcutaneous, or intramuscular injection.

In embodiments, the use comprises administering one or more compound according to the first or second aspects optionally in combination with one or more additional therapeutic agent. Suitably, the administering comprises administering the one or more compound according to any one of first or second embodiments simultaneously, sequentially or separately from the one or more additional therapeutic agent. in embodiments, the use comprises administering to a subject an effective amount of the compound according to the first or second aspects, wherein the effective amount is between about 5 nM and about 10 pM in the blood, or component thereof, of the subject. in a fifth aspect the invention provides a method of treatment of a disorder or disease where modulation of the NLRP3 inflammasome may be beneficial, wherein said method of treatment comprises administering to a patient in need thereof, one or more compounds of the first aspect of the invention or one or more pharmaceutical compositions of the second aspect of the invention.

In embodiments the disorder or disease is selected from the group consisting of: autoimmune disorder, inflammatory disease, cancer and/or oncologic disease (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis) and/or HIV infection and replication, inflammatory conditions such as rheumatoid arthritis, multiple sclerosis, psoriasis, asthma, atopic dermatitis, Crohn’s disease, autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocaicinosis), chronic liver disease, NASH, neuroinflammation- reiated disorders (e.g. brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, and wound healing and scar formation; and CNS diseases as described elsewhere herein.

In embodiments the compound is an inhibitor of NLRP3 or an inhibitor of the NLRP3 inflammasome. Within the scope of this application, it is expressly intended that the various aspects, embodiments, examples and alternatives set out in the preceding paragraphs, in the claims and/or in the following description and drawings, and in particular the individual features thereof, may be taken independently or in any combination. That is, all embodiments and/or features of any embodiment can be combined in anyway and/or combination, unless such features are incompatible. More particularly, it is specifically intended that any embodiment of any aspect may form an embodiment of any other aspect, and all such combinations are encompassed within the scope of the invention. The applicant reserves the right to change any originally filed claim or file any new claim, accordingly, including the right to amend any originally filed claim to depend on and/or incorporate any feature of any other claim although not originally claimed in that manner.

DETAILED DESCRIPTION

Described herein are compounds and compositions (e.g., organic molecules, research tools, pharmaceutical formulations and therapeutics); uses for the compounds and compositions of the disclosure (in vitro and in vivo); as well as corresponding methods, whether diagnostic, therapeutic, prophylactic or for research applications. The chemical synthesis and biological testing of the compounds of the disclosure are also described. Beneficially, the compounds, compositions, uses and methods have utility in research towards and/or the treatment of diseases or disorders in animals, such as humans. Diseases or disorders which may benefit from NLRP3 modulation, or modulation of the NLRP3 inflammasome include, for example, autoimmune disorder, inflammatory disease, cancer and/or oncologic disease (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis) and/or HIV infection and replication, inflammatory conditions such as rheumatoid arthritis, multiple sclerosis, psoriasis, asthma, atopic dermatitis, Crohn’s disease, autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g. brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, and wound healing and scar formation.

The compounds may also or alternatively be useful as lead molecules for the selection, screening and development of further derivatives that may have one or more improved beneficial drug property, as desired. Such further selection and screening may be carried out using the proprietary computational evolutionary algorithm described e.g. in the Applicant’s earlier published patent application WO 2011/061548, which is hereby incorporated by reference in its entirety.

The disclosure also encompasses salts, solvates and functional derivatives of the compounds described herein. These compounds may be useful in the treatment of diseases or disorders which may benefit from NLRP3 modulation or modulation of the NLRP3 inflammasome, such as autoimmune disorder, inflammatory disease, cancer and/or oncoiogic disease (e.g. coion cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis) and/or HIV infection and replication, inflammatory conditions such as rheumatoid arthritis, multiple sclerosis, psoriasis, asthma, atopic dermatitis, Crohn’s disease, autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation- related disorders (e.g. brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, and wound healing and scar formation.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art (e.g. in organic, physical or theoretical chemistry; biochemistry and molecular biology).

Unless otherwise indicated, the practice of the present invention employs conventional techniques in chemistry and chemical methods, biochemistry, molecular biology, pharmaceutical formulation, and delivery and treatment regimens for patients, which are within the capabilities of a person of ordinary skill in the art. Such techniques are also described in the literature cited herein. All documents cited in this disclosure are herein incorporated by reference in their entirety.

Prior to setting forth the detailed description of the invention, a number of definitions are provided that will assist in the understanding of the disclosure.

In accordance with this disclosure, the terms 'molecule' or 'molecules’ are used interchangeably with the terms 'compound' or ‘compounds’, and sometimes the term 'chemical structure'. The term 'drug' is typically used in the context of a pharmaceutical, pharmaceutical composition, medicament or the like, which has a known or predicted physiological or in vitro activity of medical significance; but such characteristics and qualities are not excluded in a molecule or compound of the disclosure. The term 'drug' is therefore used interchangeably with the alternative terms and phrases 'therapeutic (agent)', 'pharmaceutical (agent)’, and 'active (agent)’. Therapeutics according to the disclosure also encompass compositions and pharmaceutical formulations comprising the compounds of the disclosure.

Procirugs and solvates of the compounds of the disclosure are also encompassed within the scope of the disclosure. The term 'prodrug' means a compound (e.g. a drug precursor) that is transformed in vivo to yield a compound of the disclosure or a pharmaceutically acceptable salt, solvate or ester of the compound. The transformation may occur by various mechanisms (e.g. by metabolic or chemical processes), such as by hydrolysis of a hydrolysable bond, e.g. in blood (see Higuchi & Stella (1987), "Pro-drugs as Novel Delivery Systems", vol. 14 of the A.C.S. Symposium Series; (1987), "Bioreversible Carriers in Drug Design", Roche, ed., American Pharmaceutical Association and Pergamon Press). The compositions and medicaments of the disclosure therefore may comprise prodrugs of the compounds of the disclosure. In some aspects and embodiments the compounds of the disclosure are themselves prodrugs which may be metabolised in vivo to give the therapeutically effective compound.

The invention also includes various deuterated forms of the compounds of any of the Formulas disclosed herein, including Formulas I to V (inc. corresponding subgeneric formulas defined herein), respectively, or a pharmaceutically acceptable salt and/or a corresponding tautomer form thereof (including subgeneric formulas, as defined above) of the present invention. Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. A person of ordinary skill in the art will know how to synthesize deuterated forms of the compounds of any of the Formulas disclosed herein, including Formulas I to V, respectively, (including subgeneric formulas, as defined above) or a pharmaceutically acceptable salt and/or a corresponding tautomer form thereof (including subgeneric formulas, as defined above) of the present invention. For example, deuterated materials, such as alkyl groups may be prepared by conventional techniques (see for example: methyl- d3 -amine available from Aldrich Chemical Co., Milwaukee, Wl, Cat. No.489, 689-2).

The subject invention also includes isotopically-labelled compounds which are identical to those recited in any of the Formulas disclosed herein, including Formulas I to V (inc. corresponding subgeneric formulas defined herein), respectively, or a pharmaceutically acceptable salt and/or a corresponding tautomer form thereof (including subgeneric formulas, as defined above) of the present invention but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine such as 3 H, 11 C, 14 C, 18 F, 123 I or 125 I. Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically labelled compounds of the present invention, for example those into which radioactive isotopes such as 3 H or 14 C have been incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e. 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred for their ease of preparation and detectability. 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography).

In the context of the present disclosure, the terms 'individual', 'subject', or 'patient' are used interchangeably to indicate an animal that may be suffering from a medical (pathological) condition and may be responsive to a molecule, pharmaceutical drug, medical treatment or therapeutic treatment regimen of the disclosure. The animal is suitably a mammal, such as a human, cow, sheep, pig, dog, cat, bat, mouse or rat. In particular, the subject may be a human.

The term ‘alkyl’ refers to a monovalent, optionally substituted, saturated aliphatic hydrocarbon radical. Any number of carbon atoms may be present, but typically the number of carbon atoms in the alkyl group may be from 1 to about 20, from 1 to about 12, from 1 to about 6 or from 1 to about 4. Usefully, the number of carbon atoms is indicated, for example, a C1-12 alkyl (or C1-12 alkyl) refers to any alkyl group containing 1 to 12 carbon atoms in the chain. An alkyl group may be a straight chain (i.e. linear), branched chain, or cyclic. ‘Lower alkyl’ refers to an alkyl of 1 to 6 carbon atoms in the chain, and may have from 1 to 4 carbon atoms, or 1 to 2 carbon atoms. Thus, representative examples of lower alkyl radicals include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, amyl (C5H11), sec-butyl, tert-butyl, sec-amyl, tert-pentyl, 2-ethylbutyl, 2,3-dimethylbutyl, and the like. ‘Higher alkyl’ refers to alkyls of 7 carbons and above, including n-heptyl, n-octyl, n-nonyl, n-decyl, n-dodecyl, n- tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl, and the like, along with branched variations thereof. A linear carbon chain of say 4 to 6 carbons would refer to the chain length not including any carbons residing on a branch, whereas in a branched chain it would refer to the total number. Optional substituents for alkyl and other groups are described below.

The term ‘substituted’ means that one or more hydrogen atoms (attached to a carbon or heteroatom) is replaced with a selection from the indicated group of substituents, provided that the designated atom's normal valency under the existing circumstances is not exceeded. The group may be optionally substituted with particular substituents at positions that do not significantly interfere with the preparation of compounds falling within the scope of this invention and on the understanding that the substitution(s) does not significantly adversely affect the biological activity or structural stability of the compound. Combinations of substituents are permissible only if such combinations result in stable compounds. By ‘stable compound’ or ‘stable structure’, it is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and/or formulation into an efficacious therapeutic agent. By ‘optionally substituted’ it is meant that the group concerned is either unsubstituted, or at least one hydrogen atom is replaced with one of the specified substituent groups, radicals or moieties.

Any radical I group / moiety described herein that may be substituted (or optionally substituted) may be substituted with one or more (e.g. one, two, three, four or five) substituents, which are independently selected from the designated group of substituents. Thus, substituents may be selected from the group: halogen (or ‘halo’, e.g. F, Cl and Br), hydroxyl (-OH), amino or aminyl (-NH2), thiol (-SH), cyano (-CN), (lower) alkyl, (lower) alkoxy, (lower) alkenyl, (lower) alkynyl, aryl, heteroaryl, (lower) alkylthio, oxo, haloalkyl, hydroxyalkyl, nitro (-NO ₂ ), phosphate, azido (-Ns), alkoxycarbonyl, carboxy, alkylcarboxy, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, thioalkyl, alkylsulfonyl, arylsulfinyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino, arylcarbonylamino, cycloalkyl, heterocycloalkyl, unless otherwise indicated. Alternatively, where the substituents are on an aryl or other cyclic ring system, two adjacent atoms may be substituted with a methylenedioxy or ethylenedioxy group. More suitably, the substituents are selected from: halogen, hydroxy, amino, thiol, cyano, (C1- Ce)alkyl, (Ci-Ca)alkoxy, (Ci-Ce)alkenyl, (Ci-C5)alkynyl, aryl, aryl(Ci-Ce)alkyl, aryl(Ci-Ce)alkoxy, heteroaryl, (Ci-Ce)alkylthio, oxo, halo(Ci-Ce)alkyl, hydroxy(Ci-Ce)alkyl, nitro, phosphate, azido, (C1- Ce)alkoxycarbonyl, carboxy, (Ci-Cs)alkylcarboxy, (Ci-Cs)alkylamino, di(Ci-C6)alkylamino, amino(Ci- Cejalkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)alkylamino(Ci-C6)alkyl, thio(Ci-C6)alkyl, (Ci- C6)alkylsulfonyl, arylsulfinyl, (Ci-C6)alkylaminosulfonyl, arylaminosulfonyl, (Ci-C6)alkylsulfonylamino, arylsulfonylamino, carbamoyl, (Ci-C6)alkylcarbamoyl, di(Ci-C6)alkylcarbamoyl, arylcarbamoyl, (Ci- C6)alkylcarbonylamino, arylcarbonylamino, (Ci-C6)cycloalkyl, and heterocycloalkyl. Still more suitably, the substituents are selected from one or more of: fluoro, chloro, bromo, hydroxy, (Ci-C6)alkyl, (Ci- C6)haloalkyl, (Ci-Celalkoxy, (C5-Cs)aryl, a 5- or 6-membered heteroaryl, (C4-C6)cycloalkyl, a 4- to 6- membered heterocycloalkyl, cyano, (Ci-Cs)alkylthio, amino, -NH(alkyl), -NH((Ci-Cs)cycloalkyl), -N((Ci- C6)alkyl)2, -OC(O)-(Ci-Co)alkyl, -OC(O)-(C5-Ce)aryl, -OC(0)-(Ci-Ce)cycloalkyl, carboxy and -C(O)O- (Ci-Ce)alkyl. Most suitably, the substituents are selected from one or more of: fluoro, chloro, bromo, hydroxy, amino, (Ci-Ce)alkyl and (Ci-Co)alkoxy, wherein alkyl and alkoxy are optionally substituted by one or more chloro. Particularly preferred substituents are: chloro, methyl, ethyl, methoxy and ethoxy The term ‘halo’ or ‘halogen’ refers to a monovalent halogen radical chosen from chloro, bromo, iodo, and fluoro. A ‘halogenated’ compound is one substituted with one or more halo substituent. Preferred halo groups are F, Cl and Br, and most preferred is F.

When used herein, the term ‘independently’, in reference to the substitution of a parent moiety with one or more substituents, means that the parent moiety may be substituted with any of the listed substituents, either individually or in combination, and any number of chemically possible substituents may be used. In any of the embodiments, where a group is substituted, it may contain up to 5, up to 4, up to 3, or 1 and 2 substituents. As a non-limiting example, useful substituents include: phenyl or pyridine, independently substituted with one or more lower alkyl, lower alkoxy or halo substituents, such as: chlorophenyl, dichlorophenyl, trichlorophenyl, tolyl, xylyl, 2-chloro-3-methylphenyl, 2,3-dichloro- 4- methylphenyl, etc.

As used herein, the term ‘alkylene’ or ‘alkylenyl’ means a difunctional group obtained by removal of a hydrogen atom from an alkyl group as defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene. ‘Lower alkylene’ means an alkylene having from 1 to 6 carbon atoms in the chain, and may be straight or branched. Alkylene groups are optionally substituted.

The term ‘alkenyl’ refers to a monovalent, optionally substituted, unsaturated aliphatic hydrocarbon radical. Therefore, an alkenyl has at least one carbon-carbon double bond (C=C). The number of carbon atoms in the alkenyl group may be indicated, such as from 2 to about 20. For example, a C2- 12 alkenyl (or C2-12 alkenyl) refers to an alkenyl group containing 2 to 12 carbon atoms in the structure. Alkenyl groups may be straight (i.e. linear), branched chain, or cyclic. ‘Lower alkenyl’ refers to an alkenyl of 1 to 6 carbon atoms, and may have from 1 to 4 carbon atoms, or 1 to 2 carbon atoms. Representative examples of lower alkenyl radicals include ethenyl, 1-propenyl, 1-butenyl, 1-pentenyl, 1-hexenyl, isopropenyl, isobutenyl, and the like. Higher alkenyl refers to alkenyls of seven carbons and above, such as 1 -heptenyl, 1 -octenyl, 1-nonenyl, 1 -decenyl, 1 -dodecenyl, 1 -tetradecenyl, 1- hexadecenyl, 1 -octadecenyl, 1-eicosenyl, and the like, along with branched variations thereof. Optional substituents include are described elsewhere. The term ‘heteroalkenyl’ refers to an alkenyl comprising one or more heteroatoms. Suitably the heteroatoms are one or more N, O or S.

‘Alkenylene’ means a difunctional group obtained by removal of a hydrogen from an alkenyl group that is defined above. Non-limiting examples of alkenylene include -CH=CH-, -C(CH3)=CH-, and - CH=CHCH ₂ -.

‘Alkynyl’ and ‘lower alkynyl’ is defined similarly to the term ‘alkenyl’, except that it includes at least one carbon-carbon triple bond.

The term ‘alkoxy’ refers to a monovalent radical of the formula RO-, where R is any alkyl, alkenyl or alkynyl as defined herein. Alkoxy groups may be optionally substituted by any of the optional substituents described herein. ‘Lower alkoxy’ has the formula RO-, where the R group is a lower alkyl, alkenyl or alkynyl. Representative alkoxy radicals include methoxy, ethoxy, n-propoxy, n-butoxy, n- pentyloxy, n-hexyloxy, isopropoxy, isobutoxy, isopentyloxy, amyloxy, sec-butoxy, tert-butoxy, tertpentyloxy, and the like. Preferred alkoxy groups are methoxy and ethoxy.

The term ‘aryl’ as used herein refers to a substituted or unsubstituted aromatic carbocyclic radical containing from 5 to about 15 carbon atoms; and preferably 5 or 6 carbon atoms. An aryl group may have only one individual carbon ring, or may comprise one or more fused rings in which at least one ring is aromatic in nature. A ‘phenyl’ is a radical formed by removal of a hydrogen atom from a benzene ring, and may be substituted or unsubstituted. A ‘phenoxy’ group, therefore, is a radical of the formula RO-, wherein R is a phenyl radical. ‘Benzyl’ is a radical of the formula R-CH2-, wherein R is phenyl, and ‘benzyloxy’ is a radical of the formula RO-, wherein R is benzyl. Non-limiting examples of aryl radicals include, phenyl, naphthyl, benzyl, biphenyl, furanyl, pyridinyl, indanyl, anthraquinolyl, tetrahydronaphthyi, a benzoic acid radical, a furan-2-carboxylic acid radical, and the like.

A ‘heteroaryi’ group is herein defined as a substituted or unsubstituted ‘aryl’ group in which one or more carbon atoms in the ring structure has been replaced with a heteroatom, such as nitrogen, oxygen or sulphur. Generally, the heteroaryl group contains one or two heteroatoms. A preferred heteroatom is N. Exemplary heteroaryl groups include: furan, benzofuran, isobenzofuran, pyrrole, indole, isoindole, thiophene, benzothiophene, benzo[c]thiophene, imidazole, benzimidazole, purine, pyrazole, indazole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, pyridine, quinoline, isoquinoline, pyrazine, quinoxaline, acridine, pyrimidine, quinazoline, pyridazine and cinnoline.

The terms ‘heterocycle’ or ‘heterocyclic’ group or ‘heterocyclyl’ as used herein refer to a monovalent radical of from about 4- to about 15- ring atoms, and preferably 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10- ring members. Generally, the heterocyclic group contains one, two or three heteroatoms, selected independently from nitrogen, oxygen and sulphur. A preferred heteroatom is N. A heterocyclic group may have only one individual ring or may comprise one or more fused rings in which at least one ring contains a heteroatom. It may be fully saturated or partially saturated and may be substituted or unsubstituted as in the case or aryl and heteroaryi groups. Representative examples of unsaturated 5- membered heterocycles with only one heteroatom include 2- or 3-pyrrolyl, 2- or 3-furanyl, and 2- or 3- thiophenyl. Corresponding partially saturated or fully saturated radicals include 3-pyrrolin-2-yl, 2- or 3- pyrrolindinyl, 2- or 3-tetrahydrofuranyl, and 2- or 3-tetrahydrothiophenyl. Representative unsaturated 5-membered heterocyclic radicals having two heteroatoms include imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and the like. The corresponding fully saturated and partially saturated radicals are also included. Representative examples of unsaturated 6-membered heterocycles with only one heteroatom include 2-, 3-, or 4-pyridinyl, 2H-pyranyl, and 4H-pryanyl. Corresponding partially saturated or fully saturated radicals include 2-, 3-, or 4-piperidinyl, 2-, 3-, or 4-tetrahydropyranyl and the like. Representative unsaturated 6-membered heterocyclic radicals having two heteroatoms include 3- or 4- pyridazinyl, 2-, 4-, or 5-pyrimidinyl, 2-pyrazinyl, morpholino, and the like. The corresponding fully saturated and partially saturated radicals are also included, e.g. 2-piperazine. The heterocyclic radical is bonded through an available carbon atom or heteroatom in the heterocyclic ring directly to the entity or through a linker such as an alkylene such as methylene or ethylene.

Unless defined otherwise, ‘room temperature’ is intended to mean a temperature of from about 18 to 28°C, typically between about 18 and 25°C, and more typically between about 18 and 22°C. As used herein, the phrase ‘room temperature’ may be shortened to ‘rt’ or ‘RT’.

Molecules and Compounds

Disclosed herein is a compound having the structural Formula I: wherein

Ring A is a 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from N, O or S, suitably Ring A is a 6-membered heteroaryi ring containing 1-3 heteroatoms selected from N, O or S, suitably the 1-3 heteroatoms are N;

Ring B is a 5- or 6-membered heteroaryi ring containing 1-3 heteroatoms selected from N, O or S, suitably Ring B is a 6-membered heteroaryi ring containing 1-3 heteroatoms selected from N, O or S, suitably the 1-3 heteroatoms are N; wherein Ring A and Ring B may be independently optionally substituted with a further 1-2 substituents selected from the group consisting of: OR ^1a , N(R ^ia ) ₂ , CN, halogen, -C=OOH, C(R ^1a ) ₂ C=OOH, -C=ON(R ^1a ) ₂ ; -C-C=ON(R ^ia ) ₂ ; -C-N(R ^1a ) ₂ ; C1-C4 alkyl, C3-C6 cycloalkyl and C4-C6 heterocycloalkyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl groups are optionally substituted with -OH, -OR ^ia ,C1-C2 alkyl, or halogen; wherein:

R ¹ is C3-C10 monocyclic, bicyclic, spirocyclic or bridged cycloalkyl, optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen, CN, -N(R ^1a ) ₂ , -OR ^1a , -(C-O)R ^1a , -(C=O)N(R ^1a )2, .(C=O)OR ^1a , -SR ^1a , -SOR ^1a , -SO ₂ R ^1s , -SON(R ^1a ) ₂ , -SO ₂ N(R ^1a )2, -SO ₂ R ^1a , C1-C4 alkyl, C3-C6 cycloalkyl and C4-C6 heterocycloaikyl wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl group can be further substituted 'with 1-3 substituents selected from R ^ib ; or

R ¹ is a C3-C10 monocyclic, bicyclic, spirocyclic or bridged heteroalkyl or heteroalkenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, -CN, -OR ¹ ®, -N(R’ ^a ) ₂ , -(CH ₂ )mOH, (CH ₂ ) _m COOH, -O(C=O)N(R ^!a )2, -NR ^1a (C=O)N(R ^1a )?., . NR ¹ ®(C=O)OR ^1a , -SR ^1a , -SOR ^1a , -SOzR ¹⁸ , -SON(R ^1a ) ₂ , .SO ₂ N(R ^1a ) ₂ , -N=SO(R ^1a ) ₂ , -SO(=NR ^1a )(R ^1a ), - (C=O)N(R ^1a ) ₂ , -CO ₂ R ¹³ , and C1-C4 alkyl, C3-C6 cycloalkyl and C4-C6 heterocycloalkyl wherein the C1- C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl group can be further substituted with 1-3 substituents selected from R ^1b ; or

R ¹ is a C2-C6 alkyl, optionally substituted with 1 or more substituents independently selected from: F, -CN, -N(R ^1a ) _2s -OR ¹³ , -SR ¹³ , -SOR ^1a , -SO ₂ R ¹³ , -SON(R ¹³ ) ₂ , -SO ₂ N(R ¹³ ) ₂ , -SO(=NR ^1a )(R ^1a ), - N=SO(R ^1a )2, C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl group can be further substituted with 1-3 substituents selected from R ^1b ; or

R ¹ is an aryl or heteroaryl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, CN, -N(R ¹³ )2, -OR ¹³ , (C=O)R ^1a ,

(C=O)N(R ^1a ) ₂ , -(C=O)OR ^1a , -SR ¹³ , -SOR ^1a , -SO ₂ R ^ia , -SON(R ^1a ) ₂ , -SO ₂ N(R ^{1 a} ) ₂ , C1-C4 alkyl, C3-C6 cycloalkyl and C4-C6 heterocycloalkyl wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl group can be further substituted with 1-3 substituents selected from R ^1b , and wherein:

R ^1a is selected from the group consisting of: H, C1-C4 alkyl, C3-C6 cycloalkyl and C4-C6 heterocycloalkyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl groups are optionally substituted with -OH or halogen;

R ^1b is selected from the group consisting of: halogen, C1-C4 alkyl, -N(R ^1a ) ₂ and OR ^1a ;

R ² is C5-C10 monocyclic or bicyclic aryl or heteroaryl, optionally substituted with one or more substituents selected from R ^2a ;

R ^2a is selected from the group consisting of: -OR ^1a , -N(R ^1a ) ₂ , halogen, -CN, -SR ^ia , -SOR ^ia , - SO ₂ R ^1a , -SON(R ^1a ) ₂ , -SO ₂ N(R ^1a ) ₂ , -N=SO(R ^1a ) ₂ , -SO(=NR ^1a )(R ^1a ), -CO?.NR ^1a , -COzR ¹³ , or C1-C4 alkyl, C3-C6 cycioaikyl or C4-C6 heterocycloalkyl wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl group can be further substituted with 1-3 substituents selected from R ^1b , R ⁸ and R ⁷ ; wherein R ⁸ and R ⁷ are independently selected from the group consisting of: H, -N(R ^1a ) ₂ . -OR ^1a , C1-C4 alkyl, C3-C6 cycloalkyl and C4-C6 heterocycloalkyl wherein the C1-C4 alkyl, C3-C6 cycioalkyi or C4-C6 heterocycloalkyl group can be optionally substituted with 1-3 substituents selected from R1 ^b ;

In embodiments of Formula I, there is provided a compound of structural Formula la: wherein R ¹ and R ² are as defined for Formula I, and:

D is independently selected from N, S, O, CR ³ and -N(R ^1a )-C(=O)- or -N=C(OR ^ia )-, wherein R ^1a is as defined in Formula I, suitably D is independently selected from N CR ³ and -N(R ^1a )-C(=O)- or - N=C(OR ^ia )-, wherein R ^1a is as defined in Formula I;

R ³ is selected from the group consisting of: H, C1-C2 alkyl, CN, or halogen.

E is N or C; n is 1 or 2, suitably n is 2.

In embodiments of Formulae I and la, there is provided a compound of structural Formula Ila or lib: wherein Ring A or Ring B, E, R ¹ , R ^1a and R ² are as defined for Formula I (including subformulae);

Xa and Xb are each independently selected from N and CR ³ ,; or

Xa and Xb taken together are -N(R ^1a )-C(=O)- or -N=C(OR ^,a )-;

R ³ is selected from the group consisting of: H, C1-C2 alkyl, CN, or halogen; and wherein is an aromatic bond (i,e. a bond in an aromatic system between two sp2 hybridised atoms).

In embodiments of Formula I and/or Formula II (including subformulae), there is provided a compound of structural Formula Illa or lllb: wherein Ring A or Ring B, E, Xa, Xb, R ¹ , R ² , R3 and R4are as defined for Formula Ila and Formula wherein is an aromatic bond. In embodiments of Formula I, Formula II and/or Formula III (or sub-formulas thereof), there is provided a compound of structural Formula IV, V and VI: wherein Xa, Xb, R ¹ , R ^1a , R ² , and R ³ are as defined for Formula II and III (including subformulae);

Y is CR ³ , NR ⁴ , O or S

R ⁴ is H or C1-C4 alkyl.

Suitably, there is provided a compound of structural Formula V.

In embodiments of Formula IV or VI, there is provided a compound having a structural formula as follows:

wherein each of the above structures may optionally be substituted with 1 or 2 further substituents dependent on the number of ring atoms available with suitable valency, wherein the further substituents are independently selected from the group consisting of: OR ^1a , N(R ^1a )2, CN, halogen, C1-C4 alkyl, C4 amido, C1-C4 ester, C1-C4 alkoxy, C3-C6 cycloalkyl and C4-C6 heterocycloalkyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl groups are optionally substituted with -OH, C1-C2 alkyl, or halogen.

In embodiments of Formula V, there is provided a compound having a structural formula as follows:

wherein each of the above structures may optionally be substituted with 1 to 4 further substituents dependent on the number of ring atoms available with suitable valency, wherein the further substituents are independently selected from the group consisting of: OR ^1a , N(R ^1a )2, -SO ₂ ^R1a , CN, halogen, C1-C4 alkyl, C1-C4 amido, C1-C4 ester, C1-C4 alkoxy, C3-C6 cycloalkyl and C4-C6 heterocycloalkyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycioalkyl groups are optionally substituted with -OH, C1-C2 alkyl, or halogen. Suitably, embodiments of Formula IV, V or VI have a structural formula as follows: wherein each of the above structures may optionally be substituted with 1 or 2 further substituents dependent on the number of ring atoms available with suitable valency, wherein the further substituents are independently selected from the group consisting of: OR ^1a , N(R ^1a )2, CN, halogen, C1-C4 alkyl, C4 amido, C1-C4 ester, C1-C4 alkoxy, C3-C6 cycloalkyl and C4-C6 heterocycloalkyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl groups are optionally substituted with -OH, C1-C2 alkyl, or halogen. Suitably, embodiments of Formula V have a structural formula as follows: wherein each of the above structures may optionally be substituted with 1 or 2 further substituents dependent on the number of ring atoms available with suitable valency, wherein the further substituents are independently selected from the group consisting of: OR ^1a , N(R ^1a )2, CN, halogen, C1-C4 alkyl, C4 amido, C1-C4 ester, C1-C4 alkoxy, C3-C6 cycloalkyl and C4-C6 heterocycloalkyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl groups are optionally substituted with -OH, C1-C2 alkyl, or halogen.

In embodiments, the further substituents on Formulae VI, V or VI are selected from:

Suitably further substitution on the bicyclic core as defined by any of Formulae IV, V and VI, suitably Formula V is on one or more, suitably, one, of the carbon atoms adjacent (alpha to) the ring junction atom.

In embodiments, R ² has the general Form wherein: denotes the attachment point to the bicyclic core;

W is a C5-C10 monocyclic aryl or heteroaryl; x is 1 , 2, 3 or 4 wherein R ^2a is defined as in Formula I, and wherein at least one R ^2a is independently selected from the group consisting of: -OH, -[(CR ^1a )2]nOH, wherein n is 1 to 3, OR ^1a , -NHR ^1a , -NHCOR ^1a , - NHCON(R ^1a )2, -NHSO _n R ^1a -NHSO _n N(R ^1a )2, wherein n is 1 or 2, halogen (e.g. fluoro, chloro), C1-C3 alkyl optionally substituted by R ^s and/or R ⁷ , halogen and C1-C3 haloalkyl (e.g. -CHFa, -CHF2CH3, CH2CHF2); and wherein R ^ia is defined as in Formula I. In embodiments, R ² has the general Formula VII and at least one R ^2a is OH or Ome or Me. Suitably, R ^2a is positioned ortho to the attachment point to Ring A. Suitably, R ^2a is OH and positioned ortho to the attachment point to Ring A. In embodiments, R ² has the general formula Vila, Vllb, Vile or Vi Id : denotes the attachment point to the bicyclic core;

R ^2a and x are as for Formula VII.

In embodiments of Formula VII, Vila and Vllb, R ^2a is selected from the group consisting of: Me, CF3, OMe, Cl and F.

In embodiments, R ² is:

In embodiments, R ² is: wherein: denotes the attachment point to the bicyclic core. in embodiments, R ¹ is selected from the following: wherein:

R ^1c is selected from the group consisting of: halogen, -CN, -OR ¹ ®, -N(R ^1a )2, (CFfeJmOH, C6 cycloalkyl and C4-C6 heterocycloalkyl wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl group can be further substituted with 1-3 substituents selected from R ^ib . wherein R ^ib is as for Formula I; or wherein two R ^1c groups are attached to the same atom, the two R ^1c groups combine to form an optionally substituted 3-7-membered ring, wherein the 3-7 membered ring may optionally contain 1-2 heteroatoms selected from N or O;

R ^1d is selected from H, C1-C4 alkyl, -C(=O)C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, (CH ₂ )mOH, (CH ₂ )mCOOH, optionally substituted (CH ₂ ) _m -CWW COOH and (CH ₂ ) _m -CW ¹ W ¹ -CONHR’ ⁵ , wherein W ¹ and W ¹ ’ are each independently selected from optionally substituted C1-C4 alkyl, or W ¹ and W ¹ ’ are joined to form an optionally substituted C3-C7 cycloalkyl;

G is O or CH ₂ ; m is 0, 1 , 2 or 3.

In embodiments, R ¹ is selected from the following:

denotes the attachment point to the bicyclic core. In specific embodiments, the compounds of the present invention have the structure as defined in

Table 1 below.

Table 1: Exemplified compounds Suitably, compounds of the present invention have the structure of compound nos. 1-32, 33-34, 38-45, 62, 69, 76-77, 80-81 , 83-84, 87-92, 94-102, 104-107, 109, 1 11-112, 114-117, 120, 122, 125-127, 130, 134-139, 141-158, 160-168, 170, 172-175, 177-178, 180-233.

Suitably compounds of the present invention have the structure of compound nos. 4, 193, 222, 209, 156, 220, 6, 164, 29, 155, 134, 221 , 227, 148, 22, 151 , 198, 155, and 189.

In a second aspect, the invention provides a pharmaceutical composition comprising one or more compound of the first aspect of the invention or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form, or pharmaceutically active metabolite thereof, or combinations thereof, and one or more pharmaceutically acceptable carrier.

In a third aspect the invention provides the compound of the first aspect or the pharmaceutical composition of the second aspect for use in the treatment of a disorder or disease selected from inflammasome-related disease / disorders, immune diseases, inflammatory diseases, auto-immune diseases, or auto-inflammatory diseases, for example, autoinflammatory fever syndromes (e.g., cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver related disease / disorders (e.g. chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis related disorders (e.g. gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy e.g. acute, chronic), kidney related diseases (e.g. hyperoxaluria, lupus nephritis, Type I i Type II diabetes and related complications (e.g. nephropathy, retinopathy), hypertensive nephropathy, hemodialysis related inflammation), neuroinflammation-related diseases (e.g, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), cardiovascular / metabolic diseases/disorders (e.g. cardiovascular risk reduction (CvRR), hypertension, atherosclerosis, type I and type II diabetes and related complications, peripheral artery disease (PAD), acute heart failure), inflammatory skin diseases (e.g. hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age- related macular degeneration, and cancer related diseases / disorders (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis). In particular, autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis); and CNS diseases and disorders as herein before defined.

In embodiments, the disorder or disease is selected from the group consisting of: rheumatoid arthritis, multiple sclerosis, psoriasis, atopic dermatitis, autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation- related disorders (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis); and CNS diseases and disorders as herein before defined.

In embodiments, the compound is an inhibitor of NL.RP3.

In embodiments, the use comprises administering the compound orally; topically; by inhalation; by intranasal administration; or systemically by intravenous, intraperitoneal, subcutaneous, or intramuscular injection.

In embodiments, the use comprises administering one or more compound according to the first or second aspects optionally in combination with one or more additional therapeutic agent. Suitably, the administering comprises administering the one or more compound according to any one of first or second embodiments simultaneously, sequentially or separately from the one or more additional therapeutic agent.

In embodiments, the use comprises administering to a subject an effective amount of the compound according to the first or second aspects, wherein the effective amount is between about 5 nM and about 10 pM in the blood, or component thereof, of the subject.

In a fifth aspect the invention provides a method of treatment of a disorder or disease where modulation of the NLRP3 inflammasome may be beneficial wherein said method of treatment comprises administering to a patient in need thereof, one or more compounds of the first aspect of the invention or one or more pharmaceutical compositions of the second aspect of the invention.

In embodiments the disorder or disease is selected from the group consisting of: inflammasome-related disease / disorders, immune diseases, inflammatory diseases, auto-immune diseases, or auto- inflammatory diseases, for example, autoinflammatory fever syndromes (e.g., cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver related disease / disorders (e.g. chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis related disorders (e.g. gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy e.g. acute, chronic), kidney related diseases (e.g. hyperoxaluria, lupus nephritis, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), hypertensive nephropathy, hemodialysis related inflammation), neuroinflammation-related diseases (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), cardiovascular / metabolic diseases/disorders (e.g. cardiovascular risk reduction (CvRR), hypertension, atherosclerosis, type I and type li diabetes and related complications, peripheral artery disease (PAD), acute heart failure), inflammatory skin diseases (e.g. hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age- related macular degeneration, and cancer related diseases / disorders (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis). In particular, autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis); and CNS diseases and disorders as herein before defined.

In embodiments the compound is an inhibitor of NLRP3 or an inhibitor of the NLRP3 inflammasome.

NLRP3 Activity

NLRP3-induced IL-1 and IL-18 inflammatory responses have been associated with a number of different disorders (Menu et al, Clinical and Experimental Immunology, 2011 , 166, 1-15; Strowig et al, Nature, 2012, 481 , 278-286).

A number of autoimmune diseases have been shown to involve NLRP3 including, in particular, multiple sclerosis, type-1 diabetes, psoriasis, rheumatoid arthritis (RA), Behcet's disease, Schnitzler syndrome, macrophage activation syndrome (Braddock et al. Nat. Rev. Drug Disc.2004, 3, 1-10; Inoue et al., Immunology, 2013, 139, 11-18, Coll et al, Nat. Med. 2015, 21 (3), 248-55; Scott et al, Clin. Exp. Rheumatol. 2016, 34(1), 88-93), systemic lupus erythematosus and its complications such as lupus nephritis (Lu et al, J. Immunol., 2017, 198(3), 1119-29), and systemic sclerosis (Artlett et al, Arthritis Rheum.2011 , 63(11), 3563-74). NLRP3 has also been shown to play a role in a number of lung diseases including chronic obstructive pulmonary disorder (COPD), asthma (including steroid-resistant asthma), asbestosis, and silicosis (De Nardo et al, Am. J. Pathol., 2014, 184: 42-54; Kim et al. Am. J. Respir. Crit. Care Med, 2017, 196(3), 283-97). NLRP3 has also been suggested to have a role in a number of central nervous system conditions, including Multiple Sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington’s disease, cerebral malaria, brain injury from pneumococcal meningitis (Walsh et al, Nature Reviews, 2014, 15, 84- 97; and Dempsey et al. Brain. Behav. Immun.2017, 61 , 306-16), intracranial aneurysms (Zhang et al. J. Stroke and Cerebrovascular Dis., 2015, 24, 5, 972-9), and traumatic brain injury (Ismael et al. J. Neurotrauma., 2018, 35(11), 1294- 1303). NRLP3 activity has also been shown to be involved in various metabolic diseases including type 2 diabetes (T2D) and its organ-specific complications, atherosclerosis, obesity, gout, pseudo-gout, metabolic syndrome (Wen et al, Nature Immunology, 2012, 13, 352-357; Duewell et al, Nature, 2010, 464, 1357-1361 ; Strowig et al, Nature, 2014, 481 , 278- 286), and non-alcoholic steatohepatitis (Mridha et al. J. Hepatol. 2017, 66(5), 1037-46). A role for NLRP3 via IL-1 beta has also been suggested in atherosclerosis, myocardial infarction (van Hout et al. Eur. Heart J.2017, 38(1 1), 828-36), heart failure (Sano et al. J. Am. Coll. Cardiol. 2018, 71 (8), 875-66), aortic aneurysm and dissection (Wu et al. Arterioscler. Thromb. Vase. Biol., 2017,37(4), 694-706), and other cardiovascular events (Ridker et al., N. Engl. J. Med., 2017, 377(12), 11 19-31).

NLRP3 has been shown to be involved in other conditions including: ocular diseases such as both wet and dry age-related macular degeneration (Doyle et al. Nature Medicine, 2012, 18, 791-798; Tarallo et al. Cell 2012, 149(4), 847-59), diabetic retinopathy (Loukovaara et al. Acta Ophthalmol., 2017, 95(8), 803-8), non-infectious uveitis and optic nerve damage (Puyang et al. Sci. Rep.2016, 6, 20998); liver diseases including non-alcoholic steatohepatitis (NASH) and acute alcoholic hepatitis (Henao-Meija et al, Nature, 2012, 482, 179-185); inflammatory reactions in the lung and skin (Primiano et al. J. Immunol.2016, 197(6), 2421-33) including contact hypersensitivity (such as bullous pemphigoid (Fang et al. J Dermatol Sci. 2016, 83(2), 116-23)), atopic dermatitis (Niebuhr et al. Allergy, 2014, 69(8), 1058- 67), Hidradenitis suppurativa (Alikhan et al. J. Am. Acad. Dermatol., 2009 ,60(4), 539-61), and sarcoidosis (Jager et al. Am. J. Respir. Crit. Care Med., 2015, 191 , A5816); inflammatory reactions in the joints (Braddock et al, Nat. Rev. Drug Disc, 2004, 3, 1-10); amyotrophic lateral sclerosis (Gugliandolo et al. Int. J. Mol. Sci., 2018, 19(7), E1992); cystic fibrosis (lannitti et al. Nat. Commun., 2016, 7, 10791); stroke (Walsh et al, Nature Reviews, 2014, 15, 84-97); chronic kidney disease (Granata et al. PLoS One 2015, 10(3), eoi22272); and inflammatory bowel diseases including ulcerative colitis and Crohn's disease (Braddock et al., Nat. Rev. Drug Disc, 2004, 3, 1-10; Neudecker et al. J. Exp. Med. 2017, 214(6), 1737-52; Lazaridis et al. Dig. Dis. Sci. 2017, 62(9), 2348-56).

The NLRP3 inflammasome has been found to be activated in response to oxidative stress. NLRP3 has also been shown to be involved in inflammatory hyperalgesia (Dolunay et al, Inflammation, 2017, 40, 366-86). Activation of the NLRP3 inflammasome has been shown to potentiate some pathogenic infections such as influenza and Leishmaniasis (Tate et al., Sci Rep., 2016, 10(6), 27912-20; Novias et al., PLOS Pathogens 2017, 13(2), e1006196).

NLRP3 has also been implicated in the pathogenesis of many cancers (Menu et al, Clinical and Experimental Immunology, 2011 , 166, 1-15). For example, several previous studies have suggested a role for IL-1 beta in cancer invasiveness, growth and metastasis, and inhibition of IL-1 beta with canakinumab has been shown to reduce the incidence of lung cancer and total cancer mortality in a randomised, double-blind, placebo-controlled trial (Ridker et al. Lancet., 2017, 390(10105), 1833-42). Inhibition of the NLRP3 inflammasome or IL-1 beta has also been shown to inhibit the proliferation and migration of lung cancer cells in vitro (Wang et al. Oncol Rep., 2016, 35(4), 2053-64). A role for the NLRP3 inflammasome has been suggested in myelodysplastic syndromes, myelofibrosis and other myeloproliferative neoplasms, and acute myeloid leukemia (AML) (Basiorka et al. Blood, 2016, 128(25), 2960-75.) and also in the carcinogenesis of various other cancers including glioma (Li et al. Am. J. Cancer Res. 2015, 5(1), 442-9), inflammation-induced tumors (Allen et al. J. Exp. Med.2010, 207(5), 1045-56; Hu et al. PNAS., 2010, 107(50), 21635-40), multiple myeloma (Li et al. Hematology, 2016 21 (3), 144-51), and squamous cell carcinoma of the head and neck (Huang et al. J. Exp. Clin. Cancer Res., 2017, 36(1), 1 16). Activation of the NLRP3 inflammasome has also been shown to mediate ch emo resista nee of tumor cells to 5-Fluorouracil (Feng et al. J. Exp. Clin. Cancer Res., 2017, 36(1), 81), and activation of NLRP3 inflammasome in peripheral nerve contributes to chemotherapy-induced neuropathic pain (Jia et al. Mol. Pain., 2017, 13, 1-11). NLRP3 has also been shown to be required for the efficient control of viruses, bacteria, and fungi.

The activation of NLRP3 leads to cell pyroptosis and this feature plays an important part in the manifestation of clinical disease (Yan-gang et al., Cell Death and Disease, 2017, 8(2), 2579; Alexander et al., Hepatology, 2014, 59(3), 898-910; Baldwin et al., J. Med. Chem., 2016, 59(5), 1691- 1710; Ozaki et al., J. Inflammation Research, 2015, 8, 15-27; Zhen et al., Neuroimmunology Neuroinflammation, 2014, 1 (2), 60-65; Mattia et al., J. Med. Chem., 2014, 57(24), 10366-82; Satoh et al., Cell Death and Disease, 2013, 4, 644). Therefore, it is anticipated that inhibitors of NLRP3 will block pyroptosis, as well as the release of pro- inflammatory cytokines (e.g. IL-1 beta) from the cell.

The compounds of the present invention exhibit relevant pharmacological properties, e.g. NRLP3 inhibiting properties, e.g. as indicated by in vitro tests as provided in the next section, and are therefore indicated for therapy, prophylaxis (as appropriate) or for use as research chemicals, e.g. as tool compounds.

More specifically the compounds of the invention may be useful in the treatment of an indication selected from: inflammasome-related disease / disorders, immune diseases, inflammatory diseases, auto-immune diseases, or auto-inflammatory diseases, for example, autoinflammatory fever syndromes (e.g., cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver related disease / disorders (e.g. chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis related disorders (e.g. gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy e.g. acute, chronic), kidney related diseases (e.g. hyperoxaluria, lupus nephritis, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), hypertensive nephropathy, hemodialysis related inflammation), neuroinflammation-related diseases (e.g. multiple sclerosis, brain infection, acute injury, neurodeg enerative diseases, Alzheimer’s disease), cardiovascular / metabolic diseases/disorders (e.g. cardiovascular risk reduction (CvRR), hypertension, atherosclerosis, type I and type II diabetes and related complications, peripheral artery disease (PAD), acute heart failure), inflammatory skin diseases (e.g. hidraden itis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer related diseases / disorders (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis). In particular, autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. coion cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis); and CNS diseases and disorders as herein before defined.

In particular, compounds of the invention, or a pharmaceutically acceptable salt thereof, may be useful in the treatment of a disease or disorder preferably selected from autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis); and CNS diseases and disorders as herein before defined.

In order to address such concerns, in aspects and embodiments, compounds (or ‘active agents’) of the disclosure may beneficially provide a potent and selective (having a selectivity of greater than 5-fold, preferably greater than 20-fold by a suitable measure, such as plC50 in a suitable assay) NLRP3 or the NLRP3 inflammasome inhibition over other NLRP-isoforms, such as NLRP1 , 2 or 4, or other structurally similar receptors.

The active agents or compounds of the present invention may be provided as prodrugs of compounds of the disclosure.

The term ‘active agent’ is typically used to refer to a compound according to the disclosure wh ich has inhibition activity against NLRP3 or the NLRP3 inflammasome; especially under physiological conditions. However, it is often the case that the active agent may be difficult to administer or deliver to the physiological site of relevance, e.g. due to solubility, half-life or many other chemical or biological reasons. Therefore, it is known to use ‘prodrugs’ of the active agent in order to overcome physiochemical, biological or other barriers in drug efficiency and/or toxicity.

An active agent may be formed from a compound or prodrug of the disclosure by metabolism of the drug in vivo, and/or by chemical or enzymatic cleavage of the prodrug in vivo. Typically, a prodrug may be a pharmacologically inactive compound that requires chemical or enzymatic transformation to become an effective, active agent inside the body in which it is intended to have its therapeutic effect. On the other hand, since a prodrug may, in some embodiments, have very close structural similarity to the active agent, in some such embodiments, the prodrug may also have activity against the NLRP3 target. This may be particularly the case where the active agent is formed from a compound of prodrug of the disclosure by metabolism or a minor chemical transformation, such that the metabolite is closely related to the parent compound / prodrug. Accordingly, prodrugs of the disclosure may be active inhibitors of NLRP3. Suitably, however, such prodrugs may be characterised by having lower inhibition activity against NLRP3 than the drug / active agent that is derived from the prodrug of the disclosure. On the other hand, where the therapeutic effect is derived from the release of the active agent from a larger chemical entity, then the eventual active agent / compound / drug may have significant structural differences compared to the prodrug from which it was derived. In such cases, the prodrug can effectively ‘mask’ the form(s) of the active agent, and in such cases the prodrug may be completely (or essentially) completely inactive under physiological conditions.

Dosage Forms, Medicaments and Pharmaceuticals

The compounds, molecules or agents of the disclosure may be used to treat (e.g. cure, alleviate or prevent) one or more diseases, infections or disorders. Thus, in accordance with the disclosure, the compounds and molecules may be manufactured into medicaments or may be incorporated or formulated into pharmaceutical compositions.

The molecules, compounds and compositions of the disclosure may be administered by any convenient route, for example, methods of administration include intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intravaginal, transdermal, rectally, by inhalation, or topically to the skin. Delivery systems are also known to include, for example, encapsulation in liposomes, microgels, microparticles, microcapsules, capsules, etc. Any other suitable delivery system known in the art is also envisioned in use. Administration can be systemic or local. The mode of administration may be left to the discretion of the practitioner.

The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic properties of the particular active agent; the chosen mode and route of administration; the age, health and weight of the recipient; the nature of the disease or disorder to be treated; the extent of the symptoms; any simultaneous or concurrent treatments; the frequency of treatment; and the effect desired. In general, a daily dosage of active agent of between about 0.001 and about 1 ,000 mg/kg of body weight can be expected. For some applications, the dosage may suitably be within the range of about 0.01 to about 100 mg/kg; between about 0.1 to about 25 mg/kg, or between about 0.5 and 10 mg/kg.

Depending on known factors, such as those noted above, the required dosage of the active agent may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of e.g. two, three, or four times daily. Suitably, the therapeutic treatment regime according to the disclosure is devised for a single daily dose or for a divided daily dose of two doses. Dosage forms of the pharmaceutical compositions of the disclosure suitable for administration may contain from about 1 mg to about 2,000 mg of the active ingredient per unit. Typically, the daily dosage of compounds may be at least about 10 mg and at most about 1 ,500 mg per human dose; such as between about 25 and 1 ,250 mg or suitably between about 50 and 1 ,000 mg. Typically, the daily dosage of compounds may be at most about 1000 mg. In such compositions the compound of the invention will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

The 'effective amount' or 'therapeutically effective amount' is meant to describe an amount of compound or a composition of the disclosure that is effective in curing, inhibiting, alleviating, reducing or preventing the adverse effects of the diseases or disorders to be treated, or the amount necessary to achieve a physiological or biochemically-detectable effect. Thus, at the effective amount, the compound or agent is able to produce the desired therapeutic, ameliorative, inhibitory or preventative effect in relation to disease or disorder. Beneficially, an effective amount of the compound or composition of the disclosure may have the effect of inhibiting NLRP3. Diseases or disorders which may benefit from NLRP3 inhibition include, for example, autoimmune disorders, inflammatory diseases, cancers and/or oncologic diseases, inflammatory conditions such as rheumatoid arthritis, multiple sclerosis, psoriasis, Sjogren's syndrome and systemic lupus erythematosus or vasculitic conditions, cancers of hematopoietic origin or solid tumors, including chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin lymphoma and other B cell lymphomas; and CNS diseases and disorders as herein before defined.

For therapeutic applications, the effective amount or therapeutically effective amount of a compound / active agent of the disclosure may be at least about 50 nM or at least about 100 nM; typically at least about 200 nM or at least about 300 nM in the blood of the subject. The effective amount or therapeutically effective amount may be at most about 5 pM, at most about 3 pM, suitably at most about 2 pM and typically at most about 1 pM in the blood of the subject. For example, the therapeutically effective amount may be at most about 500 nM, such as between about 100 nM and 500 nM. In some embodiments the amount of therapeutic compound is measured in serum of the subject and the above concentrations may then apply to serum concentration of the compounds of the disclosure.

When administered to a subject, a compound of the disclosure is suitably administered as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle. One or more additional pharmaceutical acceptable carrier (such as diluents, adjuvants, excipients or vehicles) may be combined with the compound of the disclosure in a pharmaceutical composition. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin. Pharmaceutical formulations and compositions of the disclosure are formulated to conform to regulatory standards and according to the chosen route of administration.

Acceptable pharmaceutical vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical vehicles can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilising, thickening, lubricating and colouring agents may be used. When administered to a subject, the pharmaceutically acceptable vehicles are generally sterile. Water is a suitable vehicle when the compound is to be administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid vehicles, particularly for injectable solutions. Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or buffering agents.

The medicaments and pharmaceutical compositions of the disclosure can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, powders, gels, capsules (for example, capsules containing liquids or powders), modified-release formulations (such as slow or sustained-release formulations), suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. Other examples of suitable pharmaceutical vehicles are described in Remington's Pharmaceutical Sciences, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa., 19th ed., 1995, see for example pages 1447- 1676.

Suitably, the therapeutic compositions or medicaments of the disclosure are formulated in accordance with routine procedures as a pharmaceutical composition adapted for oral administration (more suitably for humans). Compositions for oral delivery may be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example. Thus, in one embodiment, the pharmaceutically acceptable vehicle is a capsule, tablet or pill.

Orally administered compositions may contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavouring agents such as peppermint, oil of Wintergreen, or cherry; colouring agents; and preserving agents, to provide a pharmaceutically palatable preparation. When the composition is in the form of a tablet or pill, the compositions may be coated to delay disintegration and absorption in the gastrointestinal tract, so as to provide a sustained release of active agent over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compositions. In these dosage forms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture. These dosage forms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time delay material such as glycerol monostearate or glycerol stearate may also be used. Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Such vehicles are preferably of pharmaceutical grade. For oral formulations, the location of release may be the stomach, the small intestine (the duodenum, the jejunem, or the ileum), or the large intestine. One skilled in the art is able to prepare formulations that will not dissolve in the stomach yet will release the material in the duodenum or elsewhere in the intestine. Suitably, the release will avoid the deleterious effects of the stomach environment, either by protection of the compound (or composition) or by release of the compound (or composition) beyond the stomach environment, such as in the intestine. To ensure full gastric resistance a coating impermeable to at least pH 5.0 would be essential. Examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and Shellac, which may be used as mixed films.

While it can be beneficial to provide therapeutic compositions and/or compounds of the disclosure in a form suitable for oral administration, for example, to improve patient compliance and for ease of administration, in some embodiments compounds or compositions of the disclosure may cause undesirable side-effects, such as intestinal inflammation which may lead to premature termination of a therapeutic treatment regime. Thus, in some embodiments, the therapeutic treatment regime is adapted to accommodate ‘treatment holidays’, e.g. one or more days of non-administration. For example, treatment regimens and therapeutic methods of the disclosure may comprise a repetitive process comprising administration of the therapeutic composition or compound for a number of consecutive days, followed by a treatment holiday of one or more consecutive days. For example, a treatment regime of the disclosure may comprise a repetitive cycle of administration of the therapeutic composition or compound for between 1 and 49 consecutive days, between 2 and 42 days, between 3 and 35 days, between 4 and 28 days, between 5 and 21 days, between 6 and 14 days, or between 7 and 10 days; followed by a treatment holiday of between 1 and 14 consecutive days, between 1 and 12 days, between 1 and 10 days, or between 1 and 7 days (e.g. 1 , 2, 3, 4, 5, 6 or 7 days).

To aid dissolution of the therapeutic agent into the aqueous environment a surfactant might be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents might be used and could include benzalkonium chloride or benzethomium chloride. Potential nonionic detergents that could be included in the formulation as surfactants include: lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 20, 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants, when used, could be present in the formulation of the compound or derivative either alone or as a mixture in different ratios.

Typically, compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necessary, the compositions may also include a solubilising agent.

Another suitable route of administration for the therapeutic compositions of the disclosure is via pulmonary or nasal delivery. Additives may be included to enhance cellular uptake of the therapeutic agent of the disclosure, such as the fatty acids oleic acid, linoleic acid and linolenic acid.

The therapeutic agents of the disclosure may also be formulated into compositions for topical application to the skin of a subject.

Where the invention provides more than one active compound / agent for use in combination, generally, the agents may be formulated separately or in a single dosage form, depending on the prescribed most suitable administration regime for each of the agents concerned. When the therapeutic agents are formulated separately, the pharmaceutical compositions of the invention may be used in a treatment regime involving simultaneous, separate or sequential administration with the other one or more therapeutic agent. The other therapeutic agent(s) may comprise a compound of the disclosure or a therapeutic agent known in the art).

The compounds and/or pharmaceutical compositions of the disclosure may be formulated and suitable for administration to the central nervous system (CNS) and/or for crossing the blood-brain barrier (BBB). The invention will now be described by way of the following non-limiting examples.

Materials and Methods

Sample preparation: Powders were solubilized in CDCb or DMSO-de transferred to a NMR tube for data acquisition.

NMR spectroscopy:

Liquid-state NMR experiments were recorded on a 400 MHz NMR spectrometer (400 MHz for ¹ H, 100 MHz for ¹³ C).

All the experiments used for the resonance assignment procedure and the elucidation of the products structure (1 D ¹ H, 2D WH-COSY, 2D ¹ H- ¹ H-ROESY, 2D ^! H- ¹³ C-HSQC, 2D ’H- ¹³ C-HMBC) were recorded at 300 K. ^! H chemical shifts are reported in 5 (ppm) as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), m (multiplet) or br s (broad singlet)

LCMS chromatography:

LCMS chromatography were recorded with the following methods:

Method A: 0-60AB, Agilent

Instrument: Agilent 1260\G6125B SingleQuad; Column: K Kinetex EVO C18 2.1*30mm, 5um; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0.0-0.80 min 0%-60%;B, 0.60-0.80 min 60% B; 0.80-0.85 min 60%-0% B; 0.85-1.10 min 0% B; flow 1 .5-2 ml/min; temperature: 50 °C; DAD: 220 nm & 254 nm.

Method B: 0-60AB, Agiient instrument: Agiient 1260XG6125B SingieQuad; Column: Porosheil 120 EC C18 2.7pm 3.0*30mm; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0.00-3.00 min 0%-60%;B, 3.00-3.60 min 60% B; 3.60-3.61 min 60%-0% B; 3.61-4.00 min 0% B; flow 1 .0-1 .5 ml/min; temperature: 50 °C; DAD: 220 nm & 254 nm.

Method C: 5-95AB, Agilent

Instrument: Agilent 1260XG6125B SingleQuad; Column: K Kinetex EVO C18 2.1*30mm, 5um; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0.0-0.60 min 5%-95%;B, 0.60-0.80 min 95% B; 0.80-0.85 min 95%-5% B; 0.85-1.10 min 5% B; flow 1 .5-2 ml/min; temperature: 50 °C; DAD: 220 nm & 254 nm.

Method D: 5-95AB, Agilent

Instrument: Agilent 1260\G6125B SingleQuad; Column: Porosheil 120 EC C18 2.7pm 3.0*30mm; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0.00-3.00 min 5%-95%;B, 3.00-3.60 min 95% B; 3.60-3.61 min 95%-5% B; 3.61-4.00 min 5% B; flow 1 .0-1 .5 ml/min; temperature: 50 °C; DAD: 220 nm & 254 nm.

Method E: 30-1 Q0AB, Agilent

Instrument: Agilent 1260\G6125B SingleQuad; Column: K Kinetex EVO C18 2.1*30mm, 5um; eluent A: water + 0,0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0.0-0.50 min 30%-100%;B, 0.50-0.80 min 100% B; 0.80-0.85 min 100%-30% B; 0.85-1.10 min 30% B; flow 1 .5-2 ml/min; temperature: 50 °C; DAD: 220 nm & 254 nm.

Method F: 30-100AB, Agilent

Instrument: Agilent 1260\G6125B SingleQuad; Column: Porosheil 120 EC Cl 8 2.7pm 3.0*30mm; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0.00-2.50 min 30%-100%;B, 2.50-3.60 min 100% B; 3.60-3.61 min 100%-30% B; 3.61- 4.00 min 30% B; flow 1 .0-1 .5 ml/min; temperature: 50 °C; DAD: 220 nm & 254 nm.

Method G: 0-60CD, Agilent

Instrument: Agilent 1260\G6125B SingleQuad; Column: XBridge C18 2.1*50mm, 5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0.00-0.70 min 0%-60%;B, 0.70- 1 .00 min 60% B; 1 .00-1 .01 min 60%-0% B; 1 .01-1 .10 min 0% B; flow 1 .5-2 ml/min; temperature: 40 °C; DAD: 220 nm & 254 nm.

Method H: 0-60CD, Agilent Instrument: Agilent 1260XG6125B SingleQuad; Column: Waters XBridge C18 2.1 *50mm, 5um; eluent A: water * 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0.00-3.00 min 0%-60%;B, 3.00-3.60 min 60% B; 3.60-3.61 min 60%-0% B; 3.61-4.00 min 0% B; flow 0.8 ml/min; temperature: 40 °C; DAD: 220 nm & 254 nm.

Method I: 5-95CD, Agilent

Instrument: Agilent 1260\G6125B SingleQuad; Column: XBridge C18 2.1*50mm, 5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0.00-0.70 min 5%-95%;B, 0.70- 1.00 min 95% B; 1.00-1.01 min 95%-5% B; 1.01-1.10 min 5% B; flow 1.5-2 ml/min; temperature: 40 °C; DAD: 220 nm & 254 nm.

Method J: 10-80CD, Agilent

Instrument: Agilent 1260XG6125B SingleQuad; Column: Waters XBridge C18 2.1*50mm, 5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0.00-3.00 min 10%- 80%;B, 3.00-3.60 min 80% B; 3.60-3.61 min 80%-10% B; 3.61-4.00 min 10% B; flow 0.8 ml/min; temperature: 40 °C; DAD: 220 nm & 254 nm.

Method K: 30-100CD, Agilent

Instrument: Agilent 126Q\G6125B SingleQuad; Column: XBridge C18 2.1*50mm, 5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0.00-0.60 min 30%-100%;B, 0.60- 1.00 min 100% B; 1.00-1.01 min 10Q%-30% B; 1.01-1.10 min 30% B; flow 1.5-2 ml/min; temperature: 40 °C; DAD: 220 nm & 254 nm.

Method L: 30-100CD, Agilent

Instrument: Agilent 1260\G6125B SingleQuad; Column: Waters XBridge C18 2.1 *50mm, 5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0.00-2.40 min 30%- 100%;B, 2.40-3.60 min 100% B; 3.60-3.61 min 100%-30% B; 3.61-4.00 min 30% B; flow 0.8 ml/min; temperature: 40 °C; DAD: 220 nm & 254 nm.

Method M: 0-60AB, Shimadzu

Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex® EVO C18 2.1x30mm 5um; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0.00-0.60 min 0%-60%;B, 0.60-0.78 min 60% B; 0.78-0.79 min 60%-0% B; 0.79-0.80 min 0% B; flow 2 ml/min; temperature: 50 °C; PDA: 220 nm & 254 nm.

Method N: 0-60AB, Shimadzu

Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex® EVO C18 2.1x30mm 5um; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0.00-0.80 min 0%-60%;B, 0.80-0.95 min 60% B; 0.95-0.96 min 60%-0% B; 0.96-1.00 min 0% B; flow 1 .5-2 ml/min; temperature: 50 °C; PDA: 220 nm & 254 nm. Method O: 0-60AB, Shimadzu

Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex® EVO C18 4.6x50mm 5um; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0.00-3.20 min 0%-60%;B, 3.20-3.70 min 60% B; 3.70-3.71 min 60%-0% B; 3.71-4.00 min 0% B; flow 1 .5-2 ml/min; temperature: 50 °C; PDA: 220 nm & 254 nm.

Method P: 5-95AB, Shimadzu

Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex® EVO C18 2.1x30mm 5um; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0.00-0.60 min 5%-95%;B, 0.60-0.78 min 95% B; 0.78-0.79 min 95%-5% B; 0.79-0.80 min 5% B; flow 2 ml/min; temperature: 50 °C; PDA: 220 nm & 254 nm.

Method Q: 5-95AB, Shimadzu

Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex® EVO C18 2.1x30mm 5um; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0.00-0.80 min 5%-95%;B, 0.80-0.95 min 95% B; 0.95-0.96 min 95%-5% B; 0.96-1.00 min 5% B; flow 1 .5-2 ml/min; temperature: 50 °C; PDA: 220 nm & 254 nm.

Method R: 5-95AB, Shimadzu

Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex® EVO C18 2.1x30mm 5um; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0.00-3.60 min 5%-95%;B, 3.60-3.85 min 95% B; 3.85-3.86 min 95%-5% B; 3.86-4.00 min 5% B; flow 0.4-1 .2 ml/min; temperature: 50 °C; PDA: 220 nm & 254 nm.

Method S: 30-100AB, Shimadzu

Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex® EVO C18 2.1x30mm 5um; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0.00-0.45 min 30%-90%;B, 0.45-0.78 min 90%-100% B; 0.78-0.79 min 100%-30% B; 0.79- 0.80 min 30% B; flow 2 ml/min; temperature: 50 °C; PDA: 220 nm & 254 nm.

Method T: 30-100AB, Shimadzu

Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex® EVO C182.1x30mm 5um; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0.00-0.60 min 30%-90%;B, 0.60-0.95 min 90%-100% B; 0.95-0.96 min 100%-30% B; 0.96- 1 .00 min 30% B; flow 1 .5-2 ml/min; temperature: 50 °C; PDA: 220 nm& 254 nm.

Method U: 30-100AB, Shimadzu

Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex® EVO C182.1x30mm 5um; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0.00-2.60 min 30-90%;B, 2.60-3.85 min 90%-100% B; 3.85-3.86 min 100%-30% B; 3.86-4.00 min 30% B; flow 0.4-1 .2 ml/min; temperature: 50 °C; PDA: 220 nm & 254 nm.

Method V: 0-60CD, Shimadzu instrument: SHIMADZU LCMS-2020 SingleQuad; Column: XBridge C18 2.1 *30mm, 3.5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0.00-0.80 min 0%-60%;B, 0.80-0.94 min 60% B; 0.94-0.95 min 60%-0% B; 0.95-1.00 min 0% B; flow 1.5-2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.

Method W: 0-60CD, Shimadzu

Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: XBridge C18 2.1*50mm, 5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0.00-3.00 min 0%-60%;B, 3.00-3.70 min 60% B; 3.70-3.71 min 60%-0% B; 3.71-4.00 min 0% B; flow 0.6-1 .2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.

Method X: 5-95CD, Shimadzu

Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: XBridge C18 2.1 *30mm, 3.5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0.00-0.80 min 5%-95%;B, 0.80-0.94 min 95% B; 0.94-0.95 min 95%-5% B; 0.95-1.00 min 5% B; flow 1.5-2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.

Method Y: 5-95CD, Shimadzu

Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: XBridge C18 2.1*50mm, 5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0.00-3.00 min 5%-95%;B, 3.00-3.70 min 95% B; 3.70-3.71 min 95%-5% B; 3.71-4.00 min 5% B; flow 0.6-1 .2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.

Method Z: 30-100CD, Shimadzu

Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: XBridge C18 2.1*30mm, 3.5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0.00-0.60 min 30%-100%;B, 0.60-0.94 min 100% B; 0.94-0.95 min 100%-30% B; 0.95-1.00 min 30% B; flow 1 .5-2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.

Method AA: 30-100CD, Shimadzu

Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: XBridge C18 2.1*50mm, 5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0.00-2.50 min 30%-100%;B, 2.50-3.70 min 100% B; 3.70-3.71 min 100%-30% B; 3.71-4.00 min 30% B; flow 0.6-1.2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.

Method AB: 0-60N, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex® EVO C18 2.1x30mm 5um; eluent A: water + 10mM ammonium bicarbonate, eluent B: acetonitrile; gradient: 0.00-0.80 min 0%-60%;B, 0.80-0.95 min 60% B; 0.95-0.96 min 60%-0% B; 0.96-1.00 min 0% B; flow 1.5-2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.

Method AC: 0-60N, Shimadzu

Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: XBridge C18 2.1*30mm, 5um; eluent A: water + 10mM ammonium bicarbonate, eluent B: acetonitrile; gradient: 0.00-3.60 min 0%-60%;B, 3.60-

3.85 min 60% B; 3.85-3.86 min 60%-0% B; 3.86-4.00 min 0% B; flow 0.4-1 .2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.

Method AD: 5-95N, Shimadzu

Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex® EVO C18 2.1x30mm 5um; eluent A: water + 10mM ammonium bicarbonate, eluent B: acetonitrile; gradient: 0.00-0.80 min 5%-95%;B, 0.80-0.95 min 95% B; 0.95-0.96 min 95%-5% B; 0.96-1.00 min 5% B; flow 1.5-2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.

Method AE: 5-95N, Shimadzu

Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: XBridge C18 2.1*30mm, 5um; eluent A: water * 10mM ammonium bicarbonate, eluent B: acetonitrile; gradient: 0.00-3.60 min 5%-95%;B, 3.60-

3.85 min 95% B; 3.85-3.86 min 95%-5% B; 3.86-4.00 min 5% B; How 0.4-1.2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.

Method AF: 30-100N, Shimadzu

Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: XBridge C18 2.1*30mm, 3.5um; eluent A: water* 10mM ammonium bicarbonate, eluent B: acetonitrile; gradient: 0.00-0.60 min 30%-90%;B, 0.60- 0.95 min 90%-100% B; 0.95-0.96 min 100%-30% B; 0.96-1.00 min 30% B; flow 1.5-2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.

Method AG: 30-1 DON, Shimadzu

Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex® EVO C18 2.1x30mm 5um; eluent A: water * 10mM ammonium bicarbonate, eluent B: acetonitrile; gradient: 0.00-0.60 min 30%-90%;B, 0.60-0.95 min 90%-100% B; 0.95-0.96 min 100%-30% B; 0.96-1.00 min 30% B; flow 1.5-2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.

Method AH: 5-95N, Shimadzu

Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: XBridge C18 2.1*30mm, 3.5um; eluent A: water* 10mM ammonium bicarbonate, eluent B: acetonitrile; gradient: 0.00-2.60 min 30%-90%;B, 2.60-

3.85 min 90%-100% B; 3.85-3.86 min 100%-30% B; 3.86-4.00 min 30% B; flow 0.4-1 .2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm. Method Al: 5-95N, Shimadzu

Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex® EVO C18 2.1x30mm 5um; eluent A: water + 10mM ammonium bicarbonate, eluent B: acetonitrile; gradient: 0.00-2.60 min 30%-90%;B, 2.60-3.85 min 90%-100% B; 3.85-3.86 min 100%-30% B; 3.86-4.00 min 30% B; flow 0.4-1 .2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.

Method AJ: HPLC: Instrument: SHIMADZU LC-20AD SingleQuad; Column: Kinetex C18 LC Column 4.6X50mm,5um; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0-2.40 min, 10-80% B, 2.40-3.70 min 80% B; 3.70-3.71 min 80-10% B; 3.71-4.00 min 10% B; flow 1.5 ml/min; temperature: 50 °C; PDA: 220 nm & 215 nm & 254 nm.

Temperatures are given in degrees Celsius (°C). The reactants used in the examples below may be obtained from commercial sources or they may be prepared from commercially available starting materials as described herein or by methods known in the art. All of the compounds of the invention are synthesized according to the Examples described herein. The progress of the reactions described herein were followed as appropriate by e.g. LC, GC orTLC, and as the skilled person will readily realise, reaction times and temperatures may be adjusted accordingly.

Example 1 - Chemical Synthesis Routes

Intermediate 1

2-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine

To a suspension of 2,7-dichloro-1 ,8-naphthyridine (500 mg, 2.51 mmol, 1 eq) and (2-methoxy-4,6- dimethyl-phenyl)boronic acid (452.2 mg, 2.51 mmol, 1 eq) in 1 ,4-Dioxane (15 mL) was added 2 M potassium carbonate in water (3.77 mL, 7.54 mmol, 3 eq). The mixture was purged with nitrogen for 5 min, then [1 ,1 'Bis(diphenylphosphino)ferrocene] dichloropalladium(ll), complex with dichloromethane (102.57 mg, 0.13 mmol, 0.05 eq) was added, and the reaction was heated to 80 °C for 2.5 hours. The reaction mixture was partitioned between sat. aq. sodium bicarbonate and EtOAc (25 mL of each). The layers were separated, and the aqueous was extracted with EtOAc (2 x 25 mL). The combined organics were dried with Na2SO4, filtered, and concentrated in vacuo to yield a red solid. The crude was purified by automated column chromatography (0 to 40% EtOAc in cyclohexane). The appropriate fractions were identified by TLC (50% EtOAc in cyclohexane, Rf = 0.40), combined and concentrated in vacuo to yield the title compound (114 mg, 0.3816 mmol, 15% yield) as a pale pink solid.

LC-MS (Method K): Rt = 1.71 min; MS (ESIpos): m/z = 299.3/301.3 [M+H] ⁺

^! H NMR (400 MHz, DMSO-d6) 6 8.57 (d, J = 8.6 Hz, 1 H), 8.52 (d, J = 8.4 Hz, 1 H), 7.74 (d, J = 8.4 Hz, 1 H), 7.60 (d, J = 8.3 Hz, 1 H), 6.83 (s, 1 H), 6.77 (s, 1 H), 3.66 (s, 3H), 2.35 (s, 3H), 2.01 (s, 3H). Intermediate 2

2-(2-methoxy-4,6-dimethyl-phenyl)-7-(1-methyl-3,6-dihydro -2H-pyridin-5-yl)-1 ,8-naphthyridine

To a vial was added Intermediate 1 (50 mg, 0.17 mmol, 1 eq), 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine hydrochloride (52.13 mg, 0.2mmol, 1.2 eq), and XPhos Pd G2 (13.17 mg, 0.02 mmol, 0.1 eq). The vial was evacuated and back-filled with nitrogen three times, then DMF (1 mL) was added, followed by 2 M potassium carbonate in water (0.25 mL, 0.5 mmol, 3 eq). The reaction was heated to 90 °C, and left to stir for 4 hours. The reaction mixture was partitioned between sat. aq. sodium bicarbonate and 10% MeOH in DCM (10 mL of each). The layers were separated, and the aqueous was extracted with 10% MeOH in DCM (10 mL). The combined organics were washed with brine (3 x 10 mL), passed through a hydrophobic frit, and concentrated in vacuo to yield an orange gum. The crude was purified by automated column chromatography (0 to 10% (2 M NH3 in MeOH) in DCM). The appropriate fractions were identified by TLC (10% (2 M NH3 in MeOH) in DCM, Rf = 0.54), combined and concentrated in vacuo to yield the title compound (37 mg, 0.0926 mmol, 55% yield) as a bright orange gum.

LC-MS (Method K): Rt = 1.39 min; MS (ESIpos): m/z = 360.5 [M+H] ⁺

¹ H NMR (400 MHz, Chloroform-d) 5 8.09 (d, J = 8.2 Hz, 1 H), 8.07 (d, J = 8.6 Hz, 1 H), 7.72 (d, J = 8.7 Hz, 1 H), 7.39 (d, J = 8.2 Hz, 1 H), 6.85 (tt, J = 4.0, 1 .8 Hz, 1 H), 6.72 - 6.70 (m, 1 H), 6.62 (s, 1 H), 3.78 (q, J = 2.7 Hz, 2H), 3.65 (s, 3H), 2.63 (t, J = 5.8 Hz, 2H), 2.54 - 2.50 (m, 2H), 2.49 (s, 3H), 2.35 (s, 3H), 2.09 (s, 3H). Some small impurities present, estimate purity as 90%.

Intermediate 3

2-(2-methoxy-4,6-dimethyl-phenyl)-7-(1-methyl-3-piperidyl )-1 ,8-naphthyridine

Intermediate 2 (37 mg, 0.09 mmol, 1 eq) was taken up in methanol (3 mL) and pumped twice through an H-Cube (full H2, 1 mL/min, 25 °C, 1 bar) containing a 10% Pd/C CatCart (THS-01111). The eluent was concentrated in vacuo to yield the title compound (31 mg, 0.0772 mmol, 83% yield) as a yellow glass.

LC-MS (Method K): Rt = 1 .42 min; MS (ESIpos): m/z - 362.5 [M+H] ⁺

^! H NMR (400 MHz, Chloroform-d) 6 8.16 (d, J = 8.3 Hz, 1 H), 8.15 (d, J = 8.3 Hz, 1 H), 7.46 (d, J = 8.2 Hz, 1 H), 7.43 (d, J = 8.3 Hz, 1 H), 6.72 - 6.68 (m, 1 H), 6.62 (s, 1 H), 3.82 - 3.72 (m, 1 H), 3.65 (s, 3H), 3.64 - 3.56 (m, 1 H), 3.50 - 3.42 (m, 2H), 2.72 (s, 3H), 2.65 - 2.57 (m, 1 H), 2.38 - 2.31 (m, 1 H), 2.34 (s, 3H), 2.20 - 2.12 (m, 1 H), 2.07 (s, 3H), 1.94 (dt, J = 14.4, 3.2 Hz, 1 H), 1.79 (qd, J = 13.3, 3.9 Hz, 1 H). Some small impurities present, estimate purity as 90%.

Compound 1 3,5-dimethyl-2-[7-(1-methyl-3-piperidyl)-1 ,8-naphthyridin-2-yl]phenol

To a stirring solution of Intermediate 3 (31 mg, 0.09 mmol, 1 eq) in DCM (1 mL) under nitrogen at 0 °C was added Boron tribromide (1 M in DCM) (257.28 uL, 0.26 mmol, 3 eq) dropwise. The reaction was allowed to warm to room temperature and left to stir for 4 hours. The reaction was cooled to 0 °C, and additional Boron tribromide (1 M in DCM) (0.09 mL, 0.09 mmol, 1 eq) was added dropwise. The reaction was allowed to warm to room temperature and left to stir overnight. The reaction was cooled to 0 °C and quenched by the addition of sat. aq. sodium bicarbonate (10 mL), then extracted with 10% MeOH in DCM (3 x 10 mL). The combined organics were passed through a hydrophobic frit, and concentrated in vacuo to yield an orange gum. The crude was taken up in 1 :1 MeOH:DMSO, and purified by prep- HPLC (2 x 500 uL injections, SQD, pH 6, 15 min). The appropriate fractions were dried overnight to yield the title compound (17.1 mg, 0.0492 mmol, 57% yield) as an orange solid.

LC-MS (Method K): Rt = 1.27 min; MS (ESIpos): m/z = 348.5 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d6) 5 9.82 (br s, 1 H), 8.39 (dd, J = 8.3, 2.1 Hz, 2H), 7.61 (d, J = 8.3 Hz, 1 H), 7.54 (d, J = 8.2 Hz, 1 H), 6.64 - 6.63 (m, 1 H), 6.62 - 6.61 (m, 1 H), 3.19 - 3.10 (m, 1 H), 3.06 - 2.99 (m, 1 H), 2.85 - 2.77 (m, 1 H), 2.26 (s, 3H), 2.23 (s, 3H), 2.27 - 2.16 (m, 1 H), 2.08 (s, 3H), 2.02 - 1 .91 (m, 2H), 1 .80 - 1 .70 (m, 1 H), 1 .69 - 1 .58 (m, 2H).

¹³ C NMR (101 MHz, DMSO-d6) 5 167.5, 161.3, 155.6, 155.2, 139.0, 137.9, 137.1 , 124.9, 124.8, 122.4, 121.9, 119.9, 114.4, 61.0, 55.8, 46.8, 45.1 , 29.9, 25.5, 21.4, 20.6.

Compound 2

3,5-dimethyl-2-[7-(1 -methyl-1 ,2 ,5 ,6-tetrahyd ro py rid in-3-y I)- 1 ,8-na phthy rid in-2-y I] ph enol

Compound 2 was prepared from intermediate 2 according to the procedure used for Example 1

LC-MS (Method K): Rt = 1.32 min; MS (ESIpos): m/z = 346.5[M+Hj+

¹ H NMR (400 MHz, DMSO-d6) 6 9.80 (br s, 1 H), 8.38 (dd, J = 8.4, 2.2 Hz, 2H), 7.96 (d, J = 8.7 Hz, 1 H), 7.53 (d, J = 8.3 Hz, 1 H), 7.01 (tt, J = 4.2, 1 .8 Hz, 1 H), 6.63 (s, 1 H), 6.61 (s, 1 H), 3.49 (q, J = 2.5 Hz, 2H), 2.56 -2.51 (m, 2H), 2.45 -2.40 (m, 2H), 2.39 (s, 3H), 2.26 (s, 3H), 2.08 (s, 3H). 13C NMR (101 MHz, DMSO-d6) 6 161.1 , 158.8, 155.1 , 154.8, 138.5, 137.1 , 136.6, 136.5, 135.8, 129.5, 124.5, 124.4, 121.9, 119.7, 118.0, 113.9, 54.5, 51.0, 45.8, 26.6, 21.0, 20.1 .

Intermediate 4 tert-butyl 5-(6-chloropyrido[2,3-b]pyrazin-3-yl)-3,6-dihydro-2H-pyridin e-1 -carboxylate

To a solution of 3,6-dichloropyrido[2,3-b]pyrazine (2.50 g, 12.5 mmol, 1 eq) in the mixture of dioxane (60 mL) and H2O (10 mL) was added tert-butyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6- dihydro- 2H-pyridine-1-carboxylate (3.48 g, 1 1.2 mmol, 0.9 eq), sodium carbonate (3.97 g, 37.5 mmol, 3 eq) and Pd(dppf)Cl2 (914 mg, 1.25 mmol, 0.1 eq) at 25 °C. After stirring at 60 °C for 16 h under N2 atmosphere, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate = 10/1 to 1/1) to give compound tert-butyl 5-(6- chloropyrido[2,3-b]pyrazin-3-yi)-3,6-dihydro- 2H-pyridine-1 -carboxylate (1.90 g, 3.83 mmol, 30% yield, 70% purity) as brown oil.

LC-MS (Method C): Rt - 0.560 min; MS (ESIpos): m/z = 347.2 [M+H] ⁺

Intermediate 5 tert-butyl 5-[6-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazin-3-y l]-3,6-dihydro-2H-pyridine-1- carboxylate

To a solution of tert-butyl 5-(6-chloropyrido[2,3-b]pyrazin-3-yl)-3,6-dihydro-2H-pyridin e-1-carboxylate (1.90 g, 3.83 mmol, 1 eq) in the mixture of dioxane (40 mL) and H2O (8 mL) was added (2-methoxy- 4,6-dimethyl-phenyl)boronic acid (1.38 g, 7.67 mmol, 2 eq), sodium carbonate (1.22 g, 11.5 mmol, 3 eq) and Pd(dppf)Ch (280 mg, 383 pmol, 0.1 eq) at 25 °C. After stirring at 60 °C for 16 h under N2 atmosphere, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O ₂ , Petroleum ether/Ethyl acetate = 5/1 to 3/1) to give compound tertbutyl 5-[6-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazin-3-y l]-3,6-dihydro-2H-pyridine-1- carboxylate (800 mg, 1.43 mmol, 37% yield, 80% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.630 min; MS (ESIpos): m/z = 447.2 [M+H] ⁺

Intermediate 6 tert-butyl 3-[6-(2-methoxy-4,6-dimethyi-phenyi)pyrido[2,3-b]pyrazin-3-y l]piperidine-1 -carboxylate

To a solution of tert-butyl 5-[6-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazin-3-y 0-3,6-dihydro- 2H- pyridine-1 -carboxylate (780 mg, 1.75 mmol, 1 eq) in methanol (15 mL) was added Pd/C (80.0 mg, 1 .75 mmol, 10% purity, 1 eq) at 25 °C. After stirring at 25 °C for 8 h under H2 atmosphere, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOz, Petroleum ether/Ethyl acetate = 5/1 to 3/1) to give compound tert-butyl (3R)-3-[6-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazi n-3-yl]piperidine-1- carboxylate (400 mg, 758 pmol, 43% yield, 85% purity) as yellow oil.

LC-MS (Method C): Rt = 0.608 min; MS (ESIpos): m/z - 449.2 [M+H] ⁺

Intermediate 7

6-(2-methoxy-4,6-dimethyl-phenyl)-3-[3-piperidyl]pyrido[2 ,3-b]pyrazine

To a solution of tert-butyl 3-[6-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazin-3-y l]piperidine- 1- carboxylate (400 mg, 891 pmol, 1 eq) in ethyl acetate (10 mL) was added HCI/ethyl acetate (4 M, 2.23 mL, 10 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was concentrated under reduced pressure to give compound 6-(2-methoxy-4,6-dimethyl-phenyl)-3-[(3R)-3-piperidyl]pyrido [2,3- bjpyrazine (360 mg, 513 pmol, 57% yield, 60% purity, HCI salt) as a black brown solid.

LC-MS (Method C): Rt = 0.432 min; MS (ESipos): m/z = 349.3 [M+H] ⁺

Intermediate 8

6-(2-methoxy-4,6-dimethyl-phenyl)-3-[1-methyi-3-piperidyl ]pyrido[2,3-b]pyrazine

To a solution of 6-(2-methoxy-4,6-dimethyl-phenyl)-3-[3-piperidyl]pyrido[2,3- b]pyrazine (340 mg, 975 pmol, 1 eq) in methanol (15 mL) was added (HCHO)n (146 mg, 4.88 mmol, 5 eq) and potassium acetate (287 mg, 2.93 mmol, 3 eq) at 25 °C, then the mixture was added NaBHsCN (183 mg, 2.93 mmol, 3 eq) slowly at 25 °C. After stirring at 25 °C for 0.5 h, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18 40 g, mobile phase: [water (FA) - MeCN]; B%: 25% - 65%, 8 min) to give compound 6-(2-methoxy- 4,6-dimethyl-phenyl)-3-[(3R)-1-methyl-3-piperidyl]pyrido[2,3 -b]pyrazine (170 mg, 431 pmol, 44 % yield, 92% purity) as yellow oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 = 9.07 (s, 1 H), 8.51-8.47 (m, 1 H), 7.71 (d, J = 8.4 Hz, 1 H), 6.84 (s, 1 H), 6.78 (s, 1 H), 3.66 (s, 3H), 3.06 (d, J = 11 .2 Hz, 1 H), 2.81 (d, J = 11 .2 Hz, 1 H), 2.36 (s, 3H), 2.29 (d, J = 10.8 Hz, 1 H), 2.24 (s, 3H), 2.22 (s, 1 H), 2.06 (d, J = 6.0 Hz, 1 H), 1 .99 (s, 3H), 1 .96-1 .90 (m, 1 H), 1.79-1.74 (m, 1 H), 1.71-1.63 (m, 2H)

LC-MS (Method C): Rt = 0.431 min; MS (ESipos): m/z = 363.2 [M+H] ⁺

Intermediate 9

3.5-dimethyl-2-(3-(1-methyipiperidin-3-yl)pyrido[2,3-b]py razin-6-yl)phenol (racemic)

To a solution of 6-(2-methoxy-4,6-dimethyl-phenyl)-3-[1-methyl-3-piperidyl]py rido[2,3-b]pyrazine (150 mg, 413 pmol, 1 eq) in dichloromethane (15 mL) was added BBrs (311 mg, 1.24 mmol, 119 pL, 3 eq) at -70 °C. After stirring at 25 °C for 2 h, the reaction was quenched by dropping ammonia methanol solution (7M, 10 mL) at 0 °C. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water (FA) - MeCN]; B%: 20% - 70%, 8 min) to give compound 3,5-dimethyl-2-(3- (1- methylpiperidin-3-yl)pyrido[2,3-b]pyrazin-6-yi)phenol (90 mg, 25.6 mmol, 62% yield, 99% purity) LC-MS (Method C): Rt = 0.532 min; MS (ESipos): m/z - 349.1 [M+H] ⁺

Compounds 3 and 4

3.5-dimethyl-2-[3-(1 -methylpiperidin-3-yl)pyrido[2,3-b]pyrazin-6-yl]phenol (single enantiomers) Intermediate 9 was separated by SFC: (column: Phenomenex-Cellulose-2 (250 mm x 30 mm, 10 um);mobile phase: [CO ₂ -EtOH (0.1 %NH3 ^,, H20)];B%:40%, isocratic elution mode) to give compound 3 (7.89 mg, 22.4 pmol, 5% yield, 99% purity) as a yellow solid and compound 4 (7.21 mg, 20.3 pmol, 5% yield, 98% purity) as a yellow solid.

Compound 3: ¹ H NMR (400 MHz, DMSO-c/ ₆ ) 5 = 9.55 (s, 1 H), 9.06 (s, 1 H), 8.50-8.45 (m, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 6.64 (d, J = 5.2 Hz, 2H), 3.09-3.00 (m, 1 H), 2.84-2.77 (m, 1 H), 2.34-2.31 (m, 1 H), 2.27 (s, 4H), 2.24 (s, 3H), 2.07 (s, 3H), 2.04-1.91 (m, 2H), 1 .81-1 .74 (m, 1 H), 1.71-1.61 (m, 2H) LC-MS (Method C): Rt = 0.423 min; MS (ESipos): m/z = 349.4 [M+H] ⁺ SFC (Rt = 2.001 min) Compound 4:

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 = 9.55 (s, 1 H), 9.08 (s, 1 H), 8.49 (d, J = 8.4 Hz, 1 H), 7.80 (d, J = 8.8 Hz, 1 H), 6.62 (d, J = 8.8 Hz, 2H), 3.66-3.42 (m, 2H), 2.80-2.69 (m, 2H), 2.55-2.52 (m, 3H), 2.41-2.33 (m, 1 H), 2.24 (s, 3H), 2.21-2.14 (m, 1 H), 2.06 (s, 3H), 1.96-1.78 (m, 2H), 1.59 (s, 1 H) LC-MS (Method C): Rt = 0.416 min; MS (ESipos): m/z = 349.4 [M+H] ⁺ SFC (Rt = 2.406 min)

Intermediate 10

6-chloro-3-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3-b]py razine

To a solution of 3,6-dichloropyrido[2,3-b]pyrazine (7.00 g, 35.0 mmol, 1 eq) in the mixture of dioxane (80 mL) and H2O (20 mL) was added (2-methoxy-4,6-dimethyl-phenyl)boronic acid (4.41 g, 24.5 mmol, 0.7 eq) , sodium carbonate (11.1 g, 105 mmol, 3 eq) and Pd(dppf)Ch (1.28 g, 1.75 mmol, 0.05 eq) at 25 °C. After stirring at 60 °C for 16 h under N2 atmosphere, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 10/1 to 5/1). Then the crude compound was triturated with ethyl acetate (20 mL) at 25 °C for 30 min to give compound 6-chloro-3-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyraz ine (4 g, 10.7 mmol, 30% yield, 80% purity) as a white solid.

LC-MS (Method C): Rt = 0.578 min; MS (ESipos): m/z = 300.2 [M+H] ⁺

Intermediate 11

3-(2-methoxy-4,6-dimethyl-phenyl)-6-(1-methyl-3,6-dihydro -2H-pyridin-5-yl)pyrido[2,3-b]pyrazine

To a solution of 6-chloro-3-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyraz ine (3.80 g, 12.6 mmol, 1 eq) and 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (4.24 g, 19.0 mmol, 1.5 eq) in the mixture of dioxane (60 mL) and H2O (10 mL) was added sodium carbonate (4.03 g, 38.0 mmol, 3 eq) and Pd(dppf)Cl2 (463 mg, 633 pmol, 0.05 eq) at 25 °C. After stirring at 60 °C for 16 h under N2 atmosphere, the reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (80 mL x 2). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18, 220 g, mobile phase: [water(FA)- MeCN];B%: 40% - 60%, 8 min) to give compound 3-(2-methoxy-4,6-dimethyl-phenyl)-6-(1-methyl-3,6- dihydro-2H-pyridin-5-yl)pyrido [2,3-b]pyrazine (2.3 g, 6.19 mmol, 48% yield, 97% purity) as black brown oil.

LC-MS (Method C): Rt = 0.423 min; MS (ESipos): m/z = 361 .2 [M+H] ⁺ Intermediate 12 3-(2-methoxy-4,6-dimethyl-phenyl)-6-[1-methyl-3-piperidyl]py rido[2,3-b]pyrazine (racemic)

To a solution of 3-(2-methoxy-4,6-dimethyl-phenyl)-6-(1-methyl-3,6-dihydro-2H -pyridin-5-yl)pyrido[2,3- bjpyrazine (2.20 g, 6.10 mmol, 1 eq) in methanol (10 mL) was added Pd/C (200 mg, 610 pmol, 10% purity, 0.1 eq) at 25 °C. After stirring at 25 °C for 3 h under H2 (15 psi) atmosphere, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18, 220 g, mobile phase: [water (FA)-MeCN]; B%: 30%- 70%, 10 min), to give compound 3-(2-methoxy-4,6-dimethyl-phenyl)-6-[rac-(3R)-1-methyl-3-pip eridyl] pyrido[2,3-b]pyrazine (1.00 g, 2.97 mmol, 48% yield, 98% purity) as black brown oil.

LC-MS (Method C): Rt = 0.436 min; MS (ESIpos): m/z = 363.2 [M+H] ⁺

Intermediate 13

3,5-dimethyl-2-[6-[1-methyl-3-piperidyl]pyrido[2,3-b]pyra zin-3-yl]phenol (racemic)

To a solution of 3-(2-methoxy-4,6-dimethyl-phenyl)-6-[1-methyl-3-piperidyl]py rido[2,3-b]pyrazine (300 mg, 827 pmol, 1 eq) in dichloromethane (15 mL) was added BBrs (622 mg, 2.48 mmol, 239 pL, 3 eq) at -70 °C. After stirring at 25 °C for 2 h, the reaction mixture was quenched by addition amino-methanol solution 10 mL at 0 °C, then the mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18, 80 g, mobile phase: [water(FA) - MeCN]; B%: 20% - 80%, 6 min) to give compound 3,5-dimethyl-2-[6-[1- methyl-3-piperidyl]pyrido[2,3-b]pyrazin-3-yl]phenol (140 mg, 398 pmol, 48% yield, 99% purity) as a yellow solid,

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 = 9.66 (s, 1 H), 8.93 (s, 1 H), 8.47 (d, J = 8.8 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 6.67 (s, 2H), 3.24-3.19 (m, 1 H), 3.10-3.02 (m, 1 H), 2.86-2.78 (m, 1 H), 2.45 (d, J = 3.6 Hz, 1 H), 2.28 (s, 3H), 2.25 (s, 3H), 2.13 (s, 3H), 2.05-1.96 (m, 2H), 1.80-1.74 (m, 1 H), 1.71-1.60 (m, 2H) LC-MS (Method C): Rt = 0.410 min; MS (ESIpos): m/z = 349.1 [M+H] ⁺

Compounds 5 and 6

Procedure for preparation of 3,5-dimethyl-2-[6-(1 -methylpiperidin-3-yl)pyrido[2,3-b]pyrazin-3-yl]phenol Compound (single enantiomers)

Intermediate 13 was separated by SFC: (column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 um) mobile phase: [CCh-EtOH (0.1 % NHs’HzO)]; B%:40%, isocratic elution mode) to give compound 5 (62.3 mg, 179 pmol, 28% yield) as yellow oil and compound 6 (48.2 mg, 138 pmol, 21 % yield) as yellow oil. Compound 5

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 = 9.78-9.65 (m, 1 H), 8.97 (s, 1 H), 8.55 (d, J = 8.4 Hz, 1 H), 7.94-7.88 (m, 1 H), 6.68 (d, J = 2.8 Hz, 2H), 3.64-3.43 (m, 2H), 2.81-2.68 (m, 3H), 2.53-2.51 (m, 3H), 2.28 (s, 3H), 2.14 (s, 4H), 1.98-1.80 (m, 2H), 1.77 (s, 1 H).

LC-MS (Method C): Rt = 0.405 min; MS (ESIpos): m/z - 349.1 [M+H] ⁺

SFC (Rt = 0.772 min)

Compound 6 ¹ H NMR (400 MHz, DMSO-d ₅ ) 5 = 9.69 (s, 1 H), 8.95 (s, 1 H), 8.50 (d, J = 8.4 Hz, 1 H), 7.88 (d, J = 8.8 Hz, 1 H), 6.68 (s, 2H), 3.40 (s, 2H), 3.11-2.98 (m, 1 H), 2.78-2.63 (m, 1 H), 2.49-2.41 (m, 4H), 2.28 (s, 3H), 2.13 (s, 3H), 2.11-2.03 (m, 1 H), 1.89-1.58 (m, 3H)

LC-MS (Method C): Rt = 0.404 min; MS (ESIpos): m/z = 349.1 [M+H] ⁺ SFC (Rt = 1 .028 min)

Intermediate 14

4-hydroxy-7-(2-methoxy-4,6-dimethyi-phenyl)-1 H-1 ,8-naphthyridin-2-one

To a solution of 7-chloro-1 H-1 ,8-naphthyridine-2, 4-dione (8.00 g, 36.6 mmol, 1.00 eq) and (2-methoxy-

4.6-dimethyl-phenyl)boronic acid (7.91 g, 43.9 mmol, 1.20 eq) in dioxane (160 mL) and water (16 mL) were added Xphos-Pd-G3 (3.10 g, 3.66 mmol, 0.1 eq) and K3PO4 (15.6 g, 73.2 mmol, 2 eq) at 25 °C, the reaction mixture was degassed and purged with N2 for 3 times. After stirring at 90 °C for 14 h, the reaction mixture was concentrated to give a residue. The residue was added water (200 mL) and extracted with ethyl acetate (200 mL), the water phase was collected and adjusted to pH was 3~5 by HCI (1 .00 M) solution, the mixture was filtrated and the filtrate cake was concentrated to give 4-hydroxy- 7-(2-methoxy-4,6-dimethyl-phenyl)-1 H-1 ,8-naphthyridin-2-one (10.0 g, 33.1 mmol, 90% yield, 98% purity) as a light yellow solid.

LC-MS (Method C): Rt = 0.481 min; MS (ESIpos): m/z = 297.2 [M+H] ⁺ .

Intermediate 15

2,4-dichloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine

To a solution of 4-hydroxy-7-(2-methoxy-4,6-dimethyl-phenyl)-1 H-1 ,8-naphthyridin-2-one (5.00 g, 16.5 mmol) in toluene (100 mL) was added POCI3 (12.6 g, 82.6 mmol, 7.71 mL, 5 eq) at 25 °C. After stirring at 100 °C for 16 h, the mixture was concentrated to remove solvent. The pH of the reaction mixture was adjust to 7-8 by saturated sodium bicarbonate solution. After stirring at 25 °C for 0.5 h, the residue was diluted with water (100 mL), and then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate. Filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOz, Petroleum ether/Ethyl acetate = 1/0 to 30/1). to give compound 3-(2-methoxy-

4.6-dimethyl-phenyl)-6-(1-methyl-3,6-dihydro-2H-pyridin-5 -yl)pyrido[2,3-b]pyrazine (2.30 g, 6.19 mmol, 48% yield, 97% purity) as a white solid.

LC-MS (Method C): Rt = 0.629 min; MS (ESIpos): m/z - 333.2 [M+H] ⁺

Intermediate 16 tert-butyl 5-[4-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-3,6-dihydro-2H- pyridine-1 -carboxylate

To a solution of tert-butyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1- carboxylate (2.51 g, 8.10 mmol, 0.9 eq) in the mixture of water (10 mL) and dioxane (50 mL) was added 2, 4-dichloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (3.00 g, 9.00 mmol, 1 eq), Pd(PPhs)4 (1 .04 g, 900 pmol, 0.1 eq) and sodium carbonate (1 .91 g, 18.0 mmol, 2 eq) at 25 °C. After stirring at 50 °C for 4 h under N2 atmosphere, the mixture was concentrated to remove solvent. The residue was diluted with water (60 mL), and then extracted with ethyl acetate (60 mL x 2). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate. Filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate = 10/1 to 5/1) to give compound tert-butyl 5-[4- chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-3,6-dihydro-2H-pyridine-1- carboxylate (440 mg, 825 pmol, 9 % yield, 90% purity) as a white solid.

LC-MS (Method C): Rt - 0.658 min; MS (ESIpos): m/z = 480.2 [M+H] ⁺

Intermediate 17 tert-butyl 5-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-1 ,8-naphthyridin-2-yl]-3,6-dihydro-2H- pyridine-1 -carboxylate

To a solution of tert-butyl 5-[4-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-3,6- dihydro-2H-pyridine-1-carboxylate (440 mg, 916 pmol, 1 eq) in the mixture of dioxane (15 mL) and water (5 mL) was added 2,4,6-trimethyl-1 ,3,5,2,4,6-trioxatriborinane (1.15 g, 4.58 mmol, 1 .28 mL, 5 eq), Pd(dppf)Cl2 (67.0 mg, 91.6 pmol, 0.1 eq) and sodium carbonate (291 mg, 2.75 mmol, 3 eq) at 25 °C. After stirring at 80 °C for 16 h under N2 atmosphere, the mixture was concentrated to remove solvent. The residue was diluted with water (20 mL), and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate. Filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate = 10/1 to 5/1) to give compound tert-butyl 5-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-1 ,8-naphthyridin-2-yl]-3,6-dihydro- 2H-pyridine-1 -carboxylate (230 mg, 450 pmol, 49% yield, 90% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.683 min; MS (ESIpos): m/z = 460.1 [M+H] ⁺

Intermediate 18 tert-butyl-3-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-1 ,8-naphthyridin-2-yl]piperidine-1- carboxylate (race mate)

To a solution of tert-butyl 5-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-1 ,8-naphthyridin-2-yl]-3,6- dihydro-2H-pyridine-1 -carboxylate (230 mg, 500 pmol, 1 eq) in methanol (5 mL) was added Pd/C (68.0 mg, 50.0 pmol, 10% purity, 0.1 eq) at 25 °C. After stirring at 25 °C for 2 h under H2 (15 psi) atmosphere, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give compound tert-butyl (3R)-3-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-1 ,8-naphthyridin-2-yl] piperidine-1 -carboxylate (200 mg, 389 pmol, 77% yield, 90% purity) as a yellow oil.

LC-MS (Method C): Rt = 0.535 min; MS (ESIpos): m/z - 462.4 [M+H] ⁺

Intermediate 19

7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-2-[3-piperidyl ]-1 ,8-naphthyridine (racemate)

To a solution of tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-1 ,8-naphthyridin-2-yl] piperidine-1 -carboxylate (200 mg, 389 pmol, 1 eq) in ethyl acetate (10 mL) was added HCI/ethyl acetate (4 M, 974 pL, 10 eq) at 25 °C. After stirring at 25 °C for 16 h., the reaction mixture was concentrated under reduced pressure to give compound 7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-2- [(3R)-3- piperidyi]-1 ,8-naphthyridine (200 mg, 382 pmol, 98% yield, 90% purity, HCi sait) as a yellow solid.

LC-MS (Method C): Rt = 0.558 min; MS (ESipos): m/z = 362.2 [M+H] ⁺

Intermediate 20

7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-2-[1-methyl-3- piperidyl]-1 ,8-naphthyridine (racemate).

To a solution of 7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-2-[3-piperidyl]-1 ,8-naphthyridine (200 mg, 382 pmol, 1 eq, HCI salt) in methanol (15 mL) was added (HCHO) _n (57.3 mg, 1.91 mmol, 5 eq) and potassium acetate (112 mg, 1.15 mmol, 3 eq) at 25 °C. Then the mixture was added NaBHsCN (72.0 mg, 1.15 mmol, 3 eq) slowly at 25 °C. After stirring at 25 °C for 3 h, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate. Filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water (FA) - MeCN]; B%: 30%-70%, 12 min), to give compound 7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-2-[(3R)-1-methyl- 3-piperidyl]-1 ,8- naphthyridine (90 mg, 227 pmol, 59% yield, 95% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.447 min; MS (ESipos): m/z = 376.4 [M+H] ⁺

Intermediate 21

3.5-dimethyl-2-[5-methyl-7-[1-methyl-3-piperidyl]-1 ,8-naphthyridin-2-yl]phenol (racemate).

To a solution of 7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-2-[1-methyl-3-pip eridyl]-1 ,8- naphthyridine (90.0 mg, 239 pmol, 1 eq) in dichloromethane (15 mL) was added BBrs (180 mg, 719 pmol, 69.2 pL, 3 eq) at -70 °C. After stirring at 25 °C for 1 h, the reaction is quenched by ammonia methanol solution (7 M, 10 mL) at 0 °C. Filtered and the filtrate was concentrated under reduced pressure to give a residue The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water (FA) - MeCN]; B%: 35% - 65%, 8 min) to give compound 3,5-dimethyl-2-[5-methyl-7-[(3R)-1-methyl- 3- piperidyl]-1 ,8-naphthyridin-2-yl]phenol (31 mg, 84 pmol, 35% yield, 99% purity) as a yellow solid. LC-MS (Method C): Rt = 0.409 min; MS (ESipos): m/z = 362.3 [M+H] ⁺

Compounds 7 and §

3.5-dimethyl-2-[5-methyl-7-(1-methylpiperidin-3-yl)-1,8-n aphthyridin-2-yl]phenol compound (single enantiomers)

Intermediate 21 was separated by SFC: (column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 um);mobile phase: [CO ₂ -MeCN/i-PrOH (0.1 % NHs’^O)]; B%: 60%, isocratic elution mode) to give compound 7 (6.52 mg, 17.3 pmol, 40% yield, 96% purity) as a yellow solid and compound 8 (12.04 mg, 32.64 pmol, 76% yield, 98% purity) as a yellow solid Compound 7

^! H NMR (400 MHz, DMSO-d _e ) 5 = 9.88 (s, 1 H), 8.51 (d, J = 8.4 Hz, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.47 (s, 1 H), 6.63 (d, J = 6.0 Hz, 2H), 3.14 (d, J = 6.4 Hz, 2H), 2.97-2.89 (m, 1 H), 2.71 (s, 3H), 2.46-2.40 (m, 1 H), 2.35 (s, 3H), 2.26 (s, 3H), 2.20-2.12 (m, 1 H), 2.10 (s, 3H), 2.01 (d, J = 12.0 Hz, 1 H), 1.83-1.77 (m, 1 H), 1.72-1.59 (m, 2H)

LC-MS (Method C): Rt = 0.407 min; MS (ESIpos): m/z = 362.3 [M+H] ⁺

SFC (Rt = 1 .532 min)

Compound 8

¹ H NMR (400 MHz, DMSO-d _s ) <5 = 9.80 (s, 1 H), 8.55 (d, J = 8.4 Hz, 1 H), 7.60 (d, J = 8.4 Hz, 1 H), 7.52 (s, 1 H), 6.63 (d, J = 10.0 Hz, 2H), 3.79-3.67 (m, 1 H), 3.41 (d, J = 5.6 Hz, 2H), 3.05-2.94 (m, 1 H), 2.85 (s, 3H), 2.74 (s, 3H), 2.26 (s, 3H), 2.16 (d, J = 12.8 Hz, 1 H), 2.09 (s, 3H), 2.01-1.90 (m, 2H), 1.72-1.61 (m, 1 H), 1 .26-1 .19 (m, 1 H)

LC-MS (Method C): Rt - 0.416 min; MS (ESipos): m/z = 362.0 [M+H] ⁺

SFC (Rt = 2.453 min)

Intermediate 22

7-chloro-4-hydroxy-1 H-1 ,8-naphthyridin-2-one

To a solution of methyl 2-amino-6-chloro-pyridine-3-carboxylate (25.0 g, 134 mmol, 1 eq) in Ethyl acetate (250 mL) was added t-BuOK (1 .00 M, 268 mL, 2 eq) at 25 °C. After stirring at 60 °C for 16 h, the mixture was concentrated to give a residue. The residue was added water (500 mL) and adjusted to pH was 3~4 by HCI solution (1 .00 M), the mixture was filtrated and the filtrate cake was collected and concentrated under reduced pressure to give a crude. The crude was triturated with ethyl acetate (100 mL) to give compound 7-chloro-4-hydroxy-1 H-1 ,8-naphthyridin-2-one (8.00 g, 36.6 mmol, 27% yield, 90% purity) as a light yellow solid.

LC-MS (Method C): Rt = 0.386 min; MS (ESipos): m/z = 197.1 [M+H] ⁺ .

Intermediate 23

4-hydroxy-7-(2-methoxy-4,6-dimethyl-phenyl)-1 H-1 ,8-naphthyridin-2-one

To a solution of 7-chloro-1 H-1 , 8-naphthyridine-2, 4-dione (8.00 g, 36.6 mmol, 1.00 eq) and (2-methoxy- 4,6-dimethyl-phenyl)boronic acid (7.91 g, 43.9 mmol, 1.20 eq) in dioxane (160 mL) and water (16 mL) were added Xphos-Pd-G3 (3.10 g, 3.66 mmol, 0.10 eq) and K3PO4 (15.6 g, 73.2 mmol, 2.00 eq) at 25 °C, the reaction mixture was degassed and purged with N2 for 3 times. After stirring at 90 °C for 14 h, the reaction mixture was concentrated to give a residue. The residue was added water (200 mL) and extracted with ethyl acetate (200 mL), the water phase was collected and adjusted to pH was 3-5 by HCI (1 .00 M) solution, the mixture was filtrated and the filtrate cake was concentrated to give compound 4-hydroxy-7-(2-methoxy-4,6-dimethyl-phenyl)-1 H-1 ,8-naphthyridin-2-one (10.0 g, 33.1 mmol, 90% yield, 98% purity) as a light yellow solid.

LC-MS (Method C): Rt = 0.481 min; MS (ESipos): m/z - 297.2 [M+H] ⁺ .

Intermediate 24

2,4-dichloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine

To a solution of 4-hydroxy-7-(2-methoxy-4,6-dimethyl-phenyl)-1 H-1 ,8-naphthyridin-2-one (5.00 g, 16.5 mmol, 1 eq) in toluene (100 mL) was added POCI3 (7.61 g, 49.6 mmol, 4.62 mL, 3 eq) at 25 °C, the reaction mixture was stirred at 100 °C for 16 h, the mixture was concentrated to give a residue. The crude was diluted with ethyl acetate (100 mL) and washed with saturated NaHCOs solution (200 mL) and brine (100 mL) by follow, the organic phase was collected and concentrated to give compound 2,4- dichloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (3.10 g, 9.02 mmol, 54% yield, 97% purity) as a grey solid.

¹ H NMR (400 MHz, DMSO-d _s ) 6 = 8.64 (d, J = 8.8 Hz, 1 H), 8.09 (s, 1 H), 7.74 (d, J = 8.8 Hz, 1 H), 6.85 (s, 1 H), 6.79 (s, 1 H), 3.67 (s, 3H), 2.36 (s, 3H), 2.03 (s, 3H).

LC-MS (Method C): Rt = 0.642 min; MS (ESIpos): m/z - 333.1 [M+H] ⁺ .

Intermediate 25 tert-butyl 5-[4-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-3,6-dihydro-2H- pyridine-1 -carboxylate

To a solution of 2, 4-dichloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (3.00 g, 8.73 mmol, 1 eq), tert-butyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1 -carboxylate (2.16 g, 6.99 mmol, 0.8 eq) and Na2COs (1 .39 g, 13.1 mmol, 1 .5 eq) in dioxane (50 mL) were added a solution of Pd(PPh3)4 (1.01 g, 873 pmol, 0.10 eq) in water (10 mL) at 25 °C, the reaction mixture was degassed and purged with N2 for 3 times. After stirring at 80 °C for 16 h, the mixture was concentrated to give a crude. The crude was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 10/1 to 5/1) to give compound tert-butyl 5-[4-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8- naphthyridin-2-yip3,6-dihydro-2H-pyridine-1-carboxylate (3.00 g, 5.94 mmol, 68% yield, 95% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.658 min; MS (ESIpos): m/z = 480.3 [M+H] ⁺ .

Intermediate 26 methyl 2-(1 -tert-butoxycarbonyl-3, 6-dihydro-2H-pyridin-5-yl)-7-(2-methoxy-4,6-dimethyl-phenyl) -1 ,8- naphthyridine-4-carboxylate

To a solution of tert-butyl 5-[4-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]- 3,6- dihydro-2H-pyridine-1-carboxylate (3.00 g, 5.63 mmol, 1 eq) in MeOH (50 mL) were added EfaN (1.14 g, 11.2 mmol, 1.57 mL, 2.0 eq) and Pd(dppf)Cl2 (411 mg, 562 pmol, 0.1 eq) at 25 °C, the mixture was degassed and purged with CO for 3 times. After stirring at 80 °C for 16 h under CO (50 psi) atmosphere, the mixture was concentrated to give a crude. The crude was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate - 10/1 to 3/1) to give compound methyl 2-(1 -tert-butoxycarbonyl-3, 6- dihydro-2H-pyridin-5-yl)-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine-4-carboxylate (2.40 g, 4.00 mmol, 71 % yield, 84% purity) as a yellow solid.

LC-MS (Method I:): Rt - 0.602 min; MS (ESIpos): m/z = 504.3 [M+H] ⁺ .

Intermediate 27 methyl 2-(1-tert-butoxycarbonyl-3-piperidyl)-7-(2-methoxy-4,6-dimet hyl-phenyl)-1 ,8-naphthyridine-4- carboxylate (racemate) To a solution of methyl 2-(1 -tert-butoxycarbonyl-3, 6-dihydro-2H-pyridin-5-yl)-7-(2-methoxy-4, 6- dimethyl-phenyl)-1 ,8-naphthyridine-4-carboxylate (2.40 g, 4.00 mmol, 1 eq) in MeOH (50 mL) was added Pd/C (240 mg, 50% purity) at 25 °C. After stirring at 25 °C for 2 h under H2 (15 psi) atmosphere, the mixture was filtrated and the filtrate was concentrated to give to give compound methyl 2-(1-tert- butoxycarbonyi-3-piperidyl)-7-(2-methoxy-4,6-dimethyl-phenyi )-1 ,8-naphthyridine-4- carboxylate (1 .50 g, 2.08 mmol, 52% yield, 70% purity) as a yellow solid.

LC-MS (Method C): Rt - 0.608 min; MS (ESIpos): m/z = 506.4 [M+H] ⁺ .

Intermediate 28 methyl 7-(2-methoxy-4,6-dimethyl-phenyl)-2-(3-piperidyl)-1 ,8-naphthyridine-4-carboxylate (racemate) To a solution of methyl 2-(1-tert-butoxycarbonyl-3-piperidyl)-7-(2-methoxy-4,6-dimet hyl-phenyl)-1 ,8- naphthyridine-4-carboxylate (1 .50 g, 2.08 mmol, 1 .00 eq) in ethyl acetate (20 mL) was added HCI/Ethyl acetate (4.00 M, 2.60 mL, 5 eq) at 25 °C. After stirring at 25 °C for 2 h, the mixture was concentrated to give compound methyl 7-(2-methoxy-4,6-dimethyl-phenyl)-2-(3-piperidyl)-1 ,8- naphthyridine-4- carboxylate (1 .00 g, 1 .50 mmol, 72% yield, 61 % purity, HCI salt) as a yellow solid.

LC-MS (Method C): Rt = 0.462 min; MS (ESIpos): m/z = 406.2 [M+H] ⁺ .

Intermediate 29 methyl 7-(2-methoxy-4,6-dimethyl-phenyl)-2-(1-methyl-3-piperidyl)-1 ,8-naphthyridine-4-carboxylate (racemate)

To a solution of methyl 7-(2-methoxy-4,6-dimethyl-phenyl)-2-(3-piperidyl)-1 ,8-naphthyridine-4- carboxylate (1.00 g, 1.50 mmol, 1 eq) in MeOH (10 mL) were added HCHO (610 mg, 7.52 mmol, 560 pL, 37% purity in water, 5 eq), AcOH (90.3 mg, 1.50 mmol, 86.1 pL, 1 eq) and Pd/C (100 mg, 50% purity) at 25 °C. After stirring at 25 °C for 2 h under H2 (15 psi) atmosphere, the mixture was concentrated to give a residue. The crude was purified by reversed-phase column (column: C18, 80 g, mobile phase: [water (FA) - MeCN]; B%: 35% - 65%, 9 min) to give compound methyl 7-(2-methoxy- 4,6-dimethyl-phenyl)-2-(1-methyl- 3-piperidyl)-1 ,8-naphthyridine-4-carboxylate (750 mg, 1.34 mmol, 89% yield, 75% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.460 min; MS (ESIpos): m/z = 420.3 [M+H] ⁺ .

Compound 9

Methyl 7-(2-hydroxy-4,6-dimethylphenyl)-2-(1 -methy Ipiperid I n-3-y I)- 1 ,8-naphthyridine-4-carboxylate - (racemate)

To a solution of methyl 7-(2-methoxy-4,6-dimethyl-phenyl)-2-(1-methyl-3-piperidyl)-1 ,8- naphthyridine- 4-carboxylate (650 mg, 1.16 mmol, 1 eq) in DCM (10 mL) was added BBr.3 (873 mg, 3.49 mmol, 335 pL, 3 eq) at 0 °C. After stirring at 25 °C for 2 h, the mixture was added methanol (30 mL) and concentrated under reduced pressure to give a residue. The crude was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(FA) - MeCN]; B%: 30% - 70%, 7 min) to give compound methyl 7-(2-hydroxy-4,6-dimethyl-phenyl)-2-(1-methyl-3-piperidyl)-1 ,8-naphthyridine-4- carboxylate (450 mg, 832 pmol, 71 % yield, 75% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₅ ) 6 = 9.91 (s, 1 H), 9.31 (d, J = 8.4 Hz, 1 H), 8.27 (s, 1 H), 7.98 (d, J = 8.4 Hz, 1 H), 6.71 (s, 1 H), 6.68 (s, 1 H), 4.04 (s, 3H), 3.82-3.78 (m, 1 H), 3.72-3.68 (m, 1 H), 3.55-3.45 (m, 2H), 3.10-3.05 (m, 1 H), 2.88 (d, J = 4.8 Hz, 3H), 2.28 (s, 3H), 2.25-2.20 (m, 1 H), 2.12 (s, 3H), 2.04-1 .96 (m, 2H), 1 .74-1 .68 (m, 1 H).

LC-MS (Method C): Rt = 0.440 min; MS (ESIpos): m/z = 406.1 [M+H]+.

Compound 10 2-[5-(hydroxymethyl)-7-(1-methyl-3-piperidyl)-1 ,8-naphthyridin-2-yl]-3,5-dimethyl-phenol (racemate)

To a solution of methyl 7-(2-hydroxy-4,6-dimethylphenyi)-2-(1 -methylpiperidin-3-yl)-1,8maphthyridine- 4-carboxylate (200 mg, 369 pmol, 1 eq) in THF (5 mL) was added LiAIH4 (42.1 mg, 1 .11 mmoi, 3 eq) at 0 °C. After stirring at 0 °C for 1 h, the mixture was added water (10 ml) and concentrated to give a residue. The crude was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water (FA) - MeCN]; B%: 20% - 80%, 10 min) to give compound 2-[5-(hydroxymethyl)-7-(1-methyi-3- piperidyl)- 1 ,8-naphthyridin-2-yl]-3,5-dimethyl-phenol (32.0 mg, 68.7 pmol, 18% yield, 91 % purity, FA salt) as a light yellow solid,

¹ H NMR (400 MHz, DMSO-cfe) 6 = 9.84 (s, 1 H), 8.48 (d, J = 8.4 Hz, 1 H), 8.20 (s, 1 H), 7.60 (s, 1 H), 7.54 (d, J = 8.8 Hz, 1 H), 6.63 (s, 1 H), 6.62 (s, 1 H), 5.04 (s, 2H), 3.20-3.10 (m, 4H), 2.92-2.88 (m, 1 H), 2.38-

2.35 (m, 1 H), 2.30 (s, 3H), 2.26 (s, 3H), 2.09 (s, 3H), 2.05-1 .95 (m, 2H), 1 .74-1 .55 (m, 2H).

LC-MS (Method C): Rt = 0.388 min; MS (ESIpos): m/z = 378.3 [M+H]+.

Compounds 11 and 12

2-[5-(hydroxymethyl)-7-[1-methyi-3-piperidyl]-1 ,8-naphthyridin-2-yl]-3,5-dimethyl-phenol&2-[5- (hydroxymethyl)-7-[1-methyl-3-piperidyl]-1 ,8-naphthyridin-2-yl]-3,5-dimethyl-phenol (single enantiomers)

Compound 10 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um); mobile phase: [CO ₂ -MeCN/i-PrOH(0.1 % NH3-H2O)]; B%: 30%, isocratic elution mode) to give compound 11 (5.00 mg, 13.1 pmol, 20% yield, 99% purity) as a yellow solid and compound 12 (10.0 mg, 26.2 pmol, 40% yield, 99% purity) as a yellow solid.

Compound 11

¹ H NMR (400 MHz, DMSO-d6) 5 = 9.84 (s, 1 H), 8.48 (d, J = 8.4 Hz, 1 H), 8.20 (s, 1 H), 7.60 (s, 1 H), 7.54 (d, J = 8.8 Hz, 1 H), 6.63 (s, 1 H), 6.62 (s, 1 H), 5.04 (s, 2H), 3.20-3.10 (m, 4H), 2.92-2.88 (m, 1 H), 2.38-

2.35 (m, 1 H), 2.30 (s, 3H), 2.26 (s, 3H), 2.09 (s, 3H), 2.05-1.95 (m, 2H), 1.74-1.55 (m, 2H).

LC-MS (Method C): Rt = 0.386 min; MS (ESIpos): m/z = 378.3 [M+H] ⁺ .

SFC (Rt = 1 .282 min)

Compound 12

¹ H NMR (400 MHz, DMSO-d6) 6 = 9.84 (s, 1 H), 8.48 (d, J = 8.4 Hz, 1 H), 8.20 (s, 1 H), 7.60 (s, 1 H), 7.54 (d, J = 8.8 Hz, 1 H), 6.63 (s, 1 H), 6.62 (s, 1 H), 5.04 (s, 2H), 3.20-3.10 (m, 4H), 2.92-2.88 (m, 1 H), 2.38-

2.35 (m, 1 H), 2.30 (s, 3H), 2.26 (s, 3H), 2.09 (s, 3H), 2.05-1.95 (m, 2H), 1.74-1.55 (m, 2H).

LC-MS (Method C): Rt = 0.391 min; MS (ESIpos): m/z = 378.3 [M+H] ⁺ .

SFC (Rt = 2.021 min) Intermediate 30

7-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3-d]pyrimidine- 2,4-diol

To a solution of 7-chloropyrido[2,3-d]pyrimidine-2,4-diol (4.00 g, 20.3 mmol, 1 eq) and (2-methoxy-4,6- dimethyl-phenyl)boronic acid (5.47 g, 30.4 mmol, 1.5 eq) in dioxane (100 mL) was added Pd(dppf)Cl2 (1.48 g, 2.02 mmol, 0.1 eq) and K2CO3 (7.00 g, 50.6 mmol, 2.5 eq) in water (20 mL) at 25 °C. After stirring at 90 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOs, Petroleum ether/Ethyl acetate=1/0 to 0/1) to give compound 7-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3-d]pyrimidine-2,4 -diol (5.20 g, 13.0 mmol, 69 % yield, 80% purity) as a yellow solid.

¹ H NMR (400 MHz, CD3OD) 6 [ppm] = 8.34 (d, J = 8.0 Hz, 1 H), 7.20 (d, J = 8.0 Hz, 1 H), 6.74 (d, J = 9.6 Hz, 2H), 3.70 (s, 3H), 2.35 (s, 3H), 2.07 (s, 3H)

LC-MS (Method C): Rt = 0.475 min; MS (ESIpos): m/z = 298.2 [M+H] ⁺

Intermediate 31

2,4-dichloro-7-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3- d]pyrimidine

To a solution of 7-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3-d]pyrimidine-2,4 -diol (4.70 g, 15.8 mmol,

1 eq) in POCh (80 mL). After stirring at 1 10 °C for 48 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was quenched by addition water (200 mL) at 25 °C, and then extracted with ethyl acetate (120 mL x 3), The combined organic layers were washed with saturated sodium bicarbonate aqueous solution (100 mL x 3) and brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SIO ₂ , Petroleum ether/Ethyl acetate=1/0 to 1/1) to give compound 2,4-dichloro-7-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3-d]p yrimidine (1.70 g, 4.88 mmol, 31 % yield, 96% purity) as a yellow solid.

^! H NMR (400 MHz, CDCh) 5 [ppm] = 8.55 (d, J = 8.8 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 6.78 (s, 1 H), 6.68 (s, 1 H), 3.72 (s, 3H), 2.40 (s, 3H), 2.20 (s, 3H)

LC-MS (Method C): Rt = 0.616 min; MS (ESIpos): m/z = 333.8 [M+H] ⁺

Intermediate 32

2-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-pyrid o[2,3-d]pyrimidine

To a solution of 2,4-dichloro-7-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3-d]p yrimidine (1.50 g, 4.49 mmol, 1 eq) and 2,4,6-trimethyl-1 ,3,5,2,4,6-trioxatriborinane (3.5 M, 1.28 mL, 50% purity, 1 eq) in dioxane (160 mL) was added Pd(dppf)Cl2 (328 mg, 449 umol, 0.1 eq) and K2CO3 (1.24 g, 8.98 mmol,

2 eq). After stirring at 80 °C for 16 h, the mixture was concentrated to give a crude. The residue was purified by column chromatography (SiO?, Petroleum ether/Ethyl acetate=1/0 to 0/1) to give compound 2-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-pyrido[2 ,3-d]pyrimidine (1.34 g, 3.42 mmol, 76% yield, 80% purity) as a yellow solid.

¹ H NMR (400 MHz, CDCh) 6 [ppm] = 8.42 (d, J = 8.4 Hz, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 6.77 (s, 1 H), 6.67 (s, 1 H), 3.71 (s, 3H), 3.00 (s, 3H), 2.39 (s, 3H), 2.19 (s, 3H) LC-MS (Method C): Rt = 0.555 min; MS (ESIpos): m/z = 314.1 [M+H]

Intermediate 33 tert-butyl 5-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-pyrido[2,3-d]p yrimidin-2-yi]-3,6-dihydro-2H- pyridine-1 -carboxylate

To a solution of 2-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-pyrido[2 ,3-d]pyrimidine (1.34 g, 4.27 mmol, 1 eq) and tert-butyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H- pyridine-1 -carboxylate (2.64 g, 8.54 mmol, 2 eq) in dioxane (80 ml_) was added Pd(dppf)Cl2 (312 mg, 427 pmol, 0.1 eq) and K2CO3 (1.77 g, 12.8 mmol, 3 eq) in water (10 mL) . After stirring at 80 °C for 16 h under N2, the mixture was concentrated to give a crude. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0 to 1/1) to give compound tert-butyl 5-[7-(2- methoxy-4,6-dimethyl-phenyl)-4-methyl-pyrido[2,3-d]pyrimidin -2-yl]-3,6-dihydro-2H-pyridine-1- carboxylate (1 .80 g, 3.13 mmol, 73% yield, 80% purity) as yellow oil.

¹ H NMR (400 MHz, CDCb) 5 [ppm] = 8.39 (d, J = 8.4 Hz, 1 H), 7.69 (s, 1 H), 7.51 (d, J = 8.4 Hz, 1 H), 6.75 (s, 1 H), 6.66 (s, 1 H), 4.65 (d, J = 2.0 Hz, 2H), 3.69 (s, 3H), 3.61 (t, J = 5.6 Hz, 2H), 2.96 (s, 3H), 2.45 (s, 2H), 2.38 (s, 3H), 2.13 (s, 3H), 1.49 (s, 9H)

LC-MS (Method C): Rt = 0.646 min; MS (ESIpos): m/z = 461 .2 [M+H] ⁺

Intermediate 34 tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyi-5,6-dihydropyr ido[2,3-d]pyrimidin-2- y I] piperidine- 1 -carboxylate (racemate)

To a solution of tert-butyi 5-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-pyrido[2,3-d] pyrimidin-2-yl]- 3,6-dihydro-2H-pyridine-1-carboxyiate (1.70 g, 3.69 mmol, 1 eq) in methanol (20 mL) was added Pd/C (170 mg, 369 μmol, 10% purity, 0.1 eq) at 25 °C in one portion under N2 atmosphere. After stirring at 25 °C for 16 h under H2 atmosphere, the mixture was concentrated to give compound tert-butyl 3-[7-(2- methoxy-4,6-dimethyl-phenyl)-4-methyl-5,6-dihydropyrido[2,3- d]pyrimidin- 2-yl]piperidine-1- carboxylate (1 .70 g, 3.66 mmol, 99% yield) as a yellow solid.

Intermediate 35 tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-pyrido[2,3-d]p yrimidin-2-yl]piperidine-1- carboxylate (race mate)

To a solution of tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-5,6-dihydropyr ido[2,3-d] pyrimidin-2-yl]piperidine-1-carboxylate (1.70 g, 3.66 mmol, 1 eq) in acetonitrile (15 mL) was added MnOz (1 .59 g, 18.3 mmol, 5 eq). After stirring at 80 °C for 16 h, the mixture was concentrated to give a crude. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate=1/0 to 3/1) to give compound tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-pyrido[2,3- d]pyrimidin-2-yl]piperidine-1-carboxylate (900 mg, 1.80 mmol, 49% yield, 93% purity) as a yellow solid. LC-MS (Method C): Rt = 0.623 min; MS (ESIpos): m/z = 463.3 [M+H] ⁺

Intermediate 36 7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-2-(3-piperidyl)py rido[2,3-d]pyrimidine (racemate)

To a solution of tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-pyrido[2,3-d]p yrimidin-2- ylJpiperidine-1 -carboxylate (370 mg, 800 pmol, 1 eq) in ethyl acetate (10 mL) was added hydrochloric acid/ethyl acetate (4 M, 2.00 mL, 10 eq). After stirring at 25 °C for 0.5 h, the mixture was concentrated to give compound 7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-2-(3-piperidyl)py rido[2,3- d]pyrimidine (310 mg, 777 pmol, 97% yield, HCi salt) as a yellow solid. intermediate 37

(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-2-(1-methyl-3-pi peridyl)pyrido[2,3-d]pyrimidine (racemate) To a solution of 7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-2-(3-piperidyl)py rido[2,3-d]pyrimidine (310 mg, 777 pmol, 1 eq, HCI salt) in methanol (10 mL) was added (CHzO)n (199 mg, 3.89 mmol, 5.00 eq), KOAc (229 mg, 2.33 mmol, 3 eq) and NaBHsCN (244 mg, 3.89 mmol, 5 eq). After stirring at 25 °C for 3 h, the mixture was concentrated to give a crude. The crude product was purified by reversed-phase column (column: C18, 12 g, mobile phase: [water(FA) - MeCN]; B%: 30%-70%, 12 min) to give compound 7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-2-(1-methyl-3-pip eridyl)pyrido[2,3-d] pyrimidine (208 mg, 547 pmol, 70% yield, 99% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.438 min; MS (ESIpos): m/z = 377.3 [M+H] ⁺

Compound 13

3.5-dimethyl-2-[4-methyl-2-(1 -methyl-3- piperidy I) py rido [2,3-d]pyrimidin-7-yl]phenol (racemate)

To a solution of 7-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-2-(1-methyl-3-pip eridyl)pyrido [2,3- d]pyrimidine (145 mg, 385 pmol, 1 eq) in DCM (5 mL) was added BBrs (289 mg, 1.16 mmol, 111 pL, 3 eq). After stirring at -70 °C for 3 h, the mixture was concentrated to give a crude. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water (FA) - MeCN]; B%: 40% - 70%, 7 min) to give compound 3, 5-dimethyl-2-[4-methyl-2-(1 -methyl-3- piperidyl)pyrido [2,3- d]pyrimidin-7-yl]phenol (40.0 mg, 110 pmol, 29% yield, 100% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d _e ) 6 [ppm] = 9.64 (s, 1 H), 8.68 (d, J = 8.4 Hz, 1 H), 7.67 (d, J = 8.4 Hz, 1 H),

6.64 (d, J = 6.0 Hz, 2H), 3.44-3.40 (m, 1 H), 3.27-3.21 (m, 2H), 3.11-3.05 (m, 1 H), 2.94 (s, 3H), 2.85- 2.72 (m, 1 H), 2.55 - 2.53 (m, 3H), 2.26 (s, 3H), 2.18-2.14 (m, 1 H), 2.07 (s, 3H), 1 .90-1 .83 (m, 1 H), 1 .77-

1.64 (m, 2H).

LC-MS (Method C): Rt = 0.415 min; MS (ESIpos): m/z = 363.2 [M+H] ⁺ .

Compounds 14 and 15

3.5-dimethyl-2-[4-methyl-2-[1-methyl-3-piperidyl]pyrido[2 ,3-d]pyrimidin-7-yl]phenol (single enantiomers)

Compound 13 was separated by SFC: (column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 um);mobile phase: [CO ₂ -MeCN/i-PrOH(0.1 % NH3-H2O)]; B%: 55%-55%, 4.5 min is ocratic elution mode) to give compound 14 (7.31 mg, 19.6 pmol, 35% yield, 97% purity) as a yellow solid and compound 15 (9.70 mg, 25.7 pmol, 47% yield, 96% purity) as a yellow solid.

Compound 14 ¹ H NMR (400 MHz, DMSO-ofe) 5 [ppm] = 9.65 (s, 1 H), 8.66 (d, J = 8.4 Hz, 1 H), 7.64 (d, J = 8.4 Hz, 1 H), 6.63 (d, J = 5.6 Hz, 2H), 3.15 - 3.09 (m, 2H), 2.93 (s, 3H), 2.82 - 2.77 (m, 1 H), 2.26 (s, 3H), 2.23 (s, 3H), 2.10 (s, 1 H), 2.07 (s, 3H), 1 .94 - 1 .88 (m, 1 H), 1 .79 - 1 .74 (m, 1 H), 1 .69 - 1 .58 (m, 2H), 1 .30 - 1.18 (m, 1 H)

LC-MS (Method C): Rt = 0.413 min; MS (ESIpos): m/z = 363.3 [M+H] ⁺ .

SFC (Rt = 0.763 min)

Compound 15

¹ H NMR (400 MHz, DMSO-d ₆ ) <5 [ppm]= 9.79-9.55 (m, 1 H), 8.68 (d, J = 8.4 Hz, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 6.64 (d, J = 6.8 Hz, 2H), 3.22 (s, 1 H), 3.08-2.99 (m, 1 H), 2.94 (s, 3H), 2.61-2.58 (m, 1 H), 2.56-2.53 (m, 3H), 2.46 (d, J=1.6 Hz, 2H), 2.26 (s, 3H), 2.17-2.12 (m, 1 H), 2.07 (s, 3H), 1.87-1.80 (m, 1 H), 1.78- 1.61 (m, 2H)

LC-MS (Method G): Rt = 0.644 min; MS (ESIpos): m/z = 363.2 [M+H] ⁺ .

SFC (Rt = 1.108 min)

Intermediate 38

2-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine

To a solution of 2, 7-dichloro-1 ,8-naphthyridine (20.0 g, 100 mmol, 1 eq) and (2-methoxy-4,6-dimethyl- phenyl)boronic acid (14.5 g, 80.4 mmol, 0.8 eq) in dioxane (400 mL) and water (40 mL) were added Pd(PPh3)4 (5.81 g, 5.02 mmol, 0.05 eq) and Na2COs (15.9 g, 150 mmol, 1.5 eq) at 25 °C, the reaction mixture was degassed and purged with N2 for 3 times. After stirring at 80 °C for 2 h, the mixture was filtered and concentrated to a crude. The crude was purified by column chromatography (S1O ₂ , Petroleum ether/Ethyl acetate=10/1 to 1/1) to give compound 2-chloro-7-(2-methoxy-4,6-dimethyl- phenyl)- 1 ,8-naphthyridine (17.0 g, 42.7 mmol, 42% yield, 75% purity) as a light yellow solid.

LC-MS (Method C): Rt = 0.549 min; MS (ESIpos): m/z = 299.2 [M+H] ⁺ .

Intermediate 39 tert-butyl 5-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-3,6-dihydro-2H-pyridine-1- carboxylate

To a solution of 2-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (12.0 g, 28.1 mmol, 1 eq) and tert-butyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine- 1- carboxylate (17.4 g, 56.2 mmol, 2 eq) in dioxane (200 mL) and water (20 mL) were added Pd(dppf)Cl2 (2.06 g, 2.81 mmol, 0.1 eq) and K2CO3 (9.71 g, 70.2 mmol, 2.5 eq) at 25 °C, the reaction mixture was degassed and purged with N2 for 3 times. After stirring at 100 °C for 16 h, the mixture was concentrated to give a crude. The crude was purified by column chromatography (SiOa, Petroleum ether/Ethyl acetate=10/1 to 1/1) to give compound tert-butyl 5-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8- naphthyridin-2-yl]- 3,6-dihydro-2H-pyridine-1-carboxylate (10.0 g, 20.6 mmol, 73% yield, 92% purity) as a light yellow solid.

LC-MS (Method C): Rt = 0.543 min; MS (ESIpos): m/z = 446.3 [M+H] ⁺ . Intermediate 40 tert-butyl 3-[7-(2-methoxy-4, 6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]piperidine-1 -carboxylate (racemate)

To a solution of tert-butyl 5-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-3,6-dihydro- 2H- pyridine-1 -carboxylate (10.0 g, 20.6 mmol, 1 eq) in MeOH (30 mL) was added Pd/C (1 .00 g, 2.06 mmol, 10% purity, 0.1 eq) at 25 °C, the reaction mixture was stirred at 25 °C under H2 (15 psi) atmosphere. After stirring at 25 °C for 16 h, the mixture was filtrated and concentrated to give compound tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]piperidine-1 -carboxylate (9.00 g, 20.1 mmol, 97% yield) as a light yellow solid.

LC-MS (Method C): Rt - 0.570 min; MS (ESIpos): m/z = 448.3 [M+H] ⁺ .

Intermediate 41

2-(2-methoxy-4,6-dimethyl-phenyl)-7-(3-piperidyl)-1 ,8-naphthyridine (racemate)

To a solution of tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]piperidine- 1- carboxylate (5.00 g, 11.2 mmol, 1 eq) in ethyl acetate (50 mL) was added HCI/ethyl acetate (4 M, 14 mL, 5 eq) at 25 °C. After stirring at 25 °C for 2 h, the mixture was concentrated to give compound 2-(2- methoxy-4,6-dimethyl-phenyl)-7-(3-piperidyl)-1 ,8-naphthyridine (5.00 g, 7.81 mmol, 70% yield, 60% purity, HCI salt) as a yellow solid.

LC-MS (Method C): Rt = 0.418 min; MS (ESIpos): m/z = 348.2 [M+H] ⁺ .

Intermediate 42

2-[3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1 -piperidyl]ethanol (racemate)

To a solution of 2-(2-methoxy-4,6-dimethyl-phenyl)-7-(3-piperidyl)-1 ,8-naphthyridine (1 .00 g, 2.88 mmol, 1 eq) in THF (10 mL) was added DIPEA (1 .12 g, 8.63 mmol, 1.50 mL, 3 eq) and dioxane (253 mg, 5.76 mmol, 287 pL, 2 eq). After stirring at 40 °C for 16 h, the mixture was concentrated to give a crude. The crude was purified by reversed-phase column (column: C18, 120 g, mobile phase: [water (FA) - ACN]; B%: 25% - 80%, 12 min) to give compound 2-[3-[7-(2-methoxy-4,6-dimethyl- phenyl)-1 ,8- naphthyridin-2-yl]-1-piperidyl]ethanol (330 mg, 800 pmol, 28% yield, 95% purity) as a black brown solid. LC-MS (Method C): Rt = 0.430 min; MS (ESIpos): m/z = 392.3 [M+H] ⁺ .

Intermediate 43

2-[7-[1-(2-hydroxyethyl)-3-piperidyl]-1 ,8-naphthyridin-2-yl]-3,5-dimethyl-phenol (racemate)

To a solution of 2-[3-[7-(2-methoxy-4, 6-dimethyl-phenyl)-1 , 8-naphthyridin-2-yl]-1 -piperidyl] ethanol (280 mg, 679 pmol, 1 eq) in DCM (5 mL) was added BBrs (340 mg, 1 .36 mmol, 131 pL, 2 eq) at -70 °C. After stirring at 25 °C for 2 h, the mixture was added NH3 (30 ml, 7 M in MeOH) and concentrated to give a crude. The crude was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water (FA) - MeCN]; B%: 40% - 60%, 8 min) to give compound 2-[7-[1-(2-hydroxyethyl)-3-piperidyl]-1 , 8-naphthyridin-2-yl]-3, 5-dimethyl-phenol (180 mg, 469 pmol, 69% yield, 98% purity) as a brown solid. LC-MS (Method C): Rt = 0.407 min; MS (ESIpos): m/z = 378.3 [M+H] ⁺ . Compounds 15 and 16 3,5-dimethyl-2-[7-[1-(2-hydroxyethyl)-3-piperidyi]-1 ,8-naphthyridin-2-yl]phenol (single enantiomers) Intermediate 43 was separated by SFC: (column: DAICEL CHIRALPAK IG (250mm x 50mm,10um);mobile phase: [CCh-MeCN/i-PrOH (0.1 %NH.3.H2O)];B%: 62.5%-62.5%, 9 min) to give compound 16 (44.6 mg, 117 pmol, 24% yield, 99% purity) as a yellow solid and 17 (69.1 mg, 179 pmol, 38% yield, 98% purity) as a yellow solid.

Compound 16

¹ H NMR (400 MHz, DMSO-de) 6 = 9.96-9.55 (m, 1 H), 8.40 (d, J = 1 .2 Hz, 1 H), 8.37 (d, J = 1 .2 Hz, 1 H), 7.61 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 6.63 (s, 1 H), 6.61 (s, 1 H), 4.45-4.30 (m, 1 H), 3.53 (t, J = 6.0 Hz, 2H), 3.15-3.05 (m, 2H), 2.91 (d, J = 11 .2 Hz, 1 H), 2.48-2.43 (m, 2H), 2.38-2.30 (m, 2H), 2.26 (s, 3H), 2.08 (s, 3H), 2.03-1 .98 (m, 1 H), 1 .78-1 .60 (m, 3H)

LC-MS (Method C): Rt = 0.399 min; MS (ESIpos): m/z = 378.3 [M+H] ⁺ .

SFC (Rt = 0.752 min)

Compound 17

¹ H NMR (400 MHz, DMSO-ds) 6 = 9.96-9.55 (m, 1 H), 8.40 (d, J = 1 .2 Hz, 1 H), 8.37 (d, J = 1 .2 Hz, 1 H), 7.61 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 6.63 (s, 1 H), 6.61 (s, 1 H), 4.45-4.30 (m, 1 H), 3.53 (t, J = 6.0 Hz, 2H), 3.15-3.05 (m, 2H), 2.91 (d, J = 11 .2 Hz, 1 H), 2.48-2.43 (m, 2H), 2.38-2.30 (m, 2H), 2.26 (s, 3H), 2.08 (s, 3H), 2.03-1 .98 (m, 1 H), 1 .78-1 .60 (m, 3H)

LC-MS (Method C): Rt = 0.398 min; MS (ESIpos): m/z = 378.3 [M+H] ⁺ .

SFC (Rt = 1.107 min)

Intermediate 44

2-(1-cyclopropyl-3-piperidyl)-7-(2-methoxy-4,6-dimethyl-p henyl)-1 ,8-naphthyridine

To a solution of 2-(2-methoxy-4,6-dimethyl-phenyl)-7-(3-piperidyl)-1 ,8-naphthyridine (500 mg, 1.44 mmol, 1 eq) and cyclopropylboronic acid (370 mg, 4.32 mmol, 3 eq) in dioxane (10 mL) was added diacetoxycopper (522 mg, 2.88 mmol, 2 eq), pyridine (227 mg, 2.88 mmol, 232 pL, 2 eq) and NazCOs (358 mg, 4.32 mmol, 3 eq). After stirring at 80 °C for 16 h, the reaction mixture was concentrated to give a residue, and the residue was purified by prep-HPLC (column: Phenomenex Luna C18 150 x 25mm x 10pm; mobile phase: [water(FA)-MeCN];B%: 20%-60%, 14 min) to give 2-(1-cyclopropyl-3- piperidyl)-7- (2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (200 mg, 412 pmol, 28 % yield, 80 % purity) as a black brown solid.

LC-MS (Method C): Rt = 0.454 min; MS (ESIpos): m/z = 388.3 [M+H] ⁺ .

Intermediate 44

2-[7-(1-cyclopropyl-3-piperidyl)-1 ,8-naphthyridin-2-yl]-3,5-dimethyl-phenol

To a solution of2-(1-cyclopropyl-3-piperidyl)-7-(2-methoxy-4,6-dimethyl-ph enyl)-1 ,8-naphthyridine (180 mg, 464 pmol, 1 eq) in dichloromethane (5 mL) was added BBrs (581 mg, 2.32 mmol, 223 pL, 5 eq) at -70 °C dropwise. After stirring at 20 °C for 16 h, the mixture was quenched by methanol (3 mL) and concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(FA)-MeCN];B%: 20%-80%,9 min) to give compound 2-[7-(1- cyclopropyl-3-piperidyl)-1 ,8-naphthyridin-2-yl]-3,5-dimethyi-phenol (50.0 mg, 132 pmol, 28% yield, 99% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.419 min; MS (ESIpos): m/z = 374.3 [M+H] ⁺

Compounds 18 and 19

3,5-dimethyl-2-[7-[1 -cyclopropyl-3-piperidyl]-1 ,8-naphthyridin-2-yi]phenol (single enantiomers) intermediate 44 was separated by SFC: (column: DAICEL CHIRALPAK AS (250 mm x 30 mm, 10 pm); mobile phase: [0.1 %NH3»H2O IPA];B%:25%, isocratic elution mode) to give compound 18 (11.84 mg, 31 .0 pmol, 23.% yield, 98% purity) as a yellow solid and compound 19 (11 .36 mg, 29.5 pmol, 22% yield, 97% purity) as a yellow solid.

Compound 18

¹ H NMR (400 MHz, DMSO-d6) 6 = 9.89-9.75 (m, 1 H), 8.41 (d, J = 2.0 Hz, 1 H), 8.39 (d, J = 2.24 Hz, 1 H), 7.61 (d, J = 8.4 Hz, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 6.64 (s, 1 H), 6.63 (s, 1 H), 3.26-3.17 (m, 2H), 3.09-2.96 (m, 2H), 2.27 (s, 3H), 2.25-2.19 (m, 1 H), 2.09 (s, 3H), 2.04-1.98 (m, 1 H), 1.78-1.58 (m, 4H), 0.49-0.32 (m, 4H)

LC-MS (Method C): Rt = 0.424 min; MS (ESIpos): m/z = 374.3 [M+H] ⁺ .

Compound 19

¹ H NMR (400 MHz, DMSO-d6) 6 = 9.88-9.75 (m, 1 H), 8.40 (d, J = 2.4 Hz, 1 H), 8.38 (d, J = 2.0 Hz, 1 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 6.63 (s, 1 H), 6.62 (s, 1 H), 3.26-3.15 (m, 2H), 3.10- 2.95 (m, 2H), 2.26 (s, 3H), 2.24-2.18 (m, 1 H), 2.09 (s, 3H), 2.03-1.96 (m, 1 H), 1.78-1.55 (m, 4H), 0.46- 0.30 (m, 4H)

LC-MS (Method C): Rt = 0.426 min; MS (ESIpos): m/z = 374.3 [M+H] ⁺ .

Intermediate 45

2-(1-ethyl-3-piperidyi)-7-(2-methoxy-4,6-dimethyl-phenyl) -1 ,8-naphthyridine (racemate)

To a solution of 2-(2-methoxy-4,6-dimethyi-phenyi)-7-(3-piperidyl)-1 ,8-naphthyridine (300 mg, 863 pmol, 1 eq) and acetaldehyde (475, 4.32 mmol, 605 pL, 40% in water, 5 eq) in methanol (5 mL) was added Pd/C (30.0 mg, 8.63 pmol, 10% purity, 0.01 eq) at 20 °C in one portion under nitrogen atmosphere. After stirring at 20 °C for 16 h under H2 atmosphere, the mixture was filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: (water(FA)-MeCN]; B%: 25%-75%, 11 min) to give compound 2-(1- ethyl-3-piperidyl)-7- (2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (180 mg, 474 pmol, 55% yield, 99% purity) as yellow oil.

LC-MS (Method C): Rt = 0.448 min; MS (ESIpos): m/z - 376.3 [M+H] ⁺

Compound 20

2-[7-(1 -ethyl-3-piperidyl)-1 ,8-naphthyridin-2-yl]-3,5-dimethyl-phenol (racemate)

To a solution of 2-(1-ethyl-3-piperidyl)-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (180 mg, 479 pmol, 1 eq) in dichloromethane (5 mL) was added BBr ₃ (600 mg, 2.40 mmol, 230 pL, 5 eq) at -70 °C dropwise. After stirring at 20 °C for 16 h, the mixture was quenched by methanol (3 mL) and concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(FA)-MeCN]; B%: 40%-70%,7 min) to give compound 2-[7-(1 -ethyl-3- piperidyl)-1 ,8-naphthyridin-2-yl]-3,5-dimethyl-phenol (1 10 mg, 300 pmol, 62% yield, 99% purity) as a yellow solid.

¹ H NMR (400 MHz, CDCfe) 6 [ppm] = 8.82 (dd, J = 8.4, 1 .6 Hz, 2H), 8.04 (d, J = 8.4 Hz, 1 H), 7.97 (d, J = 8.4 Hz, 1 H), 7.05 (d, J = 6.4 Hz, 2H), 3.68-3.57 (m, 2H), 3.44 (d, J = 10.8 Hz, 1 H), 2.97-2.94 (m, 2H), 2.68 (s, 3H), 2.61-2.51 (m, 2H), 2.50 (s, 3H), 2.47-2.42 (m, 1 H), 2.26-2.19 (m, 1 H), 2.16-2.03 (m, 2H), 1 .49 (t, J = 7.2 Hz, 3H)

LC-MS (Method C): Rt = 0.415 min; MS (ESIpos): m/z = 362.3 [M+H] ⁺

Compounds 21 and 22

3,5-dimethyl-2-[7-[-1-ethyl-3-piperidyl]-1 ,8-naphthyridin-2-yl]phenol (single enantiomers)

Compound 20 was separated by SFC: (column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 pm); mobile phase: [MeCN/IPA(0.1 %NH3H20)];B%:50%, isocratic elution mode) to give compound 21 (28.4 mg, 77.7 pmol, 28% yield, 99% purity) as a yellow solid and compound 22 (33.7 mg, 92.3 pmol, 33% yield, 99% purity) as a yellow solid.

Compound 21

1 H NMR (400 MHz, DMSO-de) 6 = 9.78 (s, 1 H), 8.40 (d, J = 2.0 Hz, 1 H), 8.38 (d, J = 2.4 Hz, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 6.63 (d, J = 4.8 Hz, 2H), 3.16-3.07 (m, 2H), 2.94-2.88 (m, 1 H), 2.43-2.37 (m, 2H), 2.26 (s, 3H), 2.24-2.17 (m, 1 H), 2.08 (s, 3H), 2.03-1.90 (m, 2H), 1 .81-1 .73 (m, 1 H), 1 .70-1 .61 (m, 2H), 1 .02 (t, J = 7.2 Hz, 3H)

LC-MS (Method C): Rt = 0.413 min; MS (ESIpos): m/z = 362.3 [M+H] ⁺ .

Compound 22

1 H NMR (400 MHz, DMSO-d6) 6 = 9.88-9.73 (m, 1 H), 8.41 (d, J = 1 .2 Hz, 1 H) , 8.39 (d, J = 0.8 Hz, 1 H), 7.63 (d, J = 8.0 Hz, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 6.63 (d, J = 5.2 Hz, 2H), 3.16-3.12 (m, 2H), 2.97-2.91 (m, 1 H), 2.4-2.41 (m, 2H), 2.36-2.29 (m, 1 H), 2.27 (s, 3H), 2.09 (s, 3H), 2.05-1.97 (m, 2H), 1.81-1.75 (m, 1 H), 1 .70-1 .62 (m, 2H), 1 .04 (t, J = 7.2 Hz, 3H)

LC-MS (Method C): Rt = 0.415 min; MS (ESIpos): m/z = 362.3 [M+H] ⁺ .

Intermediate 46 benzyl 3-[3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-piperidyl]propanoate

(racemate)

To a solution of 2-(2-methoxy-4,6-dimethyl-phenyl)-7-(3-piperidyl)-1 ,8-naphthyridine (600. Mg, 1.30 mmol, 1 eq) and benzyl 3-bromopropanoate (347.6 mg, 1 .43 mmol, 1.1 eq) in MeCN (10 mL) was added K2CO3 (359 mg, 2.60 mmol, 2 eq). After stirring at 80 °C for 2 h, the reaction mixture was concentrated under reduced pressure to remove MeCN. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The crude product was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water (FA)-MeCN]; B%: 30%-70%, 9 min) to give methyl 3-[3-[7-(2-methoxy- 4, -dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1 -piperidyl] propanoate (510 mg, 1.18 mmol, 90% yield) as a yellow solid.

¹ H NMR (400 MHz, CDCb) 6 = 8.25 (s, 1 H), 8.23 (s, 1 H), 7.54 (d, J = 2 Hz, 1 H), 7.52 (d, J = 2 Hz, 1 H), 6.76 (s, 1 H), 6.67 (s, 1 H), 3.87-3.79 (m, 1 H), 3.73 (s, 1 H), 3.71 (s, 3H), 3.70 (s, 3H), 3.47 (m, 2H), 3.42- 3.31 (m, 2H), 2.98-2.88 (m, 2H), 2.78 (m, 1 H), 2.39 (s, 3H), 2.26-2.15 (m, 2H), 2.11 (s, 3H), 2.05 (m, 1 H), 1.97-1.82 (m, 1 H)

LC-MS (Method C): Rt = 0.450 min; MS (ESipos): m/z - 434.5 [M+H] ⁺

Intermediate 47

3-[3-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1 -piperidyijpropanoic acid (racemate)

To a solution of methyl 3-[3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-piperidyl] propanoate (500 mg, 1.15 mmol, 1 eq) in DCM (10 mL) was added BBrs (866 mg, 3.46 mmol, 333 pL, 3 eq) at -70 °C .The mixture was stirred at 25 °C for 48 h. The mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL * 3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The crude product was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(FA)- MeCN];B%: 25%-75%, 6 min) to give compound 3-[3-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8- 157zetidine157ine-2-yl]-1 -piperidyl] propanoic acid (210 mg, 517 pmol, 44% yield) was yellow solid. LC-MS (Method C): Rt = 0.402 min; MS (ESipos): m/z = 406.1 [M+H] ⁺

Compounds 23 and 24

3-[3-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-piperidyl]propanoic acid (single enantiomers)

Intermediate 47 was purified by SFC: (column: DAICEL CHIRALPAK IG (250mmx30mm,10um);mobile phase: [CO ₂ -EtOH(0.1 %NH3 ^,, H2O)]; B%:55%, isocratic elution mode) to give compound 23 (56.2 mg, 137 pmol, 27% yield, 99% purity) as a yellow solid and compound 24 (87.9 mg, 208 pmol, 42% yield, 96% purity) as a yellow solid

Compound 23

^! H NMR (400 MHz, DMSO-d6) 6 = 9.92 - 9.51 (m, 1 H), 8.42 (d, J = 1 .2 Hz, 1 H), 8.40 (d, J = 1 .2 Hz, 1 H), 7.64 (d, J = 8.4 Hz, 1 H), 7.56 (d, J = 8 Hz, 1 H), 6.64 (s, 1 H), 6.63 (s, 1 H), 3.21 - 3.17 (m, 2H), 3.02

- 2.97 (m, 1 H), 2.72 (m, 2H), 2.46 - 2.41 (m, 3H), 2.27 (s, 3H), 2.21 - 2.12 (m, 1 H), 2.09 (s, 3H), 2.04

- 1 .98 (m, 1 H), 1 .81 (m, 1 H), 1 .67 (m, 2H)

LC-MS (Method C): Rt = 0.412 min; MS (ESipos): m/z = 406 [M+H] ⁺

Compound 24

¹ H NMR (400 MHz, DMSO-d6) 5 = 10.05-9.47 (m, 1 H), 8.42 (m, 1 H), 8.40 (m, 1 H), 7.63 (m, 1 H), 7.55 (d, J = 8.3 Hz, 1 H), 6.63 (s, 1 H), 6.62 (s, 1 H), 3.17 (s, 2H), 3.06-3.01 (m, 1 H), 2.82-2.74 (m, 2H), 2.46 (s, 3H), 2.26 (s, 3H), 2.22-2.16 (m, 1 H), 2.08 (s, 3H), 2.05-1 .98 (m, 1 H), 1.85-1.79 (m, 1 H), 1.67 (s, 2H) LC-MS (Method C): Rt = 0.410 min; MS (ESipos): m/z = 406 [M+H] ⁺

Intermediate 48 tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-5-methyl-1 ,8-naphthyridin-2-yl]piperidine-1 -carboxylate (racemate)

To a solution of tert-butyl 3-[5-chioro-7-(2-methoxy-4,6-dimethyl-phenyi)-1 ,8-naphthyridin-2-yi] piperidine-1 -carboxylate (400 mg, 830 pmol, 1 eq) and 2,4,6-trimethyl-1 ,3,5,2,4,6-trioxatriborinane (320 mg, 1.27 mmol, 356 pL, 50% purity, 1.54 eq) in 1 ,4-dioxane (10 mL) and water (2 ml_) was added cesium carbonate (540 mg, 1.66 mmol, 2 eq) and Pd(dppf)Cl2(61 .0 mg, 83.4 pmol, 0.1 eq) at 25 °C under nitrogen atmosphere. After stirring at 80 °C for 14 h, the reaction mixture was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiOa, Petroleum ether/Ethyl acetate = 100/1 to 3/1) to give compound tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-5- methyl-1 ,8-naphthyridin-2-yl] piperidine-1-carboxylate (370 mg, 802 pmol, 97% yield) as yellow oil.

¹ H NMR (400 MHz, CDCb) 5 [ppm] = 8.33 (d, J = 8.4 Hz, 1 H), 7.43 (d, J = 8.4 Hz, 1 H), 7.29 (s, 1 H), 6.73 (s, 1 H), 6.65 (s, 1 H), 5.03 (s, 1 H), 4.35-4.31 (m, 1 H), 3.69 (s, 3H), 3.31-3.28 (m, 1 H), 3.12-3.05 (m, 1 H), 2.88-2.79 (m, 1 H), 2.73 (s, 3H), 2.38 (s, 3H), 2.15-2.11 (m, 4H), 1.81-1.77 (m, 1 H), 1.66-1.57 (m, 2H), 1 .48 (s, 9H).

Intermediate 49

2-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-7-(3-piperidyl )-1 ,8-naphthyridine (racemate)

A solution of tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-5-methyl-1 ,8-naphthyridin-2-yl]piperidine-

1 -carboxylate (360 mg, 780 pmol, 1 eq) in HCI (4 M in 1 ,4-dioxane, 5,00 mL, 25.6 eq) was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuum to give 2-(2-methoxy-4,6-dimethyl-phenyl)- 4- methyl-7-(3-piperidyl)-1 ,8-naphthyridine (310 mg, 780 pmol, 100% yield, HCI salt) as a yellow solid.

Intermediate 50

2-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-7-(1-methyl-3- piperidyi)-1 ,8-naphthyridine (racemate)

To a solution of 2-(2-methoxy-4,6-dimethyi-phenyi)-4-methyl-7-(3-piperidyl)-1 ,8-naphthyridine (302 mg, 759 pmol, 1 eq, HCI salt) in methanol (3.00 mL) were added potassium acetate (112 mg, 1.14 mmol, 1.5 eq), HCHO (123 mg, 1.52 mmol, 113 pL, 37% purity in water, 2 eq) and sodium cyanoborohydride (100 mg, 1 .59 mmol, 2.1 eq) at 0 °C. After stirring at 25 °C for 1 h, the mixture was diluted with saturated sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18 80 g, mobile phase: [water (FA) - MeCN]; B%: 15% - 85%, 8 min) to give compound 2-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl- 7-(1-methyl-3- piperidyl)-1 ,8-naphthyridine (220 mg, 586 pmol, 77% yield) as a brown solid.

H NMR (400 MHz, CDCb) 5 [ppm] = 8.35 (d, J = 8.4 Hz, 1 H), 7.45 (d, J = 8.4 Hz, 1 H), 7.30 (s, 1 H), 6.73 (s, 1 H), 6.64 (s, 1 H), 3.69 (s, 3H), 3.61-3.42 (m, 2H), 3.28-3.16 (m, 1 H), 2.73 (s, 3H), 2.57 (s, 3H), 2.38 (s, 3H), 2.21-2.12 (m, 2H), 2.10 (s, 3H), 1.97-1.90 (m, 1 H), 1.87-1.76 (m, 2H), 1.68-1.58 (m, 1 H).

Compound 25

3,5-dimethyl-2-[4-methyl-7-(1-methyl-3-piperidyl)-1 ,8-naphthyridin- 2-yl]phenol (racemate) To a solution of 2-(2-methoxy-4,6-dimethyl-phenyl)-4-methyl-7-(1-methyl-3-pip eridyl)-1 ,8-naphthyridine (220 mg, 586 pmol, 1 eq) in dichloromethane (5.00 mL) was added boron tribromide (440 mg, 1.76 mmol, 169 pL, 3 eq) at -70°C. After stirring at 0 °C for 8 h, the mixture was added into ice water (10 mL) at 0 °C. The pH was adjusted to 8 with saturated sodium bicarbonate and extracted with dichloromethane (20 mL x 3). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The product was purified by reversed-phase column (column: C18 40 g, mobile phase: [water (FA) - MeCN]; B%: 30% - 50%, 8 min) to give compound 25 (16.3 mg, 45.0 pmol, 99% purity, 8% yield) as a yellow solid.

Compound 25

1 H NMR (400 MHz, CDCb) 5 [ppm] = 9.87 (s, 1 H), 8.50 (d, J = 8.4 Hz, 1 H), 8.20 (s, 1 H), 7.62 (d, J = 8.4 Hz, 1 H), 7.40 (s, 1 H), 6.62 (s, 1 H), 6.61 (s, 1 H), 3.21-3.15 (m, 1 H), 3.10-3.05 (m, 1 H), 2.87 (d, J = 12.0 Hz, 1 H), 2.71 (s, 3H), 2.34-2.31 (m, 1 H), 2.29 (s, 3H), 2.26 (s, 3H), 2.09 (s, 3H), 2.04-1 .99 (m, 2H), 1.82-1.72 (m, 1 H), 1.71-1.56 (m, 2H).

LC-MS (Method C): Rt = 0.620 min; MS (ESI) m/z = 362.1 [M+H] ⁺ .

Compounds 26 and 27

3,5-dimethyl-2-[4-methyl-7-(1-methyl-3-piperidyl)-1 ,8-naphthyridin- 2-yl]phenol (single enantiomers)

Compound 25 was separated by SFC (column: DAICEL CHIRALPAK AY-H (250 mm x 30 mm, 10 pm); mobile phase: [dioxide carbon- acetonitrile/ ethanol (0.100% NHs’HzO)]; B%: 65%-65%, 7.8 min) to give compound 26 (54.8 mg, 148 pmol, 98% purity, 25% yield) as a yellow solid and compound 27 (49.0 mg, 128 pmol, 95% purity, 22% yield) as a yellow solid. Compound 26

1 H NMR (400 MHz, CDCb) 6 [ppm] = 9.87 (s, 1 H), 8.50 (d, J = 8.8 Hz, 1 H), 7.62 (d, J = 8.4 Hz, 1 H), 7.47 (s, 1 H), 6.63 (s, 1 H), 6.62 (s, 1 H), 3.20-3.14 (m, 1 H), 3.08-3.05 (m, 1 H), 2.87-2.83 (m, 1 H), 2.71 (s, 3H), 2.31-2.26 (m, 7H), 2.09 (s, 3H), 2.04-1.97 (m, 2H), 1.81-1.75 (m, 1 H), 1.73-1.60 (m, 2H). LC-MS (Method C): Rt = 0.632 min; MS (ESI) m/z = 362.2 [M+H] ⁺ .

SFC (Rt = 0.555 min)

Compound 27

1 H NMR (400 MHz, CDCb) 5 [ppm] = 9.86 (s, 1 H), 8.50 (d, J = 8.8 Hz, 1 H), 7.62 (d, J = 8.4 Hz, 1 H), 7.40 (s, 1 H), 6.62 (s, 1 H), 6.61 (s, 1 H), 3.20-3.12 (m, 1 H), 3.08-3.05 (m, 1 H), 2.87-2.82 (m, 1 H), 2.71 (s, 3H), 2.31-2.26 (m, 7H), 2.09 (s, 3H), 2.03-1.98 (m, 2H), 1.80-1.76 (m, 1 H), 1.73-1.57 (m, 2H). LC-MS (Method C): Rt = 0.636 min; MS (ESI) m/z = 362.2 [M+H] ⁺ .

SFC (Rt = 1 .664 min)

Intermediate 51

Benzyl 3-[7-[2-benzyloxy-6-methyl-4-(trifluoromethyl)phenyl]-1 ,8-naphthyridin-2-yl]piperidine-1- carboxylate (racemate) To a solution of benzyl 3-(7-chloro-1 ,8-naphthyridin-2-yl)piperidine-1 -carboxylate (1.00 g, 2.62 mmol, 1 eq) in 1 ,4-dioxane (10 mL) was added [2-benzyloxy-6-methyl-4-(trifluoromethyl)phenyl]boronic acid (2.44 g, 7.86 mmol, 3 eq), Xphos-Pd-G3 (222 mg, 262 pmol, 0.1 eq) and K3PO4 (3 M, 2.62 mL, 3 eq) at 25 °C. After stirring at 90 °C for 15 h, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The residue was purified by reversed phase (column: C18, 40 g, mobile phase: [water (FA) - MeCN]; B%: 40%-70%, 7 min) to give compound benzyl rac-(3S)-3-[7-[2-benzyloxy-6-methyl-4-(trifluoromethyl)pheny l]-1 ,8-naphthyridin-2- yl]piperidine-1 -carboxylate (1.4 g, 2.29 mmol, 87% yield) as yellow oil.

Compounds 28 and 29 3-methyl-2-[7-[1-methyl-3-piperidyl]-1 ,8-naphthyridin-2-yl]-5-(trifluoromethyl)phenol (single enantiomers)

To a solution of benzyl 3-[7-[2-benzyloxy-6-methyl-4-(trifluoromethyl)phenyl]-1 ,8-naphthyridin-2- yl]piperidine-1 -carboxylate (500 mg, 817 pmol, 1 eq) in MeOH (5 mL) was added Pd/C (5 mg, 10% purity) and HCHO (49.1 mg, 2.73 mmol, 45.0 pL, 37% purity in water, 3.34 eq) at 25 °C. After stirring at 25 °C under H ₂ (15 psi) atmosphere for 1 h, the mixture was filtered and concentrated to the residue. The residue was purified by reversed phase (column: C18 40 g, mobile phase: [water (FA) - MeCN]; B%: 2Q%-70%, 7 min) to give the desired product. The residue was separated by SFC (column: DAICEL CHIRALPAK AY-H (250 mm x 30 mm, 10 pm); mobile phase: [CO ₂ -EtOH (0.1 % NH ₃ *H ₂ O)]; 35% B isocratic elution mode) to give compound 28 (12.3 mg, 30.0 pmol, 4% yield, 99% purity) and compound 29 (55.6 mg, 137 pmol, 17% yield, 99% purity) as a yellow solid.

Compound 28

¹ H NMR (400 MHz, DMSO-cfe) 5 [ppm] = 10.2 (s, 1 H), 8.45 (dd, J = 8.4, 15.2 Hz, 2H), 7.65 (d, J = 8.4 Hz, 1 H), 7.56 (d, J = 8.0 Hz, 1 H), 7.17 (s, 1 H), 7.1 1 (s, 1 H), 3.20-3.12 (m, 1 H), 3.06-3.04 (m, 1 H), 2.85- 2.77 (m, 1 H), 2.24 (s, 4H), 2.11 (s, 3H), 2.03-1.90 (m, 2H), 1.80-1.72 (m, 1 H), 1.70-1.58 (m, 2H) LC-MS (Method C): Rt = 0.448 min; MS (ESIpos): m/z = 402.2 [M+H] ⁺ SFC (Rt = 1 .551 min) Compound 29

^! H NMR (400 MHz, DMSO-cfe) 6 [ppm] = 8.45 (dd, J = 8.4, 13.6 Hz, 2H), 8.20 (s, 1 H), 7.65 (d, J = 8.4 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.16 (s, 1 H), 7.12 (s, 1 H), 3.20 - 3.16 (m, 1 H), 3.07 (s, 1 H), 2.88-2.86 (m, 1 H), 2.34-2.31 (m, 1 H), 2.27 (s, 3H), 2.11 (s, 3H), 2.05-1.96 (m, 2H), 1.80-1.74 (m, 1 H), 1.70-1.58 (m, 2H)

LC-MS (Method C): Rt = 0.446 min; MS (ESIpos): m/z - 402.3 [M+H] ⁺

SFC (Rt = 1 .774 min).

Intermediate 52

N-[2-(2-methoxy-4, 6-dimethyl-phenyl)-7-(3-piperidyl)-1 , 8-naphthyridin-4-yl]acetamide (racemate)

To a solution of tert -butyl 3-[5-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8- 160zetidine160ine-2- yl]piperidine-1 -carboxylate (110 mg, 228 pmol, 1 eq) and acetamide (28.0 mg, 474 pmol, 2.08 eq) in tert-butyl alcohol (5 mL) were added potassium phosphate (154 mg, 726 pmol, 3.18 eq) and BrettPhos- Pd-G3 (22.0 mg, 26.0 pmol, 0.11 eq) at 25 °C. The mixture was degassed and purged with nitrogen for 3 times. After stirring at 80 °C for 14 h under N2 atmosphere, the mixture was filtered, and the filtrate was concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water (FA) - MeCN]; B%: 20% - 80%, 12 min) to give compound tert-butyl 3-[5-acetamido-7-(2-methoxy-4, 6-dimethyl-phenyl)-1 , 8-naphthyridin-2-yl]piperidine-1- carboxylate (80.0 mg, 159 pmol, 70% yield) as a yellow solid.

LC-MS (Method C): Rt = 0.503 min; MS (ESIpos): m/z = 505.3 [M+H] ⁺ .

Intermediate 53

N-[2-(2-methoxy-4, 6-dimethyl-phenyl)-7-(3-piperidyl)-1 , 8-naphthyridin-4-yl] acetamide (racemate)

A solution of tert-butyl 3-[5-acetamido-7-(2-methoxy-4, 6-dimethyl-phenyl)-1 , 8-naphthyridin-2-yl] piperidine- 1 -carboxylate (80.0 mg, 159 pmol, 1 eq) in HCI (4.00 M in 1 , 4-dioxane, 5.00 mL, 126 eq) was stirred at 0 °C for 1 h. The mixture was concentrated in vacuum to give N-[2-(2-methoxy-4, 6- dimethyl-phenyl)-7-(3-piperidyl)-1 , 8-naphthyridin-4-yl] acetamide (64.1 mg, 159 pmol, HCI salt) as a yellow solid.

LC-MS (Method C): Rt = 0.430 min; MS (ESI): m/z = 405.2 [M+H] ⁺ .

Intermediate 54

N-[2-(2-methoxy-4, 6-dimethyl-phenyl)-7-(1-methyl-3-piperidyl)-1 , 8-naphthyridin-4-yl] acetamide (racemate)

To a solution of N-[2-(2-methoxy-4,6-dimethyl-phenyl)-7-(3-piperidyl)-1 ,8-naphthyridin-4-yl]acetamide (64.1 mg, 159 pmol, 1 eq, HCI salt) in methanol (5 mL) were added potassium acetate (25.0 mg, 255 pmol, 1.61 eq), HCHO (9.81 mg, 327 pmol, 9.00 pL, 37% purity in water, 2.06 eq) and sodium cyanoboranuide (20.0 mg, 318 pmol, 2.01 eq) at 0 °C. After stirring at 25 °C for 1 h, the mixture was diluted with saturated sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (1 OmL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water (FA) - MeCN]; B%: 30% - 70%, 8 min) to give compound N-[2-(2-methoxy-4, 6- dimethyl-phenyl)-7-(1-methyl-3-piperidyl)-1 , 8-naphthyridin-4-yl] acetamide (60.0 mg, 143 pmol, 90% yield) as a white solid.

LC-MS (Method C): Rt = 0.739 min; MS (ESI) m/z = 419.2 [M+H] ⁺ .

Compound 30

N-[2-(2-hydroxy-4,6-dimethyl-phenyl)-7-(1-methyl-3-piperi dyl)-1 ,8-naphthyridin-4-yl]acetamide (racemate)

To a solution of N-[2-(2-methoxy-4,6-dimethyl-phenyl)-7-(1-methyl-3-piperidyl )-1 ,8- 161 zetidinel 61 ine- 4-yl]acetamide (50.0 mg, 120 pmol, 1 eq) in dichloromethane (5 mL) was added boron tribromide (59.9 mg, 239 pmol, 23.0 pL, 2 eq) at -70 °C. After stirring at 0 °C for 1 h and at 25 °C for 13 h, the mixture was added dropwise into water (15 mL) at 0 °C and stirred at 0 °C for 10 min. The pH was adjusted to 6-7 with saturated sodium bicarbonate. The mixture was extracted with dichloromethane (10mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: Cl 8, 40 g, mobile phase: [water (FA) - MeCN]; B%: 40% - 70%, 10 min) to give compound 30 (racemate). Compound 30

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 10.3 (s, 1 H), 8.80 (d, J = 8.8 Hz, 1 H), 8.24 (s, 0.6H), 8.19 (s, 1 H), 7.64 (d, J = 8.4 Hz, 1 H), 6.62 (s, 1 H), 6.61 (s, 1 H), 3.19-3.13 (m, 2H), 2.91 (d, J = 10.8 Hz, 1 H), 2.41 (t, J = 10.8 Hz, 1 H), 2.33 (s, 3H), 2.26 (s, 3H), 2.25 (s, 3H), 2.12-2.00 (m, 5H), 1.81-1.60 (m, 3H). LC-MS (Method C): R _t = 0.403 min; MS (ESI) m/z = 405.3 [M+H] ⁺ .

Compounds 31 and 32

N-[2-(2-hydroxy-4,6-dimethyl-phenyl)-7-(1-methyl-3-piperi dyl)-1 ,8-naphthyridin-4-yl]acetamide (single enantiomers)

Compound 30 was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 um);mobile phase: [dioxide carbon-acetonitrile/ethanol (0.100% ammonium hydroxide)]; B%: 60%, isocratic elution mode) to give compound 31 (single enantiomer) (12.0 mg, 26.3 pmol, 22% yield, 99% purity, formate) as a yellow solid and compound 32 (single enantiomer) (15.6 mg, 34.2 pmol, 27% yield, 99% purity, formate) (15.58 mg, 38.52 pmol, 32% yield, 99% purity) as a yellow solid.

Compound 31

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 10.3 ( s, 1 H), 10.1 ( s, 1 H), 8.78 (d, J = 8.4 Hz, 1 H), 8.19 (s, 1 H), 7.63 (d, J = 8.4 Hz, 1 H), 6.62 (s, 1 H), 6.61 (s, 1 H), 3.16-3.11 (m, 2H), 3.03 (d, J = 10.8 Hz, 1 H), 2.81 (d, J = 10.8 Hz, 1 H), 2.26-2.21 (m, 10H), 2.11 (s, 3H), 2.01-1.98 (m, 2H), 1.78-1.59 (m, 3H). LC-MS (Method C): Rt = 0.701 min; MS (ESI) m/z = 405.2 [M+H] ⁺ .

SFC (Rt = 1 .588 min)

Compound 32

^! H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 10.3 ( s, 1 H), 10.1 ( s, 1 H), 8.78 (d, J = 8.8 Hz, 1 H), 8.18 (s, 1 H), 7.63 (d, J = 8.4 Hz, 1 H), 6.62 (s, 1 H), 6.61 (s, 1 H), 3.16-3.11 (m, 1 H), 3.03 (d, J = 10.8 Hz, 1 H), 2.81 (d, J = 11.2 Hz, 1 H), 2.26-2.21 (m, 10H), 2.11 (s, 3H), 2.01-1.90 (m, 2H), 1.75-1.62 (m, 3H). LC-MS (Method C): Rt = 0.698 min; MS (ESI) m/z = 405.2 [M+H] ⁺ .

SFC (Rt = 1 .248 min).

Intermediate 55 tert-butyl N-( 6-chloro-3-formyl-2-pyridyl)carbamate

To a solution of tert-butyl N-(6-chloro-2-pyridyl)carbamate (28.0 g, 122 mmol, 1 eq) and N,N,N’,N’- tetramethylethane-1 ,2-diamine (35.6 g, 306 mmol, 46.2 mL, 2.5 eq) in tetrahydrofuran (300 mL) was added dropwise n-BuLi (2.50 M in hexanes, 122 mL, 2.5 eq) at -70 °C under nitrogen atmosphere. After completion of addition of n-BuLi, the reaction mixture was slowly warmed to -10 °C and stirred at -10 °C for 2 h under nitrogen atmosphere. Then N,N-dimethylformamide (22.4 g, 306 mmol, 23.6 mL, 2.5 eq) was added into the reaction mixture at -70°C under nitrogen atmosphere. The mixture was warmed to 25 °C and stirred at 25 °C for 1 h under nitrogen atmosphere. The pH was adjusted to 2 - 3 with hydrochloric acid (1.00 M in water) at -10 °C. After warming to 25 °C, the mixture were extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with saturated sodium chloride (200 mL), dried over sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was triturated with (petroleum ether/ethyl acetate = 20/1 , 100 mL) at 25 °C. The mixture was filtered under reduced pressure. The filter cake was collected and dried under reduced pressure to give tertbutyl N-(6-chloro-3-formyl-2-pyridyi) carbamate (20.0 g, 77.9 mmol, 64% yield) as a yellow solid.

Intermediate 56

Ethyl -3-[2-(tert-butoxycarbonylamino)-6-chloro-3-pyrldyl]-2-fluor o-prop-2-enoate

To a solution of tert-butyl N-(6-chloro-3-formyl-2-pyridyl)carbamate (7.00 g, 27.3 mmol, 1 eq) in acetonitrile (100 mL) were added ethyl 2-diethoxyphosphoryl-2-fluoro-acetate (8.59 g, 35.5 mmol, 7.19 mL, 1.03 eq), 1 ,8-diazabicyclo[5.4.0]undec-7-ene (6.23 g, 40.9 mmol, 6.17 mL, 1.5 eq) and lithium chloride (8.67 g, 205 mmol, 7.50 eq) at 25 °C. After stirring at 25 °C for 4 h, the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give ethyl 3-[2-(tert-butoxycarbonylamino)-6- chloro-3-pyridyl]-2-fluoro-prop-2-enoate (9.40 g, 27.3 mmol) as a yellow solid.

Intermediate 57

Ethyl 3-(2-amino-6-chloro-3-pyridyl)-2-fluoro-prop-2-enoate

A solution of ethyl (Z)-3-[2-(tert-butoxycarbonylamino)-6-chloro-3-pyridyl]-2-fl uoro-prop-2-enoate (9.40 g, 27.3 mmol, 1 eq) in hydrogen chloride (4 M in 1 ,4-dioxane, 90 mL, 13.2 eq) was stirred at 85 °C for 12 h. The reaction mixture was concentrated in vacuum to give ethyl 3-(2-amino-6-chloro-3-pyridyl)-2- fluoro-prop-2-enoate (6.67 g, 27.3 mmol, 100% yield) as a yellow solid.

LC-MS (Method C): Rt = 0.764 min; MS (ESI): m/z = 254.1 [M+H] ⁺ .

Intermediate 58

7-chloro-3-fluoro- 1, 8-naphthyridin-2-ol

To a solution of ethyl 3-(2-amino-6-chloro-3-pyridyl)-2-fluoro-prop-2-enoate (6.67 g, 27.3 mmol, 1 eq) in methanol (70 mL) was added sodium methoxide (9.82 g, 54.5 mmol, 30% purity in methanol, 2 eq) at 25 °C. After stirring at 85 °C for 2 h, the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with (petroleum ether/ethyl acetate = 10/1 , 25 mL). The mixture was filtered under reduced pressure and the filter cake was dried under reduced pressure to give 7-chloro-3-fluoro-1 ,8-naphthyridin-2-ol (2.60 g, 13.1 mmol, 48% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO-ofe) 5 [ppm] = 12.96 (s, 1 H), 8.14 (d, J = 8.4 Hz, 1 H), 7.92 (d, J = 10.4 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H).

Intermediate 59 tert-butyl 5-(6-fluoro-7-hydroxy-1,8-naphthyridin-2-yl)-3,6-dihydro-2H- pyridine-1 -carboxylate A mixture of 7-chloro-3-fluoro-1 ,8-naphthyridin-2-ol (2.60 g, 13.1 mmol, 1 eq), tert-butyl 5-(4,4,5,5- tetramethyl-1 , 3, 2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 -carboxylate (6.07 g, 19.6 mmol, 1 .5 eq), Pd(dppf)Cl2 (958 mg, 1.31 mmol, 0.1 eq), cesium carbonate (8.53 g, 26.2 mmol, 2 eq) in a mixture of water (20 mL) and 1 ,4-dioxane (80 mL) was degassed and purged nitrogen at 25 °C. After stirring at 100 °C for 12 h under nitrogen atmosphere, the reaction mixture was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiOz, petroleum ether/ethyl acetate = 1/0 to 1/1) to give tert-butyl 5-(6-fluoro-7-hydroxy-1 ,8-naphthyridin-2-yl)-3,6-dihydro-2H-pyridine-1- carboxylate (3.60 g, 10.4 mmol, 80% yield) as a yellow solid.

LC-MS (Method C): R _t = 0.893 min; MS (ESI): m/z = 346.1 [M+H] ⁺ .

Intermediate 60 tert-butyl 5-[ 6-fluoro-7-(trifluoromethylsulfonyloxy)-1, 8-naphthyridin-2-yl]-3, 6-dlhydro-2H-pyridine- 1 - carboxylate.

To a solution of tert-butyl 5-(6-fluoro-7-hydroxy-1 ,8-naphthyridin-2-yl)-3,6-dihydro-2H-pyridine-1- carboxylate (2.00 g, 5.79 mmol, 1 eq) in N,N-dimethylformamide (50 mL) were added potassium carbonate (1.60 g, 11.6 mmol, 2 eq) and 1 ,1 ,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl) methanesulfonamide (4.14 g, 11.6 mmol, 2 eq) at 0 °C. After stirring at 25 °C for 3 h, the reaction mixture was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiOz, petroleum ether/ethyl acetate = 10/1 to 3/1) to give tert-butyl 5-[6-fluoro-7- (trifluoromethylsulfonyloxy)-l ,8-naphthyridin-2-yl]-3,6-dihydro-2H-pyridine-1 -carboxylate (2.76 g, 5.78 mmol) as a yellow solid.

LC-MS (Method C): Rt = 1.054 min; MS (ESIpos): m/z = 478.1 [M+H] ⁺ .

Intermediate 61

2,4-dichloro-7-(3-piperidyl)-1 ,8-naphthyridine

A mixture of tert-butyl 5-[6-fluoro-7-(trifluoromethyisulfonyloxy)-1 ,8-naphthyridin-2-yl]-3,6-dihydro-2H- pyridine-1 -carboxylate (2.76 g, 5.78 mmol, 1 eq), (2-methoxy-4,6-dimethyl-phenyl)boronic acid (1 .56 g, 8.67 mmol, 1.5 eq), Xphox-Pd-G3 (489 mg, 578 pmol, 0.1 eq) and potassium phosphate (2.45 g, 11.6 mmol, 2 eq) in THF (50 mL) was degassed and purged nitrogen at 25 °C. After stirring at 65 °C for 12 h under nitrogen atmosphere, the reaction mixture was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiOz, petroleum ether/ethyl acetate = 10/1 to 2/1) to give tert-butyl 5-[6-fluoro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-3,6-dihydro-2H- pyridine-1 -carboxylate (2.00 g, 4.31 mmol, 75% yield) as a yellow solid.

LC-MS (Method C): Rt = 1 .055 min; MS (ESI): m/z = 464.2 [M+H] ⁺ .

Intermediate 62 tert-butyl 3-[6-fluoro-7-(2-methoxy-4,6-dimethyl-phenyl)-1,8-naphthyndm -2-yl]piperidine-1 -carboxylate (racemate)

A solution of tert-butyl 5-[6-f!uoro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-3,6- dihydro-2H-pyridine-1 -carboxylate (2.20 g, 4.75 mmol, 1 eq) and Pd/C (0.200 g, 10% purity, 50% water) in methanol (30 mL) was stirred at 25 °C for 1 h under H2 (15 psi) atmosphere. The mixture was filtered through a pad of celite. The filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 4/1) to give tertbutyl 3-[6-fluoro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]piperidine-1 -carboxylate (1 .50 g, 3.22 mmol, 68% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 8.43 (d, J = 8.4 Hz, 1 H), 8.32 (d, J = 8.8 Hz, 1 H), 7.67 (d, J = 8.4 Hz, 1 H), 6.81 (d, J = 14.0 Hz, 1 H), 4.19 (s, 1 H), 3.98 (d, J = 13.6 Hz, 1 H), 3.65 (s, 3H), 3.07-3.00 (m, 1 H), 2.88-2.77 (m, 1 H), 2.37 (s, 3H), 2.10-2.07 (m, 1 H) 2.00 (s, 3H), 1.85-1.76 (m, 2H), 1.53-1.44 (m, 2H) 1.39 (s, 9H).

LC-MS (Method C): Rt = 0.638 min; MS (ESI): m/z = 466.3 [M+H] ⁺ .

Intermediate 63

3-fiuoro-2-(2-methoxy-4,6-dimethyi-phenyi)-7~(3-piperidyi )-1,8-naphthyridine (racemate)

A solution of tert-butyl 3-[6-f!uoro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]piperidine- 1-carboxylate (1.00 g, 2.15 mmol, 1 eq) in hydrochloric acid (4.00 M in 1 ,4-dioxane, 20 mL, 37.3 eq) was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuum to give 3-fluoro-2-(2- methoxy-4,6-dimethyl-phenyl)-7-(3-piperidyl)-1 ,8-naphthyridine (942 mg, 2.15 mmol, HCI salt) as a yellow solid.

LC-MS (Method C): Rt = 0.466 min; MS (ESI): m/z = 366.3 [M+H]*.

Intermediate 64

3-fluoro-2-(2-methoxy-4,6-dimethyl-phenyl)-7-(1-methyl-3- piperidyl)-1 ,8-naphthyridine (racemate) To a solution of 3-fluoro-2-(2-methoxy-4,6-dimethyl-phenyl)-7-(3-piperidyl)-1 ,8-naphthyridine (942 mg, 2.15 mmol, 1 eq, HCI salt) in methanol (10 mL) were added HCHO (523 mg, 6.44 mmol, 480 pL, 37% purity in water, 3 eq), potassium acetate (422 mg, 4.30 mmol, 2 eq) and sodium cyanoborohydride (405 mg, 6.44 mmol, 3 eq) at 0 °C. After stirring at 25 °C for 1 h, the mixture added into saturated ammonium chloride (20 mL) at 0 °C. The pH was adjusted to 8 - 9 with saturated sodium bicarbonate at 0 °C. And the mixture was extracted with ethyl acetate (20 mL-x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18 80 g, mobile phase: [water (FA) - MeCN]; B%: 20% - 80%, 12 min) to give 3-fiuoro-2-(2-methoxy-4,6-dimethyl-phenyl)-7-(1-methyl-3-pip eridyl)- 1 ,8-naphthyridine (455 mg, 1 .20 mmol, 56% yield) as a yellow solid.

^! H NMR (400 MHz, CDCb) 5 [ppm] = 8.11 (d, J = 8.0 Hz, 1 H), 7.79 (d, J = 8.0 Hz, 1 H), 7.45 (d, J = 8.4 Hz, 1 H), 6.75 (s, 1 H), 6.65 (s, 1 H), 3.69 (s, 3H), 3.30-3.16 (m, 2H), 2.92 (d, J = 10.0 Hz, 1 H), 2.53-2.46 (m, 1 H), 2.39 (m, 3H), 2.36 (d, J = 4.0 Hz, 3H), 2.12 (s, 3H), 2.10-2.06 (m, 2H), 1 .87-1.75 (m, 3H). LC-MS (Method C): Rt = 0.809 min; MS (ESI): m/z = 380.2 [M+H] ⁺ .

Compound 34 2~[3~fluoro-7-[1-methyl-3~piperidyl]-1,8-naphthyridin-2-yi]- 3,5-dimethyl-phenoi (single enantiomers) To a solution of 3-fluoro-2-(2-methoxy-4,6-dimethyl-phenyi)-7-(1-methyl-3-pip eridyl)-1 ,8-naphthyridine (455 mg, 1.20 mmol, 1 eq) in dichloromethane (15 ml_) was added BBrs (901 mg, 3.60 mmol, 347 pL, 3 eq) at 0 °C. After stirring at 25 °C for 1 h, the mixture was added into water (15mL) at 0 °C. The pH was adjusted to 7 - 8 with saturated sodium bicarbonate at 0 °C. The mixture was extracted with dichioromethane (15 mL * 3). The combined organic layers was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was combined with another batch and purified by reversed-phase column (column: C18, 330 g, mobile phase: [water (FA) - MeCNJ; B%: 20% - 80%, 8 min) to give a racemate of 2-(3-fluoro-7-(1-methylpiperidin-3-yl)-1 ,8- naphthyridin-2-yl)-3,5-dimethylphenol. The racemate was separated by SFC (column: DAICEL CHIRALPAK AY-H (250 mm x 30 mm, 10 um); mobile phase: [COs-MeCN/ MeOH (0.1 % NHs’HaO)]; B%: 40%, isocratic elution mode) to give Compound 34 (158 mg, 430 pmol, 36% yield, 99% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 8.40 (d, J = 8.4 Hz, 1 H), 8.29 (d, J = 8.8 Hz, 1 H), 8.22 (s, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 6.63 (s, 1 H), 6.63 (s, 1 H), 3.23-3.16 (m, 1 H), 3.13 (d, J = 11.2 Hz, 1 H), 2.90 (d, J = 1 1 .2 Hz, 1 H), 2.39 (t, J = 10.8 Hz 1 H), 2.31 (s, 3H), 2.27 (s, 3H), 2.11-2.03 (m, 2H), 1 .99 (s, 3H), 1.81-1.74 (m, 1 H) 1.71-1.55 (m, 2H).

LC-MS (Method C): Rt = 0.786 min; MS (ESI) m/z = 366.2 [M+H] ⁺ .

SFC (Rt = 2.123 min, ee% = 98%)

Intermediate 65

5-chlorG-2-(2-methoxy-4,6-dimethyl-phenyl)thiazoio[4,5-b] pyridine

To a vial was added 2-bromo-5-chloro-thiazolo[4,5-b]pyridine (350 mg, 1.4 mmol, 1 eq), (2-methoxy- 4,6-dimethyl-phenyl)boronic acid (404 mg, 2.24 mmol, 1.1 eq), and Xphos Pd G2 (110 mg, 0.14 mmol, 0.1 eq). The vial was sealed, then evacuated and back-filled with nitrogen three times. THF (7 mL) was added, followed by degassed potassium phosphate tribasic (0.5 M in water) (8.42 mL, 4.21 mmol, 3 eq). The reaction was heated to 40 °C, and left to stir overnight. The reaction mixture was partitioned between water and EtOAc (25 mL of each). The layers were separated, and the aqueous was extracted with EtOAc (2 x 25 mL). The combined organics were dried with Na2SO4, filtered, and concentrated in vacuo to yield a brown gum. The crude was purified by automated column chromatography (0 to 20% EtOAc in cyclohexane). The appropriate fractions were identified by TLC (25% EtOAc in cyclohexane, Rf = 0.44), combined and concentrated in vacuo to yield 5-chloro-2-(2-methoxy-4,6-dimethyl- phenyl)thiazolo[4,5-b]pyridine (219 mg, 0.7185 mmol, 51 % yield) as a yellow gum.

LC-MS (method K, pH 6, 3 min): Rt = 1.87 min; MS (ESIpos): m/z = 305.3/307.3 [M+H] ^{+ 1} H NMR (400 MHz, Chloroform-d) 6 8.17 (d, J = 8.2 Hz, 1 H), 7.32 (d, J = 8.3 Hz, 1 H), 6.78 (s, 1 H), 6.69 (s, 1 H), 3.85 (s, 3H), 2.51 (s, 3H), 2.37 (s, 3H). intermediate 66

2-(2-methoxy-4,6-dimethyl-phenyl)-5-(1-methyl-3,6-dihydro -2H-pyridin-5-yl)thiazolo[4,5-b]pyridine To vial was added 5-chloro-2-(2-methoxy-4,6-dimethyl-phenyl)thiazolo[4,5-b]pyr idine (219 mg, 0.72 mmol, 1 eq), 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine hydrochloride (224 mg, 0.86 mmol, 1.2 eq), and Xphos Pd G2 (56.5 mg, 0.072 mmol, 0.1 eq). The vial was evacuated and back-filled with nitrogen three times, then 1 ,4-Dioxane (5 mL) was added, followed by 2 M potassium carbonate in water (1.08 mL, 2.16 mmol, 3 eq). The reaction was heated to 90 °C, and left to stir for 1 hour. The reaction mixture was partitioned between sat. aq. Sodium bicarbonate and 10% MeOH in DCM (20 mL of each). The layers were separated, and the aqueous was extracted with 10% MeOH in DCM (20 mL). The combined organics were passed through a hydrophobic frit, and concentrated in vacuo to yield a brown gum. The crude was purified by automated column chromatography (0 to 10% (2 M NHs in MeOH) in DCM). The appropriate fractions were identified by TLC (10% (2 M NH3 in MeOH) in DCM, Rf = 0.27), combined and concentrated in vacuo to yield 2-(2- methoxy-4,6-dimethyl-phenyl)-5-(1-methyl-3,6-dihydro-2H-pyri din-5-yl)thiazolo[4,5-b]pyridine (197 mg, 0.539 mmol, 75% yield) as an orange glass.

LC-MS (SQD, pH 6, 3 min): Rt = 1 .45 min; MS (ESIpos): m/z = 366.5 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d6) 5 8.52 (d, J = 8.4 Hz, 1 H), 7.74 (d, J = 8.4 Hz, 1 H), 6.91 (s, 1 H), 6.86 - 6.79 (m, 2H), 3.79 (s, 3H), 3.45 - 3.40 (m, 2H), 2.50 - 2.47 (m, 2H), 2.38 (s, 3H), 2.44 - 2.31 (m, 2H), 2.36 (s, 3H), 2.28 (s, 3H).

¹³ C NMR (101 MHz, DMSO-d6) 6 167.5, 162.8, 157.4, 154.8, 141.4, 138.3, 135.2, 131.3, 127.0, 126.7, 123.8, 118.9, 115.7, 110.1 , 55.8, 54.7, 51.0, 45.8, 26.4, 21.3, 20.6.

Intermediate 67

2-(2-methoxy-4,6-dimethyi-phenyl)-5-(1-methyi-3-piperidyl )thiazoio[4,5-b]pyridine

To 2-(2-methoxy-4,6-dimethyl-phenyl)-5-(1-methyl-3,6-dihydro-2H -pyridin-5-yl)thiazolo[4,5-b]pyridine (169 mg, 0.46 mmol, 1 eq) was added 10% Pd/C (50% water wet) (98 mg, 0.046 mmol, 0.1 eq), and the flask was evacuated and back-filled with nitrogen three times. Ethanol (3 mL) and Ethyl acetate (3 mL) were added, and the flask was evacuated and back-filled with nitrogen three times. The reaction was evacuated, then purged with hydrogen three times, then left to stir at room temperature under an atmosphere of hydrogen for 4 days. The flask was evacuated and back-filled with nitrogen three times. The reaction mixture was filtered through Celite (washing with EtOH) to remove the Pd/C, and the filtrate was concentrated in vacuo to yield 2-(2-methoxy-4,6-dimethyl-phenyl)-5-(1-methyl-3- piperidyl)thiazolo[4,5-b]pyridine (150 mg, 0.4082 mmol, 88% yield) as a yellow gum.

LC-MS (Method K, pH 6, 3 min): Rt = 1 .35 min; MS (ESIpos): m/z = 368.3 [M+H] ⁺

^! H NMR (400 MHz, DMSO-d6) 6 8.51 (d, J = 8.3 Hz, 1 H), 7.43 (d, J = 8.3 Hz, 1 H), 6.91 (s, 1 H), 6.83 (s, 1 H), 3.78 (s, 3H), 3.13 - 3.03 (m, 1 H), 3.03 - 2.94 (m, 1 H), 2.85 - 2.78 (m, 1 H), 2.36 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H), 2.21 - 2.13 (m, 1 H), 1.97 - 1.89 (m, 2H), 1.80 - 1.71 (m, 1 H), 1.70 - 1.51 (m, 2H).

Intermediate 68

3,5-dimethyl-2-[5-(1-methyl-3-piperidyl)thiazolo[4,5-b]16 7zetidin-2-yl]phenol

To a stirring solution of 2-(2-methoxy-4,6-dimethyl-phenyl)-5-(1-methyl-3-piperidyl)th iazolo[4,5- b]py rid ine (150 mg, 0.41 mmol, 1 eq) in DCM (4 mL) under nitrogen at 0 °C was added Boron tribromide (1 M in DCM) (1.22 mL, 1.22 mmol, 3 eq) dropwise. The reaction was allowed to warm to room temperature, and left to stir overnight. The reaction was cooled to 0 °C, and quenched by the addition of sat. aq. Sodium bicarbonate (20 mL), then extracted with 10% MeOH in DCM (3 x 20 mL). The combined organics were passed through a hydrophobic frit, and concentrated in vacuo to yield an orange solid. The crude was purified by automated column chromatography (0 to 15% (2 M NHs in MeOH) in DCM). The appropriate fractions were identified by TLC (20% (2 M NH3 in MeOH) in DCM, Rf = 0.64), combined and concentrated in vacuo to yield 3,5-dimethyl-2-[5-(1-methyl-3- piperidyl)thiazolo[4,5-b]168zetidin-2-yl]phenol (79.3 mg, 0.2243 mmol, 55% yield) as an orange solid. LC-MS (SQD, pH 6, 3 min): Rt = 1 .42 min; MS (ESIpos): m/z = 354.4 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d6) 5 10.92 (br s, 1 H), 8.51 (d, J = 8.2 Hz, 1 H), 7.42 (d, J = 8.2 Hz, 1 H), 6.71 (s, 1 H), 6.70 (s, 1 H), 3.09 (td, J = 11 .0, 5.5 Hz, 1 H), 3.04 - 2.97 (m, 1 H), 2.88 - 2.78 (m, 1 H), 2.44 (s, 3H), 2.27 (s, 3H), 2.25 (s, 3H), 2.23 - 2.16 (m, 1 H), 2.02 - 1 .89 (m, 2H), 1 .80 - 1 .71 (m, 1 H), 1 .71 - 1.53 (m, 2H).

Compounds 35 and 36

3.5-dimethyl-2-[5-[1-methyl-3-piperidyl]thiazolo[4,5-b]16 8zetidin-2-yl]phenol (single enantiomers)

3.5-Dimethyl-2-[5-(1-methyl-3-piperidyl)thiazolo[4,5-b]16 8zetidin-2-yl]phenol (50 mg, 141.45 pmol, 1 EQ) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 pm); mobile phase: [COz-MeCN/MeOH (0.1 % NHz’HzO)]; B%:45%, isocratic elution mode) to give Compound 35 (16.9 mg, 46.2 pmol, 33% yield, 97% purity) as a yellow solid and Compound 36 (16.6 mg, 44.5 pmol, 31 % yield, 95% purity) as a yellow solid.

Compound 35

¹ H NMR (400 MHz, DMSO-cfe) 5 [ppm] = 8.50 (d, J = 8.2 Hz, 1 H), 7.42 (d, J = 8.4 Hz, 1 H), 6.70 (d, J = 7.0 Hz, 2H), 3.14-3.05 (m, 1 H), 3.02-2.95 (m, 1 H), 2.83-2.77 (m, 1 H), 2.44 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H), 2.18-2.16 (m, 1 H), 1.98-1.89 (m, 2H), 1.79-1.71 (m, 1 H), 1.68-1.57 (m, 2H)

LC-MS (Method C): Rt = 0.591 min; MS (ESIpos): m/z = 354.2 [M+H] ⁺

Compound 36

^! H NMR (400 MHz, DMSO-ds) 5 [ppm] = 8.50 (d, J = 8.4 Hz, 1 H), 7.41 (d, J = 8.4 Hz, 1 H), 6.70 (d, J = 9.2 Hz, 2H), 3.10-3.01 (m, 1 H), 2.98-2.96 (m, 1 H), 2.82-2.81 (m, 1 H), 2.44 (s, 3H), 2.36-2.28 (m, 1 H), 2.27 (s, 3H), 2.22 (s, 3H), 2.20-2.12 (m, 1 H), 1 .97-1 .89 (m, 2H), 1.79-1.71 (m, 1 H), 1.69-1 .57 (m, 2H) LC-MS (Method C): Rt = 0.459 min; MS (ESIpos): m/z - 354.1 [M+H] ⁺

Intermediate 69

(3,3-difluorocyclobutyl)trifluoromethanesuifonate

To a solution of 3,3-difiuorocyclobutan-1-ol (2.00 g, 18.5 mmol, 1 eq) and pyridine (4.39 g, 55.5 mmol, 4.48 mL, 3 eq) in dichloromethane (20 mL) was added TfzO (6.79 g, 24.0 mmol, 3.97 mL, 1.3 eq) at - 70 °C dropwise. After stirring at 0 °C for 0.5 h, the mixture was poured into water (60 mL) and extracted with dichloromethane (40 mL x 2). The combined organic phase was washed with hydrochloric acid aqueous solution (40 mL, 1 N) and brine (50 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give (3,3-difluorocyclobutyl)trifluoromethanesulfonate (4.00 g, 16.6 mmol, 90% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCI ₃ ) <5 [ppm] = 5.28-5.15 (m, 1 H), 3.26-3.14 (m, 2H), 3.10-2.97 (m, 2H)

Intermediate 70

2-[1-(3 _! 3-difluorocyciobutyl)-3-piperidyi]-7-(2-methoxy-4,6-di methyi-phenyi)-1,8-naphthyridine (racemate)

To a solution of 2-(2-methoxy-4,6-dimethyl-phenyl)-7-(3-piperidyl)-1 ,8-naphthyridine (250 mg, 719 pmol, 1 eq) and CS2CO3 (703 mg, 2.16 mmol, 3 eq) in MeCN (6 mL) was added (3,3- difluorocyclobutyl)trifluoromethanesulfonate (518 mg, 2.16 mmol, 3 eq) at 20 °C in one portion. After stirring at 40 °C for 1 .5 h, the mixture was concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18, 80 g, mobile phase: [water (FA) - MeCN]; B%: 25% - 75%, 10 min) to give 2-[1-(3,3-difluorocyclobutyl)-3-piperidyl]-7-(2-methoxy-4,6- dimethyl-phenyl)-1 ,8- naphthyridine (340 mg, 699 pmol, 97% yield, 90% purity) as black brown oil.

LC-MS (Method C): Rt = 0.461 min; MS (ESIpos): m/z = 438.3 [M+1 ] ⁺ .

Intermediate 71

2-[7-[ 1 -(3, 3-difluorocyciobutyi)-3-piperidyl]-1, 8-naphthyridin-2-yi]-3, 5-dimethyl-phenoi (racemate)

To a solution of 2-[1-(3,3-difluorocyclobutyl)-3-piperidyl]-7-(2-methoxy-4,6- dimethyl-phenyl)-1 ,8- naphthyridine (320 mg, 731 .39 pmol, 1 eq) in dichloromethane (0.5 mL) was added BBra (916 mg, 3.66 mmol, 352 pL, 5 eq) at -70 °C dropwise. After stirring at 20 °C for 1 h, the mixture was quenched by methanol (1 mL) and concentrated in vacuum to give a residue. The residue was purified by reversed- phase column (column: C18, 40 g, mobile phase: [water (FA) - MeCN]; B%: 30% - 75%, 12 min) to give 2-[7-[1 -(3,3-difluorocyclobutyl)-3-piperidyl]-1 ,8-naphthyridin-2-yl]-3,5-dimethyl-phenol (150 mg, 350 pmol, 47% yield, 99% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.437 min; MS (ESIpos): m/z = 424.3 [M+1 ] ⁺ .

Compound 38 3,5-dimethyi-2-[7-[1-(3,3-difiuorocyclobutyl)-3-piperidyi]-1 ,8-naphthyridin-2-yl]phenol (single enantiomers)

The reaction was set up for SFC separation. The residue was purified by SFC: (column: DAICEL CHIRALPAK IG (250mm x 30mm,10pm);mobile phase: [CO ₂ -i-PrOH(0.1 %NH3«H2O)];B%:50%, isocratic elution mode) to give Compound 38 (90.9 mg, 208 pmol, 49% yield, 97% purity) as a yellow solid.

^! H NMR (400 MHz, DMSO-d6) 6 = 9.78-970 (m, 1 H), 8.41 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 7.6 Hz, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 6.64 (s, 1 H), 6.62 (s, 1 H), 3.20-3.03 (m, 2H), 2.96-2.61 (m, 4H), 2.49-2.35 (m, 2H), 2.27 (s, 3H), 2.24-2.13 (m, 1 H), 2.08 (s, 3H), 2.06-1.97 (m, 1 H), 1.94-1.74 (m, 2H), 1.74-1.58 (m, 2H)

LC-MS (Method C): Rt = 0.444 min; MS (ESIpos): m/z = 424.3 [M+1 ] ⁺ .

SFC (Rt = 1 .867 min, ee% = 99%)

Intermediate 72 3-methyl-2-[7-[1-(2-hydroxyethyl)-3-piperidyl]-1,8-naphthynd !n-2-y!]-5-(tnfluoromethyl)phenol (racemate)

To a solution of benzyl 3-[7-[2-benzyloxy-6-methyl-4-(trifluoromethyl)phenyl]-1 ,8-naphthyridin-2- yl]piperidine-1 -carboxylate (500 mg, 817 pmol, 1 eq) in methanol (5 mL) was added Pd/C (5.00 mg, 10% purity) at 25 °C. After stirring at 25 °C under H2 (15 psi) atmosphere for 1 h, the mixture was filtered and concentrated to give 3-methyl-2-[7-[3-piperidyl]-1 ,8-naphthyridin-2-yl]-5-(trifluoromethyl)phenol (300 mg, 774 pmol, 94% yield) as yellow oil.

LC-MS (Method C): Rt - 0.441 min; MS (ESIpos): m/z = 388.2 [M+H] ⁺

Intermediate 73

3-methyl-2~[7-[1-(2-hydroxyethy!)-3~piperidyl]-1,8-naphth yridin-2-yl]~5-(trifluoromethyl)phenol

To a solution of 3-methyl-2-[7-[3-pipeddyl]~1 ,8-naphthyridin-2-yl]-5-(trifluoromethyi)phenol (300 mg, 774 pmol, 1 eq) in tetrahydrofuran (3 mL) was added oxirane (172 mg, 3.87 mmol, 195 pL, 5 eq) at 10 °C. After stirring at 25 °C for 2 h, the mixture was concentrated to give 3-methyl-2-[1 -(2-hydroxyethyl)-3- piperidyl]-1 ,8-naphthyridin-2-yl]-5-(trifluoromethyl)phenol (330 mg, 765 pmol, 98% yield) as a yellow solid.

Compounds 39 ad 40

3-methyl-2-[7-[1-(2-hydroxyethyl)-3-piperidyl]-1 ,8-naphthyridin-2-yl]-5-(trifluoromethyl)phenol (single enantiomers)

The compound 3-methyl-2-[1-(2-hydroxyethyl)-3-piperidylJ-1 ,8-naphthy rid in-2-yl]-5-

(trifluoromethyl)phenol (racemate) was purified by SFC (column: DAICEL CHIRALCEL OD(250 mm x 30 mm, 10 um);mobile phase: [CO ₂ -EtOH(0.1 %NH3*H2O)]; 35% B isocratic elution mode) to give Compound 39 (33.4 mg, 74.4 pmol, 32% yield, 96% purity) as a yellow solid and Compound 40 (16.5 mg, 37.5 pmol, 16% yield, 98% purity) as a yellow solid.

Compound 39

^! H NMR (400 MHz, DMSO-c/ ₆ ) 5 = 10.26-10.11 (m, 1 H), 8.44 (dd, J = 8.4, 15.3 Hz, 2H), 7.68-7.63 (m, 1 H), 7.56 (d, J = 8 Hz, 1 H), 7.19-7.08 (m, 2H), 4.41-4.32 (m, 1 H), 3.58-3.47 (m, 2H), 3.20-3.10 (m, 2H), 2.96-2.86 (m, 1 H), 2.47-2.43 (m, 2H), 2.37-2.29 (m, 1 H), 2.11 (s, 3H), 2.08-1 .95 (m, 2H), 1 .78-1 .71 (m, 1 H), 1.70-1.61 (m, 2H)

LC-MS (Method C): Rt = 0.450 min; MS (ESIpos): m/z - 432.2 [M+H] ⁺

SFC (Rt - 2.104 min, ee% = 100%)

Compound 40

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 = 10.75-9.98 (m, 1 H), 8.49-8.40 (m, 2H), 7.65 (d, J = 8.4 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.16 (s, 1 H), 7.12 (s, 1 H), 4.48-4.26 (m, 1 H), 3.53 (br t, J = 6.4 Hz, 2H), 3.19-3.10 (m, 2H), 2.95-2.87 (m, 1 H), 2.48-2.43 (m, 2H), 2.39-2.29 (m, 1 H), 2.11 (s, 3H), 2.07-1 .96 (m, 2H), 1 .78- 1.70 (m, 1 H), 1.69-1.61 (m, 2H)

LC-MS (Method C): Rt = 0.445 min; MS (ESIpos): m/z = 432.2 [M+H] ⁺

SFC (Rt = 2.291 min, ee% = 99%) intermediate 74

7 -chloro- 1H-1, 8-naphthyridine-2, 4-dione

To a solution of methyl 2-amino-6-chloro-pyridine-3-carboxylate (35.0 g, 188 mmol, 1 eq) in ethyl acetate (350 mL) was added dropwise potassium tert-butoxide (1 .00 M in tetra hydrofuran, 375 mL, 2 eq) at 0 °C. After stirring at 25 °C for 1 h, the reaction mixture was heated at 60 °C for 14 h. Petroleum ether (350 mL) was added into the reaction mixture. The suspension was filtered under reduced pressure. The filter cake was collected and dried to give a residue. The residue was dissolved in water (350 mL). The pH was adjusted to 5 - 6 with HCI (1 .00 M in water). The suspension was filtered and the filter cake was collected and dried to give 7-chloro-1 H-1 , 8-naphthyridine-2, 4-dione (15.0 g, 76 mmol, 41 % yield) as a white solid.

¹ H NMR (400 MHz, DMSO-ofe) 5 [ppm] = 11 .83 (s, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 7.25 (d, J = 8.0 Hz, 1 H), 7.76 (s, 1 H).

LC-MS (Method C): Rt = 0.546 min; MS (ESIpos): m/z = 196.9 [M+H] ⁺ . intermediate 75 tert-butyl 5-(5-hydroxy-7-oxo-8H-1,8-naphthyridin-2-yl)-3,6-dihydro-2H- pyridine-1 -carboxylate

A mixture of 7-chloro-4-hydroxy-1 H-1 ,8-naphthyridin-2-one (2.00 g, 10.2 mmol, 1 eq), tert-butyl 5- (4,4,5,5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 -carboxylate (3.80 g, 12.3 mmol, 1.21 eq), Pd(dppf)Cl2 (750 mg, 1.03 mmol, 0.101 eq) and cesium carbonate (5.00 g, 15.4 mmol, 1.51 eq) in 1 ,4-dioxane (20 mL) and water (4 mL) was degassed and purged with nitrogen for three times. After stirring at 90 °C for 14 h under nitrogen atmosphere, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18, 330 g, mobile phase: [water (FA) - MeCN]; B%: 25% - 60%, 8 min) to give tert-butyl 5-(5-hydroxy- 7-oxo-8H-1 ,8-naphthyridin-2-yl)-3,6-dihydro-2H-pyridine-1 -carboxylate (3.30 g, 9.61 mmol, 94% yield) as a brown solid.

^! H NMR (400 MHz, DMSO-d _s ) 5 [ppm] = 9.45 (s, 1 H), 8.00 (d, J = 7.6 Hz, 1 H), 7.11 (d, J = 8.0 Hz, 1 H), 6.73 (br. S, 1 H), 4.69 (d, J = 1 .6 Hz, 1 H), 4.31 (s, 2H), 3.46 (t, J = 5.2 Hz, 2H), 2.28 (d, J = 3.2 Hz, 2H), 1.43 (s, 9H).

LC-MS (Method C): Rt = 0.781 min; MS (ESIpos): m/z = 344.1 [M+H]*.

Intermediate 76 tert-butyl 3-(5-hydroxy-7-oxo-8H-1,8-naphthyridin-2-yl)piperidine-1 -carboxylate (racemate)

To a solution of tert-butyl 5-(5-hydroxy-7-oxo-8H-1 ,8-naphthyridin-2-yl)-3,6-dihydro-2H-pyridine-1- carboxylate (2.10 g, 6.12 mmol, 1 eq) in methanol (30 mL) was added Pd/C (200 mg, 10% purity, 50% in water) at 25 °C. After stirring at 25 °C for 14 h under H2 (15 psi) atmosphere, the reaction mixture was filtered through a pad of celite under reduced pressure. The filtrate was concentrated in vacuum to give tert-butyl 3-(5-hydroxy-7-oxo-8H-1 ,8-naphthyridin-2-yl)piperidine-1-carboxylate (2.00 g, 5.79 mmol, 95% yield) as a white solid.

LC-MS (Method C): Rt = 0.803 min; MS (ESIpos): m/z = 346.1 [M+H] ⁺ . intermediate 77

2,4-dichloro-7-(3-piperidyl)-1 _! 8-naphthyridine (racemate)

To a mixture of tert-butyi 3-(5-hydroxy-7-oxo-8H-1 ,8-naphthyridin-2-yl) piperidine-1-carboxylate (1 .70 g, 4.92 mmol, 1 eq) in toluene (20 mL) were added dropwise phosphorus oxychloride (3.77 g, 24.6 mmol, 2.29 mL, 5 eq) and /V,/V-diisopropylethylamine (1 .27 g, 9.84 mmol, 1 .71 mL, 2 eq) at 25 °C. After stirring at 100 °C for 4 h, the mixture was concentrated in vacuum to give a residue. The residue was diluted with ethyl acetate (20 mL). The mixture was added dropwise into ice-water (30 mL). And the pH was adjusted to 9 - 10 with solid of sodium carbonate. The mixture was concentrated in vacuum to remove organic solvent to give a solution of 2, 4-dichloro-7-(3-piperidyl)-1 , 8-naphthyridine (1 .39 g, 4.93 mmol) in water as a black liquid. The aqueous solution was used directly for next step.

LC-MS (Method C): Rt = 0.588 min; MS (ESIpos): m/z = 282.0 [M+H] ⁺ . intermediate 78 tert-butyl 3-(5, 7-dichloro-1, 8-naphthyridin-2-yl)piperidine-1 -carboxylate (racemate)

To a solution of 2, 4-dichloro-7-(3-piperidyl)-1 , 8-naphthyridine (1.39 g, 4.93 mmol, 1 eq) (aqueous solution from above step) in tetra hydrofuran (20 mL) was added BoczO (4.75 g, 21.8 mmol, 5.00 mL, 4.42 eq). After stirring at 25 °C for 12 h, the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (S1O ₂ , petroleum ether/ethyl acetate = 100/1 to 5/1) to give tert-butyl 3-(5, 7-dichloro-1 , 8-naphthyridin-2-yl) piperidine- 1 - carboxylate (1 ,06 g, 2.77 mmol, 56% yield) as a yellow oil.

¹ H NMR (400 MHz, CDCb) 6 [ppm] = 8.49 (d, J = 8.4 Hz, 1 H), 7.56 (s, 1 H), 7.53 (d, J = 8.8 Hz, 1 H), 4.34-4.09 (m, 2H), 3.24 (s, 1 H), 3.12-3.05 (m, 1 H), 2.83 (s, 1 H), 2.14-1.95 (m, 2H) 1.85-1.71 (m, 1 H), 1.66-1.57 (m, 1 H), 1.47 (s, 9H).

LC-MS (Method C): Rt = 0.898 min; MS (ESIpos): m/z = 382.0 [M+H] ⁺ .

Intermediate 79 tert-butyl 3-[5-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1,8-naphthyrid in-2-yl]piperidine-1 -carboxylate (racemate)

To a solution of tert-butyl 3-(5,7-dichloro-1 , 8-naphthyridin-2-yl)piperidine-1-carboxylate (1.16 g, 3.03 mmol, 1 eq) and (2-methoxy-4,6-dimethyl-phenyl) boronic acid (492 mg, 2.73 mmol, 0.9 eq) in a mixed solvent of 1 ,4-dioxane (20 mL) and water (4 mL) were added Pd(dppf)Cl2 (219 mg, 299 pmol, 0.0984 eq) and cesium carbonate (1.53 g, 4.69 mmol, 1.55 eq) at 25 °C. After stirring at 70 °C for 14 h, the mixture was added into water (50 mL) at 0 °C. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether/ethyl acetate = 5/1 to 1/1) to give tert-butyi 3-[5-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8- naphthyridin-2-yl]piperidine-1-carboxylate (490 mg, 1.02 mmol, 34% yield) as colorless oil.

LC-MS (Method C): Rt = 0.971 min; MS (ESIpos): m/z = 482.2 [M+H] ⁺ . intermediate 80 tert-butyl 3-[5-cyano-7-(2-methoxy-4, 6-dimethyl-phenyl)- 1, 8-naphthyridin-2-yl]plperldlne-1 -carboxylate (racemate)

To a solution of tert-butyl 3-[5-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]piperidine-1 -carboxylate (450 mg, 934 umol, 1 eq) and zinc cyanide (225 mg, 1 .92 mmol, 2.05 eq) in AA/V-dimethylacetamide (15 mL) were added Pd2(dba)3 (85.5 mg, 93.4 pmol, 0.1 eq) and 1 ,1- bis(diphenylphosphino)ferrocene (104 mg, 187 pmol, 0.2 eq) at 25 °C under nitrogen atmosphere. After stirring at 120 °C for 12 h under nitrogen atmosphere, the mixture was cooled to 25 °C and diluted with saturated potassium carbonate (30 mL). The mixture was extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with saturated potassium carbonate (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether/ethyl acetate = 100/1 to 4/1) to give tert-butyl 3-[5- cyano-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]piperidine-1 -carboxylate (400 mg, 846 pmol, 91 % yield) as a yellow solid.

¹ H NMR (400 MHz, CDCb) 5 [ppm] = 8.49 (d, J = 8.4 Hz, 1 H), 7.82 (s, 1 H), 7.61 (d, J = 8.4 Hz, 1 H), 6.76 (s, 1 H), 6.66 (s, 1 H), 4.40-4.33 (m, 1 H), 4.22-4.16 (m, 1 H), 3.71 (s, 3H), 3.34-3.24 (m, 1 H), 3.17- 3.10 (m, 1 H), 2.89-2.79 (m, 1 H), 2.39 (s, 3H), 2.17 (s, 3H), 2.16-2.13 (m, 1 H), 1 .83-1.79 (m, 1 H), 1.68- 1.62 (m, 2H), 1.48 (s, 9H).

LC-MS (Method C): Rt = 0.953 min; MS (ESIpos): m/z = 473.2 [M+H]*.

Intermediate 81

2-(2-methoxy-4,6-dimethyl-phenyl)-7-(3-piperldyl)-1,8-nap hthyridine-4-carbonitrile (racemate)

A solution of tert-butyl 3-[5-cyano-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]piperidine-

1-carboxylate (380 mg, 804 pmol, 1 eq) in hydrogen chloride solution (4.00 M in 1 ,4-dioxane, 10.0 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuum to give 2-(2-methoxy- 4,6-dimethyl-phenyl)-7-(3-piperidyl)-1 ,8-naphthyridine-4-carbonitrile (329 mg, 804 pmol, HCI salt) as a yellow solid.

LC-MS (Method C): Rt = 0.465 min; MS (ESIpos): m/z = 373.2 [M+H]*.

Intermediate 82

2-(2-methoxy-4,6-dimethyl-phenyl)-7-(1-methyl-3-piperidyl )-1,8-naphthyridine-4-carbonitrile (racemate)

To a solution of 2-(2-methoxy-4,6-dimethyl-phenyl)-7-(3-piperidyl)-1 ,8-naphthyridine-4-carbonitrile (329 mg, 804 pmol, 1 eq, HCI salt) in methanol (3 mL) were added potassium acetate (118 mg, 1.21 mmol, 1.5 eq), formaldehyde (1.61 mmol, 120 pL, 37% purity in water, 2 eq) and sodium cyanoborohydride (101 mg, 1.61 mmol, 2 eq) at 0 °C. After stirring at 25 °C for 1 h, the mixture was diluted with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water (FA) - MeCN]; B%: 30% - 70%, 10 min) to give 2-(2-methoxy-4,6-dimethyl-phenyl)-7-(1-methyl-3-piperidyl)-1 ,8-naphthyridine-4- carbonitrile (220 mg, 569 pmoi, 71 % yield) as a brawn solid.

¹ H NMR (400 MHz, CDCh) 6 [ppm] = 8.48 (d, J = 8.40 Hz, 1 H), 7.81 (s, 1 H), 7.63 (d, J = 8.40 Hz, 1 H), 6.76 (s, 1 H), 6.66 (s, 1 H), 3.71 (s, 3H), 3.36-3.29 (m, 1 H), 3.23-3.20 (m, 1 H), 2.96-2.93 (m, 1 H), 2.53 (t, J = 10.4 Hz, 1 H), 2.39 (s , 3H), 2.38 (s , 3H), 2.17 (s, 3H), 2.13-2.09 (m, 2H), 1 .86-1 .77 (m, 3H). LC-MS (Method C): Rt = 0.466 min; MS (ESIpos): m/z = 387.2 [M+H] ⁺ .

Compound 41

2-(2-hydroxy-4, 6-dimethyl-phenyl)-7-[ 1-methyl-3-piperidyi]-1, 8-naphthyridine-4-carbonitrile (racemate) To a solution of 2-(2-methoxy-4,6-dimethyl-phenyl)-7-(1-methyl-3-piperidyl)-1 ,8-naphthyridine-4- carbonitrile (210 mg, 543 pmol, 1 eq) in dichloromethane (5.00 mL) was added boron tribromide (272 mg, 1 .09 mmol, 105 pL, 2 eq) at -70 °C. After stirring at 0 °C for 1 h, the mixture was added dropwise into water (15 mL) at 0 °C. The mixture was stirred at 0 °C for 10 min, then and the pH was adjusted to 6 - 7 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water (FA) - MeCN]; B%: 30% - 60%, 14 min) to give Compound 41 (180 mg, 483 pmol, 89% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 9.60 (br. S, 1 H), 8.49 (d, J = 8.4 Hz, 1 H), 8.16 (s, 1 H), 7.85 (d, J = 8.8 Hz, 1 H), 6.66 (s, 1 H), 6.65 (s, 1 H), 3.27-3.20 (m, 1 H), 3.09-3.06 (m, 1 H), 2.85-2.81 (m, 1 H), 2.32-2.31 (m,1 H), 2.27 (s, 6H), 2.08 (s, 3H), 2.03-1.98 (m, 2H), 1.80-1.57 (m, 3H).

LC-MS (Method C): Rt = 0.687 min; MS (ESI) m/z = 373.1 [M+H] ⁺ .

Compounds 42 and 43

2-(2-hydroxy-4, 6-dimethyi-phenyi)-7-[ 1-methyl-3-piperidyl]-1, 8-naphthyridine-4-carbonitrile (single enantiomers)

2-(2-Hydroxy-4,6-dimethyl-phenyl)-7-(1-methyl-3-piperidyl )-1 ,8-naphthyridine-4-carbonitrile (150 mg, 403 pmol, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK IC(250mm x 30mm, 10 pm); mobile phase: [0.1 % ammonium hydroxide in ethanol]; B%: 55%-55%,4.5 min) to give Compound 42 (50.8 mg, 136 pmol, 68% yield) as a yellow solid and Compound 43 (53.7 mg, 144 pmol, 72% yield) as a yellow solid.

Compound 42

^! H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 9.61 (br. S, 1 H), 8.49 (d, J = 8.4 Hz, 1 H), 8.16 (s, 1 H), 7.85 (d, J = 8.4 Hz, 1 H), 6.66 (s, 1 H), 6.64 (s, 1 H), 3.25-3.19 (m, 1 H), 3.04 (d, J = 11 .2 Hz, 1 H), 2.80 (d, J = 10.8 Hz, 1 H), 2.27 (s, 3H), 2.25-2.19 (m, 4H), 2.08 (s, 3H), 2.02-1.90 (m, 2H), 1.78-1.75 (m, 1 H), 1.72- 1.56 (m, 2H).

LC-MS (Method C): Rt = 0.440 min; MS (ESI) m/z = 373.3 [M+HJ*.

SFC (Rt = 1 .479 min, ee% = 97%)

Compound 43 ¹ H NMR (400 MHz, DMSO-d ₅ ) 6 [ppm] = 9.68 (br. S, 1 H), 8.48 (d, J = 8.8 Hz, 1 H), 8.16 (s, 1 H), 7.85 (d, J = 8.8 Hz, 1 H), 6.66 (s, 1 H), 6.65 (s, 1 H), 3.25-3.20 (m, 1 H), 3.05-3.02 (m, 1 H), 2.80 (d, J = 10.8 Hz, 1 H), 2.27 (s, 3H), 2.23-2.19 (m, 4H), 2.08 (s, 3H), 2.02-1.90 (m, 2H), 1.78-1.74 (m, 1 H), 1.71-1.56 (m, 2H).

LC-MS (Method C): Rt = 0.439 min; MS (ESI) m/z = 373.1 [M+H] ⁺ . SFC (Rt = 2.079 min, ee% = 95%)

Intermediate §3

3,3,3-trifluoropropyl trifluoromethanesuifonate

To a solution of 3,3,3-trifluoropropan-1-ol (1 .00 g, 8.77 mmol, 1 eq) in dichloromethane (20 mL) was added TfzO (3.71 g, 13.1 mmol, 2.17 mL, 1 .5 eq) and DIPEA (3.40 g, 26.30mmol, 4.58 mL, 3 eq) at 0 °C in portions. After stirring at 0 °C for 3 h, the mixture was quenched by saturated aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give 3,3,3-trifluoropropyl triftuoromethanesulfonate (2.00 g, 8.13 mmol, 92% yield) as a brown solid.

¹ H NMR (400 MHz, CDCb) 6 [ppm] = 3.71-3.61 (m, 2H), 3.17-3.08 (m, 2H).

Intermediate 84 2-{2-methaxy-4,6-dimethyl~phei'iy!)~7-[1~(3,3 _! 3~t!'ifluoroprGpyl)-3~pipe!'idyi]--1.8--naphtliyndine To a solution of 2-(2-methoxy-4,6-dimethyl-phenyl)-7-(3-piperidyl)-1 ,8-naphthyridine (400 mg, 1.15 mmol, 1 eq) and CS2CO3 (1 .13 g, 3.45 mmol, 3 eq) in MeCN (10 mL) was added 3,3,3-trifluoropropyl trifluoromethanesulfonate (566 mg, 2.30 mmol, 2 eq) at 20 °C in one portion. After stirring at 20 °C for 16 h, the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (15 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiOz, petroleum ether/ethyl acetate = 5/1 to 1/1) to give compound 2-(2-methoxy- 4, 6-dimethyl-phenyl)-7-[1-(3, 3, 3-trifluoropropyl)-3-piperidyl]-1 ,8-naphthyridine (320 mg, 721 umol, 62% yield) as yellow oil.

^! H NMR (400 MHz, CDCb) 5 [ppm] = 8.17 (d, J = 2.4 Hz, 1 H), 8.15 (d, J = 2.8 Hz, 1 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.44 (d, J = 8.4 Hz, 1 H), 6.74 (s, 1 H), 6.65 (s, 1 H), 3.69 (s, 3H), 3.41 -3.16 (m, 2H), 3.08- 2.93 (m, 1 H), 2.82-2.69 (m, 2H), 2.58-2.40 (m, 2H), 2.39 (s, 3H), 2.12 (s, 3H), 1.94-1.79 (m, 3H), 1.69- 1.58 (m, 3H).

Compound 44 3 _; 5-<f/mef/?y/-2-f7-£f-f3,3,3-tr/f/uoropropy/J-3-p/p er/dy/J-f,3-nap/?f/iyri(f/n-2-y//p/ieno/ To a solution of 2-(2-methoxy-4,6-dimethyl-phenyl)-7-[1-(3,3,3-trifluoropropy l)-3-piperidyl]-1 ,8- naphthyridine (300 mg, 676 pmol, 1 eq) in dichloromethane (3 mL) was added BBra (847 mg, 3.38 mmol, 325 pL, 5 eq) at -70 °C in one portion. The mixture was stirred at 20 °C for 3 h. The mixture was quenched by methanol (5 mL) and concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18, 80 g, mobile phase: [water(FA) - MeCN];B%: 20% - 65%, 10 min) to give 3,5-dimethyl-2-[7-[1-(3,3,3-trifluoropropyl)-3-piperidyl]-1 ,8-naphthyridin-2- yljphenol (120 mg, 276 pmol, 41 % yield, 99% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-cfe) S [ppm] = 9.78-9.75 (m, 1 H), 8.39 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 8.4 Hz, 1 H), 6.63 (s, 1 H), 6.62 (s, 1 H), 3.16-3.08 (m, 2H), 2.96-2.88 (m, 1 H), 2.63-2.55 (m, 3H), 2.42-2.28 (m, 2H), 2.26 (s, 3H), 2.08 (s, 3H), 2.06-1.97 (m, 2H), 1.80-1.74 (m, 1 H), 1.70-1.61 (m, 2H).

LC-MS (Method C): Rt - 0.451 min; MS (ESIpos): m/z = 430.3 [M+H] ⁺ .

Compound 45 (single enantiomer)

3.5-dimethyl~2~[7~[ 1-(3, 3, 3-tnfluoi-opi'opyl)-3-pipendylJ- 1, §-naphthyndin-2-yl]phenol

The reaction was set up for SFC separation. The residue was purified by SFC: (column: DAICEL CHIRALCEL OJ (250mm*30mm,10pm);mobile phase: [0.1 % NH ₃ «H ₂ O«MeOH];B%:10%, isocratic elution mode) to give 3,5-dimethyl-2-[7-[rel-(3S)-1-(3,3,3-trifluoropropyl)-3-pipe ridyl]-1 ,8-naphthyridin- 2-yl]phenol (15.4 mg, 33.2 pmol, 14% yield, 93% purity) as a yellow solid and 3,5-dimethyl-2-[7-[rel- (3S)-1-(3,3,3-trifluoropropyl)-3-piperidyl]-1 ,8-naphthyridin-2-yl]phenol (34.1 mg, 77.1 pmol, 33% yield, 97% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d6) 5 = 9.81-9.74 (m, 1 H), 8.40 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1 H), 7.55 (d, J = 8.3 Hz, 1 H), 6.64 (s, 1 H), 6.63 (s, 1 H), 3.17-3.11 (m, 2H), 2.97-2.89 (m, 1 H), 2.64- 2.57 (m, 3H), 2.39-2.30 (m, 2H), 2.27 (s, 3H), 2.09 (s, 3H), 2.06-1.95 (m, 2H), 1.81-1.76 (m, 1 H), 1.70- 1.63 (m, 2H)

LC-MS (Method C): Rt = 0.454 min; MS (ESIpos): m/z = 430.3 [M+1 ] ⁺ .

SFC (Rt = 1 .076 min, ee% = 98%).

Compounds 52 and 53

S^-dimethyl-Z-lT-ll-methyl-S-pipendylJimidazoll^-aJpyrimi dm-Z-ylJphenol

3.5-Dimethyl-2-[7-(1-methyl-3-piperidyl)imidazo[1 ,2-a]pyrimidin-2-yl]phenol (30 mg, 89.2 pmol, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm* 30 mm, 10 pm); mobile phase: [COz-MeCN/MeOH (0.1 % NH ₃ «H ₂ O)]; B%: 60%-60%, 2 min) to give 3,5-dimethyl-2-[7-[rel-(3S)-1- methyl-3-piperidyl]imidazo[1 ,2-a]pyrimidin-2-yl]phenol (15.6 mg, 45.8 pmol, 51 % yield, 99% purity) as a white solid (peak 1) and 3,5-dimethyl-2-[7-[1-methyl-3-piperidyl]imidazo[1 ,2-a]pyrimidin-2-yl]phenol (14.6 mg, 40.4 pmol, 45 % yield, 93% purity) as a yellow solid.

Compound 52

¹ H NMR (400 MHz, DMSO-ds) 6 [ppm] = 13.0 (s, 1 H), 8.93 (d, J = 6.8 Hz, 1 H), 8.15 (s, 1 H), 7.20 (d, J = 7.2 Hz, 1 H), 6.61 (s, 2H), 3.06-2.93 (m, 2H), 2.84-2.74 (m, 1 H), 2.48 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 2.19-2.1 1 (m, 1 H), 2.02-1 .87 (m, 2H), 1 .78-1 .69 (m, 1 H), 1 .66-1 .42 (m, 2H).

LC-MS (Method C): Rt = 0.365 min; MS (ESIpos): m/z = 337.1 [M+H]*.

SFC (Rt = 1 .774 min, ee% = 100%). Compound 53

¹ H NMR (400 MHz, DMSO-cfe) 6 [ppm] = 13.0-12.9 (m, 1 H), 8.93 (d, J = 7.2 Hz, 1 H), 8.15 (s, 1 H), 7.24-7.18 (m, 1 H), 6.61 (s, 2H), 3.08-2.97 (m, 2H), 2.79-2.77 (m, 1 H), 2.48 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 2.21-2.12 (m, 1 H), 2.00-1.90 (m, 2H), 1.80-1.70 (m, 1 H), 1.68-1.50 (m, 2H).

LC-MS (Method C): Rt = 0.372 min; MS (ESIpos): m/z = 337.1 [M+H] ⁺ .

SFC (Rt = 1.185 min, ee% = 100%).

Compounds 54 and

3.5-dim&thyl~2-[2~[1-

3.5-Dimethyl-2-[2-(1-methyl-3-piperidyl)imidazo[1 ,2-a]pyrimidin-7-yl]phenol (20 mg, 59.5 pmol, 1 eq, from ODDI ) was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm* 30 mm, 10 pm); mobile phase: [CO ₂ -MeCN/i-PrOH (0.1 % NH ₃ *H ₂ O)]; B%: 55%-55%,2.6 min) to give 3,5-dimethyl-2- [2-[rel-(3S)-1-methyl-3-piperidyl]imidazo[1 ,2-a]pyrimidin-7-yl]phenol (1.54 mg, 4.49 pmol, 8% yield, 98% purity) as a white solid and 3,5-dimethyl-2-[2-[1-methyl-3-piperidyl]imidazo[1 ,2-a]pyrimidin-7- yljphenol (3.45 mg, 10.2 pmol, 17% yield, 99% purity) as a yellow solid.

Compound 54

NMR (400 MHz, DMSO-cfe) 5 [ppm] = 9.55-9.37 (m, 1 H), 8.83 (d, J = 6.8 Hz, 1 H), 8.16 (s, 1 H), 7.72-7.67 (m, 1 H), 6.95 (d, J = 6.8 Hz, 1 H), 6.60 (d, J = 5.8 Hz, 2H), 3.19-3.10 (m, 2H), 3.03-2.96 (m, 1 H), 2.89-2.81 (m, 1 H), 2.33-2.30 (m, 3H), 2.24 (s, 3H), 2.09 (s, 3H), 2.05-1.99 (m, 1 H), 1.81-1.54 (m, 3H), 1.53-1.42 (m, 1 H).

LC-MS (Method C): Rt = 0.371 min; MS (ESIpos): m/z = 337.1 [M+H] ⁺ .

Compound 55

¹ H NMR (400 MHz, DMSO-cfe) 5 [ppm] = 9.49-9.41 (m, 1 H), 8.85-8.78 (m, 1 H), 7.71-7.64 (m, 1 H), 6.97-6.88 (m, 1 H), 6.64-6.55 (m, 2H), 3.07-2.98 (m, 1 H), 2.97-2.89 (m, 1 H), 2.79-2.69 (m, 2H), 2.23 (s, 3H), 2.21 (s, 3H), 2.09 (s, 3H), 2.05-1 .97 (m, 2H), 1 .74-1 .67 (m, 1 H) , 1 .53-1 .36 (m, 2H).

LC-MS (Method C): Rt = 0.377 min; MS (ESIpos): m/z = 337.2 [M+H] ⁺ .

SFC (Rt = 0.756 min, ee% = 99%)

Intermediate 88

2-(2-methoxy-4 _! 6<fimethyl-pheny!}-7-methyl-1.§-naphthyridine

To a solution of 2-bromo-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (1.00 g, 2.91 mmol, 1 eq), methyiboronic acid (1.74 g, 29.1 mmol, 10 eq) and CS2CO3 (1.90 g, 5.83 mmol, 2 eq) in dioxane (10 mL) and H ₂ O (2 mL) was added Pd(dppf)CI ₂ (213 mg, 291 pmol, 0.1 eq) at 20 °C in one portion under nitrogen atmosphere. After stirring at 80 °C for 3 h, the mixture was poured into ice-water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 5/1 to 1/1) to give 2-(2-methoxy-4,6-dimethyl-phenyl)-7-methyl-1 ,8-naphthyridine (300 mg, 808 pmol, 27% yield, 75% purity) as a yellow solid.

¹ H NMR (400 MHz, CDCI ₃ ) 6 [ppm] = 8.36 (t, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 1 H), 7.44 (d, J = 8.0 Hz, 1 H), 6.82 (s, 1 H), 6.76 (s, 1 H), 3.65 (s, 3H), 2.70 (s, 3H), 2.35 (s, 3H), 2.00 (s, 3H).

Intermediate 89

4-[[7-(2-methoxy-4,6-dimethyl-phenyl)-1,8-naphthyridin-2- yl]methyl]tetrahydropyran-4-ol

To a solution of 2-(2-methoxy-4,6-dimethyl-phenyl)-7-methyl-1 ,8-naphthyridine (300 mg, 1.08 mmol, 1 eq) in THF (3 ml_) was added LDA (2 M in THF, 1 .08 mL, 2 eq) at 0 °C dropwise. The mixture was stirred at 0 °C for 0.5 h. Tetrahydropyran-4-one (215 mg, 2.16 mmol, 197 pL, 2 eq) in THF (2 mL) was added to the mixture. After stirring at 20 °C for 2 h, the mixture was poured into ice-water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by prep-TLC (Petroleum ether/Ethyl acetate = 0/1) to give 4-[[7-(2- methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]methyl]tetrahydropyran-4-ol (170 mg, 417.74 pmol, 38% yield, 93% purity) as a yellow solid

LC-MS (Method C): Rt = 0.438 min; MS (ESIpos): m/z = 379.3 [M+H] ⁺ .

Compound 62 4-[[7-(2-hydroxy-4,6-dimethyl-phenyl)-1,8-naphthyridin-2-yl] methylJtetrahydropyran-4-ol

To a solution of 4-[[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]methyl]tetrahydropyran-4- ol (140 mg, 369 pmol, 1 eq) in dichloromethane (3 mL) was added BBrs (926 mg, 3.70 mmol, 356 pL, 10 eq) at 20 °C in one portion. After stirring at 0 °C for 2 h, the mixture was quenched by methanol (3 mL) and concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18, 80 g, mobile phase: [water(FA) - MeCN];B%: 25% - 75%, 8 min) to give 4-[[7- (2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]methyl]tetrahydropyran-4-ol (31 .0 mg, 81 .6 pmol, 22% yield, 96% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d6) 6 [ppm] = 9.89-984 (m, 1 H), 8.40 (d , J = 8.4 Hz, 1 H), 8.37 (d, J = 8.0 Hz, 1 H), 7.60 (d, J = 8.4 Hz, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 6.64 (s, 1 H), 6.62 (s, 1 H), 5.00 (s, 1 H), 3.64-3.57 (m, 4H), 3.12 (s, 2H), 2.26 (s, 3H), 2.10 (s, 3H), 1.70-1.62 (m, 2H), 1.45-1.39 (m, 2H). LC-MS (Method C): Rt = 0.399 min; MS (ESIpos): m/z = 365.1 [M+H] ⁺ .

Intermediate 90

To a solution of 2-bromo-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (1.00 g, 2.91 mmol, 1 eq) and TMEDA (677 mg, 5.83 mmol, 879 pL, 2 eq) in THF (10 mL) was added n-BuLi (2.5 M in n- hexane, 2.33 mL, 2 eq) at -70 °C dropwise under nitrogen atmosphere. After stirring at -70 °C for 2 h, tert-butyl 3-oxopiperidine-1 -carboxylate (1.16 g, 5.83 mmol, 2 eq) in THF (5 mL) was added the reaction mixture. After stirring at 20 °C for 16 h, the mixture was poured into ice-water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine (40 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate = 5/1 to 1/1) to give tert-butyl 3-hydroxy-3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yi]piperidine-1 -carboxylate (250 mg, 539.30 pmol, 18.51% yield) as a yellow solid.

LC-MS (Method C): Rt = 0.520 min; MS (ESIpos): m/z = 464.3 [M+1] ⁺ .

Intermediate 91

3-[7-(2-methoxy-4,6-dimethyi-phenyl)-1 _! 3-naphthyndm-2-yl]pipendin-3-ol

To a solution of tert-butyl 3-hydroxy-3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]piperidine-1 -carboxylate (250 mg, 539.30 pmol, 1 eq) in dichloromethane (3 mL) was added TFA (614 mg, 5.39 mmol, 400 pL, 10 eq) at 20 °C in one portion. After stirring at 20 °C for 1 h, the mixture was concentrated in vacuum to give 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]piperidin-3-ol (190 mg, 522 pmol, 96% yield) as yellow oil.

Intermediate 92

3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1,8-naphthyndin-2-yl ]-1-methyl-pipendm-3-ol

To a solution of 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]piperidin-3-ol (190 mg, 522 pmol, 1 eq), paraformaldehyde (156 mg, 5.23 mmol, 10 eq) and KOAc (153 mg, 1.57 mmol, 3 eq) in methanol (3 mL) was added NaBHsCN (98.55 mg, 1 .57 mmol, 3 eq) at 20 °C in one portion. After stirring at 20 °C for 16 h, the mixture was poured into ice-water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(FA) - MeCN];B%: 20% - 75%, 10 min) to give 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]- 1 -methyl-piperidin-3-ol (130 mg, 340 pmol, 65% yield, 99% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.548 min; MS (ESIpos): m/z = 378.2 [M+1 ] ⁺ .

Intermediate @3

3-[7-(2-hydroxy-4,8-dimethyl-phenyl)-1.8-naphthynd!n-2-y! ]-1-methyl-pipendin-3-ol

To a solution of 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1 -methyl-piperidin-3-ol (130 mg, 344 pmol, 1 eq) in dichloromethane (3 mL) was added BBrs (431 mg, 1.72 mmol, 165 pL, 5 eq) at -70 °C dropwise. After stirring at 20 °C for 3 h, the mixture was quenched by methanol (2 mL) and concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(FA) - MeCN];B%: 25% - 60%, 12 min) to give 3-[7-(2- hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-methyl-piperidin-3-ol (100 mg, 270 pmol, 78% yield, 98% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.395 min; MS (ESIpos): m/z = 364.2 [M+1 ] ⁺ .

Compound 69 3-(7-(2-hydroxy-4,6-dimethyl-phenyl)-1,8-naphthyndin-2-yl]-1 -methyl-piperidin-3-ol

The reaction was set up for SFC separation. The residue was purified by SFC: (column: DAICEL CHIRALCEL OD (250mm x 50mm, 10 urn); mobile phase: [CO ₂ -i-PrOH (0.1 % NHs’FW)]; B%: 35%, isocratic elution mode) to give 3-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-methyl- piperidin-3-ol (15.0 mg, 40.8 pmol, 14% yield, 99% purity) as a white solid and 3-[7-(2-hydroxy-4,6- dimethyl-phenyl)-1 ,8-naphthyridin~2-yi]-1 -methyl-piperidin-3-oi (15.0 mg, 40.4 pmol, 14% yield, 98% purity) as a white solid.

¹ H NMR (400 MHz, DMSO-cfe) 6 = 8.47 (d, J = 8.4 Hz, 1 H), 8.42 (d, J = 8.0 Hz, 1 H), 8.29 (s, 1 H), 7.98 (d, J = 8.4 Hz, 1 H), 7.57 (d, J = 8.0 Hz, 1 H), 6.64 (s, 1 H), 6.63 (s, 1 H), 2.73-2.67 (m, 2H), 2.27 (s, 3H), 2.25 (s, 3H), 2.17-2.10 (m, 2H), 2.08 (s, 3H), 2.03-1.89 (m, 2H), 1.68-1.62 (m, 2H) LC-MS (Method C): Rt = 0.397 min; MS (ESIpos): m/z = 364.2 [M+1 ] ⁺ .

SFC (Rt =2.131 min, ee% = 91 %).

Intermediate 70

2-(2-methoxy-4, 8-dlmethyl-phenyl)-1 ,8- naphthyridine

To a solution 2-chloro-1 ,8-naphthyridine (10.0 g, 60.8 mmol, 1 eq) and (2-methoxy-4,6-dimethyl- phenyl) boronic acid (16.4 g, 91 .1 mmol, 1 .5 eq) in dioxane (100 mL) and water (25 mL) were added Pd(dppf)Ch (4.45 g, 6.08 mmol, 0.1 eq) and CS2CO3 (39.6 g, 122 mmol, 2 eq) at 20 °C. After stirring at 80 °C for 16 h, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3), The aqueous phase was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOz, petroleum ether/ethyl acetate = 2/1) to give 2- (2-methoxy-4,6-dimethyl-phenyl)-1 ,8- naphthyridine (14.0 g, 47.7 mmol, 78% yield, 90% purity) as a light yellow solid.

LC-MS (Method C): Rt = 0.438 min; MS (ESIpos): m/z = 265.2 [M+H] ⁺ .

Intermediate 71

(tert-butyl 4-sulfamoylpiperidine-1 -carboxylate

A mixture of 2-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (2.00 g, 7.57 mmol, 1 eq), 3- oxocyclobutanecarboxylic acid (2.59 g, 22.7 mmol, 3 eq), bis[3,5-difluoro-2-[5-(trifluoromethyl)-2- pyridyl] phe ny I] irid iu m(1 +);4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine;hexafluor ophosphate (84.9 mg, 75.7 pmol, 0.01 eq) and ammonia;sulfooxy hydrogen sulfate (6.91 g, 30.3 mmol, 6.58 mL, 4 eq) in DMSO (3 mL) was degassed and purged with Oxygen, and then the mixture was stirred at 25 °C for 16 h irradiated with a 455nm blue LED. The reaction mixture was quenched by saturated sodium bicarbonate aqueous solution (50 mL) at 0 °C, and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18, 120 g, mobile phase: [water (FA) - MeCN]; B%: 20% - 80%, 15 min) to give 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]cyclobutanone (80.0 mg, 241 pmol, 4% yield) as a brown solid.

LC-MS (Method C): Rt = 0.469 min; MS (ESIpos): m/z = 333.3 [M+H] ⁺ Intermediate 72

3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 _s 8-naphthyridin-2-yl]-1 -methyl-cyclobutanol

A mixture of 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]cyclobutanone (80 mg, 241 pmol, 1 eq) in THF (2 mL) was added MeMgBr (3 M in THF, 241 pL, 3 eq) at 0 °C under N2 atmosphere. After stirring at 0 °C for 1 h, the reaction mixture was quenched by saturated sodiumbicarbonate aqueous solution (20 mL) at 0 °C, and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water (FA) - MeCN]; B%: 30% - 75%, 10 min) to give 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-

1-methyl-cyclobutanol (40.0 mg, 115 pmol, 48% yield) was obtained as a brown solid.

LC-MS (Method C): Rt = 0.448 min; MS (ESIpos): m/z = 349.2 [M+H] ⁺

Compound 76

2-[7-(3-hydroxy-3-methyl-cyclobuty0-1 _! 8-naphthyndin-2-yl]-3.5- dimethyi-pbenol

To a solution of 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-methyl-cyclobutanol (40.0 mg, 115 pmol, 1 eq) in DCM (3 mL) was added BBrs (144 mg, 574 pmol, 55.3 pL, 5 eq) at -70 °C. After stirring at 20 °C for 1 h, the reaction was quenched by ammonia (3 mL, 7.0 M in methanol), and the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(FA) - MeCN]; B%: 35% - 75%, 10 min) to give 2-[7-(3-hydroxy-3-methyl-cyclobutyl)-1 ,8-naphthyridin-2-yl]-3,5- dimethylphenol (10.0 mg, 29.3 pmol, 26% yield, 98% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-ds) 6 [ppm] = 9.90-9.78 (m, 1 H), 8.44-8.29 (m, 2H), 7.62 - 7.45 (m, 2H), 6.64 (d, J = 5.6 Hz, 2H), 5.12 (s, 0.7H), 4.98 (s, 0.3H), 3.94-3.85 (m, 0.3H), 3.44-3.36 (m, 0.7H), 2.46- 2.38 (m, 4H), 2.27 (s, 3H), 2.16 (s, 3H), 1.40 (s, 2H), 1 .25 (s, 1 H).

LC-MS (Method C): Rt = 0.419 min; MS (ESIpos): m/z = 335.3 [M+H] ⁺

Intermediate @4

4-bromo-2-methoxy-6-methyl-phenol

To a solution of 2-methoxy-6-methyl-phenol (40.0 g, 290 mmol, 1 eq) in acetic acid (200mL) was added NBS (51 .5 g, 290 mmol, 1 eq).The mixture was stirred at 25 °C for 16 h. After stirring at 25 °C for 16 h, the reaction mixture was quenched by addition water 2000mL at 25 °C, and then extracted with dichloromethane (600mL x 3). The combined organic layers were washed with water (1000 mL) and saturated sodium bicarbonate solution (1000 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOz, petroleum ether/ethyl acetate = 10/1) to give 4-bromo-2-methoxy-6-methyl- phenol (58.9 g, 163 mmol, 56% yield, 60% purity) as brown oil.

¹ H NMR (400 MHz, CD ₃ OD) 5 [ppm] = 6.85 (d, J = 2.0 Hz, 1 H), 6.81 (d, J = 1 .6 Hz, 1 H), 3.80 (s, 3H), 2.15 (s, 3H). Intermediate 95

4-hydroxy-3-methoxy-5-methyl-benzonltrile

To a solution of 4-bromo-2-methoxy-6-methyl-phenol (10.0 g, 46.1 mmol, 1 eq) in dioxane (150 mL) were added potassium acetate (13.6 g, 138 mmol, 3eq), tBuXPhos-Pd-G3 (1.83 g, 2.30 mmol, 0.05 eq) and tetrapotassium;hexacyanoiron(4-);trihydrate (19.5 g, 46.1 mmol, 1 eq) in Water (20 mL).The mixture was stirred at 100 °C for 1 h. After stirring at 100 °C for 1 h, the mixture was concentrated to give a crude. The residue was purified by column chromatography (SiOz, Petroleum ether/Ethyl acetate = 1/0 to 20/1) to give 4-hydroxy-3-methoxy-5-methyl-benzonitrile (3.13 g, 19.2 mmol, 21 % yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 9.70 (s, 1 H), 7.25 (d, J = 2.0 Hz, 1 H), 7.20 (d, J = 1 .2 Hz, 1 H), 3.83 (s, 3H), 2.13 (s, 3H).

Intermediate 96

(4-cyano-2-methoxy-6miethy!-phenyl) trifluoromethanesulfonate

To a solution of 4-hydroxy-3-methoxy-5-methyl-benzonitrile (3.13 g, 19.2 mmol, 1 eq) in dichloromethane (30 mL) were added DIPEA (4.96 g, 38.4 mmol, 6.68 mL, 2eq) and TfzO (8.12 g, 28.8 mmol, 4.75mL, 1 ,5eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. After stirring at 25 °C for 0.5 h, the mixture was concentrated to give a crude. The residue was purified by column chromatography (SiOz, petroleum ether/ethyl acetate=1/0 to 20/1) to give (4-cyano-2-methoxy-6- methyl-phenyl) trifluoromethanesulfonate (3.86 g, 13.1 mmol, 68% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO-cfe) 6 [ppm] = 7.72 (d, J = 1 .6 Hz, 1 H), 7.55 (d, J = 1 .2 Hz, 1 H), 3.93 (s, 3H), 2.33 (s, 3H).

Intermediate @7

3-n?et/?oxy-5-mef/?y/-4-f4 _; 4 _; 5 _J 5-fetram@t/?y/-7 _; 3 _; 2-d/oxaboro/an-2-y/Jdenzon/fr//e

To a solution of (4-cyano-2-methoxy-6-methyl-phenyl) trifluoromethanesulfonate (3.86 g, 13.1 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (6.64 g, 26.2 mmol, 2 eq) in dioxane (60 mL) were added Pd(dppf)Cl2 (957 mg, 1 .31 mmol, 0.1 eq) and potassium acetate (3.85 g, 39.2 mmol, 3 eq). The mixture was stirred at 100 °C for 2 h under Nz. After stirring at 100 °C for 2 h under Nz, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiOz, petroleum ether/ethyl acetate = 1/0 to 30/1) to give 3- methoxy-5-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (3.50 g, 12.8 mmol, 98% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 7.95-7.90 (m, 1 H), 7.39-7.32 (m, 1 H), 3.75 (s, 3H), 2.27 (s, 3H), 1.30 (s, 12H).

Intermediate 98 benzyl 3-[7-(4-cyano-2-methoxy-@-inethyl-phenyl)-1,8-naphthyridln-2 -yl]piperidine-1- carboxylate To a solution of 3-methoxy-5-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (3.00 g, 11.0 mmol, 1.2eq) and benzyl 3-(7-chloro-1 ,8-naphthyridin-2-yl)piperidine-1 -carboxylate (3.50 g, 9.15 mmol, 1eq) in dioxane (30 ml_) were added Pd(dppf)Cl2 (670 mg, 915 pmol, 0.1eq) and potassium carbonate (2.53 g, 18.3 mmol, 2eq) in Water (5 mL) .The mixture was stirred at 90 °C for 16 h under N2. After stirring at 90 °C for 16 h under N2, the mixture was concentrated to give a crude. The residue was purified by reversed-phase column (column: C18, 120 g, mobile phase: [water(FA) - MeCN];B%: 20% - 60%, 10 min) to give benzyl 3-[7-(4-cyano-2-methoxy-6-methyl-phenyl)-1 ,8- naphthyridin-2-yl]piperidine-1-carboxylate (200 mg, 325 pmol, 4% yield, 80% purity) as a yellow solid. LC-MS (Method C): R _t = 0.583 min; MS (ESIpos): m/z = 493.3 [M+H] ⁺ .

Intermediate 99

3-methoxy-5-methyb4-[7-(3-pipendyl)-1,8-naphthyndin-2-yl] benzonitnle

To a solution of benzyl 3-[7-(4-cyano-2-methoxy-6-methyl-phenyl)-1 ,8-naphthyridin-2-yl]piperidine-1- carboxylate (180 mg, 365 pmol, 1eq) in hydrobromic acid (10 mL). The mixture was stirred at 80 °C for 1 h. After stirring at 80 °C for 1 h, the mixture was concentrated to give a residue. The residue was purified by reversed-phase column (column: C18, 80 g, mobile phase: [water(FA) - MeCN];B%: 15% - 60%, 10 min)to give 3-methoxy-5-methyl-4-[7-(3-piperidyl)-1 ,8-naphthyridin-2-yl]benzonitrile (84.0 mg, 206 pmol, 56% yield, 88% purity) as yellow oil.

LC-MS (Method C): Rt = 0.415 min; MS (ESIpos): m/z = 359.2 [M+H] ⁺ .

Intermediate 100

3-snethoxy-5-methyl-4-[7-(1~methyl-3-pipeddyl)~1,8-napbth yndin-2-yl]benzonitnle

To a solution of 3-methoxy-5-methyl-4-[7-(3-piperidyl)-1 ,8-naphthyridin-2-yl]benzonitrile (64.0 mg, 179 pmol, leg) in methanol (4 mL) was added (HCHO)n (45.6 mg, 893 pmol, 5 eq), potassium acetate (52.6 mg, 536 pmol, 3eq) and NaBHsCN (56.1 mg, 893 pmol, 5eq). The mixture was stirred at 25 °C for 2h. After stirring at 25 °C for 2 h, the mixture was concentrated to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(FA) - MeCN];B%: 30% - 60%, 8 min) to give 3-methoxy-5-methyl-4-[7-(1-methyl-3-piperidyl)-1 ,8-naphthyridin-2-yl]benzonitrile (20.0 mg, 43.0 pmol, 24% yield, 80% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.424 min; MS (ESIpos): m/z = 373.4 [M+H] ⁺ .

Compound 77 3-hydroxy-5-methy!-4-[7-(1-methyl-3-pipendyl)-1,8-naphthyndm -2-yl]benzonitnle

To a solution of 3-methoxy-5-methyl-4-[7-(1-methyl-3-piperidyl)-1 ,8-naphthyridin-2-yl]benzonitrile (10.0 mg, 26.9 pmol, 1eq) in dichloromethane (2mL) was added BBrs (2 M, 40.3pL, 3eq). The mixture was stirred at -70 °C for 16 h. After stirring at -70 °C for 16 h, the reaction was quenched by addition of 5mL of methanol, and a clear yellow-brown solution was obtained. The pH of mixture was adjusted to 7 by ammonia (7.0 M in methanol). The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (NHiHCOQ-MeCN]; gradient: 22%-52% B over 9 min) to give 3-hydroxy-5-methyl-4-[7-(1-methyl-3-piperidyl)-1 ,8-naphthyridin-2-yl]benzonitrile (2.00 mg, 5.08 pmol, 19% yield, 91 % purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-cfe) 6 [ppm] = 10.65-9.95 (m, 1 H), 8.47 (d, J = 8.4 Hz, 1 H), 8.43 (d, J = 8.4 Hz, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.29 (s, 1 H), 7.17 (d, J = 0.8 Hz, 1 H), 3.25- 3.18 (m, 1 H), 3.18-3.13 (m, 1 H), 3.07-3.02 (m, 1 H), 2.85-2.80 (m, 1 H), 2.24 (s, 3H), 2.07 (s, 3H), 2.02- 1 .98 (m, 1 H), 1 .97-1 .94 (m, 1 H), 1 .75 (s, 1 H), 1 .69-1 .65 (m, 1 H), 1 .63-1 .58 (m, 1 H) LC-MS (Method C): R _t = 0.406 min; MS (ESIpos): m/z = 359.3 [M+H] ⁺ .

Intermediate 159

5-chloro-2-(2-methoxy-4,6-dlmethyl-phenyl)pyrlmldm-4-amln e

A mixture of 2,5-dichloropyrimidin-4-amine (10.0 g, 61.0 mmol, 1.00 eq), (2-methoxy-4,6-dimethyl- phenyl)boronic acid (11.0 g, 61.0 mmol, 1.00 eq), [1 ,1- bis(diphenyiphosphino)ferrocene]dichioropaiiadium(li) (2.23 g, 3.05 mmol, 0.05 eq), potassium phosphate (2.00 M, 100.00 mL, 3.28 eq) in dioxane (150 mL) was degassed and purged with nitrogen three times. After stirring at 80 °C for 16 h under nitrogen atmosphere, the mixture was poured into saturated ammonium chloride solution (500 mL), the aqueous phase was extracted with ethyl acetate (500 mL x 2). The combined organic phase was washed with brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate/Petroleum ether gradient @ 120 mL/min) to give 5-chloro-2-(2-methoxy-4,6-dimethyl- phenyl)pyrimidin-4-amine (11.0 g, 39.6 mmol, 65% yield, 95% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-cfe) 6 = 8.28 (s, 1 H), 7.52 - 7.04 (m, 2H), 6.69(s, 1 H), 6.64 (s, 1 H), 3.62 (s, 3H), 2.29 (s, 3H), 1.94 (s, 3H).

LC-MS (Method L): Rt = 0.405 min; MS (ESIpos): m/z = 264.3 [M+H] ⁺

Intermediate 160 tert-butyl (3R)-3-(lmidazole-1-carbonyl)plperldlne-1 -carboxylate

To a solution of (3R)-1-tert-butoxycarbonylpiperidine-3-carboxylic acid (30 g, 131 mmol, 1.00 eq) in tetrahydrofuran (300 mL) was added 1 ,1 ’-carbonyldiimidazole (21.2 g, 131 mmol, 1.00 eq) at 20 °C. After stirring at 20 °C for 16 h, the pH of mixture was adjusted to 9 by saturated sodium hydrogen carbonate solution (300 mL), the aqueous phase was extracted with ethyl acetate (500 mL x 3). The combined organic phase was washed with brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford tert-butyl (3R)-3-(imidazole-1-carbonyl)piperidine-1- carboxylate (28.0 g, 90.2 mmol, 69% yield, 90% purity) as a white solid.

¹ H NMR (400 MHz, DMSO-cfe) 6 = 8.49 (s, 1 H), 7.77-7.72 (m, 1 H), 7.10 (d, J = 0.8 Hz, 1 H), 3.97-3.81 (m, 1 H), 3.63-3.35 (m, 2H), 3.18-3.00 (m, 1 H), 2.59-2.53 (m, 1 H), 1.98-1.66 (m, 3H), 1 .56-1 .48 (m, 1 H), 1.40-1.28 (m, 9H)

Intermediate 161

To a solution of 5-chloro-2-(2-methoxy-4,6-dimethyl-phenyl)pyrimidin-4-amine (11.0 g, 41 .7 mmol, 1 .00 eq) in tetrahydrofuran (200 mL) was added sodium hydride (2.50 g, 62.6 mmol, 60.0% purity, 1.50 eq) at 0 °C, the mixture was stirred at 20 °C for 0.5 h under nitrogen, then tert-butyl (3R)-3-(imidazole-1- carbonyl)piperidine-1-carboxylate (17.5 g, 62.6 mmol, 1.50 eq, EW36693-230) was added at 0 °C, the mixture was stirred at 20 °C for 2 h. The mixture was poured into saturated ammonium chloride solution (200 mL), the aqueous phase was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (50.0 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 120 mL/min) to give tert-butyl (3R)-3-[[5-chloro-2-(2-methoxy-4,6-dimethyl-phenyl)pyrimidin -4- yl]carbamoyl]piperidine-1 -carboxylate (20.0 g, 33.9 mmol, 81 % yield, 81 % purity) as yellow oil.

LC-MS (Method O): Rt = 0.871 min; MS (ESIpos): m/z = 475.2 [M+H] ⁺

Intermediate 162

To a solution of tert-butyl (3R)-3-[[5-chloro-2-(2-methoxy-4,6-dimethyl-phenyl)pyrimidin -4- yl]carbamoyl]piperidine-1-carboxylate (20 g, 42.11 mmol, 1.00 eq) in tetrahydrofuran (250 mL) was added Lawesson's reagent (20.4 g, 50.5 mmol, 1 .20 eq). After stirring at 70 °C for 16 h, the mixture was concentrated under vacuum, The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate/Petroleum ether gradient @ 120 mL/min) to give tert-butyl (3R)-3-[[5-chioro-2-(2-methoxy-4,6-dimethyi-phenyi)pyrimidin -4- yl]carbamothioyl] piperidine-1 -carboxylate (12.0 g, 22.2 mmoi, 53% yield, 91 % purity) as yellow oil..

¹ H NMR (400 MHz, CDCb) 5 = 8.76 (s, 1 H), 6.71 (s, 1 H), 6.63 (s, 1 H), 4.10-3.99 (m, 2H), 3.71 (s, 3H), 3.31-3.18 (m, 1 H), 2.78-2.61 (m, 1 H), 2.38 (s, 3H), 2.35-2.28 (m, 1 H), 2.13 (s, 3H), 1.60-1.53 (m, 4H), 1.41 (s, 9H)

LC-MS (Method L): Rt = 0.664 min; MS (ESIpos): m/z = 491 .2 [M+H] ⁺ .

SFC (Rt = 1 .480 min, ee% = 100%)

Intermediate 163 tert-butyl 3-[5-(2-methoxy-4,6-dimethyl-phenyl)thiazolo[4,5-d]pyrlmldln -2-yl]plper!dine-1- carboxylate (racemate)

A mixture of tert-butyl (3R)-3-[[5-chloro-2-(2-methoxy-4,6-dimethyl-phenyl)pyrimidin -4- yl]carbamothioyl]piperidine-1-carboxylate (1.00 g, 2.04 mmol, 1.00 eq), copper iodide (38.8 mg, 204 pmol, 0.1.0 eq), cesium carbonate (1.33 g, 4.07 mmol, 2.00 eq), 1 ,10-phenanthroline (73.4 mg, 407 pmol, 0.20 eq) in 1 ,2-dimethoxyethane (20 mL) was stirred at 90 °C for 16 h under nitrogen atmosphere. The mixture was poured into water (30 mL), the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient @ 50 mL/min) to give tert-butyl 3-[5-(2-methoxy-4,6-dimethyl- phenyl)thiazolo[4,5-d]pyrimidin-2-yl]piperidine-1-carboxylat e (530 mg, 1.11 mmol, 54% yield, 95% purity) as a yellow solid.

¹ H NMR (400 MHz.CDCb) 6 = 9.41 (s, 1 H), 6.73 (s, 1 H), 6.66 (s, 1 H), 4.47-4.39 (m, 1 H), 3.71 (s, 3H), 3.40-3.27 (m, 2H), 3.03-2.89 (m, 1 H), 2.38 (s, 3H), 2.36-2.29 (m, 1 H), 2.10 (s, 3H), 1.91-1.57 (m, 4H), 1 .49 (s, 9H)

LC-MS (Method L): Rt = 0.613 min; MS (ESIpos): m/z = 455.2 [M+H] ⁺

Intermediate 164

5-(2-methoxy-4,6-dimethyhphenyl)-2-[3-pipendyl]thiazolo[4 .5-d]pynmidme

To a solution of tert-butyl rac-(3R)-3-[5-(2-methoxy-4,6-dimethyl-phenyl)thiazolo[4,5-d] pyrimidin-2- yl]piperidine-1-carboxylate (530 mg, 1.17 mmol, 1 .00 eq) in dioxane (5.00 mL) was added hydrochloride acid (4.00 M in dioxane, 5 mL), the mixture was stirred at 20 °C for 1 h. The mixture was concentrated under vacuum to afford 5-(2-methoxy-4,6-dimethyl-phenyl)-2-[rac-(3R)-3-piperidyl]th iazolo[4,5- d]pyrimidine (450 mg, 1.09 mmol, 94% yield, 95% purity, HCI salt) as a yellow solid.

LC-MS (Method L): Rt = 0.406 min; MS (ESIpos): m/z = 355.2 [M+H] ⁺

Intermediate 165

5-(2-methoxy-4,S-disnethyl~phenyl)~2-[1-methyl-3~p!pendyl ]thiazolo[4,5~d]pynmidine

To a mixture of 5-(2-methoxy-4,6-dimethyl-phenyl)-2-[3-piperidyl]thiazolo[4, 5-d]pyrimidine (450 mg, 1 .27 mmol, 1 .00 eq) and formaldehyde (515 mg, 6.35 mmol, 472 pL, 37.0% purity, 5.00 eq) in methanol (10 mL) was added acetate acid(76.2 mg, 1 .27 mmol, 1 .00 eq) and sodium cyanoborohydride (239 mg, 3.81 mmol, 3.00 eq) at 20 °C, the mixture was stirred at 20 °C for 16 h. The pH of mixture was adjusted to 9 by saturated sodium hydrogen carbonate solution (30 mL), the aqueous phase was extracted with ethyl acetate (50mL x 2). The combined organic phase was washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give 5-(2-methoxy-4,6-dimethyl-phenyl)-2-[rac-(3R)- 1-methyl-3-piperidyl]thiazolo[4,5-d]pyrimidine (330 mg, 851 pmol, 67% yield, 95% purity) as a yellow solid.

LC-MS (Method L): Rt = 0.402 min; MS (ESIpos): m/z = 369.2 [M+H] ⁺

Intermediate 166

S^-dimethy^-^-ll-methyl-S-pipendylJthiazolo^S-dJpynmidinS -ylJphenol (racemate)

To a solution of 5-(2-methoxy-4,6-dimethyl-phenyl)-2-[1-methyl-3-piperidyl]th iazolo[4,5-d]pyrimidine (330 mg, 895 pmol, 1 eq) in dichloromethane (6 mL) was added tribromoborane ((897 mg, 3.58 mmol, 4 eq) at -70 °C , the mixture was stirred at 20 °C for 1 h. The mixture was quenched by methanol (5 mL), the mixture was concentrated at vacuum. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um;mobile phase: [water(FA)-MECN];B%: 15%-45%,7 min) to give 3,5-dimethyl-2-[2-[1-methyl-3-piperidyl]thiazolo[4,5-d]pyrim idin-5-yl]phenol (150 mg, 402 pmol, 45% yield, 95% purity) as a white solid.

¹ H NMR (400 MHz, DMSO-cfe) 6 = 10.63 (s, 1 H), 9.67 (s, 1 H), 6.67-6.55 (m, 2H), 3.73-3.57 (m, 1 H), 2.70-2.61 (m, 5H), 2.48-2.37 (m, 2H), 2.27-2.22 (m, 6H), 2.18-2.04 (m, 1 H), 1.94-1.69 (m, 3H).

LC-MS (Method L): Rt = 0.430 min; MS (ESIpos): m/z = 355.1 [M+H] ⁺

Compounds 78 and 79

3„5-d!methyl-2-[2-[1-fnethyl-3-p!pendyl]thiazo!o[4,5-d] pynmidin-5-yl]phenol

The reaction was set up for SFC separation. The residue was purified by SFC: (column: DAICEL CHIRALPAK AD (250mm*30mm,10 um);mobile phase: [CO ₂ -EtOH(0.1 %NH ₃ «H ₂ O)];B%: 45%-45%, 4.35 min) to give 3,5-dimethyl-2-[2-[1-methyl-3-piperidyl]thiazolo[4,5-d]pyrim idin-5-yl]phenol (13.3 mg, 37.2 pmol, 9% yield, 99% purity) as a white solid and 3,5-dimethyl-2-[2-[1-methyl-3- piperidyl]thiazolo[4,5-d]pyrimidin-5-yl]phenol (12.0 mg, 33.6 pmol, 8% yield, 99% purity) as a white soild.

Compounds 78

¹ H NMR (400 MHz, DMSO-cfe) 6 = 10.68 (s, 1 H), 9.64 (s, 1 H), 6.66-6.57 (m, 2H), 3.58-3.48 (m, 1 H), 3.00-2.91 (m, 1 H), 2.59-2.52 (m, 2H), 2.28-2.18 (m, 10H), 2.10-2.01 (m, 1 H), 1.80-1.57 (m, 3H) LC-MS (Method L): Rt = 0.420 min; MS (ESIpos): m/z = 355.2 [M+H] ⁺ SFC (Rt = 1 .310 min, ee% = 81 %) Compounds 79

¹ H NMR (400 MHz, DMSO-cfe) 0 =10.62 (s, 1 H), 9.68 (s, 1 H), 6.62 (d, J = 6.0 Hz, 2H), 3.75-3.60 (m, 1 H), 3.11-2.90 (m, 2H), 2.62-2.54 (m, 2H), 2.53-2.51 (m, 3H), 2.27-2.22 (m, 6H), 2.22-2.13 (m, 1 H), 1.97-1.69 (m, 3H)

LC-MS (Method L): Rt = 0.424 min; MS (ESIpos): m/z = 355.2 [M+H] ⁺

SFC (Rt = 1 .660 min, ee% = 82%)

Intermediate 167

2-(2-methoxy-4,6-dim&thyl-phenyl)-7-methyl-1,8-naphth yndine

To a solution of 2-bromo-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (5.00 g, 14.5 mmol, 1 eq) in THF (50 mL) was added MeMgBr (3 M in diethyl ether, 14.5 mL, 3 eq) at 0 °C dropwise. After stirring at 20 °C for 1 h, the mixture was quenched by ice-water (20 mL) and adjusted to pH=7 with aqueous hydrochloric acid solution (1 M in water). The mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 2/1) to give 2-(2-methoxy-4,6-dimethyl- phenyl)-7-methyl-1 ,8-naphthyridine (2.00 g, 6.47 mmol, 44% yield, 90% purity) as a yellow solid.

¹ H NMR (400 MHz, CDCfe) 6 [ppm] = 8.13 (d, J = 8.0 Hz, 1 H), 8.09 (d, J = 8.0 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.38 (d, J = 8.4 Hz, 1 H), 6.75 (s, 1 H), 6.66 (s, 1 H), 3.68 (s, 3H), 2.82 (s, 3H), 2.39 (s, 3H), 2.16 (s, 3H). LC-MS (Method C): Rt = 0.428 min; MS (ESIpos): m/z = 279.1 [M+H] ⁺ . intermediate 168

3,5-dimethyl-2-(7-methyl-1,8-naphthyndm-2-yl)phenol

To a soiution of 2-(2-methoxy-4,6-dimethyl-phenyl)-7-methyl-1 ,8-naphthyridine (500 mg, 1.80 mmol, 1 eq) in DMF (10 mL) was added NaSEt (1 .51 g, 17.9 mmoi, 10 eq) at 20 °C in one portion. After stirring at 120 °C for 2 days, the mixture was poured into water (30 mL) and extracted with dichloromethane (30 mL x 2). The combined organic phase was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give 3, 5-dimethyl-2-(7-methyl-1 ,8- naphthyridin-2-yl)phenol (500 mg, 1 .32 mmol, crude) as a yellow solid.

LC-MS (Method C): Rt = 0.409 min; MS (ESIpos): m/z = 265.1 [M+H] ⁺ .

Intermediate 169

- [3,5-dimethyl-2-(7-methy!-1 _! 8-naphthyndin-2-yl)phenoxy]-tnisopi'opyl-silane

To a solution of 3,5-dimethyl-2-(7-methyl-1 ,8-naphthyridin-2-yl)phenol (500 mg, 1 .32 mmol, 1 eq) and imidazole (180 mg, 2.65 mmol, 2 eq) in dichloromethane (5 mL) was added TIPSCI (510 mg, 2.65 mmol, 566 pL, 2 eq) at 20 °C dropwise. After stirring at 20 °C for 1 h, the mixture was poured into ice-water (20 mL) and extracted with dichloromethane (20 mL x 2). The combined organic phase was washed with brine (10 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether/ethyl acetate = 10/1 to 4/1) to give [3,5-dimethyl-2-(7-methyl-1 ,8-naphthyridin-2-yl)phenoxy]-triisopropyl- silane (400 mg, 884 pmol, 67% yield, 93% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.597 min; MS (ESIpos): m/z = 421 .4 [M+H] ⁺ .

Intermediate 170 f-f7-f2 _; 4-d/metf?y/-6-fr//sopropy/s//y/oxy-p/?eny/J-l _; S-napf?f/?yr/d/n-2-y//-2-met/?y/-propan-2-o/

To a solution of [3,5-dimethyl-2-(7-methyl-1 ,8-naphthyridin-2-yl)phenoxy]-triisopropyl-silane (200 mg, 475 pmol, 1 eq) in THF (2 mL) was added LDA (2 M in THF, 594 pL, 2.5 eq) at 0 °C dropwise. After stirring at 0 °C for 1 h, acetone (55.2 mg, 950 pmol, 69.9 pL, 2 eq) was added the reaction mixture. After stirring at 20 °C for 2 h, the mixture was quenched by water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by preparative TLC (petroleum ether/ethyl acetate = 1/1) to give 1-[7-(2,4-dimethyl-6- triisopropylsilyloxy-phenyl)-1 ,8-naphthyridin-2-yl]-2-methyl-propan-2-ol (75.0 mg, 155 pmol, 32% yield, 99% purity) as yellow oil.

¹ H NMR (400 MHz, CDCfe) 6 [ppm] = 8.16 (d, J = 4.0 Hz, 1 H), 8.14 (d, J = 4.0 Hz, 1 H), 7.52 (d, J = 8.4 Hz, 1 H), 7.37 (d, J = 8.4 Hz, 1 H), 6.73 (s, 1 H), 6.60 (s, 1 H), 5.16-4.98 (m, 1 H), 3.20 (s, 2H), 2.32 (s, 3H), 2.14 (s, 3H), 1.30 (s, 6H), 1.10-1.03 (m, 3H), 0.86 (d, J = 7.2 Hz, 18H).

LC-MS (Method C): Rt = 0.613 min; MS (ESIpos): m/z = 479.4 [M+1 ] ⁺ . Compound 80

2-[7-(2-hydroxy-2-methyl-propyl)- 1, 8-naphthyridin-2-yl]-3., 5-dimethyl-phenol

To a solution of 1-[7-(2,4-dimethyl-6-triisopropylsilyloxy-phenyl)-1 ,8-naphthyridin-2-yl]-2-methyl-propan- 2-ol (55.0 mg, 114 pmol, 1 eq) in DMF (0.5 mL) was added CsF (174 mg, 1.15 mmol, 42.4 pL, 10 eq) at 20 °C in one portion. After stirring at 20 °C for 0.5 h, the mixture was filtered and filtrate was purified by reversed-phase column (column: Cl 8, 40 g, mobile phase: [water(FA) - MeCN];B%: 25% - 40%, 7 min) to give 2-[7-(2-hydroxy-2-methyl-propyl)-1 ,8-naphthyridin-2-yl]-3,5-dimethyl-phenol (20.0 mg, 60.7 pmol, 52% yield, 98% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-de) 6 = 9.98-9.84 (m, 1 H), 8.40 (d, J = 8.4 Hz, 1 H), 8.36 (d, J = 8.4 Hz, 1 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 6.64 (s, 1 H), 6.62 (s, 1 H), 5.00-4.77 (m, 1 H), 3.07 (s, 2H), 2.26 (s, 3H), 2.11 (s, 3H), 1.17 (s, 6H).

LC-MS (Method C): Rt = 0.417 min; MS (ESIpos): m/z = 323.0 [M+1 ] ⁺ .

Intermediate 171 tert-butyl 5-[7-(2-methoxy-4,8-dimethyl-phenyl)-1,8-naphthyridin-2-yl]- 3,4-dihydro-2H-pyridine- 1-carboxylate

To a solution of (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (5.00 g, 21.8 mmol, 1 eq) and N.O-dimethylhydroxylamine (3.19 g, 32.7 mmol, 1 .50 eq, HCI salt) in DCM (50 mL) were added EDCI (6.27 g, 32.7 mmol, 1.5 eq), DIPEA (8.46 g, 65.4 mmol, 11.4 mL, 3 eq) and HOBt (4.42 g, 32.7 mmol, 1 .5 eq) at 20 °C. After stirring at 20 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O ₂ , petroleum ether/ethyl acetate = 1/1) to give tert-butyl (R)-2-(2-(methoxy(methyl)amino)-2-oxoethyl)pyrrolidine-1- carboxylate (5.40 g, 18.8 mmol, 86% yield, 95% purity) as colorless oil.

¹ H NMR (400 MHz, DMSO-d _s ) 6 [ppm] = 4.04-3.97 (m, 1 H), 3.65 (s, 3H), 3.26-3.16 (m, 2H), 3.08 (s, 3H), 2.86-2.68 (m, 1 H), 2.46-2.32 (m, 1 H), 1.97-1.87 (m, 1 H), 1.86-1.70 (m, 2H), 1.65-1 .63 (m, 1 H), 1.39 (s, 9H).

Intermediate 172 tert-butyl (2R)-2-acetonylpyrrolidine-1 -carboxylate

To a solution of tert-butyl (2R)-2-[2-[methoxy(methyl)amino]-2-oxo-ethyl]pyrrolidine-1-c arboxylate (5.40 g, 19.8 mmol, 1 eq) in THF (50 mL) was added MeMgBr (3.0 M in THF, 19.8 mL, 3 eq) at 0 °C. After stirring at 20 °C for 1 h, the reaction mixture was quenched by saturated ammonium chloride aqueous solution (50 mL) at 0 °C, and then extracted with ethyl acetate(100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl (2R)-2-acetonylpyrrolidine-1 -carboxylate (4.20 g, 17.5 mmol, 89% yield, 95% purity) as light yellow oil.

Intermediate 173 tert-butyl (2R)-2-[[7-(2-methoxy-4.6-dimethyl-pheuyl)-1 _! 8-uaphthyridin-2-y!]methyl]pyrro!idine-1- carboxylate To solution of 2-amino-6-(2-methoxy-4,6-dimethyl-phenyl)pyridine-3-carbalde hyde (1.00 g, 3.90 mmol, 1 eq) and tert-butyl (2R)-2-acetonylpyrrolidine-1-carboxylate (1.77 g, 7.80 mmol, 2 eq) in MeOH (20 mL) was added DBU (1 .78 g, 11.7 mmol, 1 .76 mL, 3 eq) at 20 °C. After stirring at 60 °C for 24 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SIO ₂ , petroleum ether/ethyl acetate=1/1) to give tert-butyl (2R)-2-[[7-(2- methoxy-4,6-dimethyi-phenyl)-1 ,8-naphthyridin-2-yl]methyl]pyrrolidine-1 -carboxylate (1.20 g, 2.41 mmol, 62% yield, 90% purity) as a light yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 8.39 (d, J = 8.3 Hz, 2H), 7.54-7.40 (m, 2H), 6.82 (s, 1 H), 6.77 (s, 1 H), 4.29-4.18 (m, 1 H), 3.65 (s, 3H), 3.32 - 3.29 (m, 3H), 3.01-2.90 (m, 1 H), 2.36 (s, 3H), 2.00 (s, 3H), 1.82-1.78 (m, 4H), 1.44-1.20 (m, 10H).

LC-MS (Method C): Rt = 0.519 min; MS (ESIpos): m/z = 448.3 [M+H] ⁺ .

Intermediate 174

2-f2-met/?oxy-4 _; 6-d/met/)y/-pfieny/J-7-£ff2f?J-pyrro//d/r?-2-y/Jmet/? y/J-l,8-nap/?t/?yr/d/ne -

To a solution of tert-butyl (2R)-2-[[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]methyl]pyrrolidine-1-carboxylate (1.20 g, 2.68 mmol, 1 eq) in DCM (10 mL) was added TFA (30.7 g, 269 mmol, 20 mL, 100 eq) at 20 °C. After stirring at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give 2-(2-methoxy-4,6-dimethyl-phenyl)-7-[[(2R)-pyrrolidin-2-yl]m ethyl]-1 ,8- naphthyridine (1 .5 g, crude, TFA salt ) as light yellow oil.

LC-MS (Method C): Rt = 0.413 min; MS (ESIpos): m/z = 348.2 [M+H]*.

Intermediate 175

To a solution of 2-(2-methoxy-4,6-dimethyl-phenyl)-7-[[(2R)-pyrrolidin-2-yl]m ethyl]-1 ,8-naphthyridine (1.50 g, 4.32 mmol, 1 eq) in DCM (5 mL) were added AC2O (881 mg, 8.63 mmol, 811 pL, 2 eq) and DIPEA (1 .67 g, 12.9 mmol, 2.26 mL, 3 eq) at 20 °C. After stirring at 20 °C for 1 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed- phase column (column: C18, 330 g, mobile phase: [water(FA)-MeCN]; B%: 20% - 40%, 12 min) to give 1-[(2R)-2-[[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]methyl]pyrrolidin-1-yl]ethanone (1 .40 g, 3.56 mmol, 82% yield, 99% purity) as a brown solid.

¹ H NMR (400 MHz, DMSO-d _s ) 6 [ppm] = 8.46-8.36 (m, 2H), 7.61-7.44 (m, 2H), 6.82 (s, 1 H), 6.77 (s, 1 H), 4.51-4.39 (m, 1 H), 3.65 (s, 3H), 3.52-3.39 (m, 2H), 3.35-3.33 (m, 1 H), 3.10-2.88 (m, 1 H), 2.36 (s, 3H), 2.05-1.95 (m, 6H), 1.94-1.71 (m, 4H).

LC-MS (Method C): Rt = 0.459 min; MS (ESIpos): m/z = 390.1 [M+H] ⁺ .

SFC (Rt = 1 .721 min, ee% = 96%).

Compound 81 To a solution of 1-[(2R)-2-[[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]methyl]pyrrolidin- 1-yl]ethanone (200 mg, 513 pmol, 1 eq) in DCM (2 mL) was added BBrs (643 mg, 2.57 mmoi, 247 pL, 5 eq)at -70 °C dropwise. After stirring at 20 °C for 1 h, the reaction was quenched by ammonia (5 mL, 7.0 M in methanol), and the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(NH3‘H ₂ O) - MeCN]; B%: 20% - 40%, 5 min) to give 1-[(2R)-2-[[7-(2-hydroxy-4,6-dimethyl- phenyl)-1 ,8-naphthyridin-2-yl]methyl]pyrrolidin-1-yl]ethanone (170 mg, 449 pmol, 87% yield, 99% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d _s ) 5 [ppm] = 9.88-9.78 (m, 1 H), 8.45-8.36 (m, 2H), 7.60-7.48 (m, 2H), 6.64 (s, 1 H), 6.62 (s, 1 H), 4.50-4.40 (m, 1 H), 3.51-3.40 (m, 2H), 3.39-3.34 (m, 1 H), 3.12-2.88 (m, 1 H), 2.26 (s, 3H), 2.10 (s, 3H), 1 .98 (s, 3H), 1 .93-1 .73 (m, 4H).

LC-MS (Method C): Rt = 0.429 min; MS (ESIpos): m/z = 376.4 [M+H] ⁺ .

SFC (Rt = 1 .194 min, ee% = 99%).

Intermediate 176

To a solution of. 2-bromo-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (3.00 g, 8.74 mmol, 1 eq), tert-butyl 5-(4,4,5,5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)-3,4-dihydro-2H-pyridine-1 -carboxylate (4,05 g, 13.1 mmol, 1.5 eq) and CS2CO3 (5.70 g, 18 mmol, 2 eq) in dioxane (30 mL) and H2O (6 mL) was added Pd(dppf)Cl2 (320 mg, 437 pmol, 0.05 eq) at 20 °C in one portion under N2 atmosphere. The mixture was stirred at 80 °C for 16 h, the mixture was poured into ice-water (50 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate= 1/1) to give tertbutyl 5-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-3,4-dihydro-2H-pyridine-1- carboxylate (3.60 g, 7.27 mmol, 83% yield, 90% purity) as a brown solid.

LC-MS (Method C): Rt = 0.543 min; MS (ESIpos): m/z = 446.2 [M+H] ⁺

Intermediate 177 tert-butyl 3-[7-(2-methoxy-4,8-dlmethyl-phenyl)-1,8-naplrthyridln-2-yl] piperldme-1 -carboxylate To a solution of tert-butyl 5-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]- 3,4-dihydro-2H- pyridine-1 -carboxylate (3.50 g, 7.86 mmol, 1 eq) in MeOH (40 mL) was added Pd/C (417 mg, 392 pmol, 10% purity, 0.05 eq) at 20 °C in one portion. After stirring at 20 °C for 1 h under hydrogen atmosphere (15 psi), the mixture was filtered and filtrate was concentrated in vacuum to give tert-butyl 3-[7-(2- methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]piperidine-1-carboxylate (4.00 g, 7.33 mmol, 93% yield, 82% purity) was obtained as a yellow oil.

LC-MS (Method C): Rt = 0.546 min; MS (ESIpos): m/z = 448.3 [M+H] ⁺

Intermediate 178 2-(2-methoxy-4,6-dimethyl-phenyl)-7-(3-pipendyi)-1,8-naphthy ndine

To a solution of tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]piperidine-1- carboxylate (3.4 g, 7.60 mmol, 1 eq ) in DCM (30 mL) was added TFA (30 mL). After stirring at 25 °C for 1 h, the mixture was concentrated to give 2-(2-methoxy-4,6-dimethyl-phenyl)-7-(3-piperidyi)-1 ,8- naphthyridine (3.5 g, 7.58 mmol, 99% yield, TFA salt) as a brown oil.

Intermediate 179 benzyl 4-[3-[7-(2-methaxy-4 _! 6-dimethyl-pheriyi)-1,8-riaphthyridm~2-yl]-1~piy>en dy!]butanc>ate

To a solution of 2-(2-methoxy-4,6-dimethyl-phenyl)-7-(3-piperidyl)-1 ,8-naphthyridine (650 mg, 1.87 mmol, 1 eq) and benzyl 4-bromobutanoate (529 mg, 2.06 mmol, 1.1 eq) in ACN (7 mL) was added K2CO3 (517 mg, 3.74 mmol, 2 eq) .After stirring at 80 °C for 2h, the reaction mixture was concentrated under reduced pressure to remove MeCN. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL*3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The crude product was purified by reversed-phase HPLC (0.1 % FA condition) to give benzyl 4-[3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1- piperidyl]butanoate (635 mg, 1 .21 mmol, 86.09% yield) as a yellow solid.

LC-MS (Method C): Rt = 0.525 min; MS (ESIpos): m/z = 524 [M+H] ⁺ .

Intermediate 180

To a solution of benzyl 4-[3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1- piperidyljbutanoate (600 mg, 1.15 mmol, 1 eq) in DCM (10 mL) was added BBrs (861 mg, 3.44 mmol, 331 pL, 3 eq) and phenylsulfanylbenzene (1.07 g, 5.73 mmol, 953 pL, 5 eq) at -70 °C. After stirring at 25 °C for 2h, the mixture was quenched by 20 mL of NaCICh at 25 °C and dichloromethane (30 x 3 mL) then the separated organic layer was washed with brine (40 mL), dried over (Na2SO4) and evaporated to dryness. The crude product was purified by reversed-phase HPLC (0.1 % FA condition) to give 4-[3- [7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-piperidyl]butanoic acid (330 mg, 787 pmol, 69% yield) was yellow solid.

LC-MS (Method C): Rt = 0.406 min; MS (ESIpos): m/z = 420 [M+H] ⁺ .

Compound 83 4-[(3-[7-(2diydroxy-4,8<iimethyl-phenyl)-1.8-naphthyridin -2-yl]-1-piperidyl]butanoic acid

The reaction was set up for SFC separation. The residue was separated by SFC: (column: DAICEL CHIRALPAK IG (250mmx30mm,10um);mobile phase: [CO ₂ -EtOH(0.1%NH ₃ ’H2O)];B%:55%, isocratic elution mode) to give 4-[3-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1- piperidyl]butanoic acid (114 mg, 272 pmol, 38% yield) as a yellow solid and 4-[(3-[7-(2-hydroxy-4,6- dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-piperidyl]butanoic acid (141 mg, 336 pmol, 47% yield) as a yellow solid.

Enantiomer 1 ¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 8.41 (s, 1 H), 8.38 (s, 1 H), 7.62 (d, J = 8.4 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 6.68-6.63 (m, 1 H), 6.62 (s, 1 H), 3.21-3.11 (m, 3H), 2.96 (m,1 H), 2.44 (t, J = 13.6 Hz, 2H), 2.40-2.36 (m, 1 H), 2.31-2.27 (m, 2H), 2.27-2.25 (m, 3H), 2.09-2.07 (m, 3H), 2.02 (m, 1 H), 1 .83-1 .76 (m, 1 H)

LC-MS (Method C): Rt = 0.400 min; MS (ESIpos): m/z = 420 [M+H] ⁺ .

SFC (Rt = 1 .861 min, ee% = 97%).

Compound 83

¹ H NMR (400 MHz, DMSO-d _e ) 6 [ppm]= 10.63-9.12 (m, 1 H), 8.44 (d, J = 8.4 Hz, 1 H), 8.42 (d, J = 8.4 Hz, 1 H), 7.65 (d, J = 8 Hz, 1 H), 7.57 (d, J = 8 Hz, 1 H), 6.63 (s, 1 H), 6.62 (s, 1 H), 3.23 (m, 3H), 2.80 (m, 1 H), 2.48-2.44 (m, 2H), 2.33 (m, 1 H), 2.32-2.29 (m, 2H), 2.26 (s, 3H), 2.12-2.09 (m, 1 H), 2.08 (s, 3H), 1.85-1.76 (m, 3H), 1.75-1.64 (m, 1 H).

LC-MS (Method C): Rt = 0.400 min; MS (ESIpos): m/z = 420 [M+H] ⁺ .

SFC (Rt = 2.734 min, ee% = 97%).

Intermediate 181 benzyl 3~[7-(2-niethoxy-4~inethyi~phenyl)~1 _! 8~naphthyridin-2~yl]pipe!'idme-1 -carboxylate

To a solution of benzyl 3-(7-chloro-1 ,8-naphthyridin-2-yl)piperidine-1 -carboxylate (614 mg, 1.61 mmol, 1 eq) and (2-methoxy-4-methyl-phenyl)boronic acid (400 mg, 2.41 mmol, 1.5 eq) in dioxane (20 mL) were added Pd(dppf)Cl2 (1 18 mg, 161 pmol, 0.1 eq) and CS2CO3 (1.05 g, 3.22 mmol, 2 eq) in H2O (2 mL). The mixture was stirred at 100 °C for 16 h. After stirring at 100 °C for 16 h, the mixture was concentrated to give a crude. The residue was purified by column chromatography (S1O ₂ , petroleum ether/ethyl acetate = 1/0 to 5/1) to give benzyl 3-[7-(2-methoxy-4-methyl-phenyl)-1 ,8-naphthyridin-2- yl]piperidine-1 -carboxylate (760 mg, 1.59 mmol, 99% yield, 98% purity) as yellow oil.

LC-MS (Method C): Rt = 0.527 min; MS (ESIpos): m/z = 468.3 [M+H] ⁺

Intermediate 182

2-(2-methoxy-4-methyl-phenyl)-7-(1-methyl-3-pipendyl)-1,8 -naphthyndine

To a solution of benzyl 3-[7-(2-methoxy-4-methyl-phenyl)-1 ,8-naphthyridin-2-yl]piperidine-1 - carboxylate (400 mg, 856 pmol, 1 eq) and HCHO (347 mg, 4.28 mmol, 318 pL, 37% purity, 5 eq) in MeOH (5 mL) was added Pd/C (91.0 mg, 85.6 pmol, 7.70 pL, 10% purity, 0.1 eq) at 25 °C under N2 atmosphere in one portion. After stirring at 25 °C for 16 h under H2 atmosphere, the mixture was concentrated to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(FA) - MeCN];B%: 20% - 35%, 6 min) to give 2-(2-methoxy-4-methyl-phenyi)-7- (1-methyl-3-piperidyl)-1 ,8-naphthyridine (212 mg, 604 pmol, 71 % yield, 99% purity) as a yellow solid. LC-MS (Method C): Rt = 0.421 min; MS (ESIpos): m/z = 348.2 [M+H] ⁺

Intermediate 183

5-methyl-2-[7-(1-methy!-3-piperidy!)-1.8-naphthyridbi-2-y l]phenol

To a solution of 2-(2-methoxy-4-methyl-phenyl)-7-(1-methyl-3-piperidyl)-1 ,8-naphthyridine (190 mg, 547 pmol, 1 eq) in DCM (5 mL) was added BBrs (411 mg, 1.64 mmol, 158 pL, 3 eq) at -70 °C. After stirring at 25 °C for 16 h, the reaction was quenched by ammonia (5 mL, 7.0 M in methanol), and the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: Cl 8, 80 g, mobile phase: [water(FA) - MeCN];B%: 25% - 40%, 4 min) to give 5-methyl-2-[7-(1-methyi-3-piperidyi)-1 ,8-naphthyridin-2-yl]phenol (40.0 mg, 119 pmol, 43% yield, 99% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.449 min; MS (ESipos): m/z = 334.2 [M+H] ⁺

Compound 84

5-methyl-2-[7-[1-methyl-3-p!pendyl]-1,8-naphthyndm-2-yl]p henol

The reaction was set up for SFC separation. The residue was purified by SFC: (column: DAICEL CHIRALPAK IC (250mm*30mm,10um);mobile phase: [CO ₂ -MeCN/EtOH (0.1 % NH ₃ «H ₂ O)];B%:50%, isocratic elution mode) to give 5-methyl-2-[7-[rel-(3R)-1-methyl-3-piperidyl]-1 ,8-naphthyridin-2- yljphenol (13.3 mg, 39.6 pmol, 66% yield, 99% purity) a yellow solid and 5-methyl-2-[7-[rel-(3R)-1- methyl-3-piperidy l]-1 ,8-naphthyridin-2-yl]phenol (11 .0 mg, 32.7 pmol, 55% yield, 99% purity) as a yellow solid.

Compound 84

¹ H NMR (400 MHz, DMSO-d _e ) 5 [ppm] = 15.25 (s, 1 H), 8.57 (d, J = 8.8 Hz, 1 H), 8.39 (dd, J = 8.4, 11 .4 Hz, 2H), 8.11 (d, J = 8.4 Hz, 1 H), 7.64 (d, J = 8.0 Hz, 1 H), 6.85-6.79 (m, 2H), 3.20-3.14 (m, 1 H), 3.04 (d, J = 10.8 Hz, 1 H), 2.82 (d, J = 10.8 Hz, 1 H), 2.33 (s, 3H), 2.25 (s, 4H), 2.01-1.94 (m, 2H), 1.80-1.73 (m, 1 H), 1 .70-1 .60 (m, 2H).

LC-MS (Method C): Rt = 0.448 min; MS (ESipos): m/z = 334.2 [M+H] ⁺ .

SFC (Rt = 1 .328 min, ee% = 99%).

Enantiomer 2

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 15.26 (s, 1 H), 8.57 (d, J = 8.8 Hz, 1 H), 8.43-8.36 (m, 2H), 8.12 (d, J = 8.4 Hz, 1 H), 7.64 (d, J = 8.4 Hz, 1 H), 6.85-6.79 (m, 2H), 3.21-3.12 (m, 1 H), 3.02 (dd, J = 3.2, 10.9 Hz, 1 H), 2.80 (d, J = 10.4 Hz, 1 H), 2.33 (s, 3H), 2.25-2.20 (m, 4H), 2.02-1.91 (m, 2H), 1.80-1.73 (m, 1 H), 1 .70-1 .57 (m, 2H).

LC-MS (Method C): Rt = 0.451 min; MS (ESipos): m/z = 334.2 [M+H] ⁺ .

SFC (Rt = 1 .966 min, ee% = 99%).

Intermediate 184

2-methoxy-6-methyl-4-methylsu!fonyl-phenoi

To a solution of 4-bromo-2-methoxy-6-methyl-phenol (5.00 g, 23.0 mmol, 1 eq) in DMSO (100 mL) were added sodium methanesulfinate (7.05 g, 69.1 mmol, 3 eq), L-proline (1.06 g, 9.21 mmol, 0.4 eq), Cui (877 mg, 4.61 mmol, 0.2 eq) and Cs ₂ CO ₃ (11.3 g, 34.6 mmol, 1.5 eq). After stirring at 100 °C for 16 h, the pH of mixture was adjusted to 3 with hydrochloric acid solution (1 M in water). The solution was extracted with ethyl acetate (250 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 0/1) to give 2-methoxy-6-methyl-4-methylsulfonyl-phenol (2.80 g, 13.0 mmol, 56% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO-cfe) 5 [ppm] = 9.62 (s, 1 H), 7.30-7.29 (m, 1 H), 7.27-7.26 (m, 1 H), 3.87 (s, 3H), 3.12 (s, 3H), 2.19 (s, 3H).

Intermediate 185

(2-methoxy-6-methyl-4-methylsulfonyl-phenyl) trifiuoromethanesulfonate

To a solution of 2-methoxy-6-methyl-4-methylsulfonyl-phenol (2.80 g, 13.0 mmol, 1 eq) in MeCN (30 mL) were added 1 ,1 ,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulf onamide (6.94 g, 19.4 mmol, 1.5 eq) and K2CO3 (5.37 g, 38.8 mmol, 3 eq). After stirring at 25 °C for 2 h, the mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiOz, petroleum ether/ethyl acetate = 4/1) to give (2-methoxy-6-methyl-4- methylsulfonyl-phenyi) trifiuoromethanesulfonate (4.60 g, 10.6 mmol, 82% yield, 80% purity) as a white solid.

¹ H NMR (400 MHz, DMSO-d _s ) 5 [ppm] = 7.63-7.60 (m, 2H), 3.99 (s, 3H), 3.31 (s, 3H), 2.40 (s, 3H).

Intermediate 186

2-(2-methoxy-6-methyl-4-methylsulfonyl-phenyl)-4 _! 4,5.5-tetramethyl-1,3.2-dioxaborolane

To a solution of (2-methoxy-6-methyl-4-methylsulfonyl-phenyl) trifiuoromethanesulfonate (4.50 g, 10.3 mmol, 1 eq) in 1 ,4-dioxane (50 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (2.89 g, 11.4 mmol, 1.1 eq), Pd(dppf)Cl2 (756 mg, 1.03 mmol, 0.1 eq) and KOAc (3.04 g, 31 .0 mmol, 3 eq) at 25 °C. After stirring at 80 °C for 16 h, the mixture was filtered and the filtrate was concentrated at reduced pressure to give a residue. The residue was purified by column chromatography (SIO ₂ , petroleum ether/ethyl acetate = 2/1) to give 2-(2-methoxy-6-methyl- 4-methylsulfonyl-phenyl)-4,4,5,5- tetramethyl-1 ,3,2-dioxaborolane (3.00 g, 6.44 mmol, 62% yield, 70% purity) as a white solid.

¹ H NMR (400 MHz, DMSO-cfe) 5 [ppm] = 7.32 (s, 2H), 3.80 (s, 3H), 3.19 (s, 3H), 2.38 (s, 3H), 1.31 (s, 12H).

Intermediate 187 benzyl 3-[7-(2-methoxy-6-methyl-4-methylsulfonyl-phenyl)-1.8-naphth yridln-2-yl]piperidine-1- carboxylate

To a solution of benzyl 3-(7-chloro-1 ,8-naphthyridin-2-yl)piperidine-1 -carboxylate (500 mg, 1.31 mmol, 1 eq) in 1 ,4-dioxane (10 mL) and water (1 mL) were added 2-(2-methoxy-6-methyl-4-methylsulfonyl- phenyl)-4, 4, 5, 5-tetramethyl-1 ,3,2-dioxaborolane (1.22 g, 2.62 mmol, 2 eq, EW29564-1153), Pd(dppf)Cl2 (95.8 mg, 131 pmoi, 0.1 eq) and CS2CO3 (1.28 g, 3.93 mmol, 3 eq) at 25 °C. After stirring at 100 °C for 2 h, the mixture was filtered and the filtrate was concentrated at reduced pressure to give a residue. The residue was purified by column chromatography (SiOz, petroleum ether/ethyl acetate=1/2) to give benzyl 3-[7-(2-methoxy-6-methyl-4-methylsulfonyl-phenyl)-1 ,8-naphthyridin-2- yl]piperidine-1 -carboxylate (400 mg, 674 pmol, 52% yield, 92% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-cfe) 5 [ppm] = (d, J = 8.4 Hz, 1 H), 8.47 (d, J = 8.4 Hz, 1 H), 7.67 (d, J = 8.4 Hz, 1 H), 7.56 (s, 1 H), 7.54 (s, 1 H), 7.48 (s, 1 H), 7.36 (s, 5H), 5.11 (s, 2H), 4.36-4.26 (m, 1 H), 4.10-4.08 (m, 1 H), 3.77 (s, 3H), 3.27 (s, 1 H), 3.13-3.03 (m, 1 H), 3.00-2.79 (m, 1 H), 2.16-2.14 (m, 1 H), 2.11 (s, 3H), 1 .87-1 .75 (m, 2H), 1 .66-1 .50 (m, 1 H).

LC-MS (Method C): Rt = 0.534 min; MS (ESIpos): m/z = 546.4 [M+H] ⁺ .

Intermediate 188

2-(2-methoxy-6-methy!-4-methy!sidfony!-phenyl)-7-[1-methy l-3-p!pendyl]-1,§-naphthyndme

To a solution of benzyl rac-(3R)-3-[7-(2-methoxy-6-methyi-4-methylsulfonyl-phenyl)-1 ,8-naphthyridin-2- yl]piperidine-1 -carboxylate (400 mg, 674 pmol, 1 eq) in methanol (10 mL) were added Pd/C (50.0 mg, 10% purity) and HCHO in water (101 mg, 1.35 mmol, 0.93 mL, 40% purity, 2 eq) (aq.) under Nz. The suspension was degassed under vacuum and purged with H2 several times. After stirring under H2 (15 psi) at 20 °C for 4 h, the mixture was filtered and concentrated to dry. The residue was purified by reversed phase (column: C18, 40 g, mobile phase: [water (FA) - MeCN]; B%: 40%-70%, 7 min) to give

2-(2-methoxy-6-methyl-4-methylsulfonyl-phenyl)-7-[1-methy l-3-piperidyl]-1 ,8-naphthyridine (60.0 mg, 138 pmol, 20% yield, 98% purity) as yellow oil.

LC-MS (Method C): Rt = 0.402 min; MS (ESIpos): m/z = 426.2 [M+H] ⁺ .

Intermediate 189

3-snethyl-5-snethylsulfonyl~2-[7~[1-snethyl-3-pipendyl]-1 ,8-naphthyddiin-2-yl]phenol

To a solution of 2-(2-methoxy-6-methyl-4-methylsulfonyl-phenyl)-7-[1-methyl-3 -piperidyl]-1 ,8- naphthyridine (60.0 mg, 138 pmol, 1 eq, EW29564-1 163) in DMF (1 mL) was added NaSEt (232 mg, 2.76 mmol, 20 eq). After stirring at 100 °C for 2 h, The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (column: C18 40 g, mobile phase: [water (FA) - MeCN]; B%: 20%-50%, 5 min) to give 3-methyl-5-methylsulfonyl-2-[7-[rac-(3R)-1- methyl-3-piperidyl]-1 ,8-naphthyridin-2-yl]phenol (60.0 mg, 136 pmol, 98% yield, 93% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.378 min; MS (ESIpos): m/z = 412.2 [M+H] ⁺ .

Compound 87

3-methyl-5-methylsulfonyl-2-[7-[1-methyl-3-p!pendyl]-1,8- naphthyndm-2-yl]phenol

The reaction was set up for SFC separation. The residue was purified by SFC: (column: daicel chiralpak IG (250 mm x 30 mm, 10 pm); mobile phase: [CO ₂ - MeCN/l-PrOH (0.1 % NH3-H2O)]; B%:45%, isocratic elution mode) to give 3-methyl-5-methylsulfonyl-2-[7-[rel-(3R)-1-methyl-3-piperidy l]-1 ,8-naphthyridin-2- yl]phenol (8.75 mg, 20.8 pmol, 15% yield, 98% purity) as a yellow solid and 3-methyl-5-methylsulfonyl- 2-[7-[rel-(3R)-1-methyl-3-piperidyl]-1 ,8-naphthyridin-2-yl]phenol (9.77 mg, 23.5 pmol, 17% yield, 99% purity) as a yellow solid.

Enantiomer 1 ¹ H NMR (400 MHz, DMSO-cfe) <5 [ppm] = 8.47-8.43 (m, 2H), 7.66 (d, J = 8.4 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.38 (s, 1 H), 7.34 (s, 1 H), 3.24 (s, 3H), 3.21-3.13 (m, 1 H), 3.07-3.01 (m, 1 H), 2.85-2.78 (m, 1 H), 2.23 (s, 3H), 2.13 (s, 3H), 2.04-1.90 (m, 2H), 1.81-1.73 (m, 1 H), 1.70-1.57 (m, 2H), 1.23 (s, 1 H) LC-MS (Method C): Rt = 0.404 min; MS (ESIpos): m/z = 412.3 [M+H] ⁺ .

SFC (Rt = 1 .419 min, ee% = 99%).

Compound 87

¹ H NMR (400 MHz, DMSO-cfe) 6 [ppm] = 8.48-8.42 (m, 2H), 7.66 (d, J = 8.4 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.36 (d, J = 7.2 Hz, 2H), 3.23 (s, 3H), 3.18-3.13 (m, 1 H), 3.06-2.99 (m, 1 H), 2.83-2.80 (m, 1 H), 2.23 (s, 3H), 2.13 (s, 3H), 2.02-2.00 (m, 1 H), 1.95-1 .89 (m, 1 H), 1.81-1.72 (m, 1 H), 1.70-1.57 (m, 2H), 1.24-1.22 (m, 1 H).

LC-MS (Method C): Rt = 0.396 min; MS (ESIpos): m/z = 412.3 [M+H] ⁺ .

SFC (Rt = 2.042 min, ee% = 98%).

Intermediate 190

N-methoxy-N-methyl-6-oxo-pipendine-3-cai'boxamide

To a solution of 6-oxopiperidine-3-carboxylic acid (3.00 g, 21.0 mmol, 1 eg) and N- methoxymethanamine (3.07 g, 31 .4 mmol, 1 .5 eq, HCI salt) in DCM (30 mL) were added EDCI (6.03 g, 31.4 mmol, 1.5 eq), HOBt (4.25 g, 31.44 mmol, 1.5 eq) and DIPEA (8.13 g, 62.9 mmol, 10.9 mL, 3 eg) at 20 °C. After stirring at 20 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue.

The residue was purified by column chromatography (SIOz, petroleum ether/ethyl acetate=0/1) to give rac-(3S)-N-methoxy-N-methyl-6-oxo-piperidine-3-carboxamide (3.50 g, 15.0 mmol, 72% yield, 80% purity) as light yellow oil.

LC-MS (Method C): Rt = 0.274 min; MS (ESIpos): m/z = 187.2 [M+H] ⁺ .

Intermediate 190

5-acetylpiperidin-2-one

To a solution of rac-(3S)-N-methoxy-N-methyl-6-oxo-piperidine-3-carboxamide (3.00 g, 16.1 mmoi, 1 eq) in THF (100 mL) was added MeMgBr (3 M in THF, 26.9 mL, 5 eq) at 20 °C. After stirring at 20 °C for 2 h, the reaction mixture was quenched by saturated ammonium chloride aqueous solution (20 mL) at 0 °C, and then extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give rac-(5S)-5-acetylpiperidin-2-one (2.20 g, 14.0 mmol, 87% yield, 90% purity) as light yellow oil.

Intermediate 191

5-f7-f2-mef/?oxy-4,S-d/metfiy/pf?eny/J-f _; S-nap/?t/?yrfd/n-2-y/Jpfper/d'fn-2-one

To a mixture of rac-(R)-5-acetylpiperidin-2-one (496 mg, 3.51 mmol, 3.00 eq), 2-amino-6-(2-methoxy- 4,6-dimethylphenyl)nicotinaldehyde (300 mg, 1.17 mmol, 1.00 eq) in ethanol (6.00 mL) was added 1 ,8- diazabicyclo[5.4.0]undec-7-ene (535 mg, 3.51 mmol, 529 pL, 3.00 eq) at 20 °C. After stirring at 60 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase coiumn (column: C18, 220 g, mobile phase: [water (FA) - MeCN];B%: 20% - 60%, 5 min) to give 5-(7-(2-methoxy-4,6-dimethylphenyl)-1 ,8-naphthyridin-2-yl)piperidin-2-one (350 mg, 775 pmol, 66% yield,) as a brown solid.

¹ H NMR (400 MHz, DMSO-d ₅ ) 5 [ppm] = 8.47-8.40 (m, 2H), 7.71 (d, J = 8.4 Hz, 1 H), 7.66-7.62 (m, 1 H), 7.49 (d, J = 8.4 Hz, 1 H), 6.86-6.76 (m, 2H), 3.66 (s, 3H), 3.63-3.49 (m, 2H), 3.47-3.37 (m, 1 H), 2.52 (s, 3H), 2.45-2.40 (m, 1 H), 2.36-2.28 (m, 1 H), 2.21-2.1 1 (m, 2H), 2.01 (s, 3H).

LC-MS (Method R): Rt = 0.446 min; MS (ESIpos): m/z = 362.3 [M+H] ⁺ .

Compound 88

5-(7 -(2-hydroxy-4.6-dimethylphenyQ- 1, 8-naphthyridin-2-y0piperidiii-2-one

To a solution of 5-(7-(2-methoxy-4,6-dimethylphenyl)-1 ,8-naphthyridin-2-yl)piperidin-2-one (320 mg, 885 pmol, 1.00 eq) in DCM (4.00 mL) was added dropwise boron tribromide (4.44 g, 17.7 mmol, 1.71 mL, 20.0 eq) at -70 °C. The mixture was stirred at 20 °C for 1 h. the reaction was quenched by ammonia (3 mL, 7.0 M in methanol), and the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA condition; lnstrument:80g Flash; Column: Welch Ultimate XB_C18 20-40pm; eluent A: water (0.1 % FA), eluent B: acetonitrile; gradient:0-10 min 0-33% B; flow 85 ml/min; temperature: room temperature; Detector: UV 220/254 nm ) to give desired compound (210 mg, purity 99%) as a light yellow solid. The product was separated by SFC (condition: column: DAICEL CHIRALPAK AD(250mm*30mm,10 um);mobile phase: [CO ₂ -EtOH (0.1 %NH3*H2O)];B%:5Q%, isocratic elution mode ) to give re/-(R)-5-(7-(2-hydroxy-4,6-dimethylphenyl)- 1 ,8-naphthyridin-2-yl)piperidin-2-one (72.8 mg, 205 pmol, 23% yield) as yellow solid and re/-(R)-5-(7- (2-hydroxy-4,6-dimethylphenyl)-1 ,8-naphthyridin-2-yi)piperidin-2-one (58.6 mg, 167 pmol, 19% yield) as yellow/ solid.

Compound 88

¹ H NMR (400 MHz, DMSO-d _s ) 5 [ppm] = 9.74 (s, 1 H), 8.47-8.38 (m, 2H), 7.69 (d, J = 8.0 Hz, 1 H), 7.65- 7.60 (m, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 6.62 (d, J = 5.6 Hz, 2H), 3.62-3.47 (m, 2H), 3.45-3.36 (m, 1 H), 2.42-2.30 (m, 2H), 2.26 (s, 3H), 2.19-2.10 (m, 2H), 2.08 (s, 3H).

LC-MS (Method C): Rt = 0.498 min; MS (ESIpos): m/z = 348.1 [M+H] ⁺ HPLC (Method AN): Rt - 1.517 min; purity: 98%.

SFC (Rt = 1 .980 min, ee% = 99%).

Enantiomer 2

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 9.74 (s, 1 H), 8.46-8.39 (m, 2H), 7.68 (d, J = 8.0 Hz, 1 H), 7.65- 7.60 (m, 1 H), 7.56 (d, J = 8.0 Hz, 1 H), 6.62 (d, J = 5.6 Hz, 2H), 3.61-3.48 (m, 2H), 3.45-3.36 (m, 1 H), 2.42-2.30 (m, 2H), 2.26 (s, 3H), 2.18-2.11 (m, 2H), 2.08 (s, 3H).

LC-MS (Method C): Rt = 0.498 min; MS (ESIpos): m/z = 348.2 [M+H] ⁺

HPLC (Method AN): Rt = 1.520 min; purity: 99%.

SFC (Rt = 2.526 min, ee% = 99%).

Intermediate 192 2-(7-bromo-1 _! 8-naphthyndm-2-yl)-3,5-dimethyl-phenol

To a solution of 2-bromo-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (5.00 g, 14.5 mmol, 1 eq) in dichloromethane (30 mL) was added BBr? (7.30 g, 29.1 mmol, 2.81 mL, 2eq), after stirring at 25 °C for 2h, the mixture was quenched with NHa/MeOH (6ml) and concentrated to give 2-(7-bromo-1 ,8- naphthyridin-2-yl)-3,5-dimethyl-phenol (5.00 g, 13.7 mmol, 93% yield, 90% purity) as a black solid. LC-MS (Method C): Rt = 0.546 min; MS (ESIpos): m/z = 329.2 [M+1] ⁺ .

Intermediate 193

3-[7-(2-methoxy-4,6-dimethyi-phenyl)-1,§-naphthyndm-2-yl ]cyciopentanone

A mixture of 2-(7-bromo-1 ,8-naphthyridin-2-yl)-3,5-dimethyl-phenol (3.08 g, 9.35 mmol, 1 eq) , 2-(2,5- dihydrofuran-3-yl)-4, 4, 5, 5-tetramethyl-1 ,3,2-dioxaborolane (2.20 g, 11.2 mmol, 1.2eq), Pd(dppf)Cl2 (684 mg, 935 pmol, 0.1 eq) , CS2CO3 (6.09 g, 18.70 mmol, 2eq) in dioxane (100 mL) and water (10 mL) were degassed and purged with N2 for 3 times, after stirring at 80 °C for 12 h under N2 atmosphere, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase column (column: C18, 330 g, mobile phase: [water(FA) - MeCN]; B%: 20% - 60%, 10 min) to give a 2-[7-(2,5-dihydrofuran-3-yl)-1 ,8-naphthyridin-2-yl]-3,5-dimethyl-phenol (2.00 g, 5.03 mmol, 54% yield, 80% purity) as a black solid.

LC-MS (Method C): Rt = 0.444 min; MS (ESIpos): m/z = 319.1 [M+1J*.

Intermediate 194

To a solution of 2-[7-(2,5-dihydrofuran-3-yl)-1 ,8-naphthyridin-2-yl]-3,5-dimethyl-phenol (1.70 g, 5.34 mmol, 1 eq) potassium carbonate (738 mg, 5.34 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (4.07 g, 16.0 mmol, 3 eq) in methanol (20 mL) were added cuprous oxide (76.4 mg, 534 pmol, 55 pL, 0.1 eq) and PPhs (1.82 g, 6.94 mmol, 1.3 eq), after stirring at 25 °C for 16 h, the mixture was filtered and the filtrate was concentrated at reduced pressure to give 3,5-dimethyl-2-[7-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)tetrahydrofuran-3-yl]- 1 ,8-naphthyridin-2-yl]phenol (2.00 g, 3.14 mmol, 59% yield, 70% purity) as a white solid.

LC-MS (Method C): Rt = 0.510 min; MS (ESIpos): m/z = 447.2 [M+1 ] ⁺ .

Intermediate 195

(3S)-4-[7-(2-hydi ^, oxy-4,6-dimethybphenyl)-1,8-naphthyndin-2-yl]tetrahydr ofuran-3-ol

To a solution of 3,5-dimethyl-2-[7-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)tetrahydrofuran-3-yl]- 1 ,8-naphthyridin-2-yl]phenol (2.00 g, 3.14 mmol, 1 eq) in tetrahydrofuran (15 mL) was a solution of sodium hydroxide (376 mg, 9.41 mmol, 3 eq) in water (15 mL) at 25 °C, then hydrogen peroxide (6.00 g, 53.1 mmol, 5mL, 30% purity, 16 eq) was added to the mixture at 0 °C, after stirring at 25 °C for 2 h, the mixture was quenched with saturated sodium sulfite solution (100 mL) and extracted with ethyl acetate (100 mL x 3), the combined organic phase was purified by reversed-phase column (column: C18, 220 g, mobile phase: [water(FA) - MeCN];B%: 15% - 50%, 10 min) to give a (3S)-4-[7-(2-hydroxy- 4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]tetrahydrofuran-3-ol (300 mg, 856 pmol, 27% yield, 96% purity) as a yellow solid.

1 H NMR (400 MHz, DMSO-d _s ) S = 9.79 - 9.73 (m, 1 H), 8.50 - 8.35 (m, 2H), 7.67 - 7.52 (m, 2H), 6.62 (d, J = 5.2 Hz, 2H), 5.46 - 5.15 (m, 1 H), 4.76 - 4.56 (m, 1 H), 4.38 - 4.18 (m, 1 H), 4.13 - 3.90 (m, 2H), 3.85 - 3.58 (m, 2H), 2.26 (s, 3H), 2.08 (s, 3H)

LC-MS (Method C): Rt = 0.405 min; MS (ESIpos): m/z = 337.2 [M+1] ⁺ .

Intermediate 196 and 197 4-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1,8-naphthyndin-2-yl]te trahydrofuran-3-o! and

The reaction was set up for SFC seperation. The residue was purified by purified by SFC (column: DAICEL CHIRALPAKAD(250mm*30mm,10um);mobile phase: [CO ₂ - EtOH(0.1%NH ₃ «H ₂ O)]; B%: 50%, isocratic elution mode.) to give (3S,4R)-4-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]tetrahydrofuran-3-ol (220 mg, 647 pmol, 72% yield, 99% purity) as a yellow solid and (3S,4S)-4-[7- (2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]tetrahydrofuran-3-ol (70 mg, 206 pmol, 23% yield, 99% purity) as a yellow solid.

Intermediate 196 LC-MS (Method C): Rt = 0.400 min; MS (ESIpos): m/z = 337.2 [M+1 ] ⁺ .

Intermediate 197 LC-MS (Method C): Rt = 0.402 min; MS (ESIpos): m/z = 337.1 [M+1 ] ⁺ .

Compound 90, 91 , and 92

4-[7-(2-hydroxy~4,,§~dimethyl~phenyl)-1,8-naphthyndin-2- yl]tetrahyd!'ofuran-3-ol

The reaction was set up for SFC separation. The residue was purified by SFC: column: The residue was purified by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm,10um); mobile phase: [CO ₂ - EtOH(0.1 %NH ₃ • H ₂ O)]; B%: 45%, isocratic elution mode.) to give rac-(3R,4R)-4-[7-(2-hydroxy-4,6- dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]tetrahydrofuran-3-ol (105 mg, 310 pmol, 47% yield, 99% purity) as a yellow solid; rac-(3R,4R)-4-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]tetrahydrofuran-3-ol (98.7 mg, 290 pmol, 44% yield, 99% purity) as a yellow solid; rac-(3R,4R)-4-[7- (2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]tetrahydrofuran-3-ol (28.1 mg, 81 .6 pmol, 39% yield, 98% purity) as a yellow solid and rac-(3R,4R)-4-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8- naphthyridin-2-yl]tetrahydrofuran-3-ol (28.3 mg, 83.3 pmol, 40% yield, 99% purity) as a yellow solid.

Compound 90

¹ H NMR (400 MHz, DMSO-d6) 5 = 12.67 - 11 .60 (m, 1 H), 8.20 (d, J = 8.4 Hz, 1 H), 8.12 (d, J = 8.4 Hz, 1 H), 7.74 (d, J = 8.4 Hz, 1 H), 7.46 (d, J = 8.4 Hz, 1 H), 6.79 (s, 1 H), 6.69 (s, 1 H), 4.97 - 4.85 (m, 1 H), 4.49 (dd, J = 7.6, 8.8 Hz, 1 H), 4.28 (dd, J = 5.6, 9.6 Hz, 1 H), 4.17 (dd, J = 6.4, 8.8 Hz, 1 H), 3.93 (dd, J = 4.0, 9.6 Hz, 1 H), 3.82 (dt, J = 4.0, 6.8 Hz, 1 H), 2.52 (s, 3H), 2.34 (s, 3H) LC-MS (Method C): Rt = 0.405 min; MS (ESIpos): m/z = 337.1 [M+1 ] ⁺ .

SFC (Rt = 1 .573 min, ee% = 99%).

Compound 91 ¹ H NMR (400 MHz, DMSO-c/6) 6 = 13.07 - 11.24 (m, 1 H), 8.22 (d, J = 8.4 Hz, 1 H), 8.14 (d, J = 8.4 Hz, 1 H), 7.75 (d, J = 8.8 Hz, 1 H), 7.46 (d, J = 8.4 Hz, 1 H), 6.80 (s, 1 H), 6.70 (s, 1 H), 5.03 - 4.86 (m, 1 H), 4.50 (t, J = 8.4 Hz, 1 H), 4.28 (dd, J = 5.6, 9.6 Hz, 1 H), 4.17 (dd, J = 6.8, 8.8 Hz, 1 H), 3.93 (dd, J = 4.0, 9.6 Hz, 1 H), 3.80 (dt, J = 4.0, 7.2 Hz, 1 H), 2.53 (s, 3H), 2.34 (s, 3H)

LC-MS (Method C): Rt = 0.405 min; MS (ESIpos): m/z = 337.1 [M+1]*

SFC (Rt = 2.015 min, ee% = 99%).

Compound 92

¹ H NMR (400 MHz, DMSO-d6) 6 = 12.67 - 11.60 (m, 1 H), 8.20 (d, J = 8.4 Hz, 1 H), 8.12 (d, J = 8.4 Hz, 1 H), 7.74 (d, J = 8.4 Hz, 1 H), 7.46 (d, J = 8.4 Hz, 1 H), 6.79 (s, 1 H), 6.69 (s, 1 H), 4.97 ■ 4.85 (m, 1 H), 4.49 (dd, J = 7.6, 8.8 Hz, 1 H), 4.28 (dd, J = 5.6, 9.2 Hz, 1 H), 4.17 (dd, J = 6.2, 8.8 Hz, 1 H), 3.93 (dd, J = 4.0, 9.6 Hz, 1 H), 3.82 (dt, J = 4.0, 6.8 Hz, 1 H), 2.52 (s, 3H), 2.34 (s, 3H) LC-MS (Method C): Rt = 0.405 min; MS (ESIpos): m/z = 337.1 [M+1 ]* SFC (Rt = 1 .617 min, ee% = 98%).

Diastereomer 4

¹ H NMR (400 MHz, DMSO-d _s ) 5 = 9.76 (s, 1 H), 8.40 (t, J = 8.0 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 6.63 (d, J = 6.0 Hz, 2H), 5.19 (d, J = 4.4 Hz, 1 H), 4.70 (br d, J = 4.0 Hz, 1 H), 4.33 (dd, J = 8.0, 10.4 Hz, 1 H), 4.21 (t, J = 8.0 Hz, 1 H), 4.02 (dd, J = 4.0, 9.2 Hz, 1 H), 3.81 - 3.71 (m, 2H), 2.26 (s, 3H), 2.08 (s, 3H)

LC-MS (Method C): Rt = 0.399 min; MS (ESIpos): m/z = 337.1 [M+1]*

SFC (Rt = 1 .868 min, ee% = 97%).

Intermediate 198 tert-butyl (2R)-2-[methoxy(methyl)carbamoyl]morpholme-4-carboxylate

To a solution of (2R)-4-tert-butoxycarbonylmorpholine-2-carboxylic acid (5.00 g, 21 .6 mmol, 1 .0 eq) and N-methoxymethanamine (3.16 g, 32.4 mmol, 1.50 eq, HCI salt) in dichloromethane (50.0 mL) were added 1-(3-dimethyiaminopropyl)-3-ethylcarbodiimide hydrochloride (6.22 g, 32.4 mmol, 1.5 eq), 1- hydroxybenzotriazole (4.38 g, 32.43 mmol, 1.5 eq) and N,N-diisopropylethylamine (8.38 g, 64.8 mmol, 11.30 mL, 3.0 eq) at 20 °C. After stirring at 20 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 10-50% Ethyl acetate/Petroleum ethergradient @ 80 mL/min) to give tert-butyl (2R)-2-[methoxy(methyl)carbamoyl]morpholine-4- carboxylate (5.00 g, 16.4 mmol, 56% yield, 90% purity) as colorless oil.

¹ H NMR (400 MHz, CDCb) 5 = 4.50-4.24 (m, 1 H), 4.12-3.96 (m, 2H), 3.95-3.80 (m, 1 H), 3.76 (s, 3H), 3.65-3.54 (m, 1 H), 3.22 (s, 3H), 3.15-2.95 (m, 2H), 1.47 (s, 9H).

LC-MS (Method C) Rt = 0.443 min; MS (ESIpos): m/z =219.2 [M-55] ⁺

Intermediate 199 tert-butyl (2R)-2-acetylmorphollue-4-carboxy!ate To a solution of tert-butyl (2R)-2-[methoxy(methyl)carbamoyl]morpholine-4-carboxylate (4.00 g, 14.6 mmol, 1 .0 eq) in tetrahydrofuran (30 mL) was added methylmagnesium bromide (3 M in THF, 14.6 mL, 3.0 eq) at -70 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was added into saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 45 g SepaFiash® Silica Flash Column, Eluent of 85-75% Ethyl acetate/Petroleum ether gradient @ 80 mL/min) to give tert-butyl (2R)-2-acetylmorpholine-4- carboxylate (2.90 g, 12.4 mmol, 85% yield, 98% purity) as colorless oil.

¹ H NMR (400 MHz, DMSO-c/ ₆ ) 5 [ppm] = 3.93-3.87 (m, 3H), 3.65 (d, J = 13.6 Hz, 1 H), 3.51-3.45 (m, 1 H), 2.93 (s, 2H), 2.15 (s, 3H), 1.40 (s, 9H).

LC-MS (Method C) Rt = 0.465 min; MS (ESIpos): m/z =130.3 [M-99] ⁺

Intermediate 200 tert-butyl 2-[7-(2-methoxy-4,6-dimethyl-pheny!)-1,8-naphthyrldm-2-yl]mo rpholine-4- carboxylate

To a solution of 2-amino-6-(2-methoxy-4,6-dimethyl-phenyl)pyridine-3-carbalde hyde (373 mg, 1.45 mmol, 1.00 eq) and tert-butyl (2R)-2-acetylmorpholine-4-carboxylate (1.00 g, 4.36 mmol, 3.00 eq) in ethanol (15mL) was added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (664 mg, 4.36 mmol, 3.0 eq). After stirring at 60 °C for 12 h, the mixture was concentrated under vacuum to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(FA) - MeCN];B%: 20% - 45%, 8 min) to give tert-butyl 2-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]morpholine-4-carboxylate (200 mg, 436 pmol, 30% yield, 98% purity) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₅ ) 5 [ppm] = 8.53 (d, J = 8.4 Hz, 1 H), 8.45 (d, J = 8.4 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.51 (d, J = 8.4 Hz, 1 H), 6.82 (s, 1 H), 6.77 (s, 1 H), 4.68 (d, J = 10.4 Hz, 1 H), 4.35 (s, 1 H), 4.11-4.08 (m, 2H), 3.87 (d, J = 12.8 Hz, 1 H), 3.65 (s, 3H), 3.00 (d, J = 4.8 Hz, 2H), 2.36 (s, 3H), 2.01 (s, 3H), 1.43 (s, 9H).

LC-MS (Method C) Rt = 0.555 min; MS (ESIpos): m/z =450.3 [M+H] ⁺ .

Intermediate 201 and 202 tert-butyl 2-[7-(2-hydroxy-4,6-dlmethyl-pheriyl)-1,§-naphthyridm-2-yl] morpho!lne-4- carboxylate;

To a solution of tert-butyl 2-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]morpholine-4- carboxylate (170 mg, 0.378 mmol, 1.0 eq) in DMF (10 mL) was added sodium ethanethiolate (1.59 g, 18.9 mmol, 50 eq). The mixture was stirred at 100 °C for 12 h. The mixture was diluted with saturated ammonium chloride (20 mL), extracted with ethyl acetate (20 mL x 3), washed with brine (20 mL x 3), and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(FA) - MeCN];B%: 30% - 60%, 5 min) to give desired product. The product was further separated by SFC (condition: column: DAICEL CHIRALCEL OD(250mm*30mm,10um);mobile phase: [CO ₂ -/PrOH(0.1 %NH3‘H2O)]; B%: 50%, isocratic elution mode ) to give tert-butyl rel-(2R)-2-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]morpholine-4-carboxylate (40.0 mg, 87.3 pmol, 23 % yield, 95% purity) as a yellow solid and tertbutyl rel-(2R)-2-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]morpholine-4-carboxylate (40.0 mg, 87.3 pmol, 23% yield, 95% purity) as a yellow solid.

Intermediate 201

LC-MS (Method G) Rt = 0.527 min; MS (ESIpos): m/z =336.3 [M-99] ⁺ .

SFC (Rt = 2.121 min, ee% = 99%).

Intermediate 202

LC-MS (Method G) Ri = 0.528 min; MS (ESIpos): m/z =336.2 [M-99] ⁺ .

SFC (Rt = 2.488 min, ee% = 99%).

Compound 94

3.5-dimethyb2-[7-[morpholin-2-yl]-1,8-naphthyridin-2-yl]p henol

A mixture of tert-butyl 2-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]morpholine-4- carboxylate (40.0 mg, 0.091 mmol, 1.0 eq) in hydrochloric acid (4M in dioxane, 10 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 25 °C for 2 h under nitrogen atmosphere. The mixture was concentrated under vacuum to give a residue. The crude product was purified by reversed-phase column (column: C18, 40 g, mobile phase: [wate^NHs-FhO) - MeCN];B%: 20% - 50%, 8 min) to give 3,5-dimethyl-2-[7-[morpholin-2-yl]-1 ,8-naphthyridin-2-yl]phenol (14.1 mg, 0.037 mmol, 41 % yield, 90% purity) as an off-white solid.

NMR (400 MHz, DMSO-cfe) 5 [ppm] = 9.77 (d, J = 1.2 Hz, 1 H), 8.48 (d, J = 8.4 Hz, 1 H), 8.43 (d, J = 8.4 Hz, 1 H), 7.72 (d, J = 8.4 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 6.63 (d, J = 6.4 Hz, 2H), 4.66 (dd, J = 2.4, 10.0 Hz, 1 H), 3.97 (d, J = 10.8 Hz, 1 H), 3.74-3.67 (m, 1 H), 3.26-3.22 (m, 1 H), 2.80-2.78 (m, 2H), 2.7-2.65 (m, 2H), 2.26 (s, 3H), 2.08 (s, 3H).

LC-MS (Method G) Rt = 0.534 min; MS (ESIpos): m/z =336.3 [M+H] ⁺ .

Compound 95

3.5-dimethyl-2-[7-[morpholin-2-yl]-1,8-naphthyridin-2-yl] phenol

A mixture of tert-butyl 2-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]morpholine-4- carboxylate (40.0 mg, 0.091 mmol, 1 .00 eq) in hydrochloric acid (4M in dioxane, 10 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 25 °C for 2 h under nitrogen atmosphere. The mixture was concentrated under vacuum to give a residue. The crude product was purified by reversed-phase column (column: C18, 40 g, mobile phase: [wate^NHs’HaO) - MeCN];B%: 30% - 50%, 7 min) to give 3,5-dimethyl-2-[7-[morpholin-2-yl]-1 ,8-naphthyridin-2-yl]phenol (17.1 mg, 0.046 mmol, 50 % yield, 90% purity) as an off-white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 9.77 (s, 1 H), 8.48 (d, J = 8.4 Hz, 1 H), 8.43 (d, J = 8.3 Hz, 1 H), 7.72 (d, J = 8.4 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 6.63 (d, J = 6.0 Hz, 2H), 4.66 (dd, J = 2.4, 10.4 Hz, 1 H), 3.97 (d, J = 10.4 Hz, 1 H), 3.74-3.68 (m, 1 H), 3.26-3.23 (m, 1 H), 2.81-2.78 (m, 2H), 2.70-2.65 (m, 1 H), 2.26 (s, 3H), 2.08 (s, 3H).

LC-MS (Method G) Rt = 0.529 min; MS (ESIpos): m/z =336.2 [M+H] ⁺ . Intermediate 203 7-(2-hydroxy-4,6-dimethyl-phenyi)-2-(1-methyl-3-piperidyl)-1 ,8-naphthyridine-4-carboxylic acid To a solution of methyl 7-(2-hydroxy-4,6-dimethyl-phenyl)-2-(1-methyl-3-piperidyl)-1 ,8-naphthyridine-4- carboxylate (260 mg, 519 pmol, 1 eq) in THF (5 mL) and water (5 mL) was added lithium hydroxide (37.3 mg, 1 .56 mmol, 3 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was concentrated to remove tetra hydrofuran. The residue was added water (5 mL) and the pH of the mixture was adjusted to 2 - 3 with hydrochloric acid (1 M in water) at -10 °C. The mixture were extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give 7-(2-hydroxy-4,6-dimethyl-phenyl)-2-(1-methyl-3-piperidyl)-1 ,8- naphthyridine-4-carboxylic acid (300 mg, crude) as a yellow solid..

LC-MS (Method C): Rt = 0.393 min; MS (ESI): m/z = 392.3 [M+H] ⁺ .

Intermediate 204

7-(2-hydroxy-4,6-d‘methyi-pheny!)~N~methyi~2-(1~methyi~ 3~piper‘dyi)~1 _! 8~oaphthyridine-4~ carboxamide

To a solution of 7-(2-hydroxy-4,6-dimethyl-phenyl)-2-(1-methyl-3-piperidyl)-1 ,8-naphthyridine-4- carboxylic acid (150 mg, 383 pmol, 1 eq) and MeNHz (54.4 mg, 766 pmol, 2 eq, HCI salt) in DMF (5 mL) were added DIPEA (247 mg, 1 .92 mmol, 333 pL, 5 eq) and HATU (291 mg, 766 pmol, 2 eq) at 25 °C. After stirring at 25 °C for 1 h, the mixture was added water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude. The crude was purified by reversed-phase column (column: C18, 40 g, mobile phase: fwater(FA) - MeCN];B%: 15% - 45%, 10 min) to give 7-(2- hydroxy-4,6-dimethyi-phenyl)-N-methyl-2-(1 -methy I-3- pi peridy I)- 1 ,8-naphthyridine-4-carboxamide (110 mg, 266 pmol, 69% yield, 98% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.407 min; MS (ESI): m/z = 405.3 [M+H] ⁺ .

Compound 96 and 97 7-(2-hydroxy-4,6-dimethyl-phenyl)-N-methyl-2-[1-methyi-3-pip eridyl]-1,8-naphthyridine-4- carboxamide

The reaction was set up for SFC separation. The residue was purified by SFC: (column: DAICEL CHIRALCEL OX (250mm*30mm,10um);mobile phase: [[CO ₂ -i-PrOH(0.1%NH ₃ ’H ₂ O)];B%:50%, isocratic elution mode) to give 7-(2-hydroxy-4,6-dimethyl-phenyl)-N-methyl-2-[rel-(3R)-1-met hyl-3- piperidylj-1 ,8-naphthyridine-4-carboxamide (11.8 mg, 28.4 pmol, 10% yield, 97% purity) as a yellow solid. and 7-(2-hydroxy-4,6-dimethyl-phenyl)-N-methyl-2-[rel-(3R)-1-met hyl-3-piperidyl]-1 ,8- naphthyridine-4-carboxamide (25.0 mg, 56.5 pmol, 21 % yield, 91 % purity) as a yellow solid.

Compound 96

¹ H NMR (400 MHz, DMSO-c/ _e ) 6 = 8.85-8.78 (m, 1 H), 8.56 (d, J = 8.4 Hz, 1 H), 8.27 (s, 3H), 7.64 (s, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 6.64 (s, 1 H), 6.62 (s, 1 H), 3.19 (s, 2H), 3.13-3.05 (m, 2H), 2.88 (d, J = 4.0 Hz, 3H), 2.84-2.81 (m, 1 H), 2.27 (s, 3H), 2.26 (s, 3H), 2.07 (s, 3H), 2.05-1.90 (m, 2H), 1.79-1.75 (m, 1 H), 1.68-1.64 (m, 1 H).

LC-MS (Method C): Rt = 0.407 min; MS (ESIpos): m/z = 405.3 [M+1] ⁺ .

SFC (Rt = 0.933 min, ee% = 95%).

Compound 97

¹ H NMR (400 MHz, DMSO- d ₆ ) 6 = 9.73 (s, 1 H), 8.84 (d, J = 4.4 Hz, 1 H ), 8.58 (d, J = 8.8 Hz, 1 H), 7.68 (s, 1 H), 7.61 (d, J = 8.4 Hz, 1 H), 6.65 (s, 1 H), 6.62 (s, 1 H), 3.30-3.25 (m, 3H), 3.14 (s, 1 H), 2.88 (d, J = 4.4 Hz, 3H), 2.56 (s, 4H), 2.26 (s, 3H), 2.16-2.11 (m, 1 H), 2.07 (s, 3H), 1 .90-1 .75 (m, 2H), 1 .72-1 .60 (m, 1 H).

LC-MS (Method C): Rt = 0.412 min; MS (ESIpos): m/z = 405.3 [M+1 ] ⁺ .

SFC (Rt = 1 .383 min, ee% = 85%).

Intermediate 205

7-(2-hydroxy-4,6-d‘methyi-pheny!)~N.N-dimetbyl-2~(1-met hy!~3-piperidy!)~1,8~naphthyridine~4- carboxamide

To a solution of 7-(2-hydroxy-4,6-dimethyl-phenyl)-2-(1-methyl-3-piperidyl)-1 ,8-naphthyridine-4- carboxylic acid (150 mg, 383 pmol, 1 eq) and Me ₂ NH (65.8 mg, 766 pmol, 73.9 pL, 2 eq, HCI salt) in DMF (5 mL) were added DIPEA (247 mg, 1.92 mmol, 333 pL, 5 eq) and HATU (291 mg, 766 pmol, 2 eq) at 25 °C. After stirring at 25 °C for 2 h, the mixture was added water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude. The crude was purified by reversed- phase column (column: C18, 40 g, mobile phase: [water (FA) - MeCN]; B%: 15% - 45%, 10 min) to give 7-(2-hydroxy-4,6-dimethyl-phenyl)-N,N-dimethyl-2-(1-methyl-3 -piperidyl)-1 ,8-naphthyridine-4- carboxamide (120 mg, 275. pmol, 72% yield, 96% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.417 min; MS (ESI): m/z = 419.2 [M+H] ⁺ .

Compound 98 and 99

The reaction was set up for SFC separation. The residue was purified by SFC: (column: DAICEL CHIRALCEL OX (250mm*30mm,10um);mobile phase: [[CO ₂ -i-PrOH(0.1%NH ₃ ’H ₂ O)];B%:50%, isocratic elution mode) to give 7-(2-hydroxy-4,6-dimethyl-phenyl)-N,N-dimethyl-2-[rel-(3R)-1 -methyl-3- piperidyl]-1 ,8-naphthyridine-4-carboxamide (26.0 mg, 60.1 pmol, 22% yield, 98% purity) as a yellow solid and 7-(2-hydroxy-4,6-dimethyl-phenyl)-N,N-dimethyl-2-[rel-(3R)-1 -methyl-3-piperidyl]-1 ,8- naphthyridine-4-carboxamide (21 .2 mg, 48.0 pmol, 17% yield, 95% purity) as a yellow solid.

Compound 98 ¹ H NMR (400 MHz, DMSO- d _s ) 6 = 8.28 (s, 2H), 8.14 (d, J = 8.4 Hz, 1 H), 7.60-7.56 (m, 2H), 6.64 (s, 1 H), 6.62 (s, 1 H), 3.22-3.15 (m, 2H), 3.14 (s, 3H), 3.10-3.02 (m, 2H), 2.82 (s, 3H), 2.81-2.78 (m, 1 H), 2.26 (s, 3H), 2.25 (s, 3H), 2.08 (s, 3H), 2.03-1.95 (m, 2H), 1.78-1.73 (m, 1 H), 1.68-1.64 (m, 1 H). LC-MS (Method C): Rt = 0.414 min; MS (ESIpos): m/z = 419.3 [M+1] ⁺ .

SFC (Rt = 2.233 min, ee% = 99%).

Compound 99

¹ H NMR (400 MHz, DMSO- d ₆ ) 6 = 9.48 (s, 1 H), 8.19 (d, J = 8.8 Hz, 1 H), 7.68-7.60 (m, 2H), 6.64 (s, 1 H), 6.63 (s, 1 H), 3.15 (s, 3H), 3.05-2.95 (m, 1 H), 2.91 -2.87 (m, 3H), 2.84 (s, 3H), 2.36-2.30 (m, 2 H), 2.26 (s, 3H), 2.22-2.17 (m, 2H), 2.09 (s, 3H), 2.05-1.95 (m, 2H), 1.90-1.85 (m, 1 H), 1.70-1.64 (m, 1 H). LC-MS (Method C): Rt = 0.413 min; MS (ESIpos): m/z = 419.2 [M+1 ] ⁺ .

SFC (Rt = 2.825 min, ee% = 88%).

Intermediate 206

2-(2~methQX'y-4 _! 6~diniethyl-phenyl)-7-methyl-1,8-naphthyridme

To a solution of 2-bromo-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (5.00 g, 14.5 mmol, 1 eq) in THF (50 mL) was added MeMgBr (3.00 M in diethyl ether, 14.5 mL, 3 eq) at 0 °C dropwise. After stirring at 20 °C for 1 h, the mixture was quenched by ice-water (20 mL). The pH of the mixture was adjusted to 7-8 with hydrochloric acid (1.00 M in water). The mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether/ethyi acetate = 10/1 to 2/1) to give 2-(2-methoxy-4,6- dimethyl-phenyl)-7-methyl-1 ,8-naphthyridine (2.20 g, 7.11 mmol, 48% yield, 90% purity) as a yellow solid.

¹ H NMR (400 MHz, CDCh) 5 [ppm] = 8.13 (d, J = 8.0 Hz, 1 H), 8.09 (d , J = 8.0 Hz, 1 H), 7.46 (d, J = 8.4 Hz, 1 H), 7.38 (d, J = 8.4 Hz, 1 H), 6.75 (s, 1 H), 6.66 (s, 1 H), 3.68 (s, 3H), 2.82 (s, 3H), 2.39 (s, 3H), 2.16 (s, 3H).

LC-MS (Method C): Rt = 0.429 min; MS (ESIpos): m/z = 279.2 [M+H] ⁺ .

Intermediate 207

To a solution of 2-(2-methoxy-4,6-dimethyl-phenyl)-7-methyl-1 ,8-naphthyridine (500 mg, 1.80 mmol, 1 eq) in THF (3 mL) was added LDA (2.00 M in heptane, 1.80 mL, 2 eq) at 0 °C dropwise. After stirring at 0 °C for 0.5 h, tert-butyl N-(3-oxocyclobutyl)carbamate (665 mg, 3.59 mmol, 2 eq) in THF (1 mL) was added to the reaction mixture dropwise. After stirring at 20 °C for 16 h, the mixture was quenched by water (10 mL). The pH of mixture was adjusted to 7-8 with hydrochloric acid (1 M in water). The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate = 3/1 to 1/1) to give tert-butyl N-[3-hydroxy-3-[[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]methyl]cyclobutyl]carbamate (430 mg, 834 pmol, 46% yield) as a yellow solid.

¹ H NMR (400 MHz, CDCb) 5 [ppm] = 8.21-8.12 (m, 2H), 7.51 (d, J = 8.4 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 6.77 (s, 1 H), 6.68 (s, 1 H), 4.80-4.72 (m, 1 H), 4.00-3.89 (m, 1 H), 3.71 (s, 3H), 3.28 (s, 2H), 2.57- 2.50 (m, 2H), 2.39 (s, 3H), 2.36-2.28 (m, 1 H), 2.14 (s, 3H), 2.05-2.01 (m, 1 H), 1.44 (s, 9H).

Intermediate 208

3-[[7^2-methoxy-4,6-dimethyl-phenyl)-1,8-naphthyridin-2-y l]methyl]cyclobutanamine

To a solution of tert-butyl N-[3-hydroxy-3-[[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]methyl]cyclobutyl]carbamate (380 mg, 819 pmol, 1 eq) in TFA (3 mL) was added EtsSiH (1 .91 g, 16.3 mmol, 2.62 mL, 20 eq) at 20 °C in one portion. After stirring at 80 °C for 16 h, the mixture was concentrated in vacuum to give 3-[[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]methyl]cyclobutanamine (280 mg, 805.87 pmol) as yellow oil.

LC-MS (Method C): Rt = 0.397 min; MS (ESIpos): m/z = 348.2 [M+H] ⁺ .

Intermediate 209

N-[3-[[7-(2-methoxy-4,6-dimethyl-phenyl)-1,8-naphthyridin -2-yl]methyl]cyclobutyl]acetamide

To a solution of 3-[[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]methyl]cyclobutanamine (280 mg, 805 pmol, 1 eq) in dichloromethane (3 mL) were added DIPEA (312 mg, 2.42 mmol, 421 pL, 3 eq) and AC2O (164 mg, 1.61 mmol, 151.37 pL, 2 eq) at 20 °C in one portion. After stirring at 20 °C for 1 h, the mixture was concentrated in vacuum to give a residue. The residue was purified by reversed- phase column (column: C18, 40 g, mobile phase: [water(FA) - MeCN];B%: 20% - 35%, 7 min) to give N-[3-[[7-(2-methoxy-4,6-dimethyi-phenyi)-1 ,8-naphthyridin-2-yi]methyl]cyclobutyi]acetamide (120 mg, 277 pmol, 34% yield, 90% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.433 min; MS (ESIpos): m/z = 390.3 [M+1 ] ⁺ .

Intermediate 210

N-[3-[[7-(2-hydroxy-4 _! 6-dimethyl-phenyl)-1,8-naphthyndin-2-yl]methyl]cyclobu tyl]acetamide

To a solution of N-[3-[[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]methyl]cyclobutyl]acetamide (110 mg, 282 pmol, 1 eq) in DMF (1 mL) was added NaSEt (475 mg, 5.65 mmol, 20 eq) at 20 °C in one portion. After stirring at 100 °C for 2 h, the mixture was filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(FA) - MeCN];B%: 25% - 35%, 10 min) to give N-[3- [[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]methyl]cyclobutyl]acetamide (30.0 mg, 77.5 pmol, 27% yield, 97% purity) as a yellow solid.

LC-MS (Method C): Rt - 0.418 min; MS (ESIpos): m/z = 376.2 [M+1 ] ⁺ .

Compound 100 and 101

N-[3-IJ7-(2-hydroxy-4,6-dimethyl-phenyl)-1,8-naphthyridin -2-yl]methyl]cyclobutyl]acetamide The reaction was set up for SFC separation. The residue was purified by SFC: (column: REGIS(S,S)WHELK-O1 (250mm x 25mm,10um);mobile phase: [CO ₂ -EtOH(0.1%NH ₃ ‘H ₂ O)];B%:35%, isocratic elution mode) to give N-[3-[[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]methyl]cyclobutyl]acetamide (8.20 mg, 21 .4 pmol, 26% yield, 98% purity) as a yellow solid and N-[3- [[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]methyl]cyclobutyl]acetamide (7.00 mg, 16.7 pmol, 21 % yield, 90% purity) as a yellow solid.

Compound 100

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 = 9.90 (s, 1 H), 8.38 (t, J = 8.0 Hz, 2H), 8.09-8.01 (m, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.49 (d, J = 8.0 Hz, 1 H), 6.63 (s, 1 H), 6.62 (s, 1 H), 4.10-3.95 (m, 1 H), 3.05 (d, J = 7.2 Hz, 2H), 2.46-2.39 (m, 1 H), 2.36-2.29 (m, 2H), 2.26 (s, 3H), 2.1 1 (s, 3H), 1.74 (s, 3H), 1.72-1.64 (m, 2H). LC-MS (Method C): Rt = 0.417 min; MS (ESIpos): m/z = 376.3 [M+H] ⁺ .

Compound 101

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 = 9.95-9.80 (m, 1 H), 8.41-8.33 (m, 2H), 8.18-8.10 (m, 1 H), 7.58-7.50 (m, 2H), 6.63 (d, J = 6.4 Hz, 2H), 4.43-4.28 (m, 1 H), 3.13 (d, J = 8.0 Hz, 2H), 2.79-2.71 (m, 1 H), 2.26 (s, 3H), 2.10 (s, 3H), 2.09-1 .93 (m, 4H), 1 .76 (s, 3H).

LC-MS (Method C): Rt = 0.418 min; MS (ESIpos): m/z = 376.3 [M+H] ⁺ .

Intermediate 211 tert-butyl 3-[2-[methoxy(methyl)am!Uo]-2-oxo-ethyl]morpholine-4-carboxy late

To a solution of (1 R,4R,6R)-2-tert-butoxycarbonyi-2-azabicyclop.2.1]heptane-6-c arboxylic acid (3.00 g, 12.4 mmol, 1 eq) and N-methoxymethanamine hydrochloride (2.43 g, 24.8 mmol, 2 eq) in dichloromethane (50 mL) were added EDCI (3.58 g, 18.6 mmol, 1 .5 eq), HOBt (2.52 g, 18.6 mmol, 1 .5 eq) and DIPEA (4.82 g, 37.3 mmol, 7 mL, 3 eq) at 25 °C. After stirring at 25 °C for 16 h. The mixture was purified by column chromatography (SIO ₂ , petroleum ether/Ethyl acetate=5/1 to 1/1) to give tertbutyl (1 S,4S,6S)-6-[methoxy(methyl)carbamoyl]-2-azabicyclo[2.2.1]hep tane-2-carboxylate (3.00 g, 9.50 mmol, 76% yield, 90% purity) as colorless oil.

LC-MS (Method C): Rt = 0.491 min; MS (ESI): m/z = 185.2 [M+H-Boc] ⁺ .

Intermediate 212 tert-butyl (1S,4S)-6-acety!-2-azabicyclo[2.2.1 ]heptane-2-carboxylate

To a solution of tert-butyl (1 S,4S)-6-[methoxy(methyl)carbamoyl]-2-azabicyclo[2.2.1 ]heptane-2- carboxylate (3.00 g, 10.5 mmol, 1 eq) in tetrahydrofuran (20 mL) was added MeMgBr (3M in THF, 1 1 mL, 3 eq) at 0 °C. After stirring at 25 °C for 2 h, the mixture was quenched by saturated ammonium chloride solution (20 mL) and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (1 S,4S)-6-acetyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (2.20 g, 8.73 mmol, 82% yield, 95% purity) as colorless oil.

LC-MS (Method C): Rt = 0.488 min; MS (ESI): m/z = 140.2 [M+H-Boc] ⁺ . Intermediate 213 tert-butyl (1S,4S)-6-[7-(2-methoxy-4,6-dimethyl-phenyi)-1,8-naphthyridi n-2-yl]-2- azabicycio[2.2.1 Jheptane-2-carboxyiate.

To a solution of tert-butyl (1 S,4S)-6-acetyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.03 g, 4.29 mmol, 2 eq) and 2-amino-6-(2-methoxy-4,6-dimethyl-phenyl)pyridine-3-carbalde hyde (550 mg, 2.15 mmol, 1 eq) in methanol (20 mL) was added DBU (980 mg, 6.44 mmol, 970 pL, 3 eq) at 25 °C. After stirring at 60 °C for 16 h, the reaction mixture was purified by column chromatography (SiCh, petroleum ether/ethyl acetate=10/1 to 1/1) to give tert-butyl tert-butyl (1 S,4S)-6-[7-(2-methoxy-4,6-dimethyl- phenyl)-1 ,8-naphthyridin-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxyla te (700 mg, 1.37 mmol, 63% yield, 90% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.550 min; MS (ESI): m/z = 460.3 [M+H] ⁺ .

Intermediate 214

To a solution of tert-butyl (1 S,4S)-6-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-2- azabicyclo[2.2.1]heptane-2-carboxylate (700 mg, 1.52 mmol, 1 eq) in dichloromethane (20 mL) was added TFA (521 mg, 4.57 mmol, 339 pL, 3 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was concentrated to give 2-[(1 S,4S)-2-azabicyclo[2.2.1 ]heptan-6-yl]-7-(2-methoxy-4,6-dimethyl-phenyl)- 1 ,8-naphthyridine (700 mg, 1.33 mmol, 87% yield, 90% purity, TFA salt) as yellow oil.

LC-MS (Method C): Rt = 0.422 min; MS (ESI): m/z = 460.2 [M+H] ⁺ .

Intermediate 215

To a solution of 2-[(1 S, 4S)-2-azabicyclo[2.2.1 ]heptan-6-yl]-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8- naphthyridine (700 mg, 1.48 mmol, 1 eq, TFA salt, EW38853-289) in methanol (20 mL) were added (HCHO)n (88.7 mg, 2.96 mmol, 2 eq), NaBHsCN (278 mg, 4.44 mmol, 3 eq) and potassium acetate (435 mg, 4.44 mmol, 3 eq). After stirring at 25 °C for 3 h. The mixture was filtrated and the filtrate was purified by reversed phase column (column: C18 80 g, mobile phase: [water (FA) - MeCN]; B%: 30% - 50%, 14 min). to give 2-(2-methoxy-4,6-dimethyl-phenyl)-7-[(1 S,4S)-2-methyl-2- azabicyclo[2.2.1]heptan-6-yl]-1 ,8-naphthyridine (280 mg, 674 pmol, 45% yield, 90% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.415 min; MS (ESI): m/z = 374.2 [M+H] ⁺ .

Intermediate 216 To a solution of 2-(2-methoxy-4,6-dimethyl-phenyl)-7-[(1 S,4S)-2-methyl-2-azabicyclo[2.2.1]heptan-6- yl]-1 ,8-naphthyridine (280 mg, 749.6 pmol, 1 eq) in DCM (15 mL) was added BBr ₃ (563 mg, 2.25 mmol, 216 pL, 3 eq) at -70 °C . After stirring at 25 °C for 1 h, the mixture was quenched by methanol (5ml), the pH of mixture was adjusted to 7 by ammonia (7.0 M in methanol, 2 mL). The mixture was purified by reversed column (column: C18 80 g, mobile phase: [water (FA) - MeCN]; B%: 30% - 60%, 12 min), to give 3,5-dimethyl-2-[7-[(1 S,4S)-2-methyl-2-azabicyclo[2.2.1]heptan-6-yl]-1 ,8-naphthyridin-2- yljphenol (80 mg, 178 pmol, 23% yield, 80% purity) as yellow oil.

LC-MS (Method C): Rt = 0.404 min; MS (ESI): m/z = 360.2 [M+H] ⁺ .

Compound 102

3,5-dimetbyl-2-[7-[(1S,4S)~2-methyt~2-azabicyclQ[2.2.1]he ptar<-6-yl]-1 _l 8~napbthyndin-2~ yljphenoi

The reaction was set up for SFC separation. The residue was separated by SFC: (column: DAICEL CHIRALPAK AD(250mm*30mm,10 urn); mobile phase: [CO ₂ -MeCN/i-PrOH(0.1 % NH ₃ «H ₂ O)];B%:45%, isocratic elution mode) to give 3,5-dimethyl-2-[7-[(1 S,4S,6S)-2-methyl-2-azabicyclo[2.2.1]heptan-6-yl]- 1 ,8-naphthyridin-2-yl]phenol (13.1 mg, 34.8 pmol, 15% yield, 95% purity) as a white solid, and 3,5- dimethyl-2-[7-[(1 S,4S)-2-methyl-2-azabicyclo[2.2.1]heptan-6-yl]-1 ,8-naphthyridin-2-yl]phenol (16.7 mg, 44.8 pmol, 20% yield, 96% purity) as a white solid.

Compound 102

NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 8.37 (dd, J = 2.0, 8.4 Hz, 1 H), 7.96 (d, J = 8.4 Hz, 1 H), 7.58- 7.49 (m, 1 H), 7.39-7.29 (m, 1 H), 6.87 (s, 1 H), 6.63 (d, J = 10.0 Hz, 1 H), 3.10-2.92 (m, 2H), 2.86-2.55 (m, 4H), 2.42-2.31 (m, 3H), 2.26 (s, 3H), 2.13-2.04 (m, 3H), 2.02-1.85 (m, 1 H), 1.84-1.26 (m, 2H). LC-MS (Method C): Rt = 0.416 min; MS (ESI) m/z = 360.1 [M+H] ⁺ .

SFC (Rt = 1 .737 min, ee% = 99%)

Enantiomer 2

¹ H NMR (400 MHz, DMSO-d _s ) 5 [ppm] =10.32 - 9.46 (m, 1 H), 8.49 - 8.27 (m, 1 H), 7.97 (d, J = 8.8 Hz, 1 H), 7.54 (d, J = 8.4 Hz, 1 H), 6.87 (s, 1 H), 6.63 (d, J = 8.4 Hz, 1 H), 3.15 - 2.96 (m, 2H), 2.91-2.59 (m, 4H), 2.45 - 2.34 (m, 3H), 2.26 (s, 3H), 2.16 - 1.99 (m, 3H), 1.94 - 1.74 (m, 1 H), 1.33 - 1.10 (m, 2H). LC-MS (Method C): Rt = 0.420 min; MS (ESI) m/z = 360.1 [M+H] ⁺ .

SFC (Rt = 1 .215 min, ee% = 99%).

Intermediate 217 tert-butyl 3-[2-[methoxy(methyl)amino]-2-oxo-ethyl]morpholine-4-carboxy late

To a solution of 2-(4-tert-butoxycarbonylmorpholin-3-yl)acetic acid (3.00 g, 12.2 mmol, 1 eq) and N- methoxymethanamine hydrochloride (2.39 g, 24.4 mmol, 2 eq) in DCM (40 mL) were added EDCI (3.52 g, 18.3 mmol, 1.5 eq) DIPEA (4.74 g, 36.6 mmol, 6 mL, 3 eq) and HOBt (2.48 g, 18.3 mmol, 1.5 eq). After stirring at 25 °C for 16 h. The mixture was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=5/1 to 1/1) to give tert-butyl 3-[2-[methoxy(methyl)amino]-2-oxo-ethyl]morpholine- 4-carboxylate (3.4 g, 1 1 .2 mmol, 91 % yield, 95% purity) as colorless oil.

¹ H NMR (400 MHz, DMSO-d _s ) <5 [ppm] = 4.22 (br s, 1 H), 3.79 (br d, J = 8.8 Hz, 1 H), 3.67 (s, 3H), 3.66 - 3.54 (m, 2H), 3.45 (dd, J = 2.8, 11 .6 Hz, 1 H), 3.36 - 3.26 (m, 2H), 3.08 (br s, 3H), 2.90 (br dd, J = 8.4, 14.5 Hz, 1 H), 2.49 - 2.40 (m, 1 H), 1.38 (s, 9H).

LC-MS (Method C): Rt = 0.446 min; MS (ESI): m/z = 189.2 [M+H-Boc] ⁺ .

Intermediate 218 tert-butyl 3-acetonylmorphollne-4-carboxylate

To a solution of tert-butyl 3-[2-[methoxy(methyl)amino]-2-oxo-ethyl]morpholine-4-carboxy late (3.40 g, 11 .7 mmol, 1 eq) in THF (20 mL) was added MeMgBr (3 M, 8 mL, 2 eq) at 0 °C. After stirring at 25 °C for 2 h, the mixture was quenched by addition ammonium chloride saturated solution (20 mL) and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 3- acetonylmorpholine-4-carboxylate (2.40 g, 9.67 mmol, 81 % yield, 98% purity) as colorless oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 = 4.39 (s, 1 H), 3.91 - 3.67 (m, 3H), 3.57 (dd, J = 2.0, 11.6 Hz, 1 H), 3.44 (dt, J = 2.8, 11 .8 Hz, 1 H), 3.08 (s, 2H), 2.57 (d, J = 15.2 , 1 H), 2.19 (s, 3H), 1 .45 (s, 9H).

LC-MS (Method C): Rt = 0.458 min; MS (ESI): m/z = 144.1 [M-Boc+H] ⁺ .

Intermediate 219 tert-butyl 34[7~(2~methGxy~4.6~dimethyi~phenyl)-1.8-napldhyridin'2~y!]m ethyl]morpho!irie-4- carboxylate.

To a solution of tert-butyl 3-acetonylmorpholine-4-carboxylate (949 mg, 3.90 mmol, 2 eq) and 2-amino- 6-(2-methoxy-4,6-dimethyl-phenyl)pyridine-3-carbaldehyde (500 mg, 1 .95 mmol, 1 eq) in ethyl alcohol (20 mL) was added DBU (890 mg, 5.85 mmol, 882 pL, 3 eq) at 25 °C. After stirring at 60 °C for 16 h, the reaction mixture was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate=5/1 to 1/1). to give tert-butyl 3-[[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]methyl]morpholine-4-carboxylate (600 mg, 1 .16 mmol, 59% yield, 90% purity) as a yellow solid. LC-MS (Method C): Rt = 0.506 min; MS (ESI): m/z = 464.2 [M+H] ⁺ -

Intermediate 220 tert-buty! 3-[[7-(2-hydrGxy-4,6-dimethyi-pheriyl)-1,8-riaphthyridin-2-y l]methyl]morphoHne-4- carboxylate

To a solution of tert-butyl 3-[[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]methyl]morpholine-4-carboxylate (500 mg, 1.08 mmol, 1 eq) in dimethylformamide (20 mL) was added NaSEt (1.81 g, 21.57 mmol, 20 eq) at 25 °C. After stirring at 100 °C for 16 h, the mixture was poured into ammonium chloride solution (20 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18, 80 g, mobile phase: [water (FA) - MeCN]; B%: 20% - 60%, 12 min), to give tert-butyl 3-[[7-(2-hydroxy- 4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]methyl]morpholine-4-carboxylate (130 mg, 274 pmol, 25% yield, 95% purity)as a yellow solid.

LC-MS (Method C): Rt = 0.494 min; MS (ESI): m/z = 450.2 [M+H] ⁺ .

Intermediate 221 and 222 tert-butyl 3~[[7~(2-hydroxy-4.6-dimethyl-pheriyi)-1,8‘riaphthyridm~2- yl]methyl]morpholiue-4~ carboxylate

The reaction was set up for SFC separation. The residue was separated by SFC: (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [CO ₂ -EtOH(0.1 %NH ₃ H ₂ O)];B%:30%, isocratic elution mode.) to give tert-butyl rel-(3R)-3-[[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]methyl]morpholine-4-carboxylate (40.0 mg, 84.5 pmol, 29% yield, 95% purity) and tert-butyl rel-(3R)- 3-[[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]methyl]morpholine-4-carboxylate (40.0 mg, 84.5 pmol, 29% yield, 95% purity ) as a yellow solid.

Intermediate 221 , LC-MS (Method C): Rt = 0.487 min; MS (ESI): m/z = 450.2 [M+H] ⁺ - Intermediate 222, LC-MS (Method C): Rt = 0.481 min; MS (ESI): m/z = 450.3 [M+H] ⁺ .

Compound 104

3.5-d/metfiy/-2-£7-f£morpf?o//n-3-y/Jmet/?y/J-f _; 8-napfitfiynd/n-2-y/Jpfieno/

To a solution of tert-butyl 3-[[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]methyl]morpholine-4-carboxylate (30.0 mg, 66,73 pmol, 1 eq) in dichloromethane (10 mL) was added TFA (22,8 mg, 200 pmol, 14.8 pL, 3 eq) at 25 °C. After stirring at 25 °C for 3 h, the reaction mixture was concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18 40g, mobile phase: [water (FA) - MeCN]; B%: 30% - 60%, 14 min), to give 3,5-dimethyi-2-[7-[[rel- (3R)-morpholin-3-yl]methyl]-1 ,8-naphthyridin-2-yl]phenol (14.7 mg, 41.2 pmol, 46% yield, 98% purity) as a white solid.

Compound 104

¹ H NMR (400 MHz, DMSO-d _e ) 5 [ppm] = = 9.75 (s, 1 H), 9.07 - 8.96 (m, 1 H), 8.46 (dd, J = 8.4, 11 .0 Hz, 2H), 7.61 (dd, J = 2.8, 8.3 Hz, 2H), 6.63 (d, J = 5.6 Hz, 2H), 4.08 - 3.88 (m, 3H), 3.74 - 3.53 (m, 2H), 3.30 - 3.27 (m, 2H), 3.27 - 3.11 (m, 2H), 2.26 (s, 3H), 2.10 (s, 3H).

LC-MS (Method C): Rt = 0.404 min; MS (ESI) m/z - 350.2 [M+H] ⁺ .

SFC (Rt = 1 .148 min, ee% = 99%)

Compound 105

3.5-dimethyl-2-[7-[[morpholin-3-yl]methyl]-1,8-naphthyr!d in-2-yl]phenol

To a solution of tert-butyl 3-[[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]methyl]morpholine-4-carboxylate (30.0 mg, 66.73 pmol, 1 eq) in dichloromethane (10 mL) was added TFA (22.8 mg, 200 pmol, 14.8 pL, 3 eq) at 25 °C. After stirring at 25 °C for 3 h, the reaction mixture was concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18 40g, mobile phase: [water (FA) - MeCN]; B%: 30% - 60%, 14 min), to give 3,5-dimethyl-2-[7-[[rel- (3R)-morpholin-3-yl]methyl]-1 ,8-naphthyridin-2-yl]phenol (7.92 mg, 22.2 pmol, 33% yield, 98% purity) as a white solid.

Compound 105

¹ H NMR (400 MHz, DMSO-d _e ) 5 [ppm] = 9.97 - 9.62 (m, 1 H), 8.49 - 8.39 (m, 2H), 8.16 (s, 1 H), 7.67 - 7.47 (m, 2H), 6.63 (br d, J = 6.8 Hz, 2H), 3.93 - 3.74 (m, 2H), 3.67 - 3.56 (m, 1 H), 3.56 - 3.42 (m, 2H), 3.17 - 3.06 (m, 2H), 3.05 - 2.89 (m, 2H), 2.26 (s, 3H), 2.10 (s, 3H).

LC-MS (Method C): R _t = 0.410 min; MS (ESI) m/z = 350.2 [M+H] ⁺ .

SFC (Rt = 1 .522 min, ee% = 99%).

Intermediate 223 tert-butyl 2-[2-[methoxy(methyl)amino]-2-oxo-ethyl]morpholiue-4-carboxy !ate

To a solution of 2-(4-tert-butoxycarbonylmorpholin-2-yl)acetic acid (3.00 g, 12.2 mmol, 1 eq) and N- methoxymethanamine (2.39 g, 24.5 mmol, 2 eq, HCI salt) in DCM (50 ml_) were added EDCI (3.52 g,

18.4 mmol, 1.5 eq), HOBt (2.48 g, 18.4 mmol, 1.5 eq) and DIPEA (4.74 g, 36.7 mmol, 6.39 mL, 3 eq). After stirring at 25 °C for 16 h, the mixture was concentrated to give a crude. The residue was purified by column chromatography (SiOz, petroleum ether/ethyl acetate=5/1 to 3/1) to give tert-butyl 2-[2- [methoxy(methyl)amino]-2-oxo-ethyl]morpholine-4-carboxylate (3.00 g, 9.78 mmol, 80% yield, 94% purity) as colorless oil.

NMR (400 MHz, CDCh -d) 5 [ppm] = 4.00-3.80 (m, 4H), 3.69 (s, 3H), 3.55 (dt, J = 2.8, 11 .6 Hz, 1 H), 3.19 (s, 3H), 2.92 (t, J = 10.8 Hz, 1 H), 2.82-2.64 (m, 2H), 2.40 (dd, J = 4.4, 15.6 Hz, 1 H), 1 .46 (s, 9H). LC-MS (Method C): Rt = 0.458 min; MS (ESIpos): m/z = 189.2 [M-Boc+H] ⁺ .

Intermediate 224 tert-butyl 2-acetonylmorpholine-4-carboxylate

To a solution of tert-butyl 2-[2-[methoxy(methyl)amino]-2-oxo-ethyl]morpholine-4-carboxy late (3.00 g,

10.4 mmol, 1 eq) in THF (30 mL) was added MeMgBr (3 M, 10.4 mL, 3 eq) at 0 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was quenched by addition saturated ammonium chloride solution 100 mL at 25°C, and then extracted with ethyl acetate (100 mL x3). The combined organic layers were washed with aqueous sodium chloride (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SIOs, petroleum ether/ethyl acetate=10/1 to 5/1) to give tert-butyl 2-acetonylmorpholine-4-carboxylate (2.30 g, 7.09 mmol, 68% yield, 75% purity) as colorless oil.

¹ H NMR (400 MHz, CDCh-tf) 5 [ppm] = 3.95-3.76 (m, 4H), 3.52 (dt, J = 2.8, 11 .8 Hz, 1 H), 2.99-2.83 (m, 1 H), 2.70-2.57 (m, 2H), 2.43 (dd, J = 4.8, 16.0 Hz, 1 H), 2.18 (s, 3H), 1.45 (s, 9H).

LC-MS (Method C): Rt = 0.469 min; MS (ESIpos): m/z = 144.2 [M-Boc+H] ⁺ .

Intermediate 225 tert-butyl 2-[[7-(2-methoxy-4,6-dimethyl-pheny!)-1,8-naphthyridin-2-yl] methyl]ruorpholiue-4- carboxylate To a solution of tert-butyl 2-acetonylmorpholine-4-carboxylate (1 .00 g, 4.1 1 mmol, 2 eq) and 2-amino- 6-(2-methoxy-4,6-dimethyl-phenyl)pyridine-3-carbaldehyde (527 mg, 2.06 mmol, 1 eq) in MeOH (20 mL) was added DBU (939 mg, 6.17 mmol, 930 pL, 3 eq). After stirring at 60 °C for 16 h, the mixture was concentrated to give a crude. The residue was purified by column chromatography (SIO ₂ , petroleum ether/ethyl acetate=10/1 to 3/1) to give tert-butyl 2-[[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8- naphthyridin-2-yl]methyl]morpholine-4-carboxylate (800 mg, 1.64 mmol, 80% yield, 95% purity) as colorless oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 8.40 (d, J = 2.8 Hz, 1 H), 8.38 (d, J = 2.8 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 7.48-7.45 (m, 1 H), 6.82 (s, 1 H), 6.77 (s, 1 H), 3.94-3.86 (m, 2H), 3.81-3.74 (m, 1 H), 3.69 (d, J = 14.0 Hz, 1 H), 3.65 (s, 3H), 3.40-3.34 (m, 1 H), 3.12 (d, J = 5.6 Hz, 2H), 2.94-2.83 (m, 1 H), 2.67 (td, J = 2.0, 3.9 Hz, 1 H), 2.36 (s, 3H), 2.00 (s, 3H), 1 .36 (s, 9H).

LC-MS (Method C): Rt = 0.518 min; MS (ESIpos): m/z = 464.2 [M+H] ⁺ .

Intermediate 226

3.5-dimethyb2-[7-(morpholin-2-ylmethyl)-1,8-naphthyddm-2- yl]phenol

To a solution of tert-butyl 2-[[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]methyl]morpholine-4-carboxylate (750 mg, 1.62 mmol, 1 eq) in DCM (20 mL) was added BBr ₃ (1.22 g, 4.85 mmol, 468 pL, 3 eq) at -70 °C. After stirring at 25 °C for 1 h, After stirring at 20 °C for 1 h, the reaction was quenched by ammonia (3 mL, 7.0 M in methanol), and the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: C18 220 g, mobile phase: [water(FA)-MeCN];B%: 50%-60%,20 min) to give 3,5-dimethyl-2- [7-(morpholin-2-ylmethyl)-1 ,8-naphthyridin-2-yl]phenol (180 mg, 510 pmol, 32% yield, 99% purity) as a brown solid.

¹ H NMR (400 MHz, DMSO-d _e ) 6 [ppm] = 10.0-9.78 (m, 1 H), 8.39 (d, J = 8.0 Hz, 1 H), 8.36 (d, J = 8.4 Hz, 1 H), 7.28-7.22 (m, 1 H), 7.19-7.11 (m, 1 H), 6.64 (s, 1 H), 6.62 (s, 1 H), 3.99-3.89 (m, 1 H), 3.69 (d, J = 10.8 Hz, 1 H), 3.42-3.38 (m, 1 H), 3.05-3.02 (m, 1 H), 2.92-2.84 (m, 1 H), 2.68-2.65 (m, 1 H), 2.57-2.52 (m, 1 H), 2.30 (s, 2H), 2.26 (s, 3H), 2.11 (s, 3H).

LC-MS (Method C): Rt = 0.383 min; MS (ESIpos): m/z = 350.2 [M+H] ⁺ .

Compound 106 and 107

3.5-dimethyi-2-[7-[[morphoim-2-yl]methyl]-1.8-naphthyndin -2-yl]phenol

The reaction was set up for SFC separation. The residue was separated by SFC: (column: DAICEL CHIRALPAK IG (250mm*30mm _! 10um);mobile phase: [CO ₂ -MeCN/i-PrOH(0.1% NH ₃ ’H ₂ O)];B%:32%, isocratic elution mode) to give Compound 106 3,5-dimethyl-2-[7-[[morpholin-2-yl]methyl]-1 ,8- naphthyridin-2-yl]phenol (38.2 mg, 106 pmol, 41 % yield, 97% purity) as a yellow solid and Compound 107

3.5-dimethyl-2-[7-[[morpholin-2-yl]methyl]-1 ,8-naphthyridin-2-yl]phenol (46.7 mg, 127 pmol, 49 % yield, 95% purity) as a yellow solid.

Compound 106 ¹ H NMR (400 MHz, DMSO-d _s ) 5 [ppm] = 10.09-9.73 (m, 1 H), 8.37 (dd, J = 8.4, 13.6 Hz, 2H), 7.55 (dd, J = 6.4, 8.4 Hz, 2H), 6.63 (d, J = 7.2 Hz, 2H), 3.94-3.85 (m, 1 H), 3.66 (d, J = 10.8 Hz, 1 H), 3.41-3.36 (m, 2H), 3.07-2.96 (m, 2H), 2.84 (dd, J = 2.0, 12.4 Hz, 1 H), 2.68-2.60 (m, 2H), 2.26 (s, 3H), 2.10 (s, 3H).

LC-MS (Method C): Rt = 0.393 min; MS (ESIpos): m/z = 350.2 [M+H] ⁺ .

SFC (Rt = 1 .349 min, ee% = 99%)

Compound 107

¹ H NMR (400 MHz, DMSO-d _s ) 5 [ppm] = 10.33-9.32 (m, 1 H), 8.39 (dd, J = 8.4, 10.4 Hz, 2H), 8.26 (s, 1 H), 7.56 (t, J = 8.4 Hz, 2H), 6.63 (br d, J = 9.2 Hz, 2H), 4.05-3.99 (m, 1 H), 3.74 (br d, J = 10.8 Hz, 1 H), 3.51-3.43 (m, 1 H), 3.07 (br d, J = 6.4 Hz, 2H), 3.02 (d, J = 12.0 Hz, 1 H), 2.85-2.71 (m, 2H), 2.63 (t, J = 11.2 Hz, 1 H), 2.26 (s, 3H), 2.10 (s, 3H).

LC-MS (Method C): Rt = 0.391 min; MS (ESIpos): m/z = 350.2 [M+H] ⁺ .

SFC (Rt = 1 .623 min, ee% = 97%)

Intermediate 227

O1 -benzyl O4-tert-butyl 2-[methoxy(methyl)cai'bamoyl]piperazine-1 ,4-dlcarboxylate

To a solution of 1-benzyloxycarbonyl-4-tert-butoxycarbonyl-piperazine-2-carbo xylic acid (9.00 g, 24.7 mmol, 1 eq) in dichloromethane (70 mL) were added N-methoxymethanamine (3.61 g, 37.0 mmol, 1.5 eq, HCI salt), 1-(3-dimethylaminopropyl)-3-ethyicarbodiimide hydrochloride (7.10 g, 37.0 mmol, 1 .5 eq), N,N-diisoprapylethylamine (9.58 g, 74.1 mmol, 12.9 mL, 3.0 eq) and 1 -hydroxybenzotriazole (1.18 g, 8.73 mmol, 0.35 eq). After stirring at 20 °C for 16 h, the mixture was pour into water (200 mL), extracted with ethyl acetate (50 mL x 3). The organic phase was washed with brine (50 mL x 3), and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 60-80% Ethyl acetate/Petroleum ether gradient @ 80 mL/min) to give O1 -benzyl O4-tert-butyl 2- [methoxy(methyl)carbamoyl]piperazine-1 ,4-dicarboxylate (8.40 g, 20.2 mmol, 81 % yield, 98% purity) as colorless oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 7.52-7.17 (m, 5H), 5.20-4.93 (m, 2H), 4.82-4.67 (m, 1 H), 4.30- 4.08 (m, 1 H), 3.98-3.77 (m, 1 H), 3.77-3.69 (m, 2H), 3.69-3.52 (m, 1 H), 3.51-3.21 (m, 3H), 3.20-3.03 (m, 3H), 3.02-2.75 (m, 1 H), 1.35 (s, 9H).

LC-MS (Method C): Rt = 0.557 min; MS (ESI): m/z = 408.3 [M+H] ⁺ .

Intermediate 228

O1 -benzyl O4-tert-butyl 2-acetyiplperazlne-1,4-dicarboxylate

To a solution of O1-benzyl O4-tert-butyl 2-[methoxy(methyl)carbamoyl]piperazine-1 ,4-dicarboxylate (7.00 g, 17.1 mmol, 1 eq) in tetrahydrofuran (70 mL) was added methylmagnesium bromide (3 M in THF, 17.1 mL, 3 eq) dropwise at 0 °C under nitrogen atmosphere. After stirring at 0 °C for 1 h, the reaction mixture was poured into saturated ammonium chloride (300 mL) aqueous and extracted with ethyl acetate (150 mL x 3). The organic phase was concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFiash® Silica Flash Column, Eluent of 0-40% Ethyl acetate/Petroleum ethergradient @ 90 mL/min) to give O1-benzyl O4-tert-butyl 2-acetylpiperazine-1 ,4-dicarboxylate (3.50 g, 9.17 mmol, 53% yield, 95% purity) as yellow gum.

¹ H NMR (400 MHz, CDCh) 6 [ppm] = 7.42-7.28 (m, 5H), 5.26-5.07 (m, 2H), 4.76-4.46 (m, 2H), 4.08-

3.79 (m, 2H), 3.40-3.20 (m, 1 H), 3.19-3.07 (m, 1 H), 3.03-2.72 (m, 1 H), 2.35-2.13 (m, 3H), 1 .45 (s, 9H). LC-MS (Method C): Rt = 0.572 min; MS (ESI): m/z = 263.1 [M-Boc+H] ⁺ .

Intermediate 229 tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1,§-naphthyridm-2-yl]p !perazme-1 -carboxylate

A mixture of 2-amino-6-(2-methoxy-4,6-dimethyl-phenyl)pyridine-3-carbalde hyde (1.00 g, 3.90 mmol, 1 eq), O1-benzyl O4-tert-butyl 2-acetylpiperazine-1 ,4-dicarboxylate (1 .84 g, 5.07 mmol, 1.3 eq) and NaOMe (5.40 M, 2.17 mL, 3.00 eq) in MeOH (10 mL) was stirred at 70 °C for 15 h. The reaction mixture was poured into saturated ammonium chloride aqueous (30 mL) and extracted with ethyl acetate (15 mL x 3). The organic phase was concentrated in vacuum to give a residue. The residue was purified by reversed phase (column: C18, 330 g, mobile phase: [water (FA) - MeCN]; B%: 40%-70%, 5 min) to give tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]piperazine-1 -carboxylate (1.10 g, 2.35 mmol, 60% yield, 96% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-da) 5 [ppm] = 8.50 (d, J = 8.4 Hz, 1 H), 8.44 (d, J = 8.4 Hz, 1 H), 8.16 (s, 1 H),

7.79 (d, J = 8.4 Hz, 1 H), 7.51 (d, J = 8.4 Hz, 1 H), 6.82 (s, 1 H), 6.77 (s, 1 H), 4.27-4.16 (m, 1 H), 4.06- 4.04 (m, 1 H), 3.88 (d, J = 12.8 Hz, 1 H), 3.65 (s, 3H), 3.10 (d, J = 12.0 Hz, 1 H), 3.05-2.85 (m, 2H), 2.83- 2.75 (m, 1 H), 2.36 (s, 3H), 2.01 (s, 3H), 1.41 (s, 9H).

LC-MS (Method C): Rt = 0.468 min; MS (ESI): m/z = 449.2 [M+H] ⁺ .

Intermediate 230 tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1,8-naphthyridin-2-yl]- 4-methyl-piperazine-1- carboxylate

To a solution of tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]piperazine-

1-carboxylate (1.10 g, 2.35 mmol, 1 eq), (HCHO)n (172 mg, 3.53 mmol, 158 pL, 37% purity, 1.5 eq)and NaBHsCN (444 mg, 7.06 mmol, 3 eq)in MeOH (10 mL)was added HOAc (14.1 mg, 235 pmol, 13.5 pL, 0.1 eq) at 25 °C. After stirring at 25 °C for 3 h, the mixture was filtered and the filtrate was concentrated. The residue was purified by reversed phase (column: C18 220 g, mobile phase: [water (FA) - MeCN]; B%: 40%-70%, 7min) to give tert-butyl rac-(3S)-3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-

2-yl]-4-methyl-piperazine-1-carboxylate (600 mg, 1.27 mmol, 54% yield, 98% purity) as yellow oil. LC-MS (Method C): Rt = 0.466 min; MS (ESIpos): m/z = 463.3 [M+H] ⁺ .

Intermediate 231

3 _, 5~diniethyl-2-[7-[1-methylpiperazin-2-yl]-1 _! 8-naphthyridm-2-yl]phenol

To a solution of tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-4-methyl -piperazine-1 -carboxylate (270 mg, 584 pmol, 1 eq) in DCM (5 mL) was added BBra (731 mg, 2.92 mmol, 281 pL, 5 eq) at -70 °C. After stirring at 25 °C for 15 min, the reaction was quenched by ammonia (3 mL, 7.0 M in methanol), and the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (column: Cl 8, 40 g, mobile phase: [water (0.1 % NHs'HzC^-MeCN]; B%: 20%-30%, 7 min) to give 3,5-dimethyl-2-[7-[rac-(2S)-1-methylpiperazin-2-yl]- 1 ,8-naphthyridin-2-yi]phenol (200 mg, 545 pmoi, 95% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.572 min; MS (ESIpos): m/z = 349.2 [M+H] ⁺ .

Compound 109

3.5-d!methyl-2-[7-[1-^ethylpiperazin-2-yl]-1,8-naphthyndi n-2-yl]phenol

The reaction was set up for SFC separation. The residue was separated by SFC: (column: DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 pm); mobile phase: [CO ₂ - MeCN/MeOH (0.1 % NH ₃ *H ₂ O)]; B%:70%, isocratic elution mode) to give Compound 108 3,5-dimethyl-2-[7-[1-methylpiperazin-2-yl]-1 ,8- naphthyridin-2-yl]phenol (43.3 mg, 121 pmol, 22% yield, 97% purity) as a yellow solid and Compound 109 3,5-dimethyl-2-[7-[1-methylpiperazin-2-yl]-1 ,8-naphthyridin-2-yl]phenol (38.9 mg, 106 pmol, 19 % yield, 95% purity) as a yellow solid.

Enantiomer 1

¹ H NMR (400 MHz, DMSO-cfe) 5 [ppm] = 9.83 (s, 1 H), 8.42 (t, J = 9.2 Hz, 2H), 7.71 (d, J = 8.4 Hz, 1 H),

7.58 (d, J = 8.4 Hz, 1 H), 6.63 (d, J = 6.0 Hz, 2H), 3.24 (d, J = 10.4 Hz, 2H), 2.96-2.77 (m, 4H), 2.67-

2.58 (m, 1 H), 2.26 (s, 3H), 2.22-2.15 (m, 1 H), 2.1 1 (s, 3H), 2.01 (s, 3H).

LC-MS (Method C): Rt = 0.380 min; MS (ESIpos): m/z = 349.2 [M+H] ⁺ .

SFC (Rt = 0.497 min, ee% = 99%).

Compound 109

¹ H NMR (400 MHz, DMSO-cfe) 6 [ppm] = 9.82 (s, 1 H), 8.42 (t, J = 8.8 Hz, 2H), 7.70 (d, J = 8.4 Hz, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 6.63 (d, J = 5.4 Hz, 2H), 3.24-3.20 (m, 1 H), 2.94-2.76 (m, 4H), 2.64-2.56 (m, 1 H), 2.26 (s, 3H), 2.21-2.13 (m, 1 H), 2.10 (s, 3H), 2.00 (s, 3H).

LC-MS (Method C): Rt = 0.378 min; MS (ESIpos): m/z = 349.2 [M+H] ⁺ .

SFC (Rt =1 .486 min, ee% = 73%).

Intermediate 232

3.5-dimethyl-2-[7-[1,4-d!methylpiperazin-2-y!]-1.8-naphth yndm-2-yl]phenol

To a solution of 3,5-dimethyl-2-[7-[rac-(2S)-1-methylpiperazin-2-yl]-1 ,8-naphthyridin-2-yl]phenol (200 mg, 574 pmol, 1 eq), (HCHO)n (15.5 mg, 861 pmol, 1.5 eq) and NaBH ₃ CN (54.1 mg, 861 pmol, 1.50 eq)in MeOH (10 mL) was added AcOK (84.5 mg, 861 pmol, 1 .5 eq) at 25 °C. After stirring at 25 °C for 1 h, the mixture was filtered, and the filtrate was concentrated to dry. The residue was purified by reversed phase (column: C18, 40 g, mobile phase: [water (FA) - MeCN]; B%: 20% - 60%, 8 min) to give

3.5-dimethyl-2-[7-[1 ,4-dimethylpiperazin-2-yl]-1 ,8-naphthyridin-2-yl]phenol (120 mg, 328 pmol, 58% yield, 99% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.397 min; MS (ESIpos): m/z = 363.2 [M+H] ⁺ . Compound 111

3,5~d!methyl~2‘[7~[1,4~dlmethylpipei'azm~2~yl]~1.8~riap hthyfidim2~yl]phef)ol

The reaction was set up for SFC separation. The residue was separated by SFC: (coiumn: DAiCEL CHIRALPAK AD (250 mm x 30 mm, 10 pm); mobile phase: [CO ₂ - /PrOH]; B%: 40%, isocratic elution mode) to give Compound 110 3,5-dimethyi-2-[7-[1 ,4-dimethylpiperazin-2-yl]-1 ,8-naphthyridin-2- yljphenol (45.4 mg, 136 pmoi, 99% purity) as a yellow solid and Compound 111 3,5-dimethyi-2-[7-[1 ,4- dimethylpiperazin-2-yl]-1 ,8-naphthyridin-2-yl]phenol (47.2 mg, 136 pmoi, 99% purity) as a yellow solid.

Enantiomer 1

¹ H NMR (400 MHz, DMSO-cfe) 6 [ppm] = 8.43 (dd, J = 8.4, 13.2 Hz, 2H), 7.71 (d, J = 8.4 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 6.62 (d, J = 7.6 Hz, 2H), 3.40-3.36 (m, 2H), 2.93-2.90 (m, 1 H), 2.80-2.77 (m, 2H), 2.38-2.34 (m, 1 H), 2.25 (s, 3H), 2.19 (s, 3H), 2.10 (s, 3H), 2.02 (s, 3H), 1.99 (s, 1 H).

LC-MS (Method C): Rt = 0.396 min; MS (ESIpos): m/z = 363.2 [M+H] ⁺ .

SFC (Rt = 0.875 min, ee% = 99%).

Compound 111

¹ H NMR (400 MHz, DMSO-ofe) 6 [ppm] = 8.44 (dd, J = 8.4, 13.6 Hz, 2H), 7.72 (d, J = 8.4 Hz, 1 H), 7.59 (d, J = 8.4 Hz, 1 H), 6.62 (d, J = 7.6 Hz, 2H), 3.41-3.35 (m, 2H), 2.94-2.82 (m, 1 H), 2.80-2.78 (m, 2H), 2.55-2.55 (m, 1 H), 2.26 (s, 3H), 2.20 (s, 3H), 2.11 (s, 3H), 2.03 (s, 3H), 2.0 -1.99 (m, 1 H).

LC-MS (Method C): Rt = 0.400 min; MS (ESIpos): m/z = 363.2 [M+H] ⁺ .

SFC (Rt =1 .802 min, ee% = 97%).

Intermediate 233 methyl 2-ammo-6-chloro-pyrldme-3-carboxylate

To a solution of 2-amino-6-chloro-pyridine-3-carboxylic acid (100 g, 579 mmol, 1.00 eq) in toluene (600 mL) and methanol (400 mL) was added dropwise (trimethylsilyl)diazomethane (2.0 M in hexanes, 580 mL, 2.00 eq) at 20 °C over 3 h. After addition, the reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was cooled to 0 °C. Hydrochloric acid (1 .00 M in water, 500 mL) was added dropwise into the reaction mixture. After stirring at 0 °C for 0.5 h, the reaction mixture was concentrated in vacuum to remove organic phase. The pH of the aqueous phase was adjusted to 8-9 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (700 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was triturated with petroleum ether/ethyl acetate (10/1 , 1 .00 L) at 25 °C. The mixture was filtered under reduced pressure. The filter cake was collected and dried to give methyl 2-amino-6-chloro- pyridine-3-carboxylate (105 g, 563 mmol, 97% yield) as a white solid.

¹ H NMR (400 MHz, CDCh) 5 [ppm] = 8.02 (d, J = 8.4 Hz, 1 H), 6.58 (d, J = 8.4 Hz, 1 H), 3.86 (s, 3H).

Intermediate 234 methyl 2-amlno-6-(2-methoxy-4 _! §-dlmethyl-pheny!)pyridine-3-carboxylate A mixture of methyl 2-amino-6-chloro-pyridine-3-carboxylate (5.00 g, 26.8 mmol, 1.0 eq), (2-methoxy- 4,6-dimethyl-phenyl)boronic acid (7.24 g, 40.2 mmol, 1 .5 eq), potassiumphosphate (11 .4 g, 53.6 mmol, 2.00 eq), [2-(2-aminophenyl)phenyl]palladium(1 +);dicyclohexyl-[2-(2,4,6-triisopropylphenyl) phenyl]phosphane;methanesulfonate (2.27 g, 2.68 mmol, 0.100 eq) in 1 ,4-dioxane (90.0 mL) and water (10.0 mL) was degassed and purged nitrogen for three times at 25 °C. After stirring at 90 °C for 12 h under nitrogen atmosphere, the reaction mixture was concentrated in vacuum to give a residue. The mixture was diluted with water (40 mL). The mixture was extracted with dichloromethane (80 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SIOz, petroleum ether/ethyl acetate = 10/0 to 5/1) to give methyl 2-amino-6-(2-methoxy-4,6-dimethyl- phenyi)pyridine-3-carboxylate (5.16 g, 18.0 mmol, 67% yield) as a yellow solid.

LC-MS (Method C): Rt = 0.465 min; MS (ESI): m/z = 287.3 [M+H] ⁺ . intermediate 235

2-amno-6-(2-methoxy-4,6-dimethyl-phenyl)-N-methyl-pyndine -3-carboxamide

A solution of methyl 2-amino-6-(2-methoxy-4,6-dimethyl-phenyl)pyridine-3-carboxyl ate (5.16 g, 18.0 mmol, 1.00 eq) and 3,4,6,7,8,9-hexahydro-2H-pyrimido[1 ,2-a]pyrimidine (5.02 g, 36.0 mmol, 2.0 eq) in methylamine (70.0 mL, 30% purity in ethanol) was stirred at 40 °C for 12 h. The pH of the mixture was adjusted to 5-6 with hydrochloric acid (1 .00 M in water) at 0 °C. The mixture was extracted with ethyl acetate (60 mL x 3). The combined organic layers was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether/ethyl acetate (10/1 , 20 mL). The suspension was filtered under reduced. The filter cake was collected and dried to give a 2-amino-6-(2-methoxy-4,6-dimethyl-phenyl)-N-methyl-pyridine- 3- carboxamide (3.75 g, 13.1 mmol, 73% yield) as a yellow solid.

LC-MS (Method C): Rt = 0.716 min; MS (ESI): m/z = 286.2 [M+H] ⁺ .

Intermediate 236

24iydroxy-7-(2-methoxy-4,8-dimethyl-pheny0-3-methybpyrido [2,3-d]pyrimidin-4-one

To a solution of 2-amino-6-(2-methoxy-4,6-dimethyl-phenyl)-N-methyl-pyridine- 3-carboxamide (3.75 g, 13.1 mmol, 1.00 eq) in N,N-dimethyiformamide (50 mL) were added N,N-diisopropylethylamine (3.40 g, 26.3 mmol, 4.58 mL, 2.0 eq) and 1 ,1 '-carbonyldiimidazole (6.39 g, 39.4 mmol, 3.00 eq). After stirring at 100 °C for 3 h, the mixture was added into water (60 mL) at 0 °C. The pH of the mixture was adjusted to 6-7 with hydrochloric acid (1 .0 M in water) at 0 °C. The suspension was filtered under reduced. The filter cake was collected and dried under reduced pressure to give a crude product. The crude product was triturated with petroleum ether/ethyl acetate (5/1 , 50 mL). The suspension was filtered under reduced. The filter cake was collected and dried to give 2-hydroxy-7-(2-methoxy-4,6-dimethyl-phenyl)-

3-methyl-pyrido[2,3-d]pyrimidin-4-one (1.90 g, 6.10 mmol, 46 % yield) as a light yellow solid.

LC-MS (Method C): Rt = 0.877 min; MS (ESI): m/z = 312.1 [M+H] ⁺ .

Intermediate 237 Z-chloro-T-fZ-methoxy-^S-dimethyl-phenyQS-methyl-pyndo^^-dJp yrimidin-^one

To a solution of 2-hydroxy-7-(2-methoxy-4,6-dimethyl-phenyl)-3-methyl-pyrido[ 2,3-d]pyrimidin-4-one (1.90 g, 6.10 mmol, 1.0 eq) in phosphorus oxychloride (30 mL) was added N,N-diisopropylethylamine (1.58 g, 12.2 mmol, 2.13 mL, 2.0 eq) at 20 °C. After stirring at 100 °C for 12 h, the combined reaction mixture was concentrated in vacuum to give a residue. The residue was diluted with water (10 mL) at 0 °C. The pH of the mixture was adjusted to 8-9 with saturated sodium bicarbonate at 0 °C. The mixture was extracted with ethyl acetate (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether/ethyl acetate - 100/0 to 2/1) to give 2-chloro-7-(2- methoxy-4,6-dimethyl-phenyl)-3-methyl-pyrido[2,3-d]pyrimidin -4-one (1 .20 g, 3.64 mmol, 60% yield) as a light yellow solid.

LC-MS (Method C): Rt = 0.554 min; MS (ESI): m/z = 330.2 [M+H] ⁺ .

Intermediate 238

A mixture of 2-chioro-7-(2-methoxy-4,6-dimethyi-phenyl)-3-methyl-pyrido[2 ,3-d]pyrimidin-4-one (1 .20 g, 3.64 mmol, 1.00 eq), tert-butyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-

1-carboxylate (1 .69 g, 5.46 mmol, 1 .50 eq), [1 ,1-bis(diphenylphosphino)ferrocene] dichloropalladium(ll) (266 mg, 364 pmol, 0.1 eq), cesium carbonate (2.37 g, 7.28 mmol, 2.0 eq) in water (10.0 mL) and 1 ,4- dioxane (40 mL) was degassed and purged nitrogen for three times at 25 °C. After stirring at 80 °C for 12 h under nitrogen atmosphere, the reaction mixture was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether/ethyl acetate = 100/0 to 1/1) to give tert-butyi 5-[7-(2-methoxy-4,6-dimethyl-phenyl)-3-methyl-4-oxo-pyrido[2 ,3-d]pyrimidin-2-yl]- 3,6-dihydro-2H-pyridine-1-carboxylate (1.30 g, 2.73 mmol, 75% yield) as a yellow oil.

LC-MS (Method C): Rt = 0.587 min; MS (ESIpos): m/z = 477.3 [M+H] ⁺ .

Intermediate 239

3-[7-(2~methoxy-4,6~dimethyl-phenyi)-3~methyl-4-oxo-pyrid o[2,3-d]pyrimidin-2-yl]piperidine-1- carboxylate

To a solution of tert-butyi 5-[7-(2-methoxy-4,6-dimethyl-phenyl)-3-methyi-4-oxo-pyrido[2 ,3-d]pyrimidin-

2-yl]-3,6-dihydro-2H-pyridine-1 -carboxylate (1.30 g, 2.73 mmol, 1.00 eq) in methanol (15 mL) was added Pd/C (130 mg, 10% purity) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. After stirring under hydrogen (15 psi) for 1 h at 25 °C. The reaction mixture was filtered under reduced pressure. The filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether/ethyl acetate = 100/0 to 1.5/1) to give tert-butyi 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-3-methyl-4-oxo-pyrido[2 ,3-d]pyrimidin-2- yl]piperidine-1 -carboxylate (970 mg, 2.03 mmol, 74% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-ofe) 5 [ppm] = 8.58 (d, J = 8.0 Hz, 1 H), 7.39 (d, J = 8.0 Hz, 1 H), 6.70 (s, 1 H), 6.62 (s, 1 H), 4.35 (br. s, 1 H), 3.74 (s, 3H), 3.67 (s, 3H), 3.25 (br. s, 1 H), 2.99 (br s, 1 H), 2.77 (br s, 1 H), 2.36 (s, 3H), 2.19-2.12 (m, 2H), 2.08 (s, 3H), 1 .81 (d, J = 13.2 Hz, 1 H), 1.63-1.52(m, 2H), 1.48 (s, 9H). LC-MS (Method C): Rt = 1 .037 min; MS (ESipos): m/z = 479.2 [M+H] ⁺ . intermediate 240

7-(2-methoxy-4„6-d!methy!-phenyl)-3-methyi-2-(3-p!pendy l)pyndo[2,3-d]pynm!din-4-one

A solution of tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-3-methyl-4-oxo-pyrido[2 ,3-d]pyrimidin-2- yl]piperidine-1 -carboxylate (970 mg, 2.03 mmol, 1.0 eq) in HCI (4 M in dioxane, 15 mL) was stirred at 25 °C for 30 min. The reaction mixture was concentrated in vacuum to give 7-(2-methoxy-4,6-dimethyl- phenyl)-3-methyl-2-(3-piperidyl)pyrido[2,3-d]pyrimidin-4-one (915 mg, 2.03 mmol, 100% yield, HCI salt) as a yellow solid.

LC-MS (Method L): Rt = 0.789 min; MS (ESI): m/z = 379.2 [M+H] ⁺ .

Intermediate 241

7-(2-methoxy-4,6-dimethyl-phenyl)-3-methyl-2-(1-methyl-3- piperidy0pyndo[2,3-d]pynmidin-4- one

To a solution of 7-(2-methoxy-4,6-dimethyl-phenyl)-3-methyl-2-(3-piperidyl)py rido[2,3-d]pyrimidin-4- one (915 mg, 2.03 mmol, 1.0 eq, HCI salt) in MeOH (15 mL) were added formaldehyde (493 mg, 6.08 mmol, 453 pL, 37% purity in water, 3.0 eq), potassium acetate (398 mg, 4.05 mmol, 2.0 eq) at 0 °C and sodium cyanoborohydride (382 mg, 6.08 mmol, 3.0 eq) at 0 °C. After stirring for 1 h at 25 °C, the mixture was added into saturated ammonium chloride (10 mL) at 0 °C. The pH of the mixture was adjusted to

8-9 with saturated sodium bicarbonate at 0 °C. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18, 80 g, mobile phase: [water(FA) - MeCN];B%: 10% - 40%, 15 min) to give 7-(2-methoxy-4,6- dimethyl-phenyl)-3-methyl-2-(1-methyl-3-piperidyl)pyrido[2,3 -d]pyrimidin-4-one (800 mg, 2.04 mmol) as a white solid.

¹ H NMR (400 MHz, CDCb) 6 [ppm] = 8.58 (d, J = 8.0 Hz, 1 H), 8.50 (s, 1 H), 7.39 (d, J = 8.0 Hz, 1 H), 6.70 (s, 1 H), 6.62 (s, 1 H), 3.85-3.79 (m, 1 H), 3.73 (s, 3H), 3.67 (s, 3H), 3.53-3.48 (m, 1 H), 3.37 (d, J = 11.2 Hz, 1 H), 3.27 (t, J = 1 1.6 Hz, 1 H), 2.64 (s, 3H), 2.55-2.48 (m, 1 H), 2.35 (s, 3H), 2.15 (d, J = 12.4 Hz, 2H), 2.06 (s, 3H), 2.01-1.94 (m, 1 H), 1.84-1.74 (m, 1 H).

LC-MS (Method C): Rt = 0.797 min; MS (ESI): m/z = 393.2 [M+H] ⁺ .

Compounds 112 7-(2-hydroxy-4,6-dimethylpheny!}-3-methyl-2-(1-methylp!pendi n-3-y!)pyndo[2 _l ,3-d]pynmidin- 4(3H)-one

To a solution of 7-(2-methoxy-4,6-dimethyl-phenyl)-3-methyl-2-(1-methyl-3-pip eridyl)pyrido[2,3- d]pyrimidin-4-one (780 mg, 1.99 mmol, 1 .00 eq) in dichloromethane (15 mL) was added boron tribromide (1 .49 g, 5.96 mmol, 575 pL, 3.0 eq) at 0 °C. After stirring at 25 °C for 1 h, the mixture was added into water (10.0 mL) at 0 °C. The pH of the mixture was adjusted to 7-8 with saturated sodium bicarbonate at 0 °C. The mixture was extracted with dichioromethane (20 mL x 3). The combined organic iayers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18, 80 g, mobile phase: [water (FA) - MeCN];B%: 5% - 40%, 18 min) to give a product. The product was separated by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm,10um);mobile phase: [CO ₂ -EtOH (0.1.00% NH3-H2O)];B%:50%, isocratic elution mode) to give Compound 112 7-(2-hydroxy-4,6- dimethylphenyl)-3-methyl-2-(1-methylpiperidin-3-yl)pyrido[2, 3-d]pyrimidin-4(3H)-one (92.4 mg, 232 pmol, 12% yield, 95% purity) as a yellow solid and Compoundl 13 7-(2-hydroxy-4,6-dimethylphenyl)-3- methyl-2-(1-methylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-4(3H )-one (97.4 mg, 252 pmol, 13% yield, 98% purity) as a yellow solid.

Compound 1 12

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 9.56 (s, 1 H), 8.46 (d, J = 8.0 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 1 H), 6.61 (s, 1 H), 6.59 (s, 1 H), 3.62 (s, 3H), 3.20 (t, J = 11 .6 Hz, 1 H), 3.02 (d, J = 8.4 Hz, 1 H), 2.83 (dd, J = 1.2, 5.6 Hz, 1 H), 2.25 (s, 3H), 2.22 (s, 3H), 2.18-2.08 (m, 1 H), 2.06-2.02 (m, 4H), 1.91-1.86 (m, 1 H), 1 .75-1 .59 (m, 2H), 1 .54-1 .44 (m, 1 H).

LC-MS (Method C): Rt = 0.433 min; MS (ESI) m/z = 379.3 [M+H] ⁺ .

SFC (Rt = 1 .696 min, ee% = 99%).

Enantiomer 2

¹ H NMR (400 MHz, DMSO-d«) 6 [ppm] = 9.57 (s, 1 H), 8.46 (d, J = 8.0 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 1 H), 6.61 (s, 1 H), 6.59 (s, 1 H), 3.62 (s, 3H), 3.23-3.17 (m, 1 H), 3.01 (d, J = 10.4 Hz, 1 H), 2.82 (d, J = 10.4 Hz, 1 H), 2.25 (s, 3H), 2.22-2.12 (m, 4H), 2.07-1 .96 (m, 4H), 1 .91-1 .85 (m, 1 H), 1.75-1.61 (m, 2H), 1.54- 1.44 (m, 1 H).

LC-MS (Method C): Rt = 0.434 min; MS (ESI) m/z = 379.3 [M+H] ⁺ .

SFC (Rt = 1 .395 min, ee% = 91 %).

Intermediate 242

To a solution of tert-butyl 5-[4-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-3,6- dihydro-2H-pyridine-1 -carboxylate (1 .00 g, 2.08 mmol, 1 .0 eq) in 1 ,4-dioxane (10 mL) and water (2 mL) were added potassium hydroxide (351 mg, 6.25 mmol, 3.0 eq), dicyclohexyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane (149 mg, 313 pmol, 0.15 eq) and diacetoxypalladium (46.8 mg, 208 pmol, 0.1 eq) at 25 °C. After stirring at 90 °C for 14 h under nitrogen atmosphere, the reaction mixture was concentrated in vacuum to give a residue. The residue was purified by triturating with (petroleum ether/ethyl acetate = 10/1 , 60 mL) at 25 °C for 1 h. The mixture was filtered under reduced pressure. The filter cake was collected and dried under reduced pressure to give tert-butyl 5-[4-hydroxy- 7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-3,6-dihydro-2H-pyridine-1 -carboxylate (900 mg, 1 .95 mmol, 94% yield) as a yellow solid.

LC-MS (Method C): Rt = 0.959 min; MS (ESI) m/z = 462.2 [M+H] ⁺ .

Intermediate 243 tert-butyl 3~[4-hydroxy-7~(2-methoxy-4.6-dimethy!-phenyl)-1 _! 8-naphthyridlri~2-yl]plpeddif)e-1- carboxylate

To a solution of tert-butyl 5-[4-hydroxy-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-3,6- dihydro-2H-pyridine-1-carboxylate (900 mg, 1 .95 mmol, 1 .00 eq) in methanol (10 mL) was added Pd/C (100 mg, 10% purity) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. After stirring under hydrogen (15 psi) atmosphere at 25 °C for 4 h, the mixture was filtered through a pad of celite. The nitrate was concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(FA) - MeCNj; B%: 15% - 45%, 8 min) to give tert-butyl 3-[4-hydroxy-7-(2-methoxy-4,6-dimethyl- phenyl)-1 ,8-naphthyridin-2-yl]piperidine-1 -carboxylate (500 mg, 1.08 mmol, 55% yield) as a yellow solid.

LC-MS (Method C): Rt = 0.562 min; MS (ESI) m/z = 464.2 [M+H] ⁺ .

Intermediate 244

7-(2-methoxy-4,8-dimethyl-phenyl)~2-(3-piperidyl)~1,8~nap btbyr!din-4-ol

A mixture of tert-butyl 3-[4-hydroxy-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthy ridin-2-yl]piperidine- 1 -carboxylate (500 mg, 1 .08 mmol, 1 .0 eq) in hydrochloric acid (4 M in 1 ,4-dioxane, 10 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuum to give 7-(2-methoxy-4,6-dimethyl- phenyl)-2-(3-piperidyl)-1 ,8-naphthyridin-4-ol (431 mg, 1.08 mmol, 100% yield, HCI salt) as a yellow solid.

LC-MS (Method C): Rt = 0.435 min; MS (ESI) m/z = 364.1 [M+H] ⁺ .

Intermediate 245

7-(2-methoxy-4 _! 6-dlruethyl-pheriy!)~2-(1~rnethy!-3-piperldy!)-1.8-r)a phthyddin-4-o!

To a solution of 7-(2-methoxy-4,6-dimethyl-phenyl)-2-(3-piperidyl)-1 ,8-naphthyridin-4-ol (431 mg, 1.08 mmol, 1 .00 eq, HCI salt) in methanol (5.00 mL) were added formaldehyde (263 mg, 3.24 mmol, 241 pL, 37% purity in water, 3.0 eq) and potassium acetate (212 mg, 2.16 mmol, 2.0 eq) at 0 °C, then sodium cyanoborohydride (686 mg, 3.24 mmol, 3.0 eq) was added into the mixture at 0 °C. After stirring at 25 °C for 30 min, the mixture was added to saturated ammonium chloride (10 mL). The pH was adjusted to 8 with saturated sodium bicarbonate. Then the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by reversed-phase (column: C18, 40 g, mobile phase: [water(FA) - MeCN];B%: 15% - 50%, 15 min) to give 7-(2-methoxy-4,6-dimethyl-phenyl)-2-(1- methyl-3-piperidyl)-1 ,8-naphthyridin-4-ol (360 mg, 954 pmol, 88% yield) as a yellow solid.

LC-MS (Method C): Rt = 0.445 min; MS (ESI) m/z = 378.3 [M+HJ*. Compound 114 and 115

7-f2-/?ydroxy-4,6-tf/met/3y/p/jeny/J-2-ff-met/3y/p/per/d/ n-3-y/J-1 _; S-nap/?t/jyr/d/n-4-o/

To a solution of 7-(2-methoxy-4,6-dimethyl-phenyl)-2-(1-methyl-3-piperidyl)-1 ,8-naphthyridin-4-ol (340 mg, 901 pmol, 1 .0 eq) in dichloromethane (5.00 mL) was added boron tribromide (677 mg, 2.70 mmol, 260 pL, 3.00 eq) at 0 °C. After stirring at 25 °C for 14 h, the mixture was added dropwise into ice water (5 mL) at 0 °C. The pH of the mixture was adjusted to 7-8 with saturated sodium bicarbonate. The mixture was extracted with dichioromethane (15 mL x 3). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by reversed phase (column: C18, 40 g, mobile phase: [water(FA) - MeCN];B%: 15% - 30%, 12 min) the racemate. The racemate was separated by SFC separation (column: DAICEL CHIRALPAK AS(250mm*30mm,10um);mobile phase: [CO ₂ -EtOH(0.1 %NH3«H2O)];B%:55%, isocratic elution mode) to give 7-(2-hydroxy-4,6-dimethyl-phenyl)-2-[rel-(3R)-1-methyl-3-pip eridyl]-1 ,8-naphthyridin-4-ol (24.0 mg, 65.8 pmol, 7 % yield, 99+% purity) as an off-white solid and 7-(2-hydroxy-4,6-dimethyl-phenyl)-2- [rel-(3R)-1-methyl-3-piperidyl]-1 ,8-naphthyridin-4-ol (33.6 mg, 91.2 pmol, 10% yield, 99% purity) as a yellow solid.

Compound 1 14

NMR (400 MHz, DMSO-cfe) 5 [ppm] = 12.07 (s, 1 H), 9.39 (s, 1 H), 8.37 (d, J = 8.0 Hz, 1 H), 7.29 (d, J = 8 Hz, 1 H), 6.61 (s, 1 H), 6.58 (s, 1 H), 6.04 (s, 1 H), 2.92-2.86 (m, 2H), 2.68-2.66 (m, 1 H), 2.23 (s, 3H),

2.21-2.14 (m, 4H), 2.01-1.98 (m, 4H), 1.91-1.88 (m, 1 H), 1.73-1.65 (m, 1 H), 1.60-1.46 (m, 2H).

LC-MS (Method C): Rt = 0.753 min; MS (ESI) m/z = 364.2 [M+H] ⁺ .

SFC (Rt = 1 .699 min, ee% = 97%).

Compound 115

¹ H NMR (400 MHz, DMSO-d ₆ ) <5 [ppm] = 12.08 (s, 1 H), 9.45 (s, 1 H), 8.38 (d, J = 8.0 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 6.61 (s, 1 H), 6.58 (s, 1 H), 6.04(s, 1 H) 2.92-2.86 (m, 2H), 2.69-2.66 (m, 1 H), 2.23 (s, 3H),

2.21-2.17 (m, 4H), 2.08-2.00 (m, 4H), 1.90-1.88 (m, 1 H), 1.71-1 .68 (m, 1 H), 1.60-1 .46 (m, 2H).

LC-MS (Method C): Rt = 0.757 min; MS (ESI) m/z = 364.2 [M+H] ⁺ . SFC (Rt - 1 .123 min, ee% = 98%).

Intermediate 246 tert-butyl 4-[7-(2-methoxy-4,6-dlmethyl-phenyl)-1,8-naphthyridm-2-yl]-2 ,3-dlhydropyrrole-1- carboxylate

A mixture of 2-bromo-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (800 mg, 2.33 mmol, 1 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)-2,3-dlhydropyrrole-1 -carboxylate (756.84 mg, 2.56 mmol, 1.1 eq), [1 ,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (170.55 mg, 233.09 pmol, 0.1 eq) and cesium carbonate (1.52 g, 4.66 mmol, 2 eq) in 1 , 4-dioxane (20 mL) and water (4 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 90 °C for 15 hr under nitrogen atmosphere. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate = 10/1 to 1/1) to give tert-butyl 4-[7-(2- methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-2,3-dihydropyrrole-1 -carboxylate (1 .00 g, 2.32 mmol, 99% yield) as a light yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 8.47 (d, J = 8.6 Hz, 1 H), 8.42 (d, J = 8.2 Hz, 1 H), 8.15-7.99 (m, 1 H), 7.48 (d, J = 8.2 Hz, 1 H), 7.12-6.98 (m, 1 H), 6.83 (s, 1 H), 6.78 (s, 1 H), 4.61 (s, 2H), 4.36 (s, 2H), 3.65 (s, 3H), 1.55-1.41 (m, 9H), 1.08 (s, 6H)

LC-MS (Method C): Rt = 0.534 min; MS (ESI) m/z = 432.3 [M+H] ⁺ .

Intermediate 247 tert-butyl S-lT-fZ-methoxy^.S-dimethyl-pheuylj-l^-naphthyridin-Z-ylJpyn -olidine-l- carboxylate

To a solution of tert-butyl 4-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-2,3- dihydropyrrole-1 -carboxylate (1 g, 2.32 mmol, 1 eq) in methyl alcohol (20 mL) was added Pd/C (246.61 mg, 231.74 pmol, 10% purity, 0.1 eq) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen for 3 times. The mixture was stirred under hydrogen (15Psi) at 20 °C for 2 h. The reaction mixture was filtered and the filterwas concentrated to give Tert-butyl rac-(3S)-3-[7-(2-methoxy- 4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]pyrrolidine-1 -carboxylate (0.9 g, 2.08 mmol, 89.58% yield) as yellow oil.

LC-MS (Method C): Rt = 0.937 min; MS (ESI): m/z = 434.2 [M+H] ⁺ .

Intermediate 248

2-(2-methoxy-4,6-dimethyl-phenyl)-7-[pyrrolidin-3-yl]-1,� �-naphthyridine

To a solution tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]pyrrolidine-1- carboxylate (0.9 g, 2.08 mmol, 1 eq) in ethyl acetate (10 mL) was added hydrogen chloride (4.0 M in ethyl acetate, 5.00 mL,). The reaction was stirred 20 °C for 1 h. The reaction mixture was concentrated to give 2-(2-methoxy-4,6-dimethyl-phenyl)-7-[rac-(3S)-pyrrolidin-3-y l]-1 ,8-naphthyridine (690 mg, crude) was obtained as a yellow solid.

LC-MS (Method C): Rt = 0.497 min; MS (ESI): m/z = 334.2 [M+H] ⁺ .

Intermediate 249

1 ■[3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,§-naphthyridin-2-yl]pyrrolidm-1 -yl]ethanone

A mixture of 2-(2-methoxy-4,6-dimethyl-phenyl)-7-[pyrrolidin-3-yl]-1 ,8-naphthyridine (690 mg, 2.07 mmol, 1 eq) and N-ethyl-N-propan-2-ylpropan-2-amine (802.38 mg, 6.21 mmol, 1.08 mL, 3 eq) in dichloromethane (10 mL) was added acetyl acetate (316.90 mg, 3.10 mmol, 291.53 pL, 1.5 eq). The reaction was stirred 20 °C for 1 h. The mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phase was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=1/1 to 0/1) to give 1-[rac-(3S)-3- [7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]pyrrolidin-1-yl]ethanone (630 mg, 1.68 mmol, 81 .08% yield) as a light yellow solid.

¹ H NMR (400 MHz, DMSO-c/ _e ) 6 [ppm] = 8.52-8.39 (m, 2H), 7.66 (t, J = 8.1 Hz, 1 H), 7.48 (dd, J = 1.3, 8.2 Hz, 1 H), 6.83 (s, 1 H), 6.78 (s, 1 H), 4.07-3.85 (m, 2H), 3.84-3.69 (m, 2H), 3.65 (s, 3H), 3.43-3.36 (m, 1 H), 3.33 (s, 3H), 2.37 (s, 3H), 2.00 (s, 3H), 1.99-1.95 (m, 2H)

LC-MS (Method C): Rt = 0.501 min; MS (ESI) m/z = 376.3 [M+H] ⁺ .

Intermediate 250

1-[3~[7-(2-hydi'Gxy-4 _> 6-dimethyi-ph&nyi}~1,8-naphthyridin-2-yi]pyi'i'GLi diri-1-yl]fjthanone

A solution of 1-[3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]pyrrolid in-1 -yl]ethanone (600 mg, 1 .60 mmol, 1 eq) in dichloromethane (10 mL) was added boron tribromide (2.00 g, 7.99 mmol, 5 eq) at 0 °C. After stirring 20 °C for 2 h, the reaction mixture was quenched by addition methyl alcohol 5 mL at 0 °C, The mixture was concentrated under reduced pressure to give a residue. The residue was purified reversed-phase column (column: C18, 40 g, mobile phase: [water(FA) - MeCN];B%: 20% - 50%, 5 min) to give 1-[rac-(3S)-3-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]pyrrolidin- 1-yl]ethanone (320 mg, 885.36 pmol, 55.40% yield) as a yellow solid.

LC-MS (Method C): Rt = 0.455 min; MS (ESI) m/z = 362.2 [M+H] ⁺ .

Compound 116 and 117

1-[3~[7~(24iydmxy~4.8~dimethyi~phenyl)~1,8'naphthyridm~2' y^pyrmHdin~1~y!]ethanorie

The reaction was set up for SFC separation. The residue was separated by SFC: (column: DAICEL CHIRALCEL OJ-H(250mm*30mm,5um);mobile phase: [CO ₂ -i-PrOH(0.1%NH3H2O)];B%:30%, isocratic elution mode) to give 1-[rel-(3S)-3-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]pyrrolidin-1 -yljethanone (97.7 mg, 264 pmol, 30% yield, 97.48% purity) as a yellow solid. 1-[rel-(3S)- 3-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]pyrrolidin-1-yl]ethanone (103 mg, 284 pmol, 32% yield, 99% purity) as a yellow solid.

Compound 1 16

¹ H NMR (400 MHz, DMSO-d _e ) 5 [ppm] = 9.80 (d, J = 10.3 Hz, 1 H), 8.49 - 8.39 (m, 2H), 7.66 (t, J = 8.1 Hz, 1 H), 7.58 (d, J = 8.3 Hz, 1 H), 6.64 (s, 1 H), 6.63 (s, 1 H), 4.05 - 3.53 (m, 5H), 2.47 - 2.35 (m, 1 H), 2.33-2.29 (m, 0.5H), 2.27 (s, 3H), 2.20-2.14 (m, 0.5H), 2.09 (d, J = 2.0 Hz, 3H), 2.00 (d, J = 7.2 Hz, 3H).

LC-MS (Method C): Rt = 0.432 min; MS (ESI) m/z - 362.2 [M+H] ⁺ .

SFC (Rt - 1 .452 min, ee% - 97%).

Compound 117

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 8.50-8.35 (m, 2H), 7.65 (t, J = 8.1 Hz, 1 H), 7.59 (d, J = 8.3 Hz, 1 H), 6.61 (s, 1 H), 6.56 (s, 1 H), 4.07 - 3.56 (m, 5H), 2.45-2.36 (m, 1 H), 2.32-2.28 (m, 0.5H), 2.24 (s, 3H), 2.21-2.14 (m, 0.5H), 2.08 (d, J = 1 .7 Hz, 3H), 2.00 (d, J = 7.1 Hz, 3H).

LC-MS (Method C): Rt = 0.431 min; MS (ESI) m/z = 362.2 [M+H] ⁺ . SFC (Rt = 1 .875 min, ee% = 95%). intermediate 251 tert-butyl (3-(methoxy(methyl)carbamoyl)cyclohexyl)carbamate

To a soiution of 3-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (5.00 g, 20.5 mmoi, 1.00 eq) and N-methoxymethanamine (3.01 g, 30.8 mmoi, 1.50 eq, HCi salt) in dichlorometane (80 mL) were added chloride 3-(ethyiiminomethyiideneamino)propyl-dimethyiazanium (5.91 g, 30.8 mmol, 1.50 eq), 1 -hydroxybenzotriazole (4.17 g, 30.8 mmol, 1.50 eq) and N-ethyl-N-propan-2-ylpropan-2-amine (7.97 g, 61.6 mmoi, 10.7 mL, 3.00 eq). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (80 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~34% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to give tert-butyl (3-(methoxy(methyl)carbamoyl)cyciohexyi)carbamate (4.70 g, 16.4 mmoi, 79% yield) as a yellow oil.

Intermediate 252 tert-butyl (3-acetylcyclohexyl)carbamate

To a solution of tert-butyl N-[3-[methoxy(methyl)carbamoyl]cyclohexyl]carbamate (4.7 g, 16.4 mmol, 1 .00 eq) in tetrahydrofuran (60 mL) was added methylmagnesium bromide (3 M in diethyl ether, 27.3 mL, 5.00 eq) at 0 °C under nitrogen atmosphere. The mixture was warmed to 20 °C for 2 h under nitrogen atmosphere. The reaction mixture was cooled to 0 °C, the mixture was quenched by addition with sat ammonia chloride (30 mL), The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (80 mL x 2), dried over anhydrous sodium sulfate, filtered and the filter cake was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~23% ethyl acetate/petroleum ethergradient @ 60 mL/min) to give tert-butyl (3-acetylcyclohexyl)carbamate (2.80 g, 11 .6 mmol, 70% yield) as a white gum.

Intermediate 253 tert-butyl (3-(7-(2-methoxy-4,§-d!methylpheuyl)-1$-fiaphthyridln-2-y!) cyclohexyl)carbamate

To a solution of 2-amino-6-(2-methoxy-4,6-dimethyl-phenyl)pyridine-3-carbalde hyde (1.80 g, 7.02 mmol, 1 .00 eq) and tert-butyl N-(3-acetylcyclohexyl)carbamate (2.71 g, 1 1 .2 mmol, 1 .60 eq) in methanol (30 mL) was added 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (3.21 g, 21.0 mmol, 3.18 mL, 3.00 eq). The mixture was stirred at 60 °C for 24 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-39% Ethyl acetate/Petroleum ether gradient @ 60 mL/min) to give tert-butyl (3-(7-(2-methoxy-4,6-dimethylphenyl)-1 ,8-naphthyridin-2-yl)cyclohexyl)carbamate (1 .40 g, 3.03 mmol, 43% yield) as a yellow solid. Intermediate 254

2-(7-(3-aminocyclohexyl)-1 _! 8-naphthyndin-2-yl)-3,5-dimethylphenol

To a solution of tert-butyl N-[3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]cyclohexyl]carbamate (1.30 g, 2.82 mmol, 1.00 eq) in dichloromethane (15 mL) was added boron tribromide (2.12 g, 8.45 mmoi, 814 pL, 3.00 eq) at -70 °C. The mixture was warmed to 20 °C and stirred for 2 h. The pH of the reaction mixture was adjusted to 7 with ammonia (7 M in methanol). The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed- phase column (column: C18, 80 g, mobile phase: [water (0.5% NHs’HaO] - MeCNJ; B%: 42% - 45%, 12 min) to give 2-(7-(3-aminocyclohexyl)-1 ,8-naphthyridin-2-yl)-3,5-dimethylphenol (620 mg, 1.75 mmol, 62% yield, 98.2% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d _s ) 6 [ppm] = 8.39 (d, J = 3.2 Hz, 1 H), 8.37 (d, J = 3.2 Hz, 1 H), 7.56 (d, J = 4.8 Hz, 1 H), 7.54 (d, J = 4.8 Hz, 1 H), 6.63 (s, 1 H), 6.62 (s, 1 H), 3.02-2.91 (m, 1 H), 2.76-2.65 (m, 1 H), 2.26 (s, 3H), 2.10 (s, 3H), 2.07-1.99 (m, 1 H), 1.94-1.79 (m, 3H), 1.58-1.35 (m, 3H), 1.16-0.99 (m, 1 H). LC-MS (Method C): Rt = 0.761 min; MS (ESIpos) m/z = 348.2 [M+H] ⁺ .

Compound 120

3,5-dimethyb2-[7-[3-aminocyclohexyl]-1,8-naphthyndin-2-yl ]phenol

The reaction was set up for SFC separation. The residue was separated by SFC: (column: DAICEL CHIRALPAK IG (250mm*30mm,10um);mobile phase: [Hexane-EtOH (0.1 % NH3‘>H2O)];B%:45%, isocratic elution mode) to give Compound 118 3,5-dimethyl-2-[7-[3-aminocyclohexyl]-1 ,8-naphthyridin- 2-yl]phenol (45.8 mg, 125 pmol, 7% yield, 95% purity) as a yellow solid; Compound 119 3,5-dimethyl- 2-[7-[3-aminocyclohexyl]-1 ,8-naphthyridin-2-yl]phenol (271 mg, 756.54 pmol, 43.17% yield, 97% purity) as a yellow solid; Compound 120 3,5-dimethyl-2-[7-[3-aminocyclohexyl]-1 ,8-naphthyridin-2-yl]phenol (29.36 mg, 82.81 pmol, 4.73% yield, 98% purity) as a yellow solid and Compound 121 3,5-dimethyl-2- [7-[3-aminocyclohexyl]-1 ,8-naphthyridin-2-yl]phenol (225.21 mg, 641.69 pmol, 36.62% yield, 99% purity) as a yellow solid.

Diastereomer 1

¹ H NMR (400 MHz, DMSO-d _s ) 6 [ppm] = 8.38 (d, J = 5.8 Hz, 1 H), 8.36 (d, J = 5.6 Hz, 1 H), 7.55 (t, J = 8.4 Hz, 2H), 6.63 (s, 1 H), 6.62 (s, 1 H), 3.44 - 3.38 (m, 1 H), 3.26-3.24 (m, 1 H), 2.26 (s, 3H), 2.10 (s, 3H), 1.98-1.83 (m, 3H), 1.81-1.66 (m, 3H), 1.59-1.48 (m, 3H).

LC-MS (Method C): Rt = 0.606 min; MS (ESIpos) m/z = 348.4 [M+H] ⁺ .

SFC (Rt = 1 .034 min, ee% = 91 %).

Diastereomer 2

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 8.39 (d, J = 3.2 Hz, 1 H), 8.37 (d, J = 3.2 Hz, 1 H), 7.56 (d, J = 3.2 Hz, 1 H), 7.54 (d, J = 2.8 Hz, 1 H), 6.64 (s, 1 H), 6.61 (s, 1 H), 3.01-2.90 (m, 1 H), 2.76-2.65 (m, 1 H), 2.26 (s, 3H), 2.10 (s, 3H), 2.07-1.99 (m, 1 H), 1.93-1.78 (m, 3H), 1.58-1.35 (m, 3H), 1.12-0.99 (m, 1 H). LC-MS (Method C): Rt - 0.609 min; MS (ESIpos) m/z = 348.4 [M+H] ⁺ . SFC (Rt = 1 .380 min, ee% = 99%).

Compound 120

¹ H NMR (400 MHz, DMSO-d ₅ ) 6 [ppm] = 8.40 - 8.30 (m, 2H), 7.59-7.49 (m, 2H), 6.63 (s, 1 H), 6.59 (s, 1 H), 3.45-3.39 (m, 2H), 3.27-3.22 (m, 2H), 2.25 (s, 3H), 2.09 (s, 3H), 1.97-1.61 (m, 6H), 1.60-1.47 (m, 3H).

LC-MS (Method C): Rt - 0.606 min; MS (ESIpos) m/z - 348.4 [M+H] ⁺ .

SFC (Rt - 5.299 min, ee% - 91 %).

Diastereomer 4

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 8.38 (d, J = 2.0 Hz, 1 H), 8.36 (d, J = 2.0 Hz, 1 H), 7.56 (d, J = 1.6 Hz, 1 H), 7.54 (d, J = 1.6 Hz, 1 H), 6.63 (s, 1 H), 6.60 (s, 1 H), 3.01-2.90 (m, 1 H), 2.75-2.65 (m, 1 H), 2.25 (s, 3H), 2.10 (s, 3H), 2.07-1.99 (m, 1 H), 1.94-1.78 (m, 3H), 1.58-1.34 (m, 4H), 1.11-1.01 (m, 1 H). LC-MS (Method C): Rt = 0.606 min; MS (ESIpos) m/z = 348.4 [M+H] ⁺ .

SFC (Rt = 6.365 min, ee% = 95%).

Intermediate 255 tert-butyl 2-[methoxy(methyl)carbamoyl]-1 _! 4-oxazepane-4-carboxylate

To a mixture of 4-tert-butoxycarbonyl-1 ,4-oxazepane-2-carboxylic acid (2.00 g, 8.15 mmol, 1 .00 eq), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.88 g, 9.79 mmol, 1.20 eq), 1- hydroxybenzotriazole (1.32 g, 9.79 mmol, 1.2 eq) and N,N-diisopropylethylamine (3.69 g, 28.5 mmol, 4.97 mL, 3.50 eq) in dichloromethane (20 mL) was added N-methoxymethanamine (1.19 g, 12.2 mmol, 1 .50 eq, HCI salt). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with Ethyl acetate (50 mL x 2). The combined organic layers were washed with HCI (20 mL, 1 M in water), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to give tert-butyl 2-[methoxy(methyl)carbamoyl]-1 ,4-oxazepane-4-carboxylate (1.20 g, 4.16 mmol, 51 % yield) as a light yellow solid.

Intermediate 256 tert-butyl 2-acetyl-1 ,4-oxazepane-4-carboxylate

To a mixture of tert-butyl 2-[methoxy(methyl)carbamoyl]-1 ,4-oxazepane-4-carboxylate (1.16 g, 4.02 mmol, 1.00 eq) in THF (15.0 mL) was added methylmagnesium bromide (3 M in THF, 5.36 mL, 4.00 eq) at 0 °C under nitrogen. After stirring at 25 °C for 2 h, the mixture was quenched with saturated ammonium chloride aqueous solution (10 mL) and extracted with Ethyl acetate (20 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 40~60% ethyl acetate/petroleum ether gradient @ 80 mL/min) to give tert-butyl 2-acetyl-1 ,4-oxazepane-4-carboxylate (900 mg, 3.70 mmol, 92% yield) as yellow oil.

¹ H NMR (400 MHz, CDCb) 6 [ppm] = 4.18-4.04 (m, 2H), 4.02-3.87 (m, 1 H), 3.68-3.50 (m, 2H), 3.46- 3.16 (m, 2H), 2.24 (s, 3H), 2.01-1.83 (m, 2H), 1.47 (s, 9H).

Intermediate 257 tert-butyl 2-[7-(2-methoxy-4,6-dimethyl-phenyl)-1,8-riaphthyrldin-2-yl] -1,4-oxazepane-4- carboxylate

A mixture of tert-butyl 2-acetyl-1 ,4-oxazepane-4-carboxylate (900 mg, 3.70 mmol, 1 .00 eq), 2-amino-6- (2-methoxy-4,6-dimethyl-phenyl)pyridine-3-carbaldehyde (948 mg, 3.70 mmol, 1.00 eq) and 1 ,8- diazabicyclo[5.4.0]undec-7-ene (2.25 g, 14.8 mmol, 2.23 mL, 4.00 eq) in methanol (10 mL) was stirred at 60 °C for 24 h. The mixture was concentrated in vacuo and purified by flash silica gel chromatography ((ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 20~40% Ethyl acetate/Petroleum ether gradient @ 80 mL/min) to give tert-butyl 2-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-

1 .4-oxazepane-4-carboxylate (1 .70 g, 3.67 mmol, 99% yield) as a yellow oil.

Intermediate 258

3.5-d/metfiy/-2-£7-fl _; 4-oxazepan-2-y/J-f _; S-napfitfiyr/dm-2-y/Jpfieno/

To a mixture of tert-butyl 2-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1 ,4-oxazepane- 4-carboxylate (500 mg, 1 .08 mmol, 1 .00 eq) in dichloromethane (10 mL) was added dropwise a solution of boron tribromide (1 .35 g, 5.39 mmol, 519 pL, 5.00 eq) in at -70 °C under nitrogen. The mixture was stirred for 6 h and the temperature was allowed to up to 0 °C. The mixture was quenched with ammonia (7 M in methonal) at 20 °C and concentrated in vacuo. The residue was purified by reversed phase column (instrument: 120 g Flash; Column: Welch Ultimate XB_C18 20-40pm; eluent A: water (0.1 % NH4.H2O), eluent B: acetonitrile; gradient: 0-10 min 0-60% B; flow 85 ml/min) to give 3,5-dimethyl-2-[7- (1 ,4-oxazepan-2-yl)-1 ,8-naphthyridin-2-yl]phenol (60.0 mg, 171 pmol, 16% yield, 100% purity) and 3,5- dimethyl-2-[7-(1 ,4-oxazepan-2-yl)-1 ,8-naphthyridin-2-yl]phenol (100 mg, 257 pmol, 24% yield, 90.0% purity) as a yellow solid

^! H NMR (400 MHz, DMSO-d6) 6 [ppm] = 8.48 (d, J = 8.4 Hz, 1 H), 8.43 (d, J = 8.4 Hz, 1 H), 8.27 (s, 1 H), 7.78 (d, J = 8.4 Hz, 1 H), 7.60 (d, J = 8.4 Hz, 1 H), 6.63 (d, J = 9.6 Hz, 2H), 4.94 (dd, J = 3.2, 8.8 Hz, 1 H), 4.13-4.03 (m, 2H), 3.97-3.89 (m, 2H), 3.59 (dd, J = 3.2, 14.0 Hz, 1 H), 3.17-3.04 (m, 2H), 3.02-2.92 (m, 1 H), 2.26 (s, 3H), 2.09 (s, 3H), 2.01-1.94 (m, 2H).

Intermediate 259 tert-butyl 5-(6-fluoro-7-hydroxy-1,8-naphthyrldin-2-yl)-3,6-dihydro-2H- pyridine-1 -carboxylate

To a solution of 3,5-dimethyl-2-[7-(1 ,4-oxazepan-2-yl)-1 ,8-naphthyridin-2-yl]phenol (700 mg, 2.00 mmol, 1 .00 eq) in THF (15 mL) was added tert-butoxycarbonyl tert-butyl carbonate (1 .09 g, 5.01 mmol, 1.15 mL, 2.50 eq). The mixture was stirred at 25 °C for 1 h and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 40-60% Ethyl acetate/Petroleum ethergradient @ 80mL/min) to give tert-butyl 2-[7-(2-hydroxy-4,6- dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1 ,4-oxazepane-4-carboxylate (400 mg, 1.56 mmol, 78% yield) as a yellow oil

LC-MS (Method C): Rt = 0.623 min; MS (ESI) m/z = 450.3 [M+H] ⁺ .

Compound 122

3,5~dimethyl~2‘[7~(1,4sxazepan-2~yQ‘1 _! 8‘naphthyi'idii'i~2-yi]phenol

To a solution of tert-butyl 2-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1 ,4-oxazepane- 4-carboxylate (260 mg, 578 pmol, 1.00 eq) in dioxane (5 mL) was added HCI (4.00 M in dioxane, 10 mL, 69.1 eq). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated in vacuo to give 2-(7-(1 ,4-oxazepan-2-yl)-1 ,8-naphthyridin-2-yl)-3,5-dimethylphenol (150.0 mg, crude, HCI salt). The racemate was separated by SFC (column: Chiralpak AD-3 50x4.6mm I.D., 3um;); mobile phase: [COz-MeCN/ EtOH (0.05%DEA)]; B%: 40%, isocratic elution mode) to give Compound 122

3.5-dimethyl-2-[7-[(2R)-1 ,4-oxazepan-2-yl]-1 ,8-naphthyridin-2-yl]phenol (53.3 mg, 151 pmol, 99% purity) was obtained as yellow solid and Compound 123

3.5-dimethyl-2-[7-[(2S)-1 ,4-oxazepan-2-yl]-1 ,8-naphthyridin-2-yl]phenol (79.5 mg, 216 pmol, 95% purity) was obtained as green solid.

Compound 122

NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 9.99-9.82 (m, 1 H), 8.44 (dd, J = 8.4, 13.2 Hz, 2H), 7.76 (d, J = 8.4 Hz, 1 H), 7.59 (d, J = 8.4 Hz, 1 H), 6.65 (s, 1 H), 6.62 (s, 1 H), 4.79 (dd, J = 3.2, 8.4 Hz, 1 H), 4.12- 4.04 (m, 1 H), 3.92 (ddd, J = 4.4, 8.0, 12.4 Hz, 1 H), 3.42 (dd, J = 3.2, 14.0 Hz, 1 H), 3.01 - 2.94 (m, 1 H), 2.88 (dd, J = 8.4, 14.0 Hz, 1 H), 2.80 (ddd, J = 5.2, 7.8, 13.2 Hz, 1 H), 2.27 (s, 3H), 2.10 (s, 3H), 2.01 - 1.79 (m, 2H).

LC-MS (Method C): Rt = 0.625 min; MS (ESI) m/z = 350.4 [M+H] ⁺ .

SFC (Rt = 1 .535 min, ee% = 100%)

Enantiomer 2

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 10.06-9.72 (m, 1 H), 8.44 (dd, J = 8.4, 16.0 Hz, 2H), 8.34 (s, 1 H), 7.76 (d, J = 8.4 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 6.65 (s, 1 H), 6.61 (s, 1 H), 4.85 (dd, J = 2.0, 8.0 Hz, 1 H), 4.12-4.02 (m, 1 H), 3.97-3.88 (m, 1 H), 3.49 (d, J = 3.2 Hz, 1 H), 3.07-2.99 (m, 1 H), 2.95 (br dd, J = 8.4, 14.2 Hz, 1 H), 2.90-2.81 (m, 1 H), 2.26 (s, 3H), 2.09 (s, 3H), 1.97-1.87 (m, 2H). LC-MS (Method C): Rt = 0.618 min; MS (ESI) m/z - 350.4 [M+H] ⁺ .

SFC (Rt = 2.371 min, ee% = 96%).

Compound 125

3.5-dimethyi-2-[7-[4-methyl-1,4-oxazepan-2-yl]-1,8-naphth ynd!n-2-y!]phenol

To a solution of 3,5-dimethyl-2-[7-(1 ,4-oxazepan-2-yl)-1 ,8-naphthyridin-2-yl]phenol (120 mg, 343 pmol, 1 eq) in methanol (1.00 mL) was added formaldehyde (83.6 mg, 1.03 mmol, 76.7 pL, 37% purity, 3 eq), potassium acetate (101 mg, 1.03 mmol, 3 eq) and sodium cyanoborohydride (64.7 mg, 1 .03 mmol, 3 eq). After stirring at 0 °C for 0.5 h. The reaction mixture was quenched by addition saturated ammonium chloride (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18, 60 g, mobile phase: [water (FA) - MeCN]; B%: 0% - 30%, 8 min) to give a racemate of 3,5-dimethyl-2-(7-(4-methyi-1 ,4-oxazepan-2-yl)-1 ,8-naphthyridin-2-yl)phenol. The racemate was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 pm); mobile phase: [CCh-EtOH (0.1 % NH3-H2O)]; B%: 50%, isocratic elution mode) to give Compound 124 3,5-dimethyl-2-[7-[4-methyl-1 ,4-oxazepan-2-yl]-1 ,8-naphthyridin-2-yl]phenol (30.5 mg, 81.5 pmoi, 23% yield, 96% purity) as a yellow solid and Compound 125 3,5-dimethyl-2-[7-[4-methyl-1 ,4-oxazepan-2- yl]-1 ,8-naphthyridin-2-yl]phenol (35.6 mg, 84.6 pmoi, 24% yield, 97% purity, FA salt) as a yellow solid.

Enantiomer 1

¹ H NMR (400 MHz, DMSO-ds) 6 = 8.44 (d, J = 8.4 Hz, 1 H), 8.39 (d, J = 8.4 Hz, 1 H), 7.76 (d, J = 8.4 Hz, 1 H), 7.59 (d, J = 8.4 Hz, 1 H), 6.61 (s, 1 H), 6.55 (s, 1 H), 4.95 (dd, J = 2.4, 8.8 Hz, 1 H), 4.10-3.88 (m, 2H), 3.24 (d, J = 13.2 Hz, 1 H), 2.81-2.66 (m, 2H), 2.58-2.55 (m, 1 H), 2.35 (s, 3H), 2.23 (s, 3H), 2.08 (s, 3H), 2.06-1.98 (m, 1 H), 1.94-1.83 (m, 1 H)

LC-MS (Method C): Rt = 0.425 min; MS (ESI) m/z = 364.3 [M+H] ⁺ .

SFC (Rt = 1 .084 min, ee% = 99%)

Compound 125

¹ H NMR (400 MHz, DMSO-de) 5 = 10.16-9.72 (m, 1 H), 8.44 (dd, J = 8.4, 16.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 6.65 (s, 1 H), 6.61 (s, 1 H), 4.95 (dd, J = 2.4, 8.8 Hz, 1 H), 4.12-3.86 (m, 2H), 3.24 (d, J = 13.6 Hz, 1 H), 2.84-2.64 (m, 2H), 2.57-2.54 (m, 1 H), 2.35 (s, 3H), 2.26 (s, 3H), 2.08 (s, 3H), 2.06-1.97 (m, 1 H), 2.01-1.88 (m, 1 H)

LC-MS (Method C): Rt = 0.426 min; MS (ESI) m/z = 364.4 [M+H] ⁺ .

SFC (Rt = 1 .084 min, ee% = 99%)

Intermediate 260

2-(cyclohexen-1-y0-7-(2-methoxy-4, 8-dimethyl-phenyl)-1 , 8-naphthyridme

To a solution of 2-bromo-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (3.00 g, 8.30 mmol, 1 eq) and 2-(cyclohexen-1-yl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (2.59 g, 12.5 mmol, 1.5 eq) in dioxane (100 mL) and H2O (10 mL) were added Pd(dppf)Cl2 (607 mg, 830 pmoi, 0.1 eq) and CS2CO3 (8.12 g, 24.9 mmol, 3 eq) at 25 °C. The mixture was warmed to 80 °C, degassed and purged with N2 for 3 times. After stirring at 80 °C for 16 h, the mixture was concentrated to remove dioxane. The residue was purified by column chromatography (SiO?, petroleum ether/ethyl acetate = 10/1 to 1/1) to give 2- (cyclohexen-1-yl)-7-(2-methoxy-4, 6-dimethyl-phenyl)-1 , 8-naphthyridine (3.00 g, 8.17 mmol, 98% yield, 94% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.516 min; MS (ESI): m/z = 345.2 [M+HJ*. Intermediate 261

2-(2-methoxy-4, 6-dlmethyl-phenyl)-7-[2-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dloxaborolan-2-yl) cyclohexyl]-1 , 8-naphthyridlne

To a solution of 2-(cyclohexen-1-yl)-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (2.70 g, 7.35 mmol, 1 eq) in DMF (30 mL) were added K2CO3 (2.03 g, 14.7 mmol, 2 eq), CU2O (105 mg, 735 pmol, 0.1 eq), PPhs (1.93 g, 7.35 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (7.47 g, 29.4 mmol, 4 eq) at 30 °C. After stirring at 100 °C for 16 h, the mixture was added water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(2-methoxy-4,6-dimethyl-phenyl)-7-[2-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)cyclohexyl]-1 ,8-naphthyridine (3.50 g, crude) as yellow oil.

Intermediate 262

2-[7-(2-methoxy-4, 6~dimethyl-phenyl)~1 , 8-naphthyridln-2-yl] cyclohexanol

To a solution of 2-(2-methoxy-4,6-dimethyl-phenyl)-7-[2-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2- yl)cyclohexyl]-1 ,8-naphthyridine (3.50 g, 7.41 mmol, 1 eq) in THF (100 mL) was added a solution of sodium hydroxide (889 mg, 22.2 mmol, 3 eq) in water (20 mL) at 25 °C, then H2O ₂ (5.04 g, 44.4 mmol, 30% purity, 6 eq) was added to the mixture at 0 °C. After stirring at 25 °C for 16 h, the mixture was added saturated sodium sulfite solution (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude. The crude was purified by column chromatography (S1O ₂ , petroleum ether/ethyl acetate = 10/1 to 1/1) to give 2-[7-(2-methoxy-4, 6-dimethyl-phenyl)-1 , 8-naphthyridin-2-yl] cyclohexanol (2.00 g, 4.58 mmol, 62% yield, 83% purity) as yellow oil.

LC-MS (Method C): Rt = 0.483 min; MS (ESI): m/z = 363.2 [M+H] ⁺ -

Intermediate 263

3, 5~dimethyi~2‘[7~[24)ydroxycyclohexyi]~1, 8-naphthyridin-2-yl] phenol

To a solution of 2-[7-(2-methoxy-4, 6-dimethyl-phenyl)-1 , 8-naphthyridin-2-yl] cyclohexanol (1 .90 g, 4.35 mmol, 1 eq) in DCM (30 mL) was added BBrs (3.27 g, 13.1 mmol, 3 eq) at 0 °C. After stirring at 25 °C for 4 h, the mixture was added ammonia (100 mL, 7 M in MeOH) at 0 °C and concentrated under reduced pressure to give a crude. The crude was purified by preparative HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water (ammonia hydroxide v/v)-MeCN];gradient: 40% - 70% B over min) to give 3,5-dimethyl-2-[7-[2-hydroxycyclohexyl]-1 ,8-naphthyridin-2-yl]phenol (245 mg, 679 pmol, 16% yield, 95% purity) as yellow oil.

LC-MS (Method C): Rt = 0.443 min; MS (ESI): m/z = 349.2 [M+H] ⁺ .

Compound 126 and 127

3, 5-dimethyl-2-[7-[2-hyd!-oxycyc!ohexyl]-1, 8-naphthyrldin-2-yl] phenol

The reaction was set up for SFC separation. The residue was purified by SFC: (column: DAICEL CHIRALPAK IC(250mm*30mm,10um);mobile phase: [CO ₂ -EtOH(0.1%NH ₃ *H ₂ O)];B%:55%, isocratic elution mode and column: DAICEL CHIRALPAK IC(250mm*30mm,10um);mobile phase: [CO ₂ - EtOH(0.1 %NH3 H2O)];B%:60%, isocratic elution mode) to give Compound 126 3,5-dimethyl-2-[7-[2- hydroxycyclohexyl]-1 ,8-naphthyridin-2-yl]phenol (36.0 mg, 102 pmol, 11 % yield, 99% purity, peak 1 , Rt = 1.155 min) as a yellow solid, Compound 127 3,5-dimethyl-2-[7-[2-hydroxycyclohexyl]-1 ,8- naphthyridin-2-yl]phenol (36.0 mg, 102 pmol, 11 % yield, 99% purity, peak 2, Rt = 1 .190 min) as a yellow solid, Compound 128 3,5-dimethyl-2-[7-[2-hydroxycyclohexyl]-1 ,8-naphthyridin-2-yl]phenol (50.0 mg, 142 pmol, 15% yield, 99% purity, peak 3, Rt = 1 .643 min) as a yellow solid and Compound 129 2-[7-[2- hydroxycyclohexyl]-1 ,8-naphthyridin-2-yl]-3,5-dimethyi-phenol (84.0 mg, 239 pmol, 25% yield, 99% purity, peak 4, Rt = 2.318) as a yellow solid.

Compound 126

¹ H NMR (400 MHz, DMSO-c/ ₆ ) 6 = 8.38 (d, J = 8.0 Hz, 2H), 7.58 (dd, J = 15.2 Hz, 8.4 Hz, 2H), 6.60 (d, J = 14.0 Hz, 2H), 5.09 (s, 1 H), 4.26 (s, 1 H), 3.02 (d, J = 12.8 Hz, 1 H), 2.25 (s, 3H), 2.15-2.00 (m, 4H), 1 .87-1 .80 (m, 2H), 1 .75-1 .65 (m, 2H), 1 .65-1 .55 (m, 1 H), 1 .50-1 .40 (m, 2H).

LC-MS (Method C): Rt = 0.462 min; MS (ESIpos): m/z = 349.2 [M+1 ] ⁺ .

Compound 127

¹ H NMR (400 MHz, DMSO- d ₆ ) 6 = 9.86 (s, 1 H), 8.35 (dd, J = 17.6 Hz, 8.4 Hz, 2H), 7.54 (dd, J = 8.4 Hz, 2.0 Hz, 2H), 6.62 (d, J = 8.0 Hz, 2H), 4.54 (s, 1 H), 3.90-3.80 (m, 1 H), 2.85-2.70 (m, 1 H), 2.26 (s, 3H), 2.1 1 (s, 3H), 2.04-1 .95 (m, 1 H), 1 .85-1 .65 (m, 4H), 1 .45-1 .25 (m, 3H).

LC-MS (Method C): Rt = 0.453 min; MS (ESIpos): m/z = 349.2 [M+1 ] ⁺ .

SFC (Rt = 1.190 min, ee% = 99%).

Disatereomer 3

¹ H NMR (400 MHz, DMSO-d _s ) 6 = 8.35 (dd, J = 17.6 Hz, 8.4 Hz, 2H), 7.54 (dd, J = 8.4 Hz, 2.0 Hz, 2H), 6.62 (d, J = 8.0 Hz, 2H), 4.54 (s, 1 H), 3.90-3.80 (m, 1 H), 2.85-2.70 (m, 1 H), 2.26 (s, 3H), 2.11 (s, 3H), 2.04-1.95 (m, 1 H), 1.85-1.65 (m, 4H), 1.45-1.25 (m, 3H).

LC-MS (Method C): Rt = 0.450 min; MS (ESIpos): m/z = 349.2 [M+1 ] ⁺ .

SFC (Rt = 1 .643 min, ee% = 99%).

Diastereomer 4

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 = 8.39 (d, J = 8.0 Hz, 2H), 7.58 (dd, J = 15.2 Hz, 8.4 Hz, 2H), 6.62 (d, J = 14.0 Hz, 2H), 5.09 (s, 1 H), 4.26 (s, 1 H), 3.02 (d, J = 12.8 Hz, 1 H), 2.25 (s, 3H), 2.15-2.00 (m, 4H), 1 .87-1 .80 (m, 2H), 1 .75-1 .65 (m, 2H), 1 .65-1 .55 (m, 1 H), 1 .50-1 .40 (m, 2H).

LC-MS (Method C): Rt - 0.470 min; MS (ESIpos): m/z = 349.2 [M+1 ] ⁺ .

SFC (Rt = 2.318 min, ee% = 99%).

Intermediate 264

2-(3,6-dihyd!-o-2H-pyi'an-4-yl)-7-(2-methoxy-4,§-dimethy l-pheny0-1,8-naphthyndine To a solution of 2-bromo-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (3.00 g, 8.30 mmol, 1 eq) and 2-(3, 6-dihydro-2H-pyran-4-yl)-4, 4, 5, 5-tetramethyl-1 ,3,2-dioxaborolane (2.62 g, 12.5 mmol, 1 .5 eq) in dioxane (100 mL) and H2O (10 mL) were added Pd(dppf)Cl2 (607 mg, 830 pmol, 0.1 eq) and CS2CO3 (8.12 g, 24.9 mmol, 3 eq) at 25 °C. The mixture was warmed to 80 °C, degassed and purged with N2 for 3 times. After stirring at 80 °C for 16 h, the mixture was concentrated to remove dioxane. The residue was purified by column chromatography (SIO ₂ , petroleum ether/ethyl acetate = 10/1 to 1/1) to give 2-(3, 6-dihydro-2H-pyran-4-yl)-7-(2-methoxy-4, 6-dimethyl-phenyl)-1 , 8-naphthyridine (2.80 g, 7.76 mmol, 93% yield, 96% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.467 min; MS (ESI): m/z = 347.2 [M+H] ⁺ .

Intermediate 265

2-f2-met/?oxy-4 _; 6-d/metf)y/-pfieny/J-2-f2-mef/ioxy-4,6-d/met/?y/-p/?en y/J-7-f3-(4,4,5,5-feframef/iyf-

1.3.2-dioxaboi'oian-2-y!)tetrahydro-pyran-4-y!]-1, 8-naphthyridine

To a solution of 2-(3,6-dihydro-2H-pyran-4-yl)-7-(2-methoxy-4,6-dimethyl-phen yl)-1 ,8-naphthyridine (2.50 g, 6.93 mmol, 1 eq) in DMF (30 mL) were added K2CO3 (1.92 g, 13.9 mmol, 2 eq), CU2O (99.1 mg, 693 pmol, 0.1 eq), PPhs (1.82 g, 6.93 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-

1 .3.2-dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (7.04 g, 27.7 mmol, 4 eq) at 30 °C, the reaction mixture was warmed to 100 °C. After stirring at 100 °C for 16 h, the mixture was added water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(2-methoxy-4,6-dimethyl- phenyl)-7-[3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)tetrahydropyran-4-yl]-1 ,8-naphthyridine (3,30 g, crude) as yellow oil.

Intermediate 266

4-[7-(2-methoxy-4, 8-dimethyl-phenyl)-1 , 8-naphthyridin-2-yl] tetrahydropyran-3-ol

To a solution of 2-(2-methoxy-4,6-dimethyl-phenyl)-7-[3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2- yl)tetrahydropyran-4-yl]-1 ,8-naphthyridine (3.30 g, 6.96 mmol, 1 eq) in THF (100 mL) was added a solution of NaOH (834 mg, 20.9 mmol, 3 eq) in water (20 mL) at 25 °C, then H2O ₂ (4.73 g, 41 .7 mmol, 30% purity, 6 eq) was added to the mixture at 0 °C. After stirring at 25 °C for 16 h, the mixture was added saturated sodium sulfite solution (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude. The crude was purified by column chromatography (SiCh, petroleum ether/ethyl acetate = 10/1 to 1/1) to give 4-[7-(2-methoxy-4, 6-dimethyl-phenyl)-1 , 8-naphthyridin-2-yl] tetrahydropyran-3-ol (1 .50 g, 3.29 mmol, 47% yield, 80% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.438 min; MS (ESI): m/z = 365.2 [M+H] ⁺ .

Intermediate 267

4-[7-(2-hydroxy-4, @-dimethyl-pheny!)-1 , 8-naphthyridin-2-yl] tetrahydropyran-3-o!

To a solution of 4-[7-(2-methoxy-4, 6-dimethyl-phenyl)-1 , 8-naphthyridin-2-yl] tetrahydropyran-3-ol (1.40 g, 3.07 mmol, 1 eq) in DCM (30 mL) was added BBrs (2.31 g, 9.22 mmol, 3 eq) at 0 °C. After stirring at 25 °C for 4 h, the mixture was added ammonia (100 mi_, 7 M in MeOH) at 0 °C and concentrated under reduced pressure to give a crude. The crude was purified by preparative HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (ammonia hydroxide v/v)-MeCN]; gradient: 2%-58% B over min) to give 4-[7-(2-hydroxy-4, 6-dimethyl-phenyl)-1 , 8-naphthyridin-2-yl] tetrahydropyran-3-ol (160 mg, 452 pmol, 15% yield, 99% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.412 min; MS (ESI): m/z = 351 .1 [M+H] ⁺ .

Compound 130

4-[7-(2-hydroxy-4, 6-dimethyl-phenyl)- 1, §-naphthyridm-2-yl]tetrahydropyran-3-o!

The reaction was set up for SFC separation. The residue was purified by SFC (column: DAICEL CHIRALPAK IC(250 mm*30 mm, 10 um); mobile phase: [CO ₂ -EtOH(0.1 %NH ₃ H ₂ O)];B%:55%, isocratic elution mode and column: DAICEL CHIRALPAK IC (250mm*30mm,10um);mobile phase: [CO ₂ - EtOH(0.1 %NH ₃ *H ₂ O)]; B%:45%, isocratic elution mode) to give Compound 130 4-[7-(2-hydroxy-4,6- dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]tetrahydropyran-3-ol (37.0 mg, 100 pmol, 16% yield, 95% purity, peak 1 , Rt = 1.027 min) as a yellow solid, Compound 131 4-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8- naphthyridin-2-yl]tetrahydropyran-3-ol (31.0 mg, 85.8 pmol, 14% yield, 97% purity, peak 2, Rt = 1.477 min) as a yellow solid, Compound 132 4-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]tetrahydropyran-3-ol (39.0 mg, 108 pmol, 17% yield, 97% purity, peak 3, Rt = 2.259 min) as a yellow solid and Compound 133 4-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]tetrahydropyran- 3-ol (45.0 mg, 127 pmol, 20% yield, 99% purity, peak 4, Rt = 3.920 min) as a yellow solid.

Compound 130

¹ H NMR (400 MHz, DMSO-d _s ) 6 = 8.38 (dd, J = 8.4 Hz, 6.4 Hz, 2H), 7.57 (dd, J = 14.0 Hz, 8.4 Hz, 2H),

6.60 (d, J = 12.8 Hz, 2H), 3.95-3.85 (m, 3H), 3.45-3.38 (m, 2H), 3.15-3.08 (m, 1 H), 3.03-2.95 (m, 1 H), 2.25 (s, 3H), 2.09 (s, 3H), 2.04-1 .95 (m, 1 H), 1 .88-1 .80 (m, 1 H).

LC-MS (Method C): Rt = 0.413 min; MS (ESipos): m/z = 351.2 [M+1 ] ⁺ .

SFC (Rt = 1 .027 min, ee% = 99%).

Diastereomer 2

¹ H NMR (400 MHz, DMSO- cf ₆ ) 6 = 8.38 (dd, J = 8.4 Hz, 6.4 Hz, 2H), 7.57 (dd, J = 14.0 Hz, 8.4 Hz, 2H),

6.61 (d, J = 12.8 Hz, 2H), 3.95-3.85 (m, 3H), 3.45-3.38 (m, 2H), 3.15-3.08 (m, 1 H), 3.03-2.95 (m, 1 H), 2.25 (s, 3H), 2.09 (s, 3H), 2.04-1.95 (m, 1 H), 1.88-1.80 (m, 1 H).

LC-MS (Method C): Rt = 0.411 min; MS (ESipos): m/z = 351 .2 [M+1 ] ⁺ .

SFC (Rt = 1 .477 min, ee% = 98%).

Diastereomer 3

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 = 9.85 (s, 1 H), 8.4 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1 H), 7.56 (d, J = 8.0 Hz, 1 H), 6.62 (d, J = 7.6 Hz, 2H), 5.05 (s, 1 H), 4.08 (s, 1 H), 4.05-3.98 (m, 1 H), 3.88-3.80 (m, 1 H), 3.60 (d, J = 11.2 Hz, 1 H), 3.55-3.48 (m, 1 H), 3.30-3.25 (m, 1 H), 2.42-2.30 (m, 1 H), 2.26 (s, 3H), 2.09 (s, 3H), 1.78-1.70 (m, 1 H). LC-MS (Method C): Rt = 0.411 min; MS (ESIpos): m/z = 351 .2 [M+1] ⁺ .

SFC (Rt = 2.259 min, ee% = 98%).

Diastereomer 4

¹ H NMR (400 MHz, DMSO-d _e ) 5 = 9.91 (s, 1 H), 8.4 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1 H), 7.56 (d, J = 8.0 Hz, 1 H), 6.62 (d, J = 7.6 Hz, 2H), 5.05 (s, 1 H), 4.08 (s, 1 H), 4.05-3.98 (m, 1 H), 3.88-3.80 (m, 1 H), 3.60 (d, J = 11.2 Hz, 1 H), 3.55-3.48 (m, 1 H), 3.30-3.25 (m, 1 H), 2.42-2.30 (m, 1 H), 2.26 (s, 3H), 2.09 (s, 3H), 1.78-1.70 (m, 1 H).

LC-MS (Method C): Rt = 0.416 min; MS (ESIpos): m/z - 351.2 [M+1 ] ⁺ .

SFC (Rt = 3.920 min, ee% = 95%).

Intermediate 268

To a solution of tert-butyl 5-[4-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-3,6- dihydro-2Hpyridine-1-carboxylate (2.00 g, 4.17 mmol, 1.00 eq) in 1 ,4-dioxane (30 mL) were added methanesulfonamide (1.19 g, 12.5 mmol, 3.0 eq), cesium carbonate (4.07 g, 12.5 mmol, 3.00 eq), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (482 mg, 833 pmol, 0.20 eq) and tris(dibenzylideneacetone)dipalladium(0) (382 mg, 417 pmol, 0.10 eq) at 25 °C under nitrogen atmosphere. After stirring at 90 °C for 14 h under nitrogen atmosphere. The reaction mixture was diluted with water (30 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 1/1) to give tert-butyl 5-[4-(methanesulfonamido)-7-(2-methoxy-4,6-dimethyl-phenyl)- 1 ,8-naphthyridin-2-yl]-

3.6-dihydro-2Hpyridine-1-carboxyiate (700 mg, 1.30 mmol, 31 % yield) as a yellow solid.

LC-MS (Method C): Rt = 0.573 min; MS (ESI) m/z = 539.3 [M+H] ⁺ .

Intermediate 269

To a solution of tert-butyl 5-[4-(methanesulfonamido)-7-(2-methoxy-4,6-dimethyl-phenyl)- 1 ,8- naphthyridin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (700 mg, 1.30 mmol, 1.0 eq) in methanol (10 mL) was added Pd/C (100 mg, 10% purity) at 25 °C under nitrogen atmosphere. The reaction mixture was degassed and purged with hydrogen for three times. After stirring at 25 °C under hydrogen (15 psi) for 4 h. The reaction mixture was filtered under reduced pressure. The filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiOz, petroleum ether/ethyl acetate = 20/1 to 0/1) to give tert-butyl 3-[4-(methanesulfonamido)-7-(2-methoxy-4,6- dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]piperidine-1-carboxylate (500 mg, 925 pmol, 71 % yield) as yellow solid.

LC-MS (Method C): Rt = 0.597 min; MS (ESI) m/z = 541 .2 [M+HJ*. Intermediate 270

N-[7-(2-methoxy-4,8-dimethyl-phenyl)-2-(3-pipendyl)-1,§- naphthyndin-4- yljmethanesulfonamide

A solution of tert-butyl 3-[4-(methanesulfonamido)-7-(2-methoxy-4,6-dimethyl-phenyl)- 1 ,8- naphthyridin-2-yl]piperidine-1-carboxylate (500 mg, 924 pmol, 1.0 eq) in hydrochloric acid (4.00 M in 1 ,2-dioxane, 10 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuum to give N-[7-(2-methoxy-4,6-dimethyl-phenyl)-2-(3-piperidyl)-1 ,8-naphthyridin-4-yl]methanesulfonamide (475 mg, 925 pmol, 100% yield, HCI salt) as a yellow solid.

LC-MS (Method C): R _t = 0.800 min; MS (ESI) m/z = 441 .2 [M+H] ⁺ .

Intermediate 271

To a solution of N-[7-(2-methoxy-4,6-dimethyl-phenyl)-2-(3-piperidyl)-1 ,8-naphthyridin-4- yl]methanesulfonamide (475 mg, 924 pmol, 1.00 eq, HCI salt) in methanol (10 mL) were added formaldehyde (83.3 mg, 2.77 mmol, 76.4 pL, 3.0 eq), potassium acetate (182 mg, 1.85 mmol, 2.0 eq) and sodium cyanoborohydride (174 mg, 2.77 mmol, 3.0 eq) at 0 °C. After stirring at 25 °C for 1 h, the mixture was added into ammonium chloride (5.0 mL) at 0 °C. The pH of the mixture was adjusted to 8- 9 with saturated sodium bicarbonate at 0 °C. The mixture was extracted with ethyl acetate (10 mL x 3). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18, 80 g, mobile phase: [water(FA) - MeCN];B%: 10% - 40%, 10 min) to give N-[7-(2-methoxy-4,6-dimethyl-phenyl)-2- (1-methyl-3-piperidyl)-1 ,8-naphthyridin-4-yl]methanesulfonamide (270 mg, 594 pmol, 64% yield) as a yellow solid.

¹ H NMR (400 MHz, CDCI3) 6 [ppm] = 8.78 (d, J = 8.4 Hz, 1 H), 8.39 (s, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 8.78 (d, J = 8.4 Hz, 1 H), 7.23 (s, 1 H), 6.72 (s, 1 H), 6.68 (s, 1 H), 3.70 (s, 3H), 3.59-3.22 (m, 2H), 3.15 (s, 3H), 3.12-2.74 (m, 3H), 2.62 (s, 3H), 2.38 (s, 3H), 2.12-2.02 (m, 4H), 1.92 (s, 3H).

LC-MS (Method C): Rt = 0.803 min; MS (ESI) m/z = 455.2 [M+H] ⁺ .

Compound 134 and 135

N-[7-(2-hydroxy-4, 6-dimethyl-pheny!}-2-[ 1 -methyl-3-piperidyi]- 1, 8-naphthyridin-4- yijmethanesulfonamide

To a solution of N-[7-(2-methoxy-4,6-dimethyl-phenyl)-2-(1-methyl-3-piperidyl )-1 ,8-naphthyridin-4- yl]methanesulfonamide (250 mg, 550 pmol, 1.0 eq) in dichloromethane (10 mL) was added boron tribromide (413 mg, 1 .65 mmol, 159 pL, 3.0 eq) at -78 °C. After stirring at 0 °C for 1 h, the mixture was added into water (10 mL) at 0 °C. The pH of the mixture adjusted to 7-8 with saturated aqueous sodium bicarbonate at 0 °C. The mixture was extracted with dichloromethane (10 mL x 3). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase (column: C18, 80 g, mobile phase: [water (FA) - MeCN];B%: 10% - 35%, 10 min) to give a racemate. The racemate was separated by SFC (column: DAICEL CHIRALPAK AS(250 mm*30 mm, 10 pm);mobile phase: [CO ₂ - EtOH(0.1 %NH3*H ₂ O)];B%:40%, isocratic elution mode) to give Compound 134 N-[7-(2-hydroxy-4,6- dimethyl-phenyl)-2-[1-methyl-3-piperidyl]-1 ,8-naphthyridin-4-yl]methanesulfonamide (51 .6 mg, 117 pmol, 21 % yield, 99% purity) as a yellow solid and Compound 135 N-[7-(2-hydroxy-4,6-dimethyl-phenyl)-2-[1-methyl-3-piperidyl ]-1 ,8-naphthyridin-4- yl]methanesulfonamide (55.1 mg, 125 pmol, 23% yield, 99% purity) as a yellow solid.

Compound 134

¹ H NMR (400 MHz, DMSO-d _e ) 5 [ppm] = 8.62 (d, J = 8.8 Hz, 1 H), 7.44 (d, J = 8.4 Hz, 1 H), 7.02 (s, 1 H), 6.62 (s, 1 H), 6.60 (s, 1 H), 3.04-2.95 (m, 2H), 2.92 (s, 3H), 2.80-2.72 (m, 1 H), 2.32-2.25 (m, 7H), 2.11 (s, 3H), 2.08-2.02 (m, 1 H), 1.98-1.91 (m, 1 H), 1.77-1.69 (m, 1 H), 1.65-1.45 (m, 2H).

LC-MS (Method C): Rt = 0.787 min; MS (ESI) m/z = 441 .2 [M+H] ⁺ .

SFC (Rt = 2.094 min, ee% = 99%).

Compound 135

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 8.63 (d, J = 8.4 Hz, 1 H), 8.31 (s, 1 H), 7.44 (d, J = 8.4 Hz, 1 H), 7.03 (s, 1 H), 6.63 (s, 1 H), 6.61 (s, 1 H), 3.04-2.96 (m, 2H), 2.92 (s, 3H), 2.78 (d, J = 11 .2 Hz„ 1 H), 2.34- 2.25 (m, 7H), 2.12 (s, 3H), 2.11-2.05 (m, 1 H), 1.97-1.91 (m, 1 H), 1.79-1.70 (m, 1 H), 1.68-1.46 (m, 2H). LC-MS (Method C): Rt = 0.790 min; MS (ESI) m/z = 441 .2 [M+H] ⁺ .

SFC (Rt = 1 .474 min, ee% = 99%).

Intermediate 272 tert-butyl 5-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-vinyl-1,8-naphthyrldi n-2-yl]-3,6-dihydro-2H- pyridine-1 -carboxylate

To a solution of tert-butyl 5-[4-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-3,6- dihydro-2Hpyridine-1 -carboxylate (2.00 g, 4.17 mmol, 1.00 eq) and potassium;trifluoro(vinyl)boranuide (1.12 g, 8.36 mmol, 2.01 eq) ini ,4-dioxane (10 mL) and water (2.00 mL) were added cesium carbonate (2.72 g, 8.35 mmol, 2.0 eq) and [1 ,1-bis(diphenylphosphino)ferrocene]dichloropall,adium(ll) (320 mg, 437 pmol, 0.10 eq) at 25 °C. The mixture was degassed and purged with nitrogen for three times. After stirring at 90 °C for 14 h under nitrogen atmosphere, the mixture was filtered under reduced pressure. The filtrate was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 0/1) to give tert-butyl 5-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-vinyl-1 ,8-naphthyridin-2-yl]-3,6- dihydro-2H-pyridine-1-carboxylate (1.00 g, 2.12 mmol, 51 % yield) as red oil.

Intermediate 273 A mixture of tert-butyl 5-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-vinyl-1 ,8-na phthyridin-2-yl]-3,6-dihydro- 2H-pyridine-1 -carboxylate (940 mg, 1.99 mmol, 1.00 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (759 mg, 2.99 mmol, 1.50 eq), cuprous oxide (28.5 mg, 199 pmol, 20.4 pL, 0.100 eq), triphenylphosphine (784 mg, 2.99 mmol, 1.50 eq) and potassium carbonate (275 mg, 1 .99 mmol, 1.00 eq) in methanol (10.0 mL) was stirred at 30 °C for 14 h under nitrogen atmosphere. The reaction mixture was concentrated in vacuum to give tert-butyl 5-[7-(2- methoxy-4,6-dimethyl-phenyl)-4-[2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)ethyl]-1 ,8- naphthyridin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.20 g, 2.00 mmol, 100% yield) as a brown solid.

LC-MS (Method C): R _t = 0.596 min; MS (ESI) m/z = 600.3 [M+H] ⁺ .

Intermediate 274 tert-butyl 5-[4-(2-hydroxyethyl)-7-(2-methoxy-4,6-dlmethyl-phenyl)-1,8- naphthyrldln-2-yl]-3,6- dihydro-2H-pyridine-1 -carboxylate

To a solution of tert-butyl 5-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-[2-(4,4,5,5-tetrameth yl-1 ,3,2- dioxaborolan-2-yl)ethyl]-1 ,8-naphthyridin-2-yl]-3,6-dihydro-2H-pyridine-1 -carboxylate (1 .20 g, 2.00 mmol, 1.00 eq) in tetrahydrofuran (12.0 mL) was added sodium hydroxide (3.00 M, 4.00 mL, 6.0 eq) and hydrogen peroxide (4.54 g, 40.0 mmol, 3.85 mL, 30% purity, 20.0 eq) at 0 °C. After stirring at 25 °C for 0.5 h. The reaction mixture was quenched by saturated sodium thiosulfate (20 mL) at 25 °C. The mixture extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The product was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water (NHs’HzO) - MeCNJ;B%: 20% - 75%, 16 min) to give tert-butyl 5-[4-(2-hydroxyethyl)-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8- naphthyridin-2-yl]-3,6-dihydro-2H-pyridine-1 -carboxylate (300 mg, 613 pmol, 31 % yield) as a yellow solid.

LC-MS (Method C): Rt = 0.515 min; MS (ESI) m/z = 490.3 [M+H] ⁺ .

Intermediate 275

To a solution of tert-butyl 5-[4-(2-hydroxyethyl)-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]-3,6-dihydro-2H-pyridine-1 -carboxylate (300 mg, 613 pmol, 1.00 eq, EW38698-232 ) in MeOH (3 mL) was added Pd/C (10% purity, 1 .0 eq) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen for several times. After stirring at 25 °C for 3 h under hydrogen atmosphere (15 psi). The mixture was filtered through a pad of celite. The filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiOz, petroleum ether/ethyl acetate = 1/0 to 1.5/1) to give tert-butyl 3-[4-(2-hydroxyethyl)-7-(2-methoxy-4,6-dimethyl- phenyl)-1 ,8-naphthyridin-2-yl]piperidine-1-carboxylate (170 mg, 346 pmol, 56% yield) as a yellow oil. LC-MS (Method C): Rt = 0.990 min; MS (ESI) m/z = 492.2 [M+HJ*. Intermediate 276

2-[7-(2-m&thoxy-4,6-dimethyl-phenyl)-2-(3-pipendyl)-1 ,B-naphthyndin-4-yl]ethagiol

A mixture of tert-butyl 3-[4-(2-hydroxyethyl)-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]piperidine-1 -carboxylate (270 mg, 549 pmol, 1.0 eq), hydrochloric acid (4.00 M in dioxane, 5.00 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuum to give 2-[7-(2-methoxy- 4,6-dimethyl-phenyl)-2-(3-piperidyl)-1 ,8-naphthyridin-4-yl]ethanol (235 mg, 549 pmol, 100% yield, HCI salt) as a yellow solid.

LC-MS (Method C): R _t = 0.437 min; MS (ESI) m/z = 392.3 [M+H] ⁺ .

Intermediate 277

2-[7-(2-methoxy-4,B-dimethyl-pheny0-2-(1-methyl-3-pipendy l)-1,8-naphthyddm-4-yl]ethanol

To a solution of 2-[7-(2-methoxy-4,6-dimethyl-phenyl)-2-(3-piperidyl)-1 ,8-naphthyridin-4-yl]ethanol (235 mg, 549 pmol, 1 .0 eq, HCI salt) in MeOH (5 mL) were added formaldehyde (134 mg, 1 .65 mmol, 123pL, 37% purity in water, 3.0 eq), potassium acetate (108 mg, 1.10 mmol, 2.0 eq) and sodium triacetoxyhydroborate (349 mg, 1 .65 mmol, 3.0 eq) at 0 °C. After stirring at 25 °C for 2 h, the mixture was added into saturated aqueous ammonium chloride (10 mL). The pH of the mixture was adjusted to 8 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(FA) - MeCN];B%: 10% - 40%, 20 min) to give 2-[7-(2-methoxy-4,6-dimethyl- phenyl)-2-(1-methyl-3-piperidyl)-1 ,8-naphthyridin-4-yl]ethanol (170 mg, 419 pmol, 76% yield) as a yellow solid.

LC-MS (Method C): Rt = 0.773 min; MS (ESI) m/z = 406.3 [M+Hj ⁺ .

Compound 136 and 137

2-[5-(2~hydi'oxyethyi)‘7-[1‘methyl-3~pip8ddyl]~1,S~i' iaphthyddin-2~yi]‘3 _! 5-dimethybpherioi

To a solution of 2-[7-(2-methoxy-4,6-dimethyl-phenyl)-2-(1-methyl-3-piperidyl )-1 ,8-naphthyridin-4- yljethanol (150 mg, 370 pmol, 1.00 eq) in dichloromethane (3.00 mL) was added boron tribromide (278 mg, 1.11 mmol, 107 pL, 3.00 eq) at 0 °C. After stirring at 25 °C for 4 h, the mixture was added dropwise to ice water (5.00 mL) at 0 °C. The pH of the mixture was adjusted to 7-8 with saturated sodium bicarbonate. The mixture was extracted with dichloromethane (15 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by reversed-phase (column: C18, 40 g, mobile phase: [water (NH3-H2O) - MeCN];B%: 10% - 40%, 20 min) to give racemate. The racemate was separated by SFC (column: Daicel ChiralPak IG (250*30mm, 10pm);mobile phase: [CO ₂ -EtOH(0.1 %NH3«H2O)];B%: 45%, isocratic elution mode) to give 2-[5-(2-hydroxyethyl)-7-[rel-(3R)-1-methyl-3-piperidyl]-1 ,8-naphthyridin-2-yl]-3,5- dimethyl-phenol (18.7 mg, 46.8 pmol, 13% yield, 98% purity) as a yellow solid and 2-[5-(2-hydroxyethyl)- 7-[rel-(3R)-1-methyl-3-piperidyl]-1 ,8-naphthyridin-2-yl]-3,5-dimethyl-phenol (30.2 mg, 67.9 pmol, 18% yield, 98% purity, HCOOH salt) as a brown solid. Compound 136

¹ H NMR (400 MHz, DMSO-d _e ) 5 [ppm] = 9.99 (s, 1 H), 8.57 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 1 H), 7.46 (s, 1 H), 6.64 (s, 1 H), 6.62 (s, 1 H), 4.82 (br. s, 1 H), 3.78 (t, J = 6.0 Hz, 2H), 3.24 (t, J = 6.4 Hz, 2H), 3.12-3.05 (m, 1 H), 3.01 (d, J = 11.2 Hz, 1 H), 2.81 (d, J = 10.8 Hz, 1 H), 2.26 (s, 3H), 2.22-2.16 (m, 4H), 2.10 (s, 3H), 1.99-1.88 (m, 2H), 1.74-1.58 (m, 3H).

LC-MS (Method C): Rt = 0.729 min; MS (ESI) m/z = 392.2 [M+H] ⁺ .

SFC (Rt = 2.181 min, ee% = 100%).

Compound 137

¹ H NMR (400 MHz, DMSO-d _e ) 5 [ppm] = 8.57 (d, J = 8.4 Hz, 1 H), 8.30 (s, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 7.46 (s, 1 H), 6.64 (s, 1 H), 6.61 (s, 1 H), 3.78 (t, J = 6.4 Hz, 2H), 3.24 (t, J = 6.4 Hz, 2H), 3.15-3.06 (m, 2H), 2.87 (d, J = 10.8 Hz, 1 H), 2.33-2.28 (m, 4H), 2.26 (s, 3H), 2.10 (s, 3H), 2.03-1.98 (m, 2H), 1.79- 1.59 (m, 2H).

LC-MS (Method C): Rt = 0.729 min; MS (ESI) m/z = 392.2 [M+H] ⁺ .

SFC (Rt = 3.336 min, ee% =94%).

Intermediate 278

7-chioro~4-hydmxy-1 H~1.8-naphthyrid‘n~2-Qne

To a solution of methyl 2-amino-6-chloro-pyridine-3-carboxylate (25.0 g, 133.9 mmol, 1 eq) in ethyl acetate (500 mL) was added t-BuOK (1 .00 M, 267 mL, 2 eq) after stirring at 60 °C for 2 h, the mixture was concentrated to give a residue, the residue was added water (500 mL) and adjusted to pH = 5~6 by HCI (1 N in water), the mixture was filtrated and the filtrate was collected and concentrated under reduced pressure to give 7-chloro-4-hydroxy-1 H-1 ,8-naphthyridin-2-one (13.0 g, 56.87 mmol, 21.22% yield, 86% purity) as a white solid.

LC-MS (Method C): Rt = 0.383 min; MS (ESIpos): m/z = 169.9 [M+1 ] ⁺ .

Intermediate 279

4-hydroxy-7-(2-methoxy-4,6-dimethyl-phenyl)-1H-1,8-naphth ynd!n-2-one

A mixture of 7-chloro-4-hydroxy-1 H-1 ,8-naphthyridin-2-one (13.0 g, 66.1 mmol, 1 eq) , (2-methoxy-4,6- dimethyl-phenyl) boronic acid (14.2 g, 79.3 mmol, 1.2 eq) , XPhos Pd G3 (5.60 g, 6.61 mmol, 0.1 eq) , potassium phosphate (28.1 g, 132 mmol, 2 eq) in dioxane (250 mL) and water (50 mL) was degassed and purged with N2 for 3 times, after stirring at 90 °C for 16 h under N2 atmosphere, the reaction mixture was concentrated to give a residue, and then the residue was added water (200 mL) and extracted with ethyl acetate (200 mL), the pH of mixture was adjusted to 6-7 by HCI (1 N in water), the mixture was filtrated and the filtrater was collected to give a 4-hydroxy-7-(2-methoxy-4,6-dimethyl-phenyl)-1 H-1 ,8- naphthyridin-2-one (18.0 g, 56 mmol, 85% yield, 92% purity) as a gray solid.

LC-MS (Method C): Rt = 0.478 min; MS (ESIpos): m/z = 297.2 [M+1 ] ⁺ .

Intermediate 280

2 _! 4-dichloro-7-(2-methoxy-4,8-dimethyl-phenyl)-1,8-napht hyddme To a solution of 4-hydroxy-7-(2-methoxy-4,6-dimethyl-phenyl)-1 H-1 ,8-naphthyridin-2-one (18.0 g, 60.7 mmol, 1 eq) in toluene (200 mL) was added phosphorus oxychloride (46.5 g, 303 mmol, 28 mL, 5 eq) at 20 °C. After stirring 100 °C for 16 h, the mixture was concentrated to give a residue, and then the crude was diluted with ethyl acetate (200 mL) and washed with saturated sodium bicarbonate solution (200 mL) and brine (100 mL) by follow, the organic phase was collected and concentrated to give 2,4- dichloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (14.0 g, 40.7mmol, 67% yield, 97% purity) as a gray solid.

¹ H NMR (400 MHz, DMSO-d6) 5 = 8.64 (d, J = 8.4 Hz, 1 H), 8.11 (s, 1 H), 7.74 (d, J = 8.4 Hz, 1 H), 6.91- 6.75 (m, 2H), 3.67 (s, 3H), 2.36 (s, 3H), 2.03 (s, 3H).

LC-MS (Method C): Rt = 0.619 min; MS (ESIpos): m/z = 333.0 [M+1 ] ⁺ .

Intermediate 281

To a mixture of 2, 4-dichloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (13.0 g, 39.0 mmol, 1 eq) , tert-butyl 5-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 -carboxylate (12.1 g, 39.0 mmol, 1 eq), Pd(dppf)Ch (2.85 g, 3.90 mmol, 0.1 eq), sodium carbonate (8.27 g, 78.1 mmol, 2 eq) and in dioxane (200 mL) and water (20 mL) was degassed and purged with N2 for 3 times, after stirring at 80 °C for 16 h under N2 atmosphere, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3), the combined organic phase were purified by column chromatography (SIO ₂ , petroleum ether/ethyl acetate=10/1 to 2/1). to give a tert-butyl 5-[4-chloro-7-(2- methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-3,6-dihydro-2H-pyridine-1 -carboxylate (9.50 g, 18.8 mmol, 48% yield, 95% purity) as a white solid.

¹ H NMR (400 MHz, DMSO-ofe) 6 = 8.58 (d, J = 8.4 Hz, 1 H), 8.27 (s, 1 H), 7.61 (d, J = 8.4 Hz, 1 H), 7.23 (br s, 1 H), 6.93 - 6.73 (m, 2H), 4.47 (br s, 2H), 3.66 (s, 3H), 3.52 (br t, J = 5.6 Hz, 2H), 2.39 (s, 2H), 2.36 (s, 3H), 2.04-1.97 (m, 3H), 1.43 (s, 9H).

LC-MS (Method C): Rt = 0.672 min; MS (ESIpos): m/z = 480.1 [M+1 ] ⁺ .

Intermediate 282 tert-butyl 5-[7-(2-methoxy-4,6-dimethyl-plienyl)-4-(methoxymetliyl)-1,� �-naphthyridm-2-yl]-3,6- dihydro-2H-pyridine-1 -carboxylate

To a solution of tert-butyl 5-[4-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-3,6- dihydro-2H-pyridine-1-carboxylate (500 mg, 1.04 mmol, 1 eq) , potassium;trifiuoro (methoxymethyl) boranuide (474 mg, 3.13 mmol, 3 eq), cesium carbonate (678 mg, 2.08 mmol, 2 eq) , Pd(OAc)2 (23.3 mg, 104 pmol, 0.1 eq) and bis(1-adamantyl)-butyl-phosphane (74.7 mg, 208 pmol, 0.2 eq) in dioxane (20 mL) and water (4 mL) were degassed and purged with N2 for 3 times. After stirring at 100 °C for 16 h under N2 atmosphere, the mixture was quenched with saturated water (20 mL) and extracted with ethyl acetate (10 mL x 3), the combined organic phase was purified by column chromatography (SIO ₂ , petroleum ether/ethyl acetate=5/1 to 2/1). to give a tert-butyl 5-[7-(2-methoxy-4,6-dimethyl-phenyl)-4- (methoxymethyl)-l ,8-naphthyridin-2-yl]-3,6-dihydro-2H-pyridine-1 -carboxylate (540 mg, 992 pmol, 47% yield, 90% purity) as a white solid.

LC-MS (Method C): Rt = 0.552 min; MS (ESIpos): m/z = 490.3 [M+1] ⁺ . intermediate 283

To a solution of tert-butyl 5-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-(methoxymethyl)-1 ,8-naphthyridin-2- yl]-3,6-dihydro-2H-pyridine-1 -carboxylate (540 mg, 1.10 mmol, 1 eq) in methanol (10 mL) was added Pd/C (3.52 g, 3.31 mmol, 10% purity, 3 eq) at 25 °C. After stirring at 25 °C for 1 h under Ha (15 psi) atmosphere., the mixture was filtrated and the filtrate was concentrated to give a tert-butyl 3-[7-(2- methoxy-4,6-dimethyl-phenyl)-4-(methoxymethyl)-1 ,8-naphthyridin-2-yl]piperidine-1 -carboxylate (480 mg, 878 pmol, 79% yield, 90% purity) as yellow oil.

LC-MS (Method C): Rt = 0.561 min; MS (ESIpos): m/z = 492.1 [M+1 ] ⁺ .

Intermediate 284

7-(2~methoxy-4 _! 8~dimethyl-phenyl)-4-(methoxymethyl)-2-(3-p‘peridy!) -1,8-naphthyridine

To a solution of tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-(methoxymethyl)-1 ,8-naphthyridin-2- yl]piperidine-1 -carboxylate (480 mg, 976 pmol, 1 eq) in dichloromethane (10 mL) was added TFA (333 mg, 2.93 mmol, 217,57 pL, 3 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was quenched concentrated to give 7-(2-methoxy-4,6-dimethyl-phenyl)-4-(methoxymethyl)-2-(3-pip eridyl)-1 ,8- naphthyridine (480 mg, 854 pmol, 87% yield, 90% purity, TFA salt) as yellow oil, LC-MS (Method C): Rt = 0.441 min; MS (ESIpos): m/z = 392.1 [M+1 ] ⁺ .

Intermediate 285

7-(2-methoxy-4,6-dimethyl-phenyl)-4-(methoxymethyl)-2-(1- methyl-3-plperidyl)-1,8- naphthyridine

To a solution of 7-(2-methoxy-4,6-dimethyl-phenyl)-4-(methoxymethyl)-2-(3-pip eridyl)-1 ,8- naphthyridine (480 mg, 949 pmol, 1 eq, TFA salt) in methanol (20 mL) was added NaBHsCN (179 mg, 2.85 mmol, 3 eq), potassium acetate (279 mg, 2.85 mmol, 3 eq) and (HCHO)n (56.9 mg, 1 .90 mmol, 2 eq) 25 °C. After stirring at 25 °C for 3 h, the mixture was filtrated and the filtrate was purified by reversed- phase column (column: C18, 40 g, mobile phase: [water(FA) - MeCN];B%: 20% - 40%, 5 min) to give a 7-(2-methoxy-4,6-dimethyl-phenyl)-4-(methoxymethyl)-2-(1-met hyl-3-piperidyl)-1 ,8-naphthyridine (200 mg, 468 pmol, 49% yield, 95% purity) as yellow oil.

LC-MS (Method C): Rt = 0.452 min; MS (ESIpos): m/z = 406.2 [M+1 ] ⁺ .

Intermediate 286

2-[5-(methoxymethyl)-7-(1-methyl-3-plperldyl)-1,8-naphthy ridm-2-yl]-3,5-dimethyl-phenol

To a solution of 7-(2-methoxy-4,6-dimethyl-phenyl)-4-(methoxymethyl)-2-(1-met hyl-3-piperidyl)-1 ,8- naphthyridine (200 mg, 493 pmol, 1 eq) in DMF (10 mL) was added sodium thioethylate (829 mg, 9.86 mmol, 20 eq) at 20 °C. After stirring at 100 °C for 16 h, the mixture was poured into water (30 mL) and extracted with dichloromethane (30 mL*2), the combined organic phase was purified by reversed- phase column (column: C18, 80 g, mobile phase: [water(FA) - MeCN];B%: 35% - 75%, 10 min) to give a 2-[5-(methoxymethyi)-7-(1 -methy l-3-pi peridy I)- 1 ,8-naphthyridin-2-yl]-3,5-dimethyi-phenol (80 mg, 183 pmoi, 37% yield, 90% purity) as yellow oil.

LC-MS (Method C): Rt = 0.432 min; MS (ESIpos): m/z = 392.5 [M+1] ⁺ .

Compound 138 and 139

2-[5-(methoxymethyi)-7-[1-methyl-3-pipendyl]-1,§-naphthy ndin-2-yi]-3,5-dimethyl-pheno!

The reaction was set up for SFC separation. The residue was separated by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: [CO ₂ -MeCN/i-PrOH(0.1 % NH ₃ «H ₂ O)]; B%: 45%, isocratic elution mode) to give Compound 138 2-[5-(methoxymethyl)-7-[1-methyl-3-piperidyl]-1 ,8- naphthyridin-2-yl]-3,5-dimethyl-phenol (6.42 mg, 15.7 pmol, 15% yield, 96% purity) as a white solid and Compound 139 2-[5-(methoxymethyl)-7-[1-methyl-3-piperidyl]-1 ,8-naphthyridin-2-yl]-3,5-dimethyl- phenol (8.3 mg, 20.7 pmol, 20% yield, 98% purity) as a white solid.

Compound 138

¹ H NMR (400 MHz, DMSO-c/6) 5 = 9.90-9.61 (m, 1 H), 8.50 (d, J = 8.4 Hz, 1 H), 7.68-7.56 (m, 2H), 6.63 (d, J = 5.6 Hz, 2H), 5.08-4.91 (m, 2H), 3.78 (br d, J = 8.8 Hz, 2H), 3.47 (s, 3H), 3.10-2.97 (m, 1 H), 2.88 (d, J = 4.8 Hz, 3H), 2.26 (s, 3H), 2.21-2.14 (m, 1 H), 2.09 (s, 3H), 2.06-1.97 (m, 2H), 1.94-1.78 (m, 2H), 1.72-1.60 (m, 1 H).

LC-MS (Method C): Rt = 0.447 min; MS (ESIpos): m/z = 392.4 [M+1] ⁺ .

SFC (Rt = 1 .247 min, ee% = 99%).

Compound 139

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 = 9.76 (s, 1 H), 8.49 (d, J = 8.4 Hz, 1 H), 7.75-7.44 (m, 2H), 6.63 (d, J = 8.0 Hz, 2H), 4.97 (s, 2H), 3.46 (s, 3H), 3.42 (d, J = 3.2 Hz, 1 H), 3.19 (s, 2H), 3.07-2.82 (m, 1 H), 2.69- 2.63 (m, 1 H), 2.60 (s, 3H), 2.26 (s, 3H), 2.14-2.09 (m, 1 H), 2.09 (s, 3H), 1.96-1.74 (m, 2H), 1.73-1.56 (m, 1 H).

LC-MS (Method C): Rt = 0.430 min; MS (ESIpos): m/z = 392.2 [M+1 ] ⁺

SFC (Rt = 1 .680 min, ee% = 97%).

Intermediate 287

3-hydroxy-N-methoxy-N-methyl-cyciobutanecarboxamide

A mixture of 3-hydroxycyclobutanecarboxylic acid (5.00 g, 43.0 mmol, 1.00 eq), N- methoxymethanamine (5.04 g, 51.6 mmol, 1.20 eq, HCI salt), HATU (19.6 g, 51.6 mmol, 1.20 eq) and DIPEA (16.7 g, 129 mmol, 22.5 mL, 3.0 eq) in DMF (50 mL) was stirred at 20 °C for 12 h. The mixture was diluted with water (200 mL) and extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether/ethyl acetate = 2/1) to give 3-hydroxy-N-methoxy-N-methyl- cyclobutanecarboxamide (5.00 g, 31 .4 mmol, 72% yield) as colorless oil.

¹ H NMR (400 MHz, CDCh) 5 [ppm] = 4.27-4.14 (m, 1 H), 3.66 (s, 3H), 3.19 (s, 3H), 3.01 (s, 1 H), 2.60- 2.55 (m, 2H), 2.22-2.12 (m, 2H).

Intermediate 288

1-(3-hydroxycyclobutyl)ethanone

To a solution of 3-hydroxy-N-methoxy-N-methyl-cyclobutanecarboxamide (4.00 g, 25.1 mmol, 1.0 eq) in THF (100 mL) was added methylmagnesium bromide (3 M in THF, 41.8 mL, 5.0 eq) at 0 °C. After stirring at 20 °C for 1 h, the reaction mixture was poured into saturated ammonium chloride aqueous (200 mL) and extracted with ethyl acetate (80 mL x 5). The organic phase was concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 30~80% ethyl acetate/petroleum ethergradient @ 100 mL/min) to give 1-(3-hydroxycyclobutyl)ethanone (1.20 g, 9.46 mmol, 37% yield, 90% purity) as colorless oil.

¹ H NMR (400 MHz, DMSO-ds) 6 [ppm] = 5.07 (d, J = 7.0 Hz, 1 H), 3.99-3.91 (m, 1 H), 2.73-2.66 (m, 1 H), 2.35-2.28 (m, 2H), 2.02 (s, 3H), 1.91-1.77 (m, 2H).

Intermediate 289

3-/7-(2-methoxy-4,6-dimethyl-phenyl)-1,8-naphthyridin-2-y l]cyclobutanol

The reaction was set up for 4 batches in parallel. A mixture of 1-(3-hydroxycyclobutyl)ethanone (222 mg, 1 ,95 mmol, 2.00 eq), 2-amino-6-(2-methoxy-4,6-dimethyl-phenyl)pyridine-3-carbalde hyde (250 mg, 0.975 mmol, 1 .00 eq) and sodium methoxide (5.4 M, 0.722 mL, 4.00 eq) in methanol (10 mL) was stirred at 70 °C for 12 h. The reaction mixture was poured into saturated ammonium chloride (100 mL) aqueous and extracted with ethyl acetate (50 mL x 3). The organic phase was concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 40-80% Ethyl acetate/Petroleum ethergradient @ 80 mL/min) to give 3-[7-(2- methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]cyclobutanol (700 mg, 1.88 mmol, 48% yield, 90% purity) as a yellow solid.

¹ H NMR (400 MHz, CDCh) 6 [ppm] = 8.25-8.20 (m, 1 H), 8.20-8.14 (m, 1 H), 7.52-7.46 (m, 1 H), 7.44- 7.36 (m, 1 H), 6.72 (s, 1 H), 6.65 (s, 1 H), 4.35-4.28 (m, 1 H), 3.67 (s, 3H), 3.37-3.29 (m, 1 H), 2.85-2.78 (m, 2H), 2.51-2.40 (m, 2H), 2.38 (s, 3H), 2.08 (s, 3H).

LC-MS (Method C): Rt = 0.586 min; MS (ESI): m/z = 335.3 [M+H] ⁺ .

Intermediate 290

3-[7-(2-methoxy-4,8-d!methyl-phenyi)-1,8-naphthyndin-2-y! ]cyclobutanone

To a mixture of 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]cyclobutanol (900 mg, 2.69 mmol, 1.0 eq) in dichloromethane (20 mL) was added (1 ,1 ,1 -Triacetoxy)- 1 , 1 -dihydro-1 ,2-benziodoxol- 3(1 H)-one (1 .71 g, 4.04 mmol, 1 .5 eq) at 0 °C. After stirring at 20 °C for 1 h, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was concentrated in vacuum to give a residue. The residue was purified by reversed-phase flash(0.1 % FA) (Instrument: 20g Flash; Column: Welch Ultimate XB_C18 20-40pm; eluent A: water (0.1 % FA), eluent B: acetonitrile; gradient: 0-15 min 30-80% B; flow 60 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]cyclobutanone (600 mg, 1 .62 mmol, 60% yield, 90% purity) as a yellow solid.

¹ H NMR (400 MHz, CDCh) 6 [ppm] = 8.21 (s, 1 H), 8.19 (s, 1 H), 7.49 (dd, J = 6.0, 8.2 Hz, 2H), 6.75 (s, 1 H), 6.66 (s, 1 H), 4.01-3.82 (m, 3H), 3.69 (s, 3H), 3.53-3.40 (m, 2H), 2.39 (s, 3H), 2.13 (s, 3H).

Intermediate 291

3-[7-(2-methoxy-4,6-dimethyi-phenyl)-1,§-naphthyndm-2-yl ]-1-methyl-cyciobutanol

To a mixture of 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]cyclobutanone (600 mg, 1.81 mmol, 1.0 eq) in THF (20 mL) was added methylmagnesium bromide (3 M in THF, 3.01 mL, 5.0 eq) at 0°C dropwise. After stirring at 0 °C for 1 h, the reaction mixture was poured into saturated ammonium chloride (40 mL) aqueous and extracted with ethyl acetate (20 mL x 3). The organic phase was concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18, 80 g, mobile phase: [water(FA) - MeCN];B%: 15% - 40%, 5 min) to give 3-[7-(2-methoxy- 4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-methyl-cyclobutanol (260 mg, 0.671 mmol, 37.% yield, 90% purity) as a yellow solid.

¹ H NMR (400 MHz, CDCh) 5 [ppm] = 8.22-8.14 (m, 1 H), 8.12 (d, J = 8.4 Hz, 1 H), 7.53-7.43 (m, 1 H), 7.41-7.34 (m, 1 H), 6.75 (s, 1 H), 6.66 (s, 1 H), 3.77-3.62 (m, 3H), 3.53-3.35 (m, 1 H), 2.79-2.48 (m, 4H), 2.39 (s, 3H), 2.17-2.11 (m, 3H), 1.56-1.32 (m, 3H).

LC-MS (Method C): Rt = 0.441 min; MS (ESI): m/z = 349.3 [M+H]*.

Compound 141

2-[7-(34iydroxy-3-methyl-cyclobutyl)-1$-naphthyridin-2-yl ]-3 _! 5<limethybphenol

A mixture of 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-methyl-cyclobutanol (230 mg, 0.660 mmol, 1.00 eq) and NaSEt (555 mg, 6.60 mmol, 10.0 eq) in DMF (10.0 mL) was stirred at 120 °C for 12 h. The reaction mixture was poured into saturated ammonium chloride aqueous (30.0 mL) and extracted with ethyl acetate (15 mL x 3). The organic phase was concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(FA) - MeCN];B%: 10% - 35%, 6 min) to give a crude product. The product was separated by SFC (column: Phenomenex-Ceilulose-2 (250mm*30mm,10um); mobile phase: [CO ₂ - IPrOH (0.1 %NH3-H20)];B%:40%, isocratic elution mode) to give Compound 140 2-[7-(3-hydroxy-3-methyl- cyclobutyl)-1 ,8-naphthyridin-2-yl]-3,5-dimethyl-phenol (31.1 mg, 0.092 mmol, 13% yield, 99% purity) as a yellow solid and Compound 141 2-[7-(3-hydroxy-3-methyl-cyclobutyl)-1 ,8-naphthyridin-2-yl]-3,5- dimethyl-phenol (11.6 mg, 0.034 mmol, 5% yield, 99% purity) as a brown solid.

Enantiomer 1

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 9.84 (s, 1 H), 8.40 (d, J = 4.4 Hz, 1 H), 8.38 (d, J = 4.4 Hz, 1 H), 7.58 (d, J = 8.3 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 6.64 (s, 1 H), 6.63 (s, 1 H), 5.13 (s, 1 H), 3.45-3.39 (m, 1 H), 2.48-2.35 (m, 4H), 2.27 (s, 3H), 2.10 (s, 3H), 1.40 (s, 3H). LC-MS (Method C): Rt = 0.425 min; MS (ESI) m/z = 335.1 [M+H] ⁺ .

HPLC (Method K): Rt = 1.113 min; purity: 99%.

SFC (Rt = 2.031 min, ee% = 99%).

Compound 141

¹ H NMR (400 MHz, DMSO-d _e ) 5 [ppm] = 9.82 (s, 1 H), 8.39 (d, J = 8.4 Hz, 1 H), 8.36 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 4.8 Hz, 1 H), 7.52 (d, J = 4.8 Hz, 1 H), 6.63 (s, 1 H), 6.62 (s, 1 H), 4.98 (s, 1 H), 3.92-3.84 (m, 8.6 Hz, 1 H), 2.45 (s, 2H), 2.43 (s, 2H), 2.26 (s, 3H), 2.08 (s, 3H), 1.24 (s, 3H).

LC-MS (Method C): Rt = 0.431 min; MS (ESI) m/z = 335.1 [M+H] ⁺ .

HPLC (Method K): Rt - 1.095 min; purity: 99%.

SFC (Rt = 2.322 min, ee% = 99%).

Intermediate 292 methyl 2-hydroxycyclopentanecarboxy!ate

To a solution of methyl 2-oxocyclopentanecarboxylate (5.00 g, 35.2 mmol, 1 eq) in THF (50 mL) was added NaBH4 (2.00 g, 52.8 mmol, 1.5 eq) at 0 °C under Nz atmosphere. After stirring at 0 °C for 1 h, the mixture was quenched with hydrochloric acid solution (100 mL, 1 M in water) at 0 °C and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl 2-hydroxycyclopentanecarboxylate (4.00 g, 27.8 mmol, 79 % yield) as colorless oil.

Intermediate 293 methyl 2-[tert-butyl (diphenyl) silyl] oxycyclopentanecarboxylate

To a solution of methyl 2-hydroxycyclopentanecarboxylate (4.00 g, 27.8 mmol, 1 eq) and imidazole (5.67 g, 83.2 mmol, 3 eq) in DCM (50 mL) was added tert-butyl-chloro-diphenylsilane (9.15 g, 33.3 mmol, 1 .2 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SIO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to give methyl 2-[tert-butyl (diphenyl) silyl] oxycyclopentanecarboxylate (10.0 g, 20.9 mmol, 75% yield, 80% purity) as colorless oil.

LC-MS (Method C): Rt = 0.761 min; MS (ESI): m/z = 405.2 [M+Na] ⁺ .

Intermediate 294

2-[tert-butyl (diphenyl) silyl] oxycyclopentanecarboxylic acid

To a solution of methyl 2-[tert-butyl (diphenyl) silyl] oxycyclopentanecarboxylate (9.00 g, 18.8 mmol, 1 eq) in MeOH (100 mL) and H2O (20 mL) was added LIOH.H2O (2.37 g, 56.5 mmol, 3 eq) at 25 °C. After stirring at 25 °C for 16 h, the reaction mixture was concentrated to remove MeOH. The crude was adjusted to PH to 4~5 by hydrochloric acid solution (1 M) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-[tert-butyl(diphenyl)silyl]oxycyclopentanecarboxylic acid (7.00 g, crude) as colorless oil. Intermediate 295

2-[tert-butyi (diphenyl) silyi] oxy-N-methoxy-N-methyl-cyclopentanecarboxamide

To a solution of 2-[tert-butyl (diphenyl) silyl] oxycyclopentanecarboxylic acid (7.00 g, 19.0 mmol, 1 eq) and N-methoxymethanamine (3.71 g, 38.0 mmol, 2 eq, HCI salt) in DCM (100 mL) were added HOBt (3.85 g, 28.5 mmol, 1.5 eq), EDCI (5.46 g, 28.5 mmol, 1.5 eq) and DIPEA (7.36 g, 57.0 mmol, 3 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiOz, petroleum ether/ethyl acetate=10/1 to 1/1) to give 2-[tert- butyl (diphenyl) silyl] oxy-N-methoxy-N-methyl-cyclopentanecarboxamide (3.80 g, 8.31 mmol, 43% yield, 90% purity) as colorless oil.

¹ H NMR (400 MHz, CDCb) 6 = 7.70-7.60 (m, 4H), 7.45-7.30 (m, 6H), 4.64-4.56 (m, 1 H), 3.58 (s, 3H), 3.30-3.20 (m, 1 H), 3.11 (s, 3H), 2.10-2.00 (m, 1 H), 1.85-1.75 (m, 1 H), 1.70-1.55 (m, 4H), 1.06 (s, 9H).

Intermediate 296

1-[2-[tert-butyl (diphenyl) silyl] oxycyc!opentyl]ethanone

To a solution of 2-[tert-butyl (diphenyl) silyl] oxy-N-methoxy-N-methyl-cyclopentanecarboxamide (3.80 g, 8.31 mmol, 1 eq) in THF (40 mL) was added methyl magnesium bromide (3 M, 8.31 mL, 3 eq) at 0 °C. After stirring at 25 °C for 1 h, the mixture was quenched with saturated ammonium chloride solution (100 mL) at 0 °C and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-[2- [tert-butyl (diphenyl) silyl] oxycyclopentyl] ethanone (3.00 g, 8.18 mmol, 98% yield) as colorless oil.

Intermediate 297

2-[2-[tert-butyl (diphenyl) silyl] oxycyciopentyl]-2-oxo-acetaldehyde

To a solution of 1 -[2-[tert-butyl (diphenyl) silyl] oxycyclopentyl] ethanone (1.00 g, 2.73 mmol, 1 eq) in dioxane (20 mL) was added SeCh (0.91 g, 8.18 mmol, 3 eq) at 25 °C. After stirring at 90 °C for 16 h, the reaction mixture was filtrated and the filtrate was concentrated to give 2-[2-[tert- butyl(diphenyl)silyl]oxycyclopentyl]-2-oxo-acetaldehyde (1 g, crude) as a yellow solid.

Intermediate 298

2-[3-[2-[tert-butyl(dlphenyl)silyl]oxycyclopentyl]pyrido[ 2,3-b]pyrazin-6-yl]-3 _l ,5-dimethyl-phenol To a solution of 2-[2-[tert-butyl (diphenyl) silyl] oxycyclopentyl]-2-oxo-acetaldehyde (1.00 g, 2.63 mmol, 1 eq) in EtOH (20 mL) was added 2-(5, 6-diamino-2-pyridyl)-3, 5-dimethyl-phenol (542 mg, 2.36 mmol, 0.9 eq, EW29564-1261) at 25 °C. After stirring at 60 °C for 4 h, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SIO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to 2-[3-[2-[tert-butyl(diphenyl)silyl]oxycyclopentyl]pyrido[2,3 -b]pyrazin-6-yl]-3, 5-dimethyl-phenol (1 .00 g, 1 .70 mmol, 65% yield, 98% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.789 min; MS (ESI): m/z = 574.3 [M+H] ⁺ .

Intermediate 299 2-]3-(2-hydroxycyclopentyI) pyrido [2, 3-b] pyrazin-6-yl]-3, 5-dimethyl-phenol

To a solution of 2-[3-[2-[tert-butyl(diphenyl)silyl]oxycyclopentyl]pyrido[2,3 -b]pyrazin-6-yl]-3,5-dimethyl- phenol (900 mg, 1.53 mmol, 1 eq) in DMF (10 ml_) was added cesium fluoride (698 mg, 4.60 mmol, 3 eq) at 25 °C. After stirring at 40 °C for 2 h, the mixture was added water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude. The crude product was purified by reversed flash (Instrument: 40g Flash; Column: Welch Ultimate XB_C18 20-40pm; Eluent A: water (0.1 % NHs-FteO), eluent B: acetonitrile; gradient: 0-10 min 0-40% B; flow 60 ml/min; temperature: room temperature; Detector: UV220/254 nm) to give 2-[3-(2-hydroxycyclopentyl)pyrido[2,3-b]pyrazin-6-yl]- 3,5-dimethyl-phenol (300 mg, 796 pmol, 52% yield, 89% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.535 min; MS (ESI): m/z = 336.1 [M+H] ⁺ .

Compound 142, 143, 144 and 145

2-[3-(2-hydroxycyclopentyl) pyrido [2, 3-b] pyrazm-6-yl]-3 _s S-dimethyi-phenoi

The reaction was set up for SFC separation. The residue was purified by SFC: (column: DAICEL CHIRALPAK IC (250mm*30mm,10 um); mobile phase: [CO ₂ -EtOH(0.1 %NH ₃ H ₂ O)]; B%: 50%, isocratic elution mode) to give Compound 142 3,5-dimethyl-2-[3-[2-hydroxycyclopentyl]pyrido[2,3-b]pyrazin -6- yl]phenol (21.1 mg, 61.6 pmol, 8% yield, 98% purity, peak 1 , Rt = 0.771 min) as a yellow solid, Compound 143 3,5-dimethyl-2-[3-[2-hydroxycyclopentylJpyrido[2,3-b]pyrazin -6-yl]phenol (19.3 mg, 56.8 pmol, 7% yield, 99% purity, peak 2, Rt = 0.910 min) as a yellow solid, Compound 144 3,5-dimethyl- 2-[3-[2-hydroxycyclopentyl]pyrido[2,3-b]pyrazin-6-yl]phenol (82.3 mg, 242 pmol, 30% yield, 99% purity, peak 3, Rt = 1 ,055 min) as a yellow solid and Compound 145 3,5-dimethyl-2-[3-[2- hydroxycyclopentyl]pyrido[2,3-b]pyrazin-6-yl]phenol (67.5 mg, 199 pmol, 25% yield, 99% purity, peak 4, Rt = 1 .281 min) as a yellow solid.

Compound 142

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 = 9.02-8.96 (m, 1 H), 8.48-8.43 (m, 1 H), 7.80-7.73 (m, 1 H), 6.64 (s, 1 H), 6.60 (s, 1 H), 4.55 (s, 1 H), 3.50-3.45 (m, 2H), 2.45-2.38 (m, 1 H), 2.25 (s, 3H), 2.07 (s, 3H), 2.05- 1.90 (m, 3H), 1.83-1.65 (m, 2H).

LC-MS (Method C): Rt = 0.540 min; MS (ESIpos): m/z = 336.2 [M+1 ] ⁺ .

SFC (Rt = 0.771 min, ee% = 70%).

Compound 143

¹ H NMR (400 MHz, DMSO- d ₆ ) 6 = 9.02-8.96 (m, 1 H), 8.48-8.43 (m, 1 H), 7.80-7.73 (m, 1 H), 6.64 (s, 1 H), 6.61 (s, 1 H), 4.55 (s, 1 H), 3.50-3.45 (m, 2H), 2.45-2.38 (m, 1 H), 2.26 (s, 3H), 2.07 (s, 3H), 2.05- 1.90 (m, 3H), 1.83-1.65 (m, 2H).

LC-MS (Method C): Rt = 0.543 min; MS (ESIpos): m/z = 336.2 [M+1 ] ⁺ .

SFC (Rt = 0.910 min, ee% = 74%).

Compound 144 ¹ H NMR (400 MHz, DMSO-c/ _s ) 6 = 8.98 (s, 1 H), 8.47 (d, J = 8.8 Hz, 1 H), 7.76 (d, J = 8.4 Hz, 1 H), 6.63 (s, 1 H), 6.60 (s, 1 H), 5.20-4.80 (m, 1 H), 4.40-4.28 (m, 1 H), 3.40-3.38 (m, 1 H), 2.25 (s, 3H), 2.20-2.12 (m, 1 H), 2.07 (s, 3H), 2.05-1.98 (m, 2H), 1.87-1.75 (m, 2H), 1.70-1.60 (m, 1 H).

LC-MS (Method C): Rt = 0.543 min; MS (ESIpos): m/z = 336.2 [M+1] ⁺ .

SFC (Rt = 1 .055 min, ee% = 94%).

Compound 145

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 =8.97 (s, 1 H), 8.46 (d, J = 8.4 Hz, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 6.63 (s, 1 H), 6.58 (s, 1 H), 5.20-4.80 (m, 1 H), 4.40-4.28 (m, 1 H), 3.40-3.38 (m, 1 H), 2.25 (s, 3H), 2.20-2.12 (m, 1 H), 2.07 (s, 3H), 2.05-1 .98 (m, 2H), 1 .87-1 .75 (m, 2H), 1 .70-1 .60 (m, 1 H).

LC-MS (Method C): Rt = 0.540 min; MS (ESIpos): m/z = 336.2 [M+1 ] ⁺ .

SFC (Rt = 1 .281 min, ee% = 95%).

Intermediate 300 tert-butyl 5-[6-(tert-butoxycarbonylamino)-5-formyl-2-pyrldyl]-3,6-dihy dro-2H-pyridine-1- carboxylate

To a mixture of tert-butyl N-(6-chloro-3-formyl-2-pyridyl)carbamate (3.00 g, 11.7 mmol, 1 eq) , tert-butyl 5-(4,4,5,5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 -carboxylate (5.42 g, 17.5 mmol, 1 .5 eq) and CS2CO3 (11.4 g, 35.0 mmol, 3 eq) in dioxane (30 mL) and H2O (3 mL) was added Pd(dppf)Cl2 (855 mg, 1.17 mmol, 0.1 eq) at 25 °C in one portion under N2 atmosphere. After stirring at 80 °C for 16 h, the mixture was poured into ice-water (50 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phase were washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 2/1) to give tert-butyi 5-[6-(tert- butoxycarbonyiamino)-5-formyl-2-pyridyl]-3,6-dihydro-2H-pyri dine-1-carboxyiate (4.10 g, 10.0 mmol, 87% yield) as yellow oil.

¹ H NMR (400 MHz, CDCh) 5 [ppm] = 9.82 (s, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 6.89 (m, 1 H), 6.86 (d, J = 8.0 Hz, 1 H), 4.38 (s, 2H), 3.57 (s, 2H), 2.40 (m, 2H), 1.56 (s, 9H), 1.51 (s, 9H).

LC-MS (Method C): Rt = 0.635 min; MS (ESIpos): m/z = 404.3 [M+H] ⁺ .

Intermediate 301 tert-butyl 5-(S-amino-5-formyl-2-pyridyl)-3,6-dihydro-2H-pyridine-1 -carboxylate

To a mixture of tert-butyl 5-[6-(tert-butoxycarbonyiamino)-5-formyl-2-pyridyl]-3,6-dihy dro -2H-pyridine- 1 -carboxylate (4.10 g, 10.0 mmol, 1 eq) in dioxane (40 mL) and H2O (4 mL)was added CS2CO3 (13.2 g, 40.0 mmol, 4 eq) at 25 °C. After stirring at 80 °C for 12 h, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The residue was purified by reversed-phase HPLC (column: C18, 40 g, mobile phase: [water (FA) - MeCN]; B%: 35% - 60%, 8 min) to give tert-butyl 5-(6-amino-5-formyl-2-pyridyl)-3,6-dihydro-2H-pyridine-1- carboxylate (2.00 g, 6.59 mmol, 65% yield) as black brown oil. LC-MS (Method C): Rt = 0.483 min; MS (ESIpos): m/z = 304 [M+H] intermediate 302

1-(2-hydroxy-4-methoxy-8-methyl-phenyl)ethanone

To a solution of 3-methoxy-5-methyl-phenol (1.00 g, 7.24 mmoi, 1 eq) and AczO (813 mg, 7.96 mmoi, 748 pL, 1.1 eq) in DCM (50 mL) was added TiCU (1 M, 11 .0 mL, 1 .5 eq) at 0 °C in portions. After stirring at 20 °C for 16 h, the reaction mixture was quenched by ammonium chloride solution (150 mL), and then extracted with dichioromethane (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOa, petroleum ether/ethyi acetate = 15/1 to 8/1), then the crude product was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water (FA) - MeCN]; B%: 30% - 70%, 10 min) to give 1-(2- hydroxy-4-methoxy-6-methyl-phenyl)ethanone (600 mg, 3.00 mmol, 41 % yield, 90% purity) as a white solid.

LC-MS (Method C): Rt = 0.496 min; MS (ESIpos): m/z = 181.1 [M+H] ⁺ intermediate 303 tert-butyl 5-[7-(2-hydi'oxy-4-msthoxy-6-methyl-phsnyl)-1,8-naphthyndin- 2-yl]-3 _! 6-dihydro-2H- pyridlne-1 -carboxylate

To a mixture of 1-(2-hydroxy-4-methoxy-6-methyi-phenyi)ethanone (900 mg, 4.99 mmoi, 2 eq) , tert- butyi 5-(6-amino-5-formyl-2-pyridyi)-3,6-dihydro-2H-pyridine-1 -carboxylate (758 mg, 2.50 mmol, 1 eq) in EtOH (10 mL) and H2O (5 mL) was added KOH (420 mg, 7.49 mmoi, 3 eq) at 25 °C. After stirring at 80 °C for 16 h, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiOz, petroleum ether/ethyi acetate=100/1 to 1/1) .to give tert-butyl 5-[7-(2-hydroxy-4-methoxy-6- methyl-phenyl)-1 ,8-naphthyridin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (200 mg, 447 pmol, 18% yield) as yellow oil.

¹ H NMR (400 MHz, CDCI ₃ ) 5 [ppm] = 8.25 (d, J = 8.4 Hz, 1 H), 8.16 (d, J = 8.4 Hz, 1 H), 7.76-7.68 (d, J = 8.4 Hz, 2H), 7.04 (s, 1 H), 6.56 (d, J = 2.8 Hz, 1 H), 6.44 (d, J = 2.4 Hz, 1 H), 4.63 (s, 2H), 3.85 (s, 3H), 3.64 (t, J = 5.6 Hz, 2H), 2.53 (s, 4H), 2.48 (m, 2H), 1 .52 (s, 9H).

LC-MS (Method C): Rt = 0.512 min; MS (ESIpos): m/z = 448.2 [M+H] ⁺ .

Intermediate 304 benzyl 4-[3-[7-(2-methoxy-4 _l ,8-dlmethyl-phenyl)-1,8-naphthyridln-2-yl]-1-p!peridyl ]butanoate

To a solution of tert-butyl 5-[7-(2-hydroxy-4-methoxy-6-methyl-phenyi)-1 ,8-naphthyridin-2-yl]-3,6- dihydro- 2H-pyridine-1 -carboxylate (250 mg, 559 pmol, 1 eq) in MeOH (10 mL) were added Pd/C (250 mg, 235 pmol, 10% purity, 0.05 eq) at 20 °C in one portion. After stirring at 20 °C for 1 h under hydrogen atmosphere (15 psi), the mixture was filtered and filtrate was concentrated in vacuum to give tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]piperidine-1-carboxylate (270 mg, 420 pmol, 75% yield, 70% purity) as a yellow solid.

¹ H NMR (400 MHz, CDCI ₃ ) 6 [ppm] = 8.21 (d, J = 8.8 Hz, 1 H), 8.12 (d, J = 8.4 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 1 H), 6.52 (d, J = 2.4 Hz, 1 H), 6.43 (d, J = 2.4 Hz, 1 H), 4.49-4.27 (m, 1 H), 3.85 (s, 3H), 3.09 (m, 1 H), 2.91-2.80 (m, 1 H), 2.56 (s, 3H), 2.17-2.11 (m, 1 H), 2.05-1.93 (m, 1 H), 1.90- 1.75 (m, 2H), 1.68-1.61 (m, 2H), 1.50 (s, 9H).

LC-MS (Method G): Rt = 0.738 min; MS (ESIpos): m/z = 450.3 [M+H] ⁺ .

Intermediate 305

5-methoxy-3-methyl-2-[7-(3-pipendy0-1,8-naphthyndin-2-y!] phenol

To a mixture of tert-butyl 3-[7-(2-hydroxy-4-methoxy-6-methyl-phenyl)-1 ,8-naphthyridin-2-yl] piperidine- 1-carboxylate (270 mg, 600 pmol, 1 eq) in DCM (3 mL) was added TFA (3.39 g, 29.7 mmol, 2.21 mL) at 25 °C. After stirring at 25 °C for 2 h, the mixture was concentrated to give 5-methoxy-3-methyl-2-[7- (3-piperidyl)-1 ,8-naphthyridin-2-yl]phenol (220 mg, 475 pmol, 79% yield, TFA salt) as brown oil.

Intermediate 306

5-methoxy-3-methyl-2-[7-(1-methyl-3-pipendyl)-1,8-naphthy ndin-2-yl]phenol

To a mixture of 5-methoxy-3-methyl-2-[7-(3-piperidyl)-1 ,8-naphthyridin-2-yl]phenol (270 mg, 583 pmol, 1 eq, TFA salt) , (HCHO)n (155 mg, 3.86 mmol, 6.63 eq), KOAc (286 mg, 2.91 mmol, 5 eq) in MeOH (2 mL) was added NaBHsCN (183 mg, 2.91 mmol, 5 eq) at 25 °C . After stirring at 25 °C for 2h, the mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by reversed- phase column (column: C18, 40 g, mobile phase: [water (FA) - MeCN]; B%: 20% - 50%, 8 min) to give 5-methoxy-3-methyl-2-[7-(1-methyl-3-piperidyl)-1 ,8-naphthyridin-2-yl]phenol (70.0 mg, 193 pmol, 33% yield) as a yellow solid.

LC-MS (Method C): Rt = 0.439 min; MS (ESIpos): m/z = 364.3 [M+H] ⁺ .

Compound 146 and 147

5-methoxy-3-methyl-2-[7-[1-methyl-3-pipendyl]-1,8-naphthy ridin-2-yl]ph&nol

The reaction was set up for SFC separation. The residue was separated by SFC: ( column: DAICEL CHIRALPAK IG (250mm x 30mm, 10um);mobile phase: [CO ₂ -MeCN/i-PrOH(0.1 % NH3H2O)]; B%:50%, isocratic elution mode) to give Compound 146 5-methoxy-3-methyl-2-[7-[1-methyl-3-piperidyl]-1 ,8- naphthyridin-2-yl]phenol (18.6 mg, 50.5pmol, 26% yield, 99% purity) as a orange solid and Compound 147 5-methoxy-3-methyl-2-[7-[1-methyl-3-piperidyl]-1 ,8-naphthyridin-2-yl]phenol (19.9 mg, 54.4 pmol, 28% yield, 99% purity) as a orange solid.

Compound 146

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 10.53-10.38 (m, 1 H), 8.40 (d, J = 3.2 Hz, 1 H), 8.37 (d, J = 2.8 Hz, 1 H), 7.61 (d, J = 6.8 Hz, 1 H), 7.59 (d, J = 6.8 Hz, 1 H), 6.41 (d, J = 2 Hz, 1 H), 6.39 (d, J = 2.4 Hz, 1 H), 3.76 (s, 3H), 3.22-3.11 (m, 2H), 3.03 (d, J = 1 1 .6 Hz, 1 H), 2.81 (d, J = 11 .2 Hz, 1 H), 2.23 (s, 3H), 2.22 (s, 1 H), 2.17 (s, 3H), 2.01-1.96 (m, 1 H), 1.95 - 1.88 (m, 1 H), 1.82-1.73 (m, 1 H), 1.66-1.62 (m, 1 H). LC-MS (Method C): Rt = 0.403 min; MS (ESIpos): m/z = 364 [M+H] ⁺ .

SFC (Rt = 0.703 min, ee% = 98%).

Compound 147

¹ H NMR (400 MHz, DMSO-d _s ) 6 [ppm]= 10.44 (d, J = 2.4 Hz, 1 H), 8.40 (d, J = 2.8 Hz, 1 H), 8.38 (d, J = 2.8 Hz, 1 H), 7.61 (d, J = 6.8 Hz, 1 H), 7.59 (d, J = 6.8 Hz, 1 H), 6.41 (s, 1 H), 6.39 (s, 1 H), 3.76 (s, 3H), 3.20-3.10 (m, 2H), 3.04 (d, J = 10.8 Hz, 1 H), 2.82 (d, J = 11.2 Hz, 1 H), 2.25 (s, 3H), 2.22 (s, 1 H), 2.17 (s, 3H), 2.00 (d, J = 9.2 Hz, 1 H), 1 .97-1 .92 (m, 1 H), 1 .78 (s, 1 H), 1 .64 (d, J = 11 .6 Hz, 1 H).

LC-MS (Method C): Rt = 0.396 min; MS (ESIpos): m/z - 364 [M+H] ⁺ .

SFC (Rt = 0.968 min, ee% = 97%).

Intermediate 307

@-(4<;hloro-2-methoxy-6-methy!-phenyl)pyridine-2,3-dla mme

To a solution of 6-chloropyridine-2,3-diamine (740 mg, 5.15 mmol, 1 eq) and 2-(4-chloro-2-methoxy-6- methyl-phenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (728 mg, 2.58 mmol, 0.5 eq) in dioxane (8 mL) were added Pd(dppf)Ch (377 mg, 515 pmol, 0.1 eq) and NazCCh (1.09 g, 10.3 mmol, 2 eq) in HzO (2 mL). After stirring at 80 °C for 16 h under Nz, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with aqueous sodium chloride (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O ₂ , Petroleum ether/Ethyl acetate = 1/1 to 0/1) to give 6-(4-chioro-2- methoxy-6-methyl-phenyl)pyridine-2,3-diamine (888 mg, 2.19 mmol, 42% yield, 65% purity) as a brown solid.

LC-MS (Method C): Rt = 0.403 min; MS (ESIpos): m/z = 264.0 [M+H] ⁺ .

Intermediate 308

5-chloro-2-(5,6-diamino-2-pyndyl)-3-methyl-phenol

To a solution of 6-(4-chloro-2-methoxy-6-methyl-phenyl)pyridine-2,3-diamine (888 mg, 3.37 mmol, 1 eq) in DCM (10 mL) was added BBrs (2.53 g, 10.10 mmol, 973.33 pL, 3 eq) at -70 °C under N2. After stirring at -70 °C for 2 h, the reaction was quenched by addition of 10 mL of methanol, and a clear yellow-brown solution was obtained. The pH of mixture was adjusted to around 7 by ammonia (7.0 M in methanol). The residue was purified by reversed-phase column (column: C18, 120 g, mobile phase: [water (FA)-MeCN]; B%: 20%-25%, 20 min) to give 5-chloro-2-(5,6-diamino-2-pyridyl)-3-methyl-phenol (800 mg, 2.08 mmol, 62% yield, 65% purity) as a brown solid.

LC-MS (Method D): Rt = 0.405 min; MS (ESI): m/z = 250.1 [M+H] ⁺ .

Intermediate 309 To a solution of 5-chloro-2-(5,6-diamino-2-pyridyl)-3-methyl-phenol (800 mg, 3.20 mmol, 1 eq) in EtOH (8 mL) was added tert-butyl (3R)-3-oxaldehydoylpiperidine-1-carboxylate (1.16 g, 4.81 mmol, 1.5 eq). After stirring at 60 °C for 2 h,.the mixture was concentrated to give a crude.The residue was purified by reversed-phase column (column: C18 120 g, mobile phase: [water(FA)-MeCN];B%: 70% - 80%, 10 min) to give tert-butyl (3R)-3-[6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyrido[2,3-b]p yrazin-3-yl]piperidine-1 - carboxylate (180 mg, 356 pmol, 11 % yield, 90% purity) as brown oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) <5 [ppm] = 10.15-10.03 (m, 1 H), 9.09 (s, 1 H), 8.53 (d, J = 8.4 Hz, 1 H), 7.82-7.78 (m, 1 H), 6.89 (d, J = 8.8 Hz, 2H), 3.98-3.91 (m, 1 H), 3.65-3.61 (m, 1 H), 3.27-3.18 (m, 2H), 2.95-2.86 (m, 1 H), 2.17-2.12 (m, 1 H), 2.07 (s, 3H), 1.94 (br d, J = 5.2 Hz, 1 H), 1.89-1.80 (m, 2H), 1.52 (s, 9H).

LC-MS (Method C): Rt = 0.612 min; MS (ESIpos): m/z = 455.1 [M+H] ⁺ .

Intermediate 310

5-chloi'o-3-methyl-2-[3-[(3R)-3-pipendyl]pyndo[2 _! 3-b]pyi-azin-6-yl]phenol

To a solution of tert-butyl (3R)-3-[6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyrido[2,3-b]p yrazin-3- yl]piperidine-1 -carboxylate (180 mg, 396 pmol, 1 eq) in TFA (2 mL) and DCM (2 mL). After stirring at 25 °C for 2 h, the mixture was concentrated to give 5-chloro-3-methyl-2-[3-[(3R)-3-piperidyl]pyrido[2,3- b]pyrazin-6-yl]phenol (278 mg, crude, TFA salt) as brown oil.

Compound 148

5~chioro~3'rriethyb2-[3~[(3R)-1~methyb3-piperidyl]pyrido[ 2.3-b]pyraziri~6~yl]phenol

To a solution of 5-chloro-3-methyl-2-[3-[(3R)-3-piperidyl]pyrido[2,3-b]pyrazi n-6-yl]phenol (278 mg, 399 pmol, 1 eq, TFA salt) in MeOH (10 mL) were added NaBHsCN (125 mg, 1.99 mmol, 5 eq) , KOAc (1.17 g, 12.0 mmol, 30 eq) and (HCHO) _n (59.8 mg, 1 .99 mmol, 5 eq). After stirring at 25 °C for 2 h, the mixture was concentrated to give a residue. The residue was purified by reversed-phase column (column: Cl 8 40 g, mobile phase: [water(FA) - MeCN];B%: 8% - 10%, 10 min) to give 5-chloro-3-methyl-2-[3-[(3R)-1- methyl-3-piperidyl]pyrido[2,3-b]pyrazin-6-yl]phenol (60.0 mg, 151 pmol, 38% yield, 93% purity) as a brown solid.

¹ H NMR (400 MHz, DMSO-d _s ) 5 [ppm] = 9.09 (s, 1 H), 8.52 (d, J = 8.4 Hz, 1 H), 8.23 (s, 2H), 7.78 (d, J = 8.4 Hz, 1 H), 6.89 (s, 2H), 3.38-3.27 (m, 2H), 3.09 (br d, J = 11 .2 Hz, 1 H), 2.83 (br d, J = 10.8 Hz, 1 H), 2.36-2.31 (m, 1 H), 2.26 (s, 3H), 2.07 (s, 3H), 2.02-1.97 (m, 1 H), 1.80-1.75 (m, 1 H), 1.70-1.62 (m, 2H). LC-MS (Method C): Rt = 0.422 min; MS (ESIpos): m/z - 369.2 [M+H] ⁺ .

SFC (Rt - 0.752 min, ee% = 85%).

Intermediate 311

6-(2-fliioro-6-methoxy-4-methyl-pheny!}pyridme-2,3-diamme

To a solution of 6-chloropyridine-2,3-diamine (583 mg, 4.06 mmol, 1.2 eq) and 2-(2-f!uoro-6-methoxy- 4-methyl-phenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (900 mg, 3.38 mmol, 1 eq) in dioxane (20 mL) were added CS2CO3 (2.20 g, 6.76 mmol, 2 eq) and [2-(2- aminophenyl)phenyl]palladium(1 +);dicyclohexyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane;methanesulfonate (286 mg, 338 pmol, 0.1 eq) in H2O (10 mL) at 20 °C under nitrogen atmosphere in one portion. After stirring at 90 °C for 16 h, the mixture was diluted with water (30 mL), then the mixture were extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated sodium chloride (30 mL), dried over sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyi acetate = 20/1 to 0/1).to give 6-(2-fluoro-6-methoxy-4-methyl- phenyl)pyridine-2,3-diamine (750 mg, 3.00 mmol, 89% yield, 99% purity) as a red solid.

¹ H NMR (400 MHz, CDCI3) 5 [ppm] = 2.36 (s, 3 H), 3.37 (d, J = 2.0 Hz, 2 H), 3.75 (s, 3 H), 4.39 (s, 2 H), 6.55 (s, 1 H), 6.58 (d, J = 10.0 Hz, 1 H), 6.70 (d, J = 7.6 Hz, 1 H), 6.94 (d, J = 7.6 Hz, 1 H).

LC-MS (Method C): Rt = 0.409 min; MS (ESI): m/z = 248.2 [M+H] ⁺ .

Intermediate 312

2-(S,6-diair>inQ-2-pyridyl)-3-fluoro-S-methyl~phenoi

To a solution of 6-(2-fluoro-6-methoxy-4-methyl-phenyl)pyridine-2,3-diamine (750 mg, 2.75 mmol, 1 eq) in DCM (8 mL) was added BBr ₃ (6.89 g, 27.5 mmol, 2.65 mL, 10 eq) at -70 °C dropwise. After stirring at 20 °C for 2 h, the mixture was added into water (25 mL) at 0 °C. The pH of the reaction mixture was adjust to 7-8 by saturated sodium bicarbonate solution at 0 °C. The mixture was extracted with DCM (40 mL x 3). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a 2-(5,6-diamino-2-pyridyl)-3-fluoro-5-methyl-phenol (560 mg, 2.16 mmol, 79% yield, 90% purity) as a brown solid.

LC-MS (Method C): Rt = 0.386 min; MS (ESI): m/z = 234.0 [M+H] ⁺ .

Intermediate 313 tert-butyl (3R)-3-[6-(2-fluoro-6-hydroxy-4-methyl-phenyl)pyrido[2,3-b]p yrazin-3-yl]plperidlne-1- carboxylate

To a solution of 2-(5,6-diamino-2-pyridyl)-3-fluoro-5-methyl-phenol (560 mg, 2.06 mmol, 0.7 eq) in EtOH (10 mL) was added tert-butyl (3R)-3-oxaldehydoylpiperidine-1 -carboxylate (709 mg, 2.94 mmol, 1 eq) at 20 °C in one portion. After stirred at 60 °C for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2).The combined organic layers were washed with saturated sodium chloride (20 mL x 2), dried over anhydrous sodium sulfate. The filtered was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyi acetate = 50/1 to 5/1).to give tert-butyl (3R)-3-[6-(2-fluoro-6-hydroxy-4-methyl- phenyl)pyrido[2,3-b]pyrazin-3-yl]piperidine-1 -carboxylate (290 mg, 536 pmol, 18% yield, 81 % purity) as a yellow solid.

¹ H NMR (400 MHz, CDCh) 5 [ppm] = 1.49 (s, 9 H), 1.67 (dt, J = 12.8, 4.11 Hz, 1 H), 1 .88 (dt, J = 13.2, 3.2 Hz, 1 H), 2.01 (d, J = 12.4 Hz, 1 H), 2.18 (d, J = 12.8 Hz, 1 H), 2.38 (s, 3 H), 2.90 (td, J = 12.8, 2.75 Hz, 1 H), 3.13-3.32 (m, 2 H), 4.14-4.24 (m, 1 H), 4.38 (d, J = 12.0 Hz, 1 H), 6.56 (dd, J = 13.6, 1.13 Hz, 1 H), 6.78 (s, 1 H) 8.46-8.53 (m, 2 H), 8.85 (s, 1 H).

LC-MS (Method C): Rt = 0.691 min; MS (ESI): m/z = 439.1 [M+HJ*. Intermediate 314

3-fluoro-5-methyl-2-[3-[(3R)-3-piperidyl]pyndo[2,3-b]pyra zin-6-yl]phenol

To a solution of tert-butyl (3R)-3-[6-(2-fluoro-6-hydroxy-4-methyl-phenyl)pyrido[2,3-b]p yrazin-3- ylJpiperidine-1 -carboxylate (290 mg, 547 pmol, 1 eq) in DCM (4 mL) was added TFA (2 mL) at 0 °C dropwise. After stirring at 20 °C for 1 h, the reaction was concentrated under reduced pressure to give 3-fluoro-5-methyl-2-[3-[(3R)-3-piperidyl]pyrido[2,3-b]pyrazi n-6-yl]phenol (350 mg, 514 pmol, 94% yield, TFA salt) as red oil.

LC-MS (Method C): Rt = 0.454 min; MS (ESI): m/z = 339.3 [M+H] ⁺ .

Compound 149

3-fluoi'o-5-methyb2-[3-[(3R)-1-methyb3-pipendyl]pyndo[2 _! 3-b]pyrazin-6-yl]phenol

To a solution of 3-fluoro-5-methyl-2-[3-[(3R)-3-piperidyl]pyrido[2,3-b]pyrazi n-6-yl]phenol (210 mg, 620 pmol, 1 eq) in MeOH (2 mL) was added KOAc (305 mg, 3.10 mmol, 5 eq), NaBHsCN (1 17 mg, 1.86 mmol, 3 eq) and (HCHO)n (37.2 mg, 1 .24 mmol, 2 eq) at 20 °C in one portion. After stirring at 20 °C for 1 h, the reaction mixture was concentrated in vacuum to give a residue. The residue was combined with another batch and purified by reversed phase (column: C18, 330 g, mobile phase: [water (FA) - MeCN]; B%: 20% - 80%, 8 min) to give 3-fluoro-5-methyl-2-[3-[(3R)-1-methyl-3-piperidyl]pyrido[2,3 - b]pyrazin-6-yl]phenol (41.3 mg, 108 pmol, 17% yield, 92% purity) as a yellow solid. [ppm] = 1.61-1 .71 (m, 2 H), 1.75-1.82 (m, 1 H), 1.93-2.08 (m, 2 H), 2.25 (s, 3 H), 2.32 (s, 3 H), 2.81 (d, J = 1 1 .6 Hz, 1 H), 3.03-3.10 (m, 1 H), 3.25-3.38 (m, 2 H), 6.70 (d, J = 13.2 Hz, 1 H), 6.74 (s, 1 H), 8.24 (d, J = 8.8 Hz, 1 H), 8.39 (s, 2 H), 8.64 (d, J = 8.8 Hz, 1 H), 9.11 (s, 1 H).

LC-MS (Method C): Rt = 0.449 min; MS (ESI): m/z = 353.1 [M+H] ⁺ .

Compound 150

2-[3-[(3R)-1-(cyclopropylmethyl)-3-piperidyl]pyrido[2,3-b ]pyrazin-6-yl]-3,5-dimethyl-phenol

To a solution of 3,5-dimethyl-2-[3-[(3R)-3-piperidyl]pyrido[2,3-b]pyrazin-6-y l]phenol (500 mg, 552 pmol, 1 eq, TFA salt) in methanol (10 mL) was added cyclopropanecarbaldehyde (116 mg, 1.66 mmol, 123 pL, 3 eq) , potassium acetate (162 mg, 1.66 mmol, 3 eq) and NaBHsCN (104 mg, 1.66 mmol, 3 eq) at 25 °C. After stirring at 25 °C for 1 h, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: C18, 220 g, mobile phase: [water(FA) - MeCN];B%: 35% - 40%, 5 min) to give 2-[3-[(3R)-1-(cyclopropylmethyl)-3-piperidyl]pyrido[2,3-b]py razin-6-yl]-3,5- dimethyl-phenol (165 mg, 395 pmol, 71 % yield, 93% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d _s ) 6 = 9.08 (s, 1 H), 8.48 (d, J = 8.4 Hz, 1 H), 8.23 (s, 1 H), 7.77 (d, J = 8.8 Hz, 1 H), 6.64 (d, J = 10.0 Hz, 2H), 3.30 (br s, 2H), 3.05 (br d, J = 10.8 Hz, 1 H), 2.45 (br t, J = 10.8 Hz, 1 H), 2.33 (dd, J = 4.0, 6.4 Hz, 2H), 2.26 (s, 3H), 2.16-2.10 (m, 1 H), 2.07 (s, 3H), 2.06-2.00 (m, 1 H), 1.85-1.75 (m, 1 H), 1.74-1.65 (m, 2H), 0.94-0.84 (m, 1 H), 0.51-0.43 (m, 2H), 0.13-0.07 (m, 2H). LC-MS (Method C): Rt = 0.450 min; MS (ESI): m/z = 389.3 [M+H] ⁺ -

SFC (Rt = 1 .693 min, ee% = 94%).

Intermediate 315

6-[2-benzyloxy-6-methyl-4-(trifluoromethyl)phenyl]pyridme -2,3-diamine

To a solution of 6-chloropyridine-2,3-diamine (500 mg, 3.48 mmol, 1 eq) in dioxane (10 mL) was added [2-benzyloxy-6-methyl-4-(trifluoromethyl)phenyl]boronic acid (1 .62 g, 5.22 mmol, 1 .5 eq), XPhos Pd G3 (295 mg, 348 pmol, 0.1 eq) and K3PO4 (2.22 g, 10. 5 mmol, 3 eq) at 25 °C under N2 atmosphere. After stirring at 60 °C for 2 h, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The residue was purified by reversed-phase column (column: C18 120 g, mobile phase: [water (FA) - MeCN]; B%: 40% - 70%, 7 min) to give 6-[2- benzyloxy-6-methyl-4-(trifluoromethyl)phenyl]pyridine-2,3-di amine (500 mg, 1.34 mmol, 38% yield) as yellow oil.

¹ H NMR (400 MHz, DMSO-d _e ) 5 [ppm] = 7.34-7.24 (m, 5H), 7.18 (s, 2H), 6.77 (d, J = 7.6 Hz, 1 H), 6.39 (d, J= 7.6 Hz, 1 H), 5.38 (s, 2H), 5.10 (s, 2H), 4.72 (s, 2H), 2.12 (s, 3H).

Intermediate 316

2-(5,§-diamino-2-pyr!dyl)-3-methyl-5-(trifluorometbyl)ph enol

To a solution of 6-[2-benzyloxy-6-methyl-4-(trifluoromethyl)phenyl]pyridine-2 ,3-diamine (500 mg, 1.34 mmol, 1 eq) in MeOH (10 mL) was added Pd/C (50.0 mg, 47.0 pmol, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2 several times. After stirring under H2 (15 psi) atmosphere at 25 °C for 2 h, the reaction mixture was filtered and the filtrate was concentrated to give 2-(5,6-diamino-2-pyridyl)-3-methyl-5-(trifluoromethyl)phenoi (400 mg, 1.30 mmol, 97% yield, 92% purity) as a white solid.

¹ H NMR (400 MHz, DMSO-cf _e ) 5 [ppm] = 12.2-11.9 (m, 1 H), 7.01 (s, 1 H), 6.93 (d, J = 1.2 Hz, 1 H), 6.85 (d, J = 8.0 Hz, 1 H), 6.65 (d, J = 8.0 Hz, 1 H), 5.85 (s, 2H), 5.03 (s, 2H), 2.35 (s, 3H).

Intermediate 317

A mixture of 2-(5,6-diamino-2-pyridyl)-3-methyl-5-(trifluoromethyl)phenol (400 mg, 1 .30 mmol, 1 eq) and tert-butyl (3R)-3-oxaldehydoylpiperidine-1-carboxylate (470 mg, 1.95 mmol, 1.5 eq, EW35506-540) in EtOH (10 mL) was stirring at 60 °C for 1 h. The mixture was filtered, and the filtrate was concentrated to dry to give a residue. The residue was purified by reversed-phase column (column: C18 40 g, mobile phase: [water (FA) - MeCN]; B%: 40% - 70%, 7 min) to give tert-butyl (3R)-3-[6-[2-hydroxy-6-methyl-4- (trifluoromethyl)phenyl]pyrido[2,3-b]pyrazin-3-yl]piperidine -1 -carboxylate (400 mg, 778 pmol, 60% yield, 95% purity) as yellow oil. ¹ H NMR (400 MHz, DMSO-d _e ) 5 [ppm] = 10.3 (d, J = 2.0 Hz, 1 H), 9.1 1 (s, 1 H), 8.58 (d, J = 8.4 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.18 (s, 1 H), 7.13 (s, 1 H), 4.29-4.13 (m, 1 H), 3.96-3.92 (m, 1 H), 3.27-3.20 (m, 2H), 3.17 (s, 1 H), 2.94-2.90 (m, 1 H), 2.19-2.14 (m, 1 H), 2.13 (s, 3H), 1.90-1.80 (m, 2H), 1.37 (s, 9H). LC-MS (Method C): Rt = 0.627 min; MS (ESI): m/z = 489.0 [M+H] ⁺ .

Intermediate 318

3-msthy^2-[3-[(3R)-3-pip&i'idyi]pyi-!do[2,3-b]pyrazm- 6-y!]-5-(ti-ifU!Oi-amefhyQphenal

To a solution of tert-butyl (3R)-3-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyri do[2,3-b]pyrazin- 3-yl]piperidine-1 -carboxylate (200 mg, 389 pmol, 1 eq) in DCM (4 ml_) was added TFA (1 mL) at 0 °C. After stirring at 25 °C for 1 h, the mixture was concentrated to give 3-methyl-2-[3-[(3R)-3- piperidyl]pyrido[2,3-b]pyrazin-6-yl]-5-(trifluoromethyl)phen ol (150 mg, 367 pmol, 94% yield, 95% purity, TFA salt) as a wh ite solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 8.97 (s, 1 H), 8.36 (d, J = 8.4 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 6.78-6.71 (m, 1 H), 6.64-6.53 (m, 1 H), 3.19 (s, 1 H), 3.15-3.08 (m, 2H), 3.03-2.92 (m, 2H), 2.10 (s, 3H), 1.87-1.83 (m, 1 H), 1.73-1.65 (m, 1 H), 1.55-1.51 (m, 1 H), 1.28-1.18 (m, 1 H).

LC-MS (Method C): Rt = 0.453 min; MS (ESI) m/z = 389.0 [M+H] ⁺ .

Compound 151

3-methyl-2-[3-[(3R)-1~methyl-3~pipendyl]pyndo[2,3~b^pyi� �azin~S-yl]-5~(tnfluoi'Ofnethyl)phenol

To a solution of 3-methyl-2-[3-[(3R)-3-piperidyl]pyrido[2,3-b]pyrazin-6-yl]-5 -(trifluoromethyl)phenol (150 mg, 367 pmol, 1 eq, TFA salt) in MeOH (5 mL) was added (HCHO)n (16.5 mg, 917 pmol, 2.5 eq), AcOK (108 mg, 1.10 mmol, 3 eq) and NaBHsCN (57.6 mg, 917 pmol, 2.5 eq) at 25 °C. After stirring at 25 °C for 1 h, the mixture was filtered, and the filtrate was concentrated to dry. The residue was purified by reversed-phase column (column: C18 40 g, mobile phase: [water (FA) - MeCN]; B%: 40% - 70%, 7 min) to give 3-methyl-2-[3-[(3R)-1-methyl-3-piperidyl]pyrido[2,3-b]pyrazi n-6-yl]-5-(trifluoromethyl)phenol (98.0 mg, 221 pmol, 60% yield, 99% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d _s ) 5 [ppm] = 10.3 (s, 1 H), 9.14 (s, 1 H), 8.59 (d, J = 8.4 Hz, 1 H), 7.85 (d, J = 8.4 Hz, 1 H), 7.19 (s, 1 H), 7.13 (s, 1 H), 3.53-3.48 (m, 1 H), 3.18-3.10 (m, 2H), 2.96-2.84 (m, 1 H), 2.57 (s, 3H), 2.19-2.15 (m, 1 H), 2.13 (s, 3H), 2.11-2.06 (m, 1 H), 1.96-1.87 (m, 1 H), 1.82-1.78 (m, 1 H), 1.72- 1.62 (m, 1 H)

LC-MS (Method C): Rt = 0.441 min; MS (ESI) m/z = 403.1 [M+H] ⁺ .

SFC (Rt - 1 .258 min, ee% = 84%).

Intermediate 319

6-ch!oro-5-methyl-pyndme-2,3-diamine

To a solution of 6-chloro-5-methyl-3-nitro-pyridin-2-amine (2.00g, 10.7 mmol, 1 eq) in MeOH (20 mL) and H2O (10 mL) was added Fe (1.79 g, 32.0 mmol, 3 eq) and NH4CI (3.42 g, 64.0 mmol, 6 eq) at 20 °C in one portion. After stirring at 80 °C for 2 h. The mixture was filtered and the filtrate was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated sodium chloride (20 mL x 2), dried over anhydrous sodium sulfate. The filtered was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 0/1).to give 6-chloro-5-methyl-pyridine-2,3- diamine (1.50 g, 9.14 mmol, 86% yield, 96% purity) as a black solid.

¹ H NMR (400 MHz, METHANOL-^) <5 [ppm] = 2.12 (s, 3 H), 4.85 (s, 4 H), 6.81 (s, 1 H). LC-MS (Method C): Rt = 0.317 min; MS (ESI): m/z = 158.0 [M+H] ⁺ .

Intermediate 320

2-(5,6-diamino-3-methyl-2-pyridyl)-5-methyl-phenol

To a solution of 6-chloro-5-methyl-pyridine-2,3-diamine (500 mg, 3.17 mmol, 1 eq) and (2-hydroxy-4- methyl-phenyl) boronic acid (627 mg, 4.12 mmol, 1 .3 eq) in dioxane (6 ml_) and H2O (3 mL) was added CS2CO3 (2.07 g, 6.35 mmol, 2 eq) and XPhos Pd G3 (269 mg, 317 pmol, 0.1 eq) at 20 °C in one portion. After stirring at 80 °C for 16 h under nitrogen atmosphere, the reaction mixture was diluted with water (10 mL), and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated sodium chloride (10 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed- phase column (column: C18, 330 g, mobile phase [water (FA) - MeCN]; B%: 25% - 70%, 10 min) to give 2-(5,6-diamino-3-methyl-2-pyridyl)-5-methyl-phenol (450 mg, 1.94 mmol, 61 % yield, 99% purity) as a black brown solid.

LC-MS (Method C): Rt = 0.386 min; MS (ESI): m/z = 230.0 [M+H] ⁺ .

Intermediate 321 tert-butyl (3R)-3-[6-(2-hydroxy-4~metbyl-phenyl)-7-methyl~pyrido[2,3-b] pyrazin-3-yl]plperidlne-1- carboxylate

To a solution of 2-(5,6-diamino-3-methyl-2-pyridyl)-5-methyl-phenol (450 mg, 1.96 mmol, 0.6 eq) in EtOH (8 mL) was added tert-butyl (3R)-3-oxaldehydoylpiperidine-1 -carboxylate (789 mg, 3.27 mmol, 1 eq) at 20 °C in one portion. After stirring at 60 °C for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2).The combined organic layers were washed with saturated sodium chloride (20 mL x 2), dried over anhydrous sodium sulfate. The filtered was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 30/1 to 2/1) to give tert-butyl (3R)-3-[6-(2-hydroxy-4-methyl-phenyl)-7- methyl-pyrido[2,3-b]pyrazin-3-yl]piperidine-1-carboxylate (200 mg, 446 pmol, 14% yield, 97% purity) as a yellow solid.

¹ H NMR (400 MHz, CDCb) 6 [ppm] = 1 .46-1 .53 (m, 9 H), 1 .64-1 .74 (m, 1 H), 1 .80-1 .92 (m, 1 H), 1 .96- 2.09 (m, 1 H), 2.17 (d, J = 13.2 Hz, 1 H), 2.40 (s, 3 H), 2.79 (s, 3 H), 2.87 (d, J = 10.4 Hz, 1 H), 3.10- 3.36 (m, 2 H), 4.07-4.27 (m, 1 H), 4.29-4.52 (m, 1 H), 6.80 (d, J = 8.0, 1.13 Hz, 1 H), 6.98 (d, J = 0.8 Hz, 1 H), 7.60 (d, J = 8.0 Hz, 1 H), 8.36 (s, 1 H), 8.81 (s, 1 H).

LC-MS (Method C): Rt = 0.450 min; MS (ESI): m/z = 353.2 [M+H] ⁺ .

Intermediate 322 S-methyl^-p-methyl-S-KSRJS-pIpendylJpyndo^^-bJpyrazin-d-ylJp henol

To a solution of tert-butyl (3R)-3-[6-(2-hydroxy-4-methyl-phenyl)-7-methyl-pyrido[2,3-b] pyrazin-3- yl]piperidine-1 -carboxylate (200 mg, 460 pmol, 1 eq) in DCM (2 mL) was added TFA (1 mL) at 0 °C dropwise. After stirring at 20 °C for 1 h, the reaction was concentrated under reduced pressure to give 5-methyl-2-[7-methyl-3-[(3R)-3-piperidyl]pyrido[2,3-b]pyrazi n-6-yl]phenol (300 mg, 443 pmol, 96% yield, TFA salt) as red oil.

LC-MS (Method C): Rt = 0.413 min; MS (ESI): m/z = 335.2 [M+H] ⁺ .

Compound 152

5-methyl-2-[7miethyl-3-[(3R)-1-methyl-3-plperidyl]pyrido[ 2,3-b]pyi'azin-6-yl]phenol

To a solution of 5-methyl-2-[7-methyl-3-[(3R)-3-piperidyl]pyrido[2,3-b]pyrazi n-6-yl]phenol (300 mg, 897 pmol, 1 eq) in MeOH (4 mL) was added KOAc (880 mg, 8.97 mmol, 10 eq), (HCHO)n (80.7 mg, 2.69 mmol, 3 eq) and NaBHsCN (169 mg, 2.69 mmol, 3 eq) at 20 °C in one portion. After stirring at 20 °C for 1 h, the reaction mixture were concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (column: C18, 330 g, mobile phase: [water (FA) - MeCN]; B%: 30% - 75%, 8 min) to give 5-methyl-2-[7-methyl-3-[(3R)-1-methyl-3-piperidyl]pyrido[2,3 -b]pyrazin-6-yl]phenol (85.5 mg, 228 pmol, 25% yield, 93% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 1.64 (d, J = 6.8 Hz, 2 H), 1.75 (s, 1 H), 1.90-2.06 (m, 2 H), 2.23 (s, 3 H), 2.32 (s, 3 H), 2.39 (s, 3 H), 2.81 (d, J = 10.8 Hz, 1 H), 3.04 (d, J = 10.4 Hz, 1 H), 3.20- 3.38 (m, 2 H), 6.75 (d, J = 7.6 Hz, 1 H), 6.81 (s, 1 H), 7.11-7.20 (m, 1 H), 8.33 (s, 1 H), 8.38 (s, 3 H), 9.01 (s, 1 H),

LC-MS (Method C): Rt = 0.415 min; MS (ESI): m/z = 349.2 [M+H] ⁺ .

Intermediate 323 methyl 1-methyl-2-oxo-pyrrolidme-3-carboxylate

To a solution of N,N-diisopropyiamine (42.9 g, 424 mmol, 59.9 mL, 2.10 eq) in tetrahydrofuran (200 mL) was added dropwise n-butyllithium (2.50 M in hexane, 161 mL, 2.00 eq) at -70 °C under nitrogen atmosphere. After stirring for 1 h at -70 °C under nitrogen atmosphere, 1-methylpyrrolidin-2-one (20.0 g, 202 mmol, 19.6 mL, 1 .0 eq) in tetra hydrofuran (10 mL) was added dropwise into the reaction mixture at -70 °C under nitrogen atmosphere. After stirring at -70 °C for 1 h under nitrogen atmosphere, dimethyl carbonate (21 .8 g, 242 mmol, 20.4 mL, 1 .20 eq) in tetrahydrofuran (20 mL) was added into the reaction mixture at -70 °C under nitrogen atmosphere. After stirring at 25 °C for 4 h, the reaction mixture was quenched by saturated ammonium chloride aqueous solution (150 mL) at 0 °C, and then extracted with ethyl acetate (150 mL x 3. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiOa, petroleum ether/ethyl acetate = 20/1 to 0/1) to give methyl 1-methyl-2-oxo- pyrrolidine-3-carboxylate (18.7 g, 119 mmol, 59% yield) as yellow oil.

Intermediate 324 tert-butyl 5-[4-(3-methoxycarbonyl-1-methyl-2-oxo-pyrrolidln-3-yl)-7-(2 -methoxy-4,6-dlmethyl- phenyl)-1,8-naphthyridm-2-yl]-3,6-dihydro-2H-pyridme-1 -carboxylate

To a solution of tert-butyl 5-[4-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-3,6- dihydro-2H-pyridine-1-carboxylate (2.70 g, 5.63 mmol, 1.00 eq) in N,N-dimethylformamide (30 mL) were added methyl 1-methyl-2-oxo-pyrrolidine-3-carboxylate (1.77 g, 11.3 mmol, 2.0 eq) and cesium carbonate (3.67 g, 11 .3 mmol, 2.0 eq) at 25 °C. After stirring at 100 °C for 14 h, the mixture was poured slowly into ice-water (250 mL). The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether/ethyl acetate = 1/0 to 0/1) to give tert-butyl 5-[4-(3-methoxycarbonyl-1-methyl-2-oxo-pyrrolidin-3- yl)-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-3,6-dihydro-2H-pyridine-1 -carboxylate (1.38 g, 2.30 mmol, 41 % yield) as brown oil and tert-butyl 5-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-(1- methyl-2-oxo-pyrrolidin-3-yl)-1 ,8-naphthyridin-2-yl]-3,6-dihydro-2H-pyridine-1 -carboxylate (1 .29 g, 2.38 mmol, 42% yield) as a brown solid.

LC-MS (Method C): Rt = 0.942 min; MS (ESI) m/z = 601 .3 [M+H] ⁺ .

Intermediate 325

To a solution of tert-butyl 5-[4-(3-methoxycarbonyl-1-methyl-2-oxo-pyrrolidin-3-yl)-7-(2 -methoxy-4,6- dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.38 g, 2,30 mmol, 1.0 eq) in dimethylsulfoxide (15 mL) was added lithium chloride (292 mg, 6,89 mmol, 141 pL, 3,0 eq) at 25 °C. After stirring at 100 °C for 14 h, the mixture was poured slowly into ice-water (250 mL) (250 mL icewater). The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The mixture was purified by reversed-phase (column: Cl 8, 330 g, mobile phase: [water(FA) - MeCN];B%: 20% - 75%, 18 min) to give tert-butyl 5-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-[rac-(3S)-1-methyl-2- oxo- pyrrolidin-3-yl]-1 ,8-naphthyridin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.10 g, 2.03 mmol, 88% yield) as a brown solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 8.53 (d, J = 8.4 Hz, 1 H), 7.76 (s, 1 H), 7.46 (d, J = 8.4 Hz, 1 H), 7.05 (s, 1 H), 6.83 (s, 1 H), 6.78 (s, 1 H), 4.56 (t, J = 9.2 Hz, 1 H), 4.49-4.43 (m, 2H), 3.66 (s, 3H), 3.60- 3.51 (m, 4H), 2.88 (s, 3H), 2.64-2.56 (m, 1 H), 2.44-2.36 (m, 5H), 2.29-2.22 (m, 1 H), 2.01 (s, 3H), 1.43 (s, 9H).

LC-MS (Method C): Rt = 0.903 min; MS (ESI) m/z - 543.3 [M+H] ⁺ .

Intermediate 326

To a solution of tert-butyl 5-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-[rac-(3S)-1-methyl-2- oxo-pyrrolidin- 3-yl]-1 ,8-naphthyridin-2-yl]-3,6-dihydro-2H-pyridine-1 -carboxylate (1.10 g, 2.03 mmol, 1.00 eq) in methanol (11 mL) was added palladium on carbon (1 10 mg, 10% purity) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. After stirring for 4 h under hydrogen atmosphere (15 psi) at 25 °C, the mixture was filtered through a pad of celite. The filtrate was concentrated in vacuum to give a residue. The residue was purified by reversed-phase (column: C18, 80 g, mobile phase: [water (FA) - MeCN];B%: 20% - 80%, 20 min) to give tert-butyl rac- (3S)-3-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-[rac-(3S)-1-meth yl-2-oxo-pyrrolidin-3-yl]-1 ,8- naphthyridin-2-yl]piperidine-1-carboxylate (850 mg, 1.56 mmol, 77% yield) as a yellow solid.

LC-MS (Method C): R _t = 0.533 min; MS (ESI) m/z = 454.4 [M+H] ⁺ .

Intermediate 327

A mixture of tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-4-[1-methyl-2-oxo-pyrro lidin-3-yl]-1 ,8- naphthyridin-2-yl]piperidine-1-carboxylate (850 mg, 1.56 mmol, 1.00 eq, EW38698-260) in hydrochloric acid (4.00 M in 1 ,4-dioxane, 5 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuum to give rac-(3S)-3-[7-(2-methoxy-4,6-dimethyl-phenyl)-2-[rac-(3S)-3- piperidyl]-1 ,8- naphthyridin-4-yl]-1-methyl-pyrrolidin-2-one (751 mg, 1.56 mmol, 100% yield, HCI salt) as a yellow solid.

LC-MS (Method C): Rt = 0.431 min; MS (ESI) m/z = 445.3 [M+H] ⁺ .

Intermediate 328

To a solution of 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-2-[3-piperidyl]-1 ,8-naphthyridin-4-yl]-1-methyl- pyrrolidin-2-one (751 mg, 1.56 mmol, 1.0 eq, HCI salt) in methanol (5 mL) were added formaldehyde (380 mg, 4.68 mmol, 349 pL, 37% purity, 3.0 eq), potassium acetate (306 mg, 3.12 mmol, 2.0 eq) and sodium cyanoborohydride (294 mg, 4.68 mmol, 3.0 eq) at 0 °C. After stirring for 1 h at 0 °C, the mixture was added slowly into saturated ammonium chloride (15 mL). The pH was adjusted to 8 with saturated sodium bicarbonate. Then the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by reversed-phase (column: C18, 80 g, mobile phase: [water (FA) - MeCN];B%: 15% - 75%, 30 min) to give rac-(3S)-3-[7-(2-methoxy-4,6-dimethyl-phenyl)-2-[rac-(3S)-1- methyl-3-piperidyl]-1 ,8-naphthyridin-4-yl]-1-methyl-pyrrolidin-2-one (700 mg, 1.53 mmol, 98% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 8.56 (d, J = 8.4 Hz, 1 H), 8.18 (s, 1 H), 7.48 (d, J = 8.4 Hz, 1 H), 7.45 (s, 1 H), 6.82 (s, 1 H), 6.77 (s, 1 H), 4.56 (t, J = 9.2 Hz, 1 H), 3.64 (s, 1 H), 3.57-3.53 (m, 2H), 3.35- 3.29 (m, 2H), 2.87 (s, 1 H), 2.64-2.57 (m, 2H), 2.53 (s, 3H), 2.36 (s, 3H), 2.33-2.31 (m, 1 H), 2.25-2.19 (m, 2H), 2.00 (s, 3H), 1.88-1.77 (m, 2H), 1.68-1.59 (m, 1 H).

LC-MS (Method C): Rt = 0.795 min; MS (ESI) m/z = 459.3 [M+HJ* Compound 153 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-2-[1-methyl-3-pipendyl] -1,8-naphthyridm-4-yl]-1 -methyl- pyrrolidm-2-one

To a solution of 3-[7-(2-methoxy-4,6-dimethyl-phenyi)-2-[1-methyl-3-piperidyl ]-1 ,8-naphthyridin-4-yl]-1- methyi-pyrrolidin-2-one (200 mg, 436 pmol, 1 eq) in dichloromethane (3 mL) was added boron tribromide (328 mg, 1 .31 mmol, 126 pL, 3 eq) at -70 °C. The mixture was warmed to 25 °C and stirred for 2 h. The pH of the reaction mixture was adjusted to 7 with ammonia (7 M in methanol). The mixture was concentrated under reduced pressure to give a crude product. The two batches crude product were combined and purified by flash reverse phase (instrument: 60 g Flash; Column: Welch Ultimate XB_C18 20-40pm; eluent A: water (0.1 % NHs’HaO), eluent B: acetonitrile; gradient: 43% B; flow 50 ml/min) and lyophilized to give 3-[7-(2-hydroxy-4,6-dimethyl-phenyl)-2-[1-methyl-3-piperidyl ]-1 ,8-naphthyridin-4-yl]- 1-methyl-pyrrolidin-2-one (221 mg, 487pmol, 36% yield, 98% purity) as a yellow solid.

Compound 153

¹ H NMR (400 MHz, DMSO-d _s ) 6 [ppm] = 9.96-9.72 (m, 1 H), 8.53 (d, J = 8.8 Hz, 1 H), 7.55 (d, J = 8.8 Hz, 1 H), 7.40 (s, 1 H), 6.63 (s, 1 H), 6.62 (s, 1 H), 4.53 (t, J = 9.2 Hz, 1 H), 3.60-3.47 (m, 2H), 3.17-3.06 (m, 1 H), 3.04-2.96 (m, 1 H), 2.87 (s, 3H), 2.84-2.77 (m, 1 H), 2.64-2.54 (m, 1 H), 2.26 (s, 3H), 2.24-2.15 (m, 5H), 2.10 (s, 3H), 2.00-1.87 (m, 2H), 1.79-1.72 (m, 1 H), 1.71-1.52 (m, 2H).

LC-MS (Method C): Rt = 0.819 min; MS (ESI) m/z = 445.2 [M+HJ*.

Intermediate 329 methyl 2-chloro~5-fluoro~§-(2~methoxy-4 _! 6~d!methyl-phenyl)pyndme-3-carboxylate

A mixture of methyl 2,6-dichioro-5-fluoro-pyridine-3-carboxylate (5.00 g, 22.3 mmol, 1.00 eq), (2- methoxy-4,6-dimethyi-phenyl)boronic acid (4.42 g, 24.5 mmol, 1.10 eq), cesium carbonate (14.5 g, 44.6 mmol, 2.00 eq) and [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(il) (1.63 g, 2.23 mmol, 0.10 eq) in dioxane (50 mL) and water (5 mL) was degassed and purged with nitrogen for 3 times. After stirring at 90 °C for 12 h under nitrogen atmosphere. The reaction mixture was filtered with using ethyl acetate (100 mL) over a plug of celite. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate=100/1 to 10/1) to give methyl 2-chloro-5-fluoro-6-(2-methoxy-4,6-dimethyl- phenyl)pyridine-3-carboxylate (5.70 g, 17.6 mmol, 78% yield) as yellow oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 8.29 (d, J = 8.4 Hz, 1 H), 6.82 (s, 1 H), 6.77 (s, 1 H), 3.92 (s, 3H), 3.68 (s, 3H), 2.34 (s, 3H), 2.00 (s, 3H).

Intermediate 330

A mixture of methyl 2-chloro-5-f!uoro-6-(2-methoxy-4,6-dimethyl-phenyl)pyridine- 3-carboxylate (5.70 g, 17.6 mmol, 1.00 eq), tert-butyl carbamate (6.19 g, 52.8 mmol, 3.00 eq), dicyclohexyl-[2-(2,6- diisopropoxyphenyl)phenyl]phosphane (1.64 g, 3.52 mmol, 0.20 eq), [2-(2-aminophenyl)phenyl]- methylsulfonyloxy-palladium;dicyclohexyl-[2-(2,6-diisopropox yphenyl)phenyl]phosphane (1 .47 g, 1 .76 mmol, 0.10 eq) and cesium carbonate (11.4 g, 35.2 mmol, 2.00 eq) in dioxane (100 mLJ was degassed and purged with nitrogen for 3 times. After stirring at 90 °C for 16 h under nitrogen atmosphere. The reaction mixture was poured into water 200 mL at 25 °C and extracted with ethyl acetate 150 mL (50 mL x 3). The combined organic layers were washed with brine 100 mL, dried over sodium sulfate, filtered and concentrated under reduced pressure to give methyl 2-(tert- butoxycarbonylamino)-5-fluoro-6-(2-methoxy-4,6-dimethyl-phen yl)pyridine-3-carboxylate (5.00 g, crude) as yellow solid.

LCMS (Method C): Rt = 0.964 min; MS (ESI): m/z = 405.1 [M-Boc+H] ⁺ .

Intermediate 331 methyl 2-amlno-5-fluoro-3-(2-methoxy-4,6-dimethyl-phenyl)pyridine-3 -carboxy!ate

A solution of methyl 2-(tert-butoxycarbonylamino)-5-fluoro-6-(2-methoxy-4,6-dimet hyl-phenyl)pyridine- 3-carboxylate (5 g, 12.36 mmol, 1 .00 eq) in hydrochloric acid (4 M in dioxane, 33.3 mL, 10.7 eq) was stirred at 20 °C for 4 h.The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOa, Petroleum ether/Ethyl acetate=100/1 to 0/1) to give methyl 2-amino-5-fluoro-6-(2-methoxy-4,6-dimethyl-phenyl)pyridine-3 - carboxylate (2.3 g, 7.56 mmol, 61% yield) as yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 7.98 (br d, J = 9.2 Hz, 1 H), 6.78 (s, 1 H), 6.73 (s, 1 H), 4.48- 4.28 (m, 2H), 3.85 (s, 3H), 3.67 (s, 3H), 2.32 (s, 3H), 2.01 (s, 3H)

Intermediate 332

To a solution of (3R)-1-tert-butoxycarbonylpiperidine-3-carboxylic acid (1 .91 g, 8.31 mmol, 1.10 eq) in pyridine (20 mL) was added phosphoryl trichloride (2.32 g, 15.1 mmol, 1 .41 mL, 2.00 eq), at 25 °C. After stirring at 20 °C for 0.5 hr, and then methyl 2-amino-5-fluoro-6-(2-methoxy-4,6-dimethyl- phenyl)pyridine-3-carboxylate (2.30 g, 7.56 mmol, 1.00 eq) was added. The resulting mixture was stirred at 20 °C for 11 .5 hr. The reaction mixture was put into water 200 mL at 25 °C and extracted with ethyl acetate 150 mL (50 mL x 3). The combined organic layers were washed with brine 100 mL, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/1 to 5/1) to give methyl 2-[[(3R)-1-tert-butoxycarbonylpiperidine-3-carbonyl]amino]-5 -fluoro-6-(2-methoxy-4,6- dimethyl-phenyl)pyridine-3-carboxylate (2.00 g, 3.88 mmol, 51% yield) as yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 10.81 (s, 1 H), 7.99 (d, J = 8.4 Hz, 1 H), 6.80 (s, 1 H), 6.75 (s, 1 H), 3.88 - 3.84 (m, 1 H), 3.74 (s, 3H), 3.67 (br d, J = 1 .6 Hz, 3H), 2.72 (br d, J = 5.2 Hz, 1 H), 2.67 (br s, 2H), 2.57-2.56 (m, 1 H), 2.33 (s, 3H), 1 .99 (br d, J = 4.4 Hz, 2H), 1 .82-1 .81 (m, 2H), 1 .40 (s, 9H).

Intermediate 333 tert-butyl (3R)-3-[6-fluoro-4-hydroxy-7-(2-methoxy-4,6-dimethyl-pheny!) pyrido[2,3-d]pyrimldm- 2-yl]plperidme-1 -carboxylate A mixture of methyl 2-[[(3R)-1-tert-butoxycarbonylpiperidine-3-carbonyl]amino]-5 -fluoro-6-(2-methoxy- 4,6-dimethyl-phenyl)pyridine-3-carboxylate (2.00 g, 3.88 mmol, 1.00 eq) in ammonia in methanol (7 M, 32.0 mL, 57.7 eq) was stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give tert-butyl (3R)-3-[6-fluoro-4-hydroxy-7-(2-methoxy-4,6-dimethyl- phenyl)pyrido[2,3-d]pyrimidin-2-yi]piperidine-1-carboxylate (2.20 g, crude) as white solid.

LC-MS (Method C): Rt = 0.966 min; MS (ESI): m/z = 483.3 [M+H] ⁺ .

Intermediate 334

A mixture of tert-butyl (3R)-3-[6-fluoro-4-hydroxy-7-(2-methoxy-4,6-dimethyl-phenyl) pyrido[2,3- d]pyrimidin-2-yl]piperidine-1-carboxylate (2.00 g, 4.14 mmol, 1.00 eq), diisopropylethylamine (1.07 g, 8.29 mmol, 1.44 mL, 2.00 eq) and phosphorus oxybromide (4.75 g, 16.5 mmol, 1.69 mL, 4.00 eq) in dichloromethane (20 mL) was degassed and purged with nitrogen for 3 times. After stirring at 20 °C for 2 h under nitrogen atmosphere. The mixture was concentrated to afford the crude. The crude was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate=10/1 to 5/1) to give tert-butyl (3R)-3-[4-bromo-6-fluoro-7-(2-methoxy-4,6-dimethyl-phenyl)py rido[2,3-d]pyrimidin-2-yl]piperidine-1- carboxylate (1 .10 g, 1 .87 mmol, 45% yield, 92.9% purity) as a yellow oil.

LC-MS (Method C): Rt = 1.158 min; MS (ESI): m/z = 547.1 [M+H] ⁺ .

Intermediate 335

A mixture of tert-butyl (3R)-3-[4-bromo-6-fluoro-7-(2-methoxy-4,6-dimethyl-phenyl)py rido[2,3- d]pyrimidin-2-yl]piperidine-1-carboxylate (500 mg, 916 pmol, 1.00 eq, EW45039-5) and triethylamine (278 mg, 2.75 mmol, 382 pL, 3.00 eq) in ethyl acetate (10 mL) was degassed and purged with nitrogen for 3 times, palladium on carbon (97.5 mg, 91 .6 pmol, 10% purity, 0.10 eq) was added into mixture and was degassed and purged with hydrogen for 3 times. After stirring at 20 °C for 1 h under hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate=10/1 to 5/3) to give tert-butyl (3R)-3-[6-fluoro-7-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3 - d]pyrimidin-2-yl]piperidine-1 -carboxylate (400 mg, 857 pmol, 46% yield) as a yellow solid.

^! H NMR (400 MHz, DMSO-d ₆ ) 5 = 9.69 (s, 1 H), 8.51 (d, J = 8.0 Hz, 1 H), 6.86 (s, 1 H), 6.82 (s, 1 H), 3.93 (br d, J = 12.4 Hz, 1 H), 3.66 (s, 3H), 3.38-3.35 (m, 2H), 3.18-3.06 (m, 1 H), 2.87 (brt, J = 12.4 Hz, 1 H), 2.37 (s, 3H), 2.22 (br d, J = 10.6 Hz, 1 H), 2.01 (s, 3H), 1.90-1.76 (m, 2H), 1.61-1.49 (m, 1 H), 1.37 (br s, 9H).

LC-MS (Method C): Rt = 1 .022 min; MS (ESI): m/z = 467.3 [M+H] ⁺ .

Intermediate 336

§-f!uoro-7-(2-methoxy-4 _! @-dimethyl-pheriy!)-2-[(3R)-3-plperidyl]pyrido[2,3-d]p yrimldirie To a solution of tert-butyl (3R)-3-[6-fluoro-7-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3 -d]pyrimidin-2- y!]piperidine-1 -carboxylate (380 mg, 814 pmol, 1.00 eq) in dichloromethane (4 mL) and trifluoroacetic acid (1 .54 g, 13.4 mmol, 1 .00 mL, 16.5 eq) was added. After stirring at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a 6-fluoro-7-(2-methoxy-4,6-dimethyl- phenyl)-2-[(3R)-3-piperidyl]pyrido[2,3-d]pyrimidine (391 mg, crude, TFA salt) as red oil and then was used into the next step without further purification. To a solution of 6-fluoro-7-(2-methoxy-4,6- dimethyl-phenyl)-2-[(3R)-3-piperidyl]pyrido[2,3-d]pyrimidine (391 mg, 813 pmol, 1.00 eq, TFA salt) in acetonitrile (5 mL) was added potassium carbonate (1 .91 g, 13.8 mmol, 17 eq). After stirring at 20 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a 6-fluoro- 7-(2-methoxy-4,6-dimethyl-phenyl)-2-[(3R)-3-piperidyl]pyrido [2,3-d]pyrimidine (298mg, crude, free) as a yellow solid and then used into the next step without further purification.

¹ H NMR (400 MHz, DMSO-d _s ) 5 = 9.69 (s, 1 H), 8.53 (d, J = 8.0 Hz, 1 H), 6.86 (s, 1 H), 6.81 (s, 1 H), 3.66 (s, 3H), 3.46 (br d, J = 13.1 Hz, 1 H), 3.32-3.23 (m, 1 H), 3.17-3.03 (m, 2H), 2.81-2.65 (m, 1 H), 2.37 (s, 3H), 2.26-2.15 (m, 1 H), 2.01 (s, 3H), 1.88-1.75 (m, 2H), 1.74-1.62 (m, 1 H).

LC-MS (Method C): Rt = 0.447 min; MS (ESI): m/z = 367.3 [M+H] ⁺ .

Intermediate 337

6-fluoi'o-7-(2-methoxy-4,6-dmethylphenyl)-2-(1-methylpipe ndin-3-yl)pyddo[2 _! 3-d]pydmidine To a solution of 6-fluoro-7-(2-methoxy-4,6-dimethyl-phenyl)-2-[(3R)-3-piperid yljpyrido[2,3-djpyrimidine (278 mg, 758 pmol, 1.00 eq) in methyl alcohol (3 mL) was added formaldehyde (184 mg, 2.28 mmol, 169 pL, 37% purity, 3.00 eq), potassium acetate (223 mg, 2.28 mmol, 3.00 eq) and sodium cyanoborohydride (143 mg, 2.28 mmol, 3.00 eq). After stirring at 20 °C for 1 h. The reaction mixture was quenched by addition saturated ammonium chloride at 20 °C and then the mixture was purified by reversed phase (instrument: 60g Flash; Column: Welch Ultimate XB_C18 20-40pm; eluent A: water (0.05% FA), eluent B: acetonitrile; gradient: 0-50min 0-20% B; flow 50 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give 6-fluoro-7-(2-methoxy-4,6-dimethyl-phenyl)-2- [1 -methyl-3-piperidyl]pyrido[2,3-d]pyrimidine (290 mg, 724 pmol, 95% yield, 95% purity, FA salt) as a white solid.

^! H NMR (400 MHz, DMSO-d ₈ ) 6 = 9.72 (s, 1 H), 8.55 (d, J = 8.0 Hz, 1 H), 6.86 (s, 1 H), 6.82 (s, 1 H), 3.71-3.63 (m, 4H), 3.54 (br t, J = 11.2 Hz, 1 H), 3.32 (br d, J = 10.8 Hz, 1 H), 3.27-3.17 (m, 1 H), 2.82 (br t, J = 11.2 Hz, 1 H), 2.74 (s, 3H), 2.37 (s, 3H), 2.30-2.19 (m, 1 H), 2.01 (s, 3H), 1.97-1.82 (m, 2H), 1.73 (br dd, J = 7.2, 12.0 Hz, 1 H).

LC-MS (Method C): Rt = 0.436 min; MS (ESI): m/z = 381 .2 [M+H] ⁺ .

Compound 154 and 155

2-(6-fliioro-2-(1-methylpipendm-3-yl)pyndo[2,3-d]pynm!din -7-yl)-3,5-dimethy!phenol

To a solution of 6-fluoro-7-(2-methoxy-4,6-dimethyl-phenyl)-2-[1-methyl-3-pip eridyl]pyrido[2,3- d]pyrimidine (270 mg, 601 pmol, 1.00 eq, FA salt) in dichloromethane (15 mL) was added boron tribromide (4.52 g, 18.0 mmol, 1 .74 mL, 30.0 eq) at -70 °C. The mixture was stirred at 0 °C for 6 h. The pH of the reaction mixture was adjusted to 7 with ammonia in methanol (7 M). The mixture was concentrated under reduced pressure to afford a residue. The residue was purified by reversed phase (instrument: 60g Fiash; Coiumn: Welch Ultimate XB_C18 20-40pm; eluent A: water (0.05% FA), eluent B: acetonitrile; gradient: 0-50min 0-20% B; flow 50 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give a racemate of 2-(6-fluoro-2-(1-methylpiperidin-3-yl)pyrido[2,3- d]pyrimidin-7-yl)-3,5-dimethylphenol. The racemate was separated by SFC (column: DAICEL

CHIRALPAK AY-H(250mm • 30mm,10um);mobile phase: [CO ₂ -EtOH(0.1% NH3*H ₂ O)];B%:40%, isocratic elution mode) to give Compound 154 2-[6-fluoro-2-[1-methyl-3-piperidyl]pyrido[2,3- d]pyrimidin-7-yl]-3,5-dimethyl-phenol (6.81 mg, 18.5 pmol, 3% yield, 99% purity) as brown gum, and Compound 155 2-[6-fluoro-2-[1-methyl-3-piperidyl]pyrido[2,3-d]pyrimidin-7 -yl]-3,5-dimethyl-phenol (65.9 mg, 179 pmol, 29% yield, 99% purity) as a yellow solid.

Compound 154

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 = 9.66 (s, 1 H), 9.56 (s, 1 H), 8.48 (d, J = 8.0 Hz, 1 H), 6.64 (d, J = 6.4 Hz, 2H), 3.28 (br d, J = 7.6 Hz, 2H), 2.89 (s, 1 H), 2.59-2.52 (m, 1 H), 2.34 (br s, 3H), 2.27 (s, 3H), 2.12 (br s, 2H), 2.00 (s, 3H), 1.87-1.78 (m, 1 H), 1.77-1.60 (m, 2H).

LC-MS (Method C): Rt = 0.425 min; MS (ESI) m/z = 367.4 [M+H] ⁺ .

SFC (Rt = 2.073 min, ee% = 98.43%)

Compound 155

¹ H NMR (400 MHz, DMSO-d ₈ ) 6 = 9.66 (s, 1 H), 9.55 (s, 1 H), 8.47 (d, J = 8.0 Hz, 1 H), 6.64 (d, J = 6.4 Hz, 2H), 3.25 (ddd, J = 3.6, 7.2, 10.8 Hz, 1 H), 3.18 (br d, J = 11.2 Hz, 1 H), 2.83 (br d, J = 10.4 Hz, 1 H), 2.39-2.31 (m, 1 H), 2.27 (d, J = 3.6 Hz, 6H), 2.16-2.07 (m, 1 H), 2.00 (s, 3H), 1.96 (br s, 1 H), 1.84- 1.76 (m, 1 H), 1.73-1.57 (m, 2H)

LC-MS (Method C): Rt = 0.427 min; MS (ESI) m/z = 367.4 [M+H]*.

SFC (Rt = 2.317 min, ee% = 100%)

Intermediate 338

3-[3-[tert-butyl (diphenyl) silyl] oxycyclobutyl]-2-oxo-propanal 24

To a solution of 1-[3-[tert-butyl (diphenyl) silyl] oxycyclobutyl] propan-2-one (200 mg, 545 pmol, 1 eq) in dioxane (4 mL) was added SeO ₂ (182 mg, 1 .64 mmol, 3 eq) at 25 °C. After stirring at 90 °C for 16 h, the reaction mixture was filtrated and the filtrate was concentrated to give 2-(3- hydroxycyclobutyl)acetic acid (4.10 g, crude) as yellow oil.

Intermediate 339

To a solution of 3-[3-[tert-butyl (diphenyl) silyl] oxycyclobutyl]-2-oxo-propanal (200 mg, 525 pmol, 1 eq) in EtOH (5 mL) was added 2-(5,6-diamino-2-pyridyl)-3,5-dimethyl-phenol (96.4 mg, 420 pmol, 0.8 eq) at 25 °C. After stirring at 60 °C for 16 h, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to give 2-[3-[[3-[tert-butyl(diphenyl)silyl]oxycyclobutyl]methyl]pyr ido[2,3-b]pyrazin-6-yl]-3,5-dimethyl- phenol (150 mg, 256 pmol, 49% yield, 98% purity) as a light yellow solid. LC-MS (Method C): Rt = 0.775 min; MS (ESIpos): m/z = 574.3 [M+1] ⁺ . intermediate 340

2-[3-[(3-hydroxycyclobutyl) methyl] pyrido [2,3-b]pyrazin-6-yl]-3,5-dlmethyl-phenol

To a solution of 2-[3-[[3-[tert-butyl(diphenyl)sily0oxycyclobutyl]methyi]pyri do[2,3-b]pyrazin-6-yl]-3,5- dimethyi-phenol (100 mg, 170 pmol, 1 eq) in DMF (2 mL) was added cesium fluoride (77.8 mg, 512 pmol, 3 eq) at 25 °C. After stirring at 60 °C for 2 h, the mixture was added water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude. The crude product was purified by reversed flash (Instrument: 40g Flash; Column: Welch Ultimate XB_C18 20-40pm; Eluent A: water (0.1 % NFL H2O), eluent B: acetonitrile; gradient: 0-10 min 0-50% B; flow 60 ml/min; temperature: room temperature; Detector: UV220/254 nm) to give 2-[3-[(3- hydroxycyclobutyl)methyl]pyrido[2,3-b]pyrazin-6-yl]-3,5-dime thyl-phenol (35.0 mg, 100 pmol, 59% yield, 96% purity) as yellow oil.

LC-MS (Method C): Rt = 0.511 min; MS (ESIpos): m/z = 336.0 [M+1J*.

Compound 156 and 157 2-[3-[(3-hydroxycyclobutyl)methyl]pyrido[2,3-b]pyrazin-6-yl] -3,5-dimethyl-phenol The reaction was set up for SFC separation. The residue was purified by SFC: (column: DAICEL CHIRALPAK IG (250mm*30mm,10um);mobile phase: [CO ₂ -MeCN/i-PrOH(0.1% NH ₃ *H ₂ O)];B%:45%, isocratic elution mode) to give Compound 156 2-[3-[(3-hydroxycyciobutyl)methyi]pyrido[2,3-b]pyrazin- 6-yl}-3,5-dimethyi-phenol (14.5 mg, 42.9 pmol, 43% yield, 99% purity, peak 1 , Rt = 1 .436 min) as a yellow solid, and Compound 157 2-[3-[(3-hydroxycyclobutyl)methyl]pyrido[2,3-b]pyrazin-6-yl] -3,5- dimethyl-phenol (13.8 mg, 40.7 pmol, 41 % yield, 99% purity, peak 2, Rt = 1.781 min) as a yellow solid.

Compound 156

¹ H NMR (400 MHz, DMSO-d ₅ ) 6 = 8.91 (s, 1 H), 8.43 (d, J = 8.4 Hz, 1 H), 7.79 (d, J = 8.4 Hz, 1 H), 6.61 (s,1 H), 6.54 (s, 1 H), 3.95-3.85 (m, 1 H), 3.12 (d, J = 7.2 Hz, 2H), 2.37-2.30 (m, 2H), 2.28-2.18 (m, 5H), 2.08 (s, 3H), 1.68-1.60 (m, 2H).

LC-MS (Method C): Rt = 0.497 min; MS (ESIpos): m/z = 335.9 [M+1 ] ⁺ . SFC (Rt = 1 .436 min, ee% = 95%)

Compound 157 ¹ H NMR (400 MHz, DMSO- d ₆ ) 6 = 8.96 (s, 1 H), 8.46 (d, J = 8.4 Hz, 1 H), 7.77 (d, J = 8.8 Hz, 1 H), 6.66 (s,1 H), 6.62 (s, 1 H), 4.35-4.28 (m, 1 H), 3.16 (d, J = 7.6 Hz, 2H), 2.72-2.68 (m, 2H), 2.26 (s, 3H), 2.20-2.15 (m, 1 H), 2.08 (s, 3H), 1.95-1.98 (m, 1 H), 1.11-1.05 (m, 2H).

LC-MS (Method C): Rt = 0.503 min; MS (ESIpos): m/z = 336.0 [M+1 ] ⁺ . SFC (Rt = 1 .781 min, ee% = 95%) Intermediate 341 4-bromo-7-(2-methoxy-4 _! 6-dimethyl-phenyl)-2-[3-piperidyl]-1,8-naphthyridine

To a solution of tert-butyl rac-(3R)-3-[4-hydroxy-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin- 2-yl]piperidine-1 -carboxylate (1.68 g, 3.62 mmol, 1.00 eq) in acetonitrile (20 mL) was added phosphorus oxybromide (3.12 g, 10.9 mmol, 1.11 mL, 3.00 eq) and N,N-diisopropylethylamine (937 mg, 7.25 mmol, 1 .26 mL, 2.00 eq) at 25 °C. After stirring for 14 h at 25 °C, the mixture was added dropwise to ice water (5 mL) at 0 °C. The pH was adjusted to 7-8 with saturated sodium bicarbonate. The mixture was extracted with dichloromethane (15 mL x 3). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give 4-bromo-7-(2-methoxy-4,6- dimethyl-phenyl)-2-[3-piperidyl]-1 ,8-naphthyridine (1.55 g, 3.64 mmol, 100% yield, crude) as a brown solid.

LC-MS (Method C): Rt = 0.861 min; MS (ESI) m/z = 462.1 [M+H] ⁺ .

Intermediate 342 tert-butyl 3-[4-bromo-7-(2-methoxy-4, 6-dimethyl-phenyl) -1, 8-naphthyridin-2-yl]piperidine-1- car boxy late

To a solution of 4-bromo-7-(2-methoxy-4, 6-dimethyl-phenyl) -2-[3-piperidyl]-1 , 8-naphthyridine (1.55 g, 3.64 mmol, 1 .00 eq) in water (20 mL) and tetrahydrofuran (20 mL) were added Sodium hydrogen carbonate (916 mg, 10.9 mmol, 424 pL, 3.00 eq) and tert-butoxycarbonyl tert-butyl carbonate (1 .59 g, 7.27 mmol, 1 .67 mL, 2.00 eq). The reaction mixture was stirred at 25 °C for 16 h. Water was added (20 mL). The mixture was extracted with Ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated brine (20 mL x 2) and the organic layer was dried over anhydrous sodium sulfate. The reaction mixture was concentrated in vacuum. The crude product was purified by silica gel column chromatography (SIO ₂ , petroleum ether/ethyl acetate = 1/0 to 0/1) to give tert-butyl 3-[4- bromo-7-(2-methoxy-4, 6-dimethyl-phenyl) -1 , 8-naphthyridin-2-yl]piperidine-1-carboxylate (730 mg,

1 .39 mmol, 38 % yield) as a light yellow oil.

LC-MS (Method C): Rt = 0.722 min; MS (ESI) m/z = 526.3, 528.3 [M+H] ⁺ .

Intermediate 343 tert-butyl 3-[7-(2-methoxy-4, 6-dimethyl-phenyl) -4-methylsulfonyl-1 , 8-naphthyrldin-2- yi]piperidine-1 -carboxylate

To a solution of tert-butyl 3-[4-bromo-7-(2-methoxy-4, 6-dimethyl-phenyl) -1 , 8-naphthyridin-2- yl]piperidine-1 -carboxylate (680 mg, 1.29 mmol, 1.00 eq) in N,N-dimethylacetamide (10 mL) were added cuprous bromide (185 mg, 1.29 mmol, 39.3 pL, 1.00 eq) and sodium;methanesulfinate (263 mg, 2.58 mmol, 2.00 eq) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 5 h. The reaction mixture was filtered and the filter was concentrated. Water(20 mL) was added to the mixture, the mixture was extracted with Ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated brine (20 mL x 2) and the organic layer was dried over anhydrous sodium sulfate. The reaction mixture was concentrated in vacuum. The crude product was purified by silica gel column chromatography (SIOz, Petroleum ether/Ethyl acetate = 1 :0~1 :1) to give tert-butyl 3-[7-(2- methoxy-4, 6-dimethyl-phenyl) -4-methylsulfonyl-1 , 8-naphthyridin-2-yl]piperidine-1-carboxylate (400 mg, 760 pmol, 58 % yield) as light yellow oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 8.99 (d, J = 8.8 Hz, 1 H), 8.12 (s, 1 H), 7.71 (d, J = 8.8 Hz, 1 H), 6.91-6.73 (m, 2H), 3.96 (br d, J = 14.4 Hz, 1 H), 3.67 (s, 3H), 3.55 (s, 3H), 2.96-2.80 (m, 2H), 2.38 (s, 3H), 2.25-2.09 (m, 2H), 2.03 (s, 3H), 1.91-1.79 (m, 2H), 1.63-1.48 (m, 2H), 1.39 ( s, 9H).

Intermediate 344

(2-methoxy-4, S-dimethyl-phenyi) -4-methylsu!fonyl-2-[3-pipendy!]-1, 8-naphthyndine

To a solution of tert-butyl 3-[7-(2-methoxy-4, 6-dimethyl-phenyl) -4-methylsulfonyl-1 , 8-naphthyridin-2- yl]piperidine-1 -carboxylate (400 mg, 760 pmol, 1.00 eq) in Ethyl acetate (10 ml_) was added HCI (4 M in EtOAc, 16.0 mL, 84.1 eq). After stirring at 25 °C for 1 h. The reaction mixture was concentrated in vacuum to afford the 7-(2-methoxy-4, 6-dimethyl-phenyl) -4-methylsulfonyl-2-[3-piperidyl]-1 , 8- naphthyridine (350 mg, crude, HCI salt) as a light yellow solid.

LC-MS (Method C): Rt = 0.464 min; MS (ESI) m/z = 426.3, [M+H] ⁺ .

Intermediate 345

(2-methoxy-4, 6-dimethyhphenyl) -4-methy!su!fonyl-2-[ 1 ~inethyl~3-pipendyl]-1 , 8-naphthyndine

To a solution of 7-(2-methoxy-4, 6-dimethyl-phenyl)-4-methylsulfonyl-2-[3-piperidyl]-1 , 8-naphthyridine (330 mg, 714 pmol, 1.00 eq, HCI salt) in methanol (10 mL) were added formaldehyde (122 mg, 1.43 mmol, 112 pL, 2.00 eq) and potassium acetate (140. mg, 1.43 mmol, 2.00 eq), The reaction mixture was stirred at 25 °C for 0.5 h. Then the Sodium cyanoborohydride (89.7 mg, 1 .43 mmol, 2.00 eq) was added. The reaction mixture was stirred at 25 °C for 2.5 h. The reaction mixture was concentrated in vacuum. Water (20 mL) was added to the mixture, the mixture was extracted with ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated brine (20 mL x 2) and the organic layer was dried over anhydrous sodium sulfate. The reaction mixture was concentrated in vacuum. The mixture was further purification by reverse-phase column (column: C18, 40 g, mobile phase: [water (NHs’HzO) - MeCN];B%: 0% - 80%, 15 min) to give compound 7-(2-methoxy-4, 6-dimethyl- phenyl) -4-methylsulfonyl-2-[1-methyl-3-piperidyl]-1 , 8-naphthyridine (255 mg, 580 pmol, 81 % yield) as a light yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 8.98 (d, J = 8.6 Hz, 1 H), 8.10 (s, 1 H), 7.69 (d, J = 8.6 Hz, 1 H), 6.90-6.73 (m, 2H), 3.66 (s, 3H), 3.54 (s, 3H), 3.06 (br d, J = 11 .6 Hz, 1 H), 2.83-2.75 (m, 1 H), 2.37 (s, 3H), 2.31-2.20 (m, 4H), 2.10-1.99 (m, 4H), 1.99-1.91 (m, 1 H), 1.89 (s, 1 H), 1.81-1.73 (m, 1 H), 1.72-1.59 (m, 2H).

Compound 158

3, 5-dimethyl-2-[5-methylsulfonyl-7-[1 -methyb-3-piperidyl]-1 , 8-naphthyridm-2-yl]phenol To a solution of 7-(2-methoxy-4, 6-dimethyl-phenyl) -4-methylsulfonyl-2-[1-methyl-3-piperidyl]-1 , 8- naphthyridine (210 mg, 477 pmol, 1.00 eq) in dichloromethane (3 mL) was added boron tribromide (359 mg, 1 .43 mmol, 138 pL, 3.00 eq) under -78 °C, Then the reaction mixture was stirred at 20 °C for 2 h. The pH of the reaction mixture was adjusted to 7 with ammonia (7 M in methonai). The mixture was concentrated under reduced pressure to give a residue. The mixture was further purification by reverse-phase coiumn (coiumn: C18, 80 g, mobile phase: [water (NH3*H2O)-MeCN];B%: 0% - 55%, 14 min) to give Compound 3, 5-dimethyl-2-[5-methylsulfonyl-7-[1-methyi-3-piperidyl]-1 , 8-naphthyridin-

2-yi]phenoi (65.0 mg, 141 pmol, 29 % yield) as a light yellow solid. Then the 3, 5-dimethyi-2-[5- methylsulfonyl-7-[1-methyl-3-piperidyl]-1 , 8-naphthyridin-2-yl]phenol (65.0 mg ) was further purification by Prep-SFC (column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10um) ;mobile phase: [CCh-EtOH (0.1 % NH3-H2O) ];B%:40%, isocratic elution mode to afford Compound 158 3, 5-dimethyl-2-[5- methylsulfonyl-7-[1-methyl-3-piperidyl]-1 , 8-naphthyridin-2-yl]phenol (15.7 mg, 36.8 pmol, 24 % yield, 100% purity) as a light yellow solid, and Compound 159 3, 5-dimethyl-2-[5-methylsulfonyl-7-[1-methyl-

3-piperidyl]-1 , 8-naphthyridin-2-yl]phenol (19.5 mg, 45.9 pmol, 30 % yield, 100% purity) as a light yellow solid.

Compound 158

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 8.95 (d, J = 8.8 Hz, 1 H), 8.07 (s, 1 H), 7.76 (d, J = 8.8 Hz, 1 H), 6.62 (br d, J = 16.0 Hz, 2H), 3.53 (s, 3H), 3.07 (br d, J = 11.2 Hz, 1 H), 2.80 (br d, J = 10.4 Hz, 1 H), 2.30 - 2.20 (m, 8H), 2.08 (s, 3H), 2.06-2.00 (m, 1 H), 2.00-1 .91 (m, 1 H), 1 .81 -1 .74 (m, 1 H), 1 .73- 1.59 (m, 2H).

LC-MS (Method C): Rt = 0.443 min; MS (ESI) m/z = 426.3, [M+H] ⁺ . SFC (Rt = 1 .506 min, ee% = 99%).

Enantiomer 2

¹ H NMR (400 MHz, DMSO-d ₅ ) 6 [ppm] = 8.95 (d, J = 8.8 Hz, 1 H), 8.07 (s, 1 H), 7.76 (d, J = 8.8 Hz, 1 H), 6.62 (br d, J = 18.4 Hz, 2H), 3.53 (s, 3H), 3.06 (br d, J = 9.6 Hz, 1 H), 2.79 (br d, J = 10.4 Hz, 1 H), 2.32-2.18 (m, 8H), 2.08 (s, 3H), 2.04 (br d, J = 10.4 Hz, 1 H), 1.98-1.93 (m, 1 H), 1.82-1.74 (m, 1 H), 1.71-1.60 (m, 2H).

LC-MS (Method C): Rt = 0.445 min; MS (ESI) m/z = 426.3, [M+H] ⁺ . SFC (Rt = 2.015 min, ee% = 98%).

Intermediate 346 methyl 2-(5-bromo-3-pyndyl)acetate

To a solution of 2-(5-bromo-3-pyridyl)acetic acid (9.80 g, 45.4 mmol, 1.00 eq) in methanol (100 mL) was added dropwise thionyl chloride (16.4 g, 138 mmol, 10.0 mL, 3.04 eq) at 0 °C. After stirring at 70 °C for 1 h, the reaction mixture was cooled to 0 °C. The pH was adjusted to 7-8 with hydrogen chloride (1 M in water). The reaction mixture was stirred at 0 °C for 0.5 h. The mixture was concentrated in vacuum to remove organic phase. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give methyl 2-(5-bromo-3-pyridyl)acetate (10.0 g, 43.5 mmol, 96% yield) as a red oil.

Intermediate 347 methyl 2-(5-acetyl-3-pyiidyl)acetate

To a solution of methyl 2-(5-bromo-3-pyrldyl)acetate (6.50 g, 28.3 mmol, 1 .00 eq) in 1 ,4-dioxane (100 mL) were added bis(triphenylphosphine)palladium(ll) chloride (1 .98 g, 2.83 mmol, 0.10 eq) and tributyl(1-ethoxyvinyl)stannane (15.3 g, 42.4 mmol, 14.3 mL, 1 .50 eq) at 25 °C under nitrogen atmosphere. After stirring at 90 °C for 12 h, the reaction mixture was cooled to 25 °C. The reaction mixture was diluted with hydrogen chloride (5.0 M in water, 40 mL). After stirring for 1 h at 25 °C, the pH of mixture was adjusted to 8-9 with saturated sodium bicarbonate at 0 °C. The reaction mixture was extracted with ethyl acetate (80 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiOz, petroleum ether/ethyl acetate = 100/0 to 1/1) to give methyl 2-(5- acetyl-3-pyridyl)acetate (4.00 g, 20.7 mmol, 73% yield) as a yellow oil.

¹ H NMR (400 MHz, CDCh) <5 [ppm] = 9.06 (s, 1 H), 8.68 (s, 1 H), 8.15 (s, 1 H), 3.71 (s, 3H), 3.70 (s, 2H), 2.63 (s, 3H).

LC-MS (Method C): Rt = 0.343 min; MS (ESI) m/z = 194.0 [M+H] ⁺ .

Intermediate 348 methyl 2-[5-( 1-hydroxyethyl)-3-plperidy!]acetate

To a solution of methyl 2-(5-acetyl-3-pyridyl)acetate (4.00 g, 20.7 mmol, 1.00 eq) in methanol (40.0 mL) was added dropwise acetic acid (12.4 g, 207 mmol, 11 .9 mL, 10.0 eq) and platinum dioxide (470 mg, 2.07 mmol, 0.10 eq) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen for 3 times. After stirring for 60 h under hydrogen atmosphere (50 Psi) at 80 °C, the mixture was filtered under reduced pressure. The filtrate was concentrated in vacuum to give methyl 2-[5-(1- hydroxyethyl)-3-piperidyl] acetate (5.41 g, 20.7 mmol, 100% yield, acetate) as a faint yellow oil.

Intermediate 349

2,4-dichloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1,8-naphth yridme

To a solution of methyl 2-[5-(1-hydroxyethyl)-3-piperidyl]acetate (5.41 g, 20.7 mmol, 1.00 eq, acetate) in tetrahydrofuran (50.0 mL) and water (50.0 mL) were added sodium carbonate (6.58 g, 62.1 mmol, 3.00 eq) and benzyl (2,5-dioxopyrrolidin-1 -yl) carbonate (6.71 g, 26.9 mmol, 1.30 eq) at 20 °C. After stirring at 20 °C for 3 h, the mixture was added into water (50 mL) at 0 °C. The mixture was extracted with ethyl acetate (80 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/0 to 1/1) to give benzyl 3-(1- hydroxyethyl)-5-(2-methoxy-2-oxo-ethyl)piperidine-1-carboxyl ate (5.74 g, 17.1 mmol, 82.7% yield) as a colorless oil.

LC-MS (Method C): Rt = 0.886 min; MS (ESI) m/z = 336.2 [M+H] ⁺ .

Intermediate 350 benzyl 3-acetyl-5-(2-methoxy-2-oxo-ethyl)piperldme-1 -carboxylate To a solution of benzyl 3-(1 -hydroxyethyl)-5-(2-methoxy-2-oxo-ethyl)piperidine-1 -carboxylate (5.74 g, 17.1 mmol, 1.00 eq) in dichioromethane (100 mL) were added Dess-Martin periodinane (10.9 g, 25.7 mmol, 8.00 mL, 1.50 eq) and sodium bicarbonate (2.16 g, 25. 7 mmol, 1.50 eq) at 0 °C. After stirring for 12 h at 25 °C, the mixture was added into saturated sodium sulfite (60 mL) at 0 °C. After stirring for 30 min at 25 °C, the mixture was extracted with ethyl acetate (60 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether/ethyl acetate = 100/0 to 1/1) to give benzyl 3-acetyl-5-(2-methoxy-2-oxo-ethyl)piperidine-1 -carboxylate (5.20 g, 15.6 mmol, 91 % yield) as a colorless oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 7.40-7.32 (m, 5H), 5.12-5.01 (m, 2H), 4.18-4.00 (m, 1 H), 3.60 (s, 3H), 3.55 (br. s, 1 H), 3.33 (s, 1 H), 2.73-2.50 (m, 1 H), 2.34-2.25 (m, 2H), 2.12-2.03 (m, 4H), 1.91-1.83 (m, 1 H), 1.58-1.45 (m, 0.5H), 1.16-1.06 (m, 0.5H).

LC-MS (Method C): Rt = 0.905 min; MS (ESI) m/z = 334.2 [M+H] ⁺ .

Intermediate 351

2-[1-benzyloxycarbonyl-5-[7-(2-methoxy-4,6-dimethyl-pheny l)-1,8-naphthyridin-2-yl]-3- piperidyljacetic acid Intermediate 352 benzyl 3-[7~(2-methoxy-4,8-dimethyl-phenyl)-1,8-naphthyridin-2-yl]- 5-(2-fnethoxy-2-oxo- ethyl)piperidine-1 -carboxylate

To a solution of benzyl 3-acetyl-5-(2-methoxy-2-oxo-ethyl)piperidine-1-carboxylate (2.65 g, 7.95 mmol, 1.00 eq) and 2-amino-6-(2-methoxy-4,6-dimethyl-phenyl)pyridine-3-carbalde hyde (2.04 g, 7,95 mmol, 1 .00 eq) in methanol (40 mL) was added sodium methylate (5.73 g, 31 .8 mmol, 30% purity in methanol, 4.00 eq) at 0 °C. After stirring at 60 °C for 5 h, the pH was adjusted to 6-7 with hydrogen chhloride (1 M in water). The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by reversed-phase (column: C18, 330 g, mobile phase: [water (FA) - MeCN];B%: 20% - 70%, 18 min) to give Intermediate 351 2-[1-benzyloxycarbonyl-5-[7-(2-methoxy-4,6-dimethyl- phenyl)-1 ,8-naphthyridin-2-yl]-3-piperidyl]acetic acid (2.60 g, 4.82 mmol, 61 % yield) as a yellow solid, and Intermediate 352 benzyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-5-(2-methoxy-2-oxo- ethyl)piperidine-1 -carboxylate (420 mg, 758 pmol, 9.54% yield) as a yellow solid.

LC-MS (Method C): Rt = 0.541 min; MS (ESI) m/z = 540.3 [M+H] ⁺ and Ri = 0.574 min; MS (ESI) m/z = 554.3 [M+H] ⁺ .

Intermediate 353

To a solution of 2-[1-benzyloxycarbonyl-5-[7-(2-methoxy-4,6-dimethyl-phenyl)- 1 ,8-naphthyridin-2-yl]-3- piperidyl]acetic acid (2.60 g, 4.82 mmol, 1 .00 eq) in methanol (30 mL) was added (trimethylsilyl) diazomethane solution (2.00 M in hexanes, 9.64 mL, 4.00 eq) at 0 °C. After stirring at 25 °C for 1 h, the mixture was quenched by hydrogen chloride (1 .00 M in water) up to pH = 4-5 at 0 °C. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layer were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether/ethyl acetate = 10/0 to 1/1) to give benzyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-5-(2-methoxy-2-oxo-ethyl)piperidine-1- carboxylate (1 .20 g, 2.17 mmol, 45% yield) as a yellow solid.

LC-MS (Method C): Rt = 0.565 min; MS (ESI) m/z = 554.3 [M+H] ⁺ . intermediate 354 methyl 2-[5-[7-(2-methoxy-4.6-dlmethyl-phenyl)-1,8-naphthyndln-2-yl ]-3-piperidyl]acetate

To a solution of benzyl 3-[7-(2-methoxy-4,6-dimethyi-phenyi)-1 ,8-naphthyridin-2-yi]-5-(2-methoxy-2- oxo-ethyl) piperidine- 1 -carboxylate (1.62 g, 2.93 mmol, 1.00 eq) in acetonitrile (25.0 mL) was added iodotrimethylsilane (1 .76 g, 8.78 mmol, 1.19 mL, 3.00 eq) at 0 °C. After stirring for 1 h at 25 °C, triethyiamine (888 mg, 8.78 mmol, 1 .22 mL, 3.00 eq) was added into the reaction mixture at 0 °C. The mixture was continued to stir at 25 °C for 1 h. The mixture was added into water (10 mL) at 0 °C. The mixture was extracted with ethyl acetate (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl 2-[5-[7-(2-methoxy- 4,6-dimethyi-phenyi)-1 ,8-naphthyridin-2-yl]-3-piperidyi]acetate (1.20 g, 2.86 mmol, 98% yield) as a yellow solid.

LC-MS (Method C): Rt = 0.443 min; MS (ESI) m/z = 420.2 [M+H] ⁺ . intermediate 355 methyl 2-[5-[7-(2-methoxy-4,6-dimethyl-phenyl)-1,8-naphthyndm-2-yl] -1-methyl-3- piperidyl]acetate

To a solution of methyl 2-[5-[7-(2-methoxy-4,6-dimethyi-phenyi)-1 ,8-naphthyridin-2-yi]-3- piperidyljacetate (1 .20 g, 2.86 mmol, 1 .00 eq) in methanol (20 mL) were added formaldehyde (696 mg, 8.58 mmol, 639 pL, 37% purity in water, 3.00 eq) and potassium acetate (562 mg, 5.72 mmol, 2.00 eq) at 0 °C. Sodium cyanoborohydride (539 mg, 8.58 mmol, 3.00 eq) was added to the mixture at 0 °C. After stirring for 1 h at 25 °C, the mixture was added into saturated ammonium chloride (15 mL) at 0 °C. The pH was adjusted to 8-9 with saturated sodium bicarbonate at 0 °C. Then the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase (column: C18, 330 g, mobile phase: [water (NH3 H2O) - MeCN];B%: 20% - 90%, 40 min) to give methyl 2-[5-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-methyl- 3-piperidyi]acetate (735 mg, 1.70 mmol, 59% yield) as a yellow oil.

¹ H NMR (400 MHz, CDCh) 5 [ppm] = 8.15 (d, J = 5.2 Hz, 1 H), 8.13 (d, J = 5.6 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.41 (d, J = 8.0 Hz, 1 H) , 6.73 (s, 1 H), 6.65 (s, 1 H), 3.68 (s, 3H), 3.67 (s, 3H), 3.39-3.31 (m, 1 H), 3.23-3.20 (m, 1 H), 2.99 (d, J = 10.0 Hz, 1 H), 2.49-2.43 (m, 1 H), 2.38 (s, 6H), 2.30 (d, J = 6.8 Hz, 2H), 2.19-2.13 (m, 5H), 1.83-1 .78 (m, 1 H), 1.70-1.61 (m, 1 H), 0.90-0.84 (m, 2H).

LC-MS (Method C): Rt = 0.486 min; MS (ESI) m/z = 434.3 [M+HJ*. Intermediate 356 methyl 2-[5-[7-(2-hydroxy-4,§-dimethyi-phenyl)-1,8-naphthyndin-2-y l]-1-methyi-3- piperidyl]acetate

To a solution of methyl 2-[5-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-methyl-3- piperidyl]acetate (635 mg, 1.46 mmol, 1.00 eq) in dichloromethane (10 mL) was added boron tribromide (1.10 g, 4.39 mmol, 423 pL, 3.00 eq) at -70 °C. After stirring for 1 h at 0 °C, the mixture was added into water (10 mL) at 0 °C. The pH was adjusted to 7-8 with saturated sodium bicarbonate at 0 °C. The mixture was extracted with dichloromethane (15 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was combined with EW38703-286. The mixture was purified by reversed-phase (column: C18, 80 g, mobile phase: [water (FA) - MeCN];B%: 10% - 50%, 10 min) and concentrated to give methyl 2-[5-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-methyl-3-piperidyl]acetate (300 mg, 715 pmol, 49% yield) as a yellow solid.

LC-MS (Method C): Rt = 0.781 min; MS (ESI) m/z = 420.2 [M+H] ⁺ .

Intermediate 357

2-[5-[7-(2-hydroxy-4, 6-dimethyl-phenyl) -1, 8-naphthyndin-2-yl]-1-methyl-3-pipendyl]acetic acid To a solution of methyl 2-[5-[7-(2-hydroxy-4, 6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-methyl-3- piperidyljacetate (350 mg, 834 pmol, 1 .00 eq) in methanol (10 mL) and water (8 mL) was added lithium hydroxide (39.9 mg, 1 .67 mmol, 2.00 eq) under 0 °C. After stirring at 20 °C for 1 h, the reaction mixture was concentrated in vacuum. The mixture was further purification by reverse-phase column (column: C18, 40 g, mobile phase: [water (NK-H-hQ) - MeCN];B%: 0% - 20%, 8 min) to give 2-[5-[7- (2-hydroxy-4, 6-dimethyl-phenyl) -1 , 8-naphthyridin-2-yl]-1-methyl-3-piperidyl]acetic acid (280 mg, 690 pmol, 82 % yield) as a light yellow solid.

LC-MS (Method C): Rt = 0.481 min; MS (ESI) m/z = 406.3 [M+H] ⁺ .

Compound 160 and 161 2-[5-[7-(2-hydroxy-4, 6-dimethyl-phenyl) -1, 8-naphthyridin-2-yl]-1-methyl-3-piperidyl]acetic acid The reaction was set up for SFC separation. The residue was separated by SFC: (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10um) ;mobile phase: [CO ₂ -MeCN/MeOH (0.1% NH3*H2O)];B%:50%, isocratic elution mode) to give Compound 160 2-[5-[7-(2-hydroxy-4, 6-dimethyl- phenyl) -1 , 8-naphthyridin-2-yl]-1 -methyl-3-piperidyl]acetic acid (83.8 mg, 206 pmol, 24.6 % yield, 100% purity) as a light yellow solid, and Compound 161 2-[5-[7-(2-hydroxy-4, 6-dimethyl-phenyl)-1 ,8- naphthyridin-2-yl]-1 -methyl-3-piperidyl]acetic acid (129 mg, 318 pmol, 37 % yield, 100% purity) as a light yellow solid.

Compound 160 ¹ H NMR (400 MHz, DMSO- d ₆ ) 6 [ppm] = 10.73-9.12 (m, 1 H), 8.39 (dd, J = 8.4 Hz, 2H), 7.57 (dd, J = 16.4 Hz, 2H), 6.63 (d, J = 11.6 Hz, 2H), 3.24-3.17 (m, 1 H), 3.06 (brd, J = 10.4 Hz, 1 H), 2.89 (br d, J = 10.4 Hz, 1 H), 2.26 (s, 3H), 2.23 (s, 3H), 2.18-2.01 (m, 8H), 1.60 (brt, J = 10.4 Hz, 1 H), 1.34 (q, J =

11.6 Hz, 1 H).

LC-MS (Method C): Rt = 0.407 min; MS (ESI) m/z = 406.4 [M+H] ⁺ .

Compound 161 ¹ H NMR (400 MHz, DMSO- d ₆ ) 6 [ppm] = 10.94-9.17 (m, 1 H), 8.38 (dd, J = 8.4 Hz, 2H), 7.56 (dd, J = 13.2 Hz, 2H), 6.63 (d, J = 17.2 Hz, 2H), 3.22-3.15 (m, 1 H), 3.05 (br d, J = 10.4 Hz, 1 H), 2.90 (d, J =

9.6 Hz, 1 H), 2.26 (s, 3H), 2.22 (s, 3H), 2.15-2.01 (m, 8H), 1.57 (brt, J = 10.4 Hz, 1 H), 1.37-1.24 (m, 1 H).

LC-MS (Method C): R _t = 0.413 min; MS (ESI) m/z = 406.4 [M+H] ⁺ .

Intermediate 358 methyl 2-amino-6-(2-methoxy-4, 6-dimethyl-phenyl) pyridine-3-carboxylate

To a solution of methyl 2-amino-6-chloro-pyridine-3-carboxylate (2.00 g, 10.7 mmol, 1.00 eq) in dioxane (20 mL) were added (2-methoxy-4, 6-dimethyl-phenyl) boronic acid (1.97 g, 10.9 mmol, 1.02 eq), Methanesulfonato(2-dicyclohexylphosphino-2,4,6-tri-i-propyl- 1 ,1-biphenyl)(2-amino-1 , 1 -biphenyl-

2-yl)palladium(ll) (907 mg, 1.07 mmol, 0.10 eq) and potassium phosphate anhydrous (6.83 g, 32.2 mmol, 3.00 eq) under nitrogen atmosphere. After stirring at 60 °C for 16 h, the reaction mixture was filtered and the filter was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (SiCh, Petroleum ether/Ethyl acetate = 1/0 to 4/1) to afford the methyl 2-amino-6-(2-methoxy-4, 6-dimethyl-phenyl) pyridine-3-carboxylate (1.50 g, 5.24 mmol, 49% yield) as a light yellow solid.

Intermediate 359 methyl 6-(2-methoxy-4, 6-dimethyl-phenyl) -2-[[1-tert-butoxycarbonylpiperidine-3- carbonyl]amino]pyridine-3-carboxyiate

To a solution of 1-tert-butoxycarbonylpiperidine-3-carboxylic acid (1 .73 g, 7.54 mmol, 1 .20 eq) in Pyridine (30 mL) were added methyl 2-amino-6-(2-methoxy-4, 6-dimethyl-phenyl) pyridine-3- carboxylate (1 .80 g, 6.29 mmol, 1 .00 eq) and phosphorus oxychloride (1 .93 g, 12.6 mmol, 1 .17 mL, 2.00 eq). After stirring at 20 °C for 3 h, water (10 mL). was added to the mixture, the mixture was extracted with Ethyl acetate (50 mL x 2), the combined organic phase was washed with saturated brine (50 mL) and the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated in vacuum to afford the residue The residue was purified by silica gel column chromatography (SiCh, Petroleum ether/Ethyl acetate = 1/0 to 2/1) to afford the methyl 6-(2-methoxy-4, 6-dimethyl-phenyl) -2- [[1-tert-butoxycarbonylpiperidine-3-carbonyl]amino]pyridine- 3-carboxylate (700 mg, 1.41 mmol, 22 % yield) as a light yellow solid.

Intermediate 360 To a solution of methyl 6-(2-methoxy-4, 6-dimethyl-phenyl) -2-[[1-tert-butoxycarbonylpiperidine-3- carbonyl]amino]pyridine-3-carboxylate (1 .10 g, 2.21 mmol, 1 eq) in methanol (5 mL) was added ammonia (7 M in methanol, 22 mL, 69.7 eq). After stirring at 20 °C for 16 h, the reaction mixture was concentrated in vacuum to afford the residue ,The residue was purified by reverse-phase column (column: C18, 40 g, mobile phase: [water (NHs'HzO) - MeCN];B%: 0%-55, 8 min) to afford tert-butyl 3- [7-(2-methoxy-4, 6-dimethyl-phenyl) -4-oxo-3H-pyrido[2, 3-d]pyrimidin-2-yl]piperidine-1 -carboxylate (480 mg, 1 .03 mmol, 46 % yield) as a light yellow solid.

¹ H NMR (400 MHz, DMSO- d6) 6 [ppm] = 12.51-12.49 (m, 1 H), 8.46 (d, J = 8.0 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 6.87-6.72 (m, 2H), 3.83 (s, 2H), 3.64 (s, 3H), 3.17 (d, J = 5.2 Hz, 1 H), 2.98-2.82 (m, 1 H), 2.79-2.69 (m, 1 H), 2.35 (s, 3H), 2.31 (s, 1 H), 2.14-2.03 (m, 1 H), 1.97 (s, 3H), 1.90-1.72 (m, 2H), 1.46- 1.38 (m, 9H).

Intermediate 361

7-(2-methoxy-4, 6-dimethyl-phenyl) -2-[3-piperidyi]-3H-pyrido[2, 3-d]pyrimidin-4-one

To a solution of tert-butyl 3- [7- (2- meth oxy-4, 6-dimethyl-phenyl) -4-oxo-3H-pyrido[2, 3-d]pyrimidin-2- yl]piperidine-1 -carboxylate (480 mg, 1 .03 mmol, 1 .00 eq) in methanol (5 mL) was added HCI (4 M in MeOH, 2 mL, 10.0 eq). After stirring at 20 °C for 1 h, the reaction mixture was concentrated in vacuum.to afford the 7- (2- meth oxy-4, 6-dimethyl-phenyl) -2-[3-piperidyl]-3H-pyrido[2, 3-d]pyrimidin-4- one (414 mg, crude, HCI salt) as a light yellow solid.

LC-MS (Method C): Rt = 0.498 min; MS (ESI) m/z = 365.2 [M+H] ⁺ .

Intermediate 362

7-(2-methoxy-4, 6-dimethyl-phenyl) -2-[ 1-methyl-3-piperidyl]-3H-pyrido[2, 3-d]pyrimidin-4-one To a solution of 7-(2-methoxy-4, 6-dimethyl-phenyl) -2-[3-piperidyl]-3H-pyrido[2, 3-d]pyrimidin-4-one (414 mg, 1.03 mmol, 1.00 eq, HCI salt) in methanol (10 mL) was added potassium acetate (304 mg, 3.10 mmol, 3.00 eq) and paraformaldehyde (93.0 mg, 3.10 mmol, 85.3 pL, 3.00 eq). The reaction mixture was stirred at 20 °C for 0.5 h. Then sodium cyanoborohydride (129.8 mg, 2.07 mmol, 2.00 eq) was added. After stirring at 20 °C for 1 .5 h. The reaction mixture was concentrated in vacuum. The mixture was further purification by reverse-phase column (column: Cis, 40 g, mobile phase: [water (NH3"H2O) - MeCN];B%: 0% - 40%, 12 min) to afford the 7-(2-methoxy-4, 6-dimethyl-phenyl) -2-[rac- (3R) -1-methyl-3-piperidyl]-3H-pyrido[2, 3-d]pyrimidin-4-one (240 mg, 634 pmol, 61 % yield) as a light yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 6[ppm]= 12.74-11.99 (m, 1 H), 8.47-8.37 (m, 1 H), 7.39-7.27 (m, 1 H), 6.84-6.65 (m, 2H), 3.63 (s, 3H), 3.16 (s, 1 H), 3.01-2.80 (m, 2H), 2.77-2.65 (m, 1 H), 2.34 (s, 3H), 2.23- 2.14 (m, 3H), 1.96 (s, 5H), 1.71 (br s, 1 H), 1.57-1.41 (m, 2H).

Intermediate 363

7-(2-hydroxy-4, 6-dimethyl-pheny!) -2-[ 1-methyl-3-piperidyl]-3H-pyddo[2, 3-d]pyrimidm-4-one To a solution of 7-(2-methoxy-4, 6-dimethyl-phenyl) -2-[1-methyl-3-piperidyl]-3H-pyrido[2, 3- d]pyrimidin-4-one (240 mg, 634 pmol, 1.00 eq) in dichloromethane (10 mL) was added boron tribromide (477 mg, 1 .90 mmol, 183 pL, 3.00 eq) under -78 °C. The reaction mixture was stirred at 20 °C for 3 h. The pH of the reaction mixture was adjusted to 7 with ammonia (7 M in methanol). The mixture was concentrated under reduced pressure to give a residue. The mixture was further purification by reverse-phase column (column: Cw, 40 g, mobile phase: [water (NHaH-TQ) - MeCN];B%: 0% - 35%, 12 min) to give 7-(2-hydroxy-4, 6-dimethyl-phenyl) -2-[rac-(3R) -1-methyl-3- piperidyi]-3H-pyrido[2, 3-d]pyrimidin-4-one (110 mg, 302 pmol, 47.6% yield) as a light yellow solid. LC-MS (Method C): R _t = 0.408 min; MS (ESI) m/z = 365.3 [M+H] ⁺

Compound 162 and 163

7-(2~hydroxy-4, 6-dimethyl-phenyl) -2-[ 1-methyi-3-piperidyl]-3H-pyrido[2, 3-d]pynmidin-4-one The reaction was set up for SFC separation. The residue was separated by SFC: (column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10um) ;mobile phase: [CO ₂ -EtOH (0.1 % NH ₃ »H ₂ O) ];B%:30%, isocratic elution mode) to give Compound 162 7-(2-hydroxy-4, 6-dimethyl-phenyl) -2-[1-methyl-3- piperidyl]-3H-pyrido[2, 3-d]pyrimidin-4-one (36.4 mg, 99.8 pmol, 33 % yield, 100% purity) as a light yellow solid, and Compound 163 7-(2-hydroxy-4, 6-dimethyl-phenyl) -2-[1-methyl-3-piperidyl]-3H- pyrido[2, 3-d]pyrimidin-4-one (53.8 mg, 148 pmol, 48.9% yield, 100% purity) as a light yellow solid. Compound 162

¹ H NMR (400 MHz, DMSO- d6) 0 [ppm] = 11 .33-9.93 (m, 1 H), 8.35 (d, J = 8.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 6.59 (d, J = 7.2 Hz, 2H), 2.94 (d, J = 11.6 Hz, 1 H), 2.80-2.70 (m, 2H), 2.24 (s, 3H), 2.19 (s, 3H), 2.13 (s, 4H), 1 .96-1 .83 (m, 2H), 1 .76-1 .67 (m, 1 H), 1 .60-1 .47 (m, 2H).

LC-MS (Method C): Rt = 0.412 min; MS (ESI) m/z = 365.3 [M+H] ⁺ .

SFC (Rt = 1.513 min, ee% = 99%).

Compound 163

¹ H NMR (400 MHz, DMSO- d ₆ ) 6 [ppm] = 11 .51-10.03 (m, 1 H), 8.35 (d, J = 8.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 6.59 (d, J = 8.0 Hz, 2H), 2.95 (br d, J = 10.4 Hz, 1 H), 2.79-2.69 (m, 2H), 2.24 (s, 3H), 2.19 (s, 3H), 2.18-2.10 (m, 4H), 1.97-1.83 (m, 2H), 1.75-1.67 (m, 1 H), 1.61-1.45 (m, 2H).

LC-MS (Method C): Rt = 0.408 min; MS (ESI) m/z = 365.4 [M+H] ⁺ .

SFC (Rt = 1 .829 min, ee% = 98%).

Intermediate 364 methyl 3-chioro-5-(2-methoxy-4„6-dimethyl-phenyl)pyrazine-2-carbo xylate

A mixture of methyl 3,5-dichloropyrazine-2-carboxylate (4.35 g, 21 .01 mmol, 1 .00 eq) and (2- methoxy-4,6-dimethyl-phenyl)boronic acid (3.78 g, 21.0 mmol, 1.00 eq), [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (1.54 g, 2.10 mmol, 0.10 eq), potassium phosphate(5.81 g, 42.0 mmol, 2.00 eq) in dioxane (40 mL) and H ₂ O (4 mL) was degassed and purged with N ₂ for 3 times. After stirring at 90 °C for 12 h under N ₂ atmosphere, the mixture was filtered and concentrated to afford the residue, the residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 8/1) to afford the methyl 3-chloro-5-(2-methoxy-4,6-dimethyl- phenyl)pyrazine-2-carboxylate (2.80 g, 9.13 mmol, 21 % yield) as a white solid. LC-MS (Method C): Rt = 0.602 min; MS (ESI) m/z = 307.2 [M+H] ⁺ .

Intermediate 365 methyl 3-(tert-butoxycarbonylamino)-5-(2-methoxy-4, 6-dimethyl-phenyl)pyrazme-2- carboxylate

A mixture of methyl 3-chloro-5-(2-methoxy-4,6-dimethyl-phenyl)pyrazine-2-carboxy late (3.40 g, 11.0 mmol, 1 .00 eq), tert-butyl carbamate (2.60 g, 22.1 mmol, 2.00 eq), dicyclohexyl-[2-(2,6- diisopropoxyphenyl)phenyl]phosphane(1 .03 g, 2.22 mmol, 0.20 eq), [2-(2-aminophenyl)phenyl]- methylsulfonyloxy-palladium;dicyclohexyl-[2-(2,6-diisopropox yphenyl)phenyl]phosphane (927 mg, 1 .11 mmol, 0.10 eq) and cesium carbonate (7.22 g, 22.1 mmol, 2.00 eq) in dioxane (30 mL) was degassed and purged with N2 for 3 times. After stirring at 90 °C for 12 h under N2, the mixture was filtered and concentrated to afford the methyl 3-(tert-butoxycarbonylamino)-5-(2-methoxy-4, 6- dimethyl-phenyl)pyrazine-2-carboxylate (10.0 g, crude) as yellow oil.

Intermediate 366 tert-butyl 3-[7-(2-methoxy-4, 6-dimethyl-phenyl) -4-oxo-3H-pyrido[2. 3-d)pyrimidin-2- yl]piperidine-1 -carboxylate

The methyl 3-(tert-butoxycarbonylamino) -5-(2-methoxy-4, 6-dimethyl-phenyl) pyrazine-2-carboxylate (10.0 g, 2.58 mmol, 1 .00 eq) was dissolved in methanol (10 mL), then HCi (4 M in methanol, 24 mL, 37.3 eq) was added to the mixture, After stirring at 20 °C for 12 h. The mixture was concentrated to afford the residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(FA) - MeCN];B%: 20% - 50%, 8 min) to afford the methyl 3-amino-5-(2-methoxy-4, 6- dimethyl-phenyl) pyrazine-2-carboxylate (420 mg, 1.34 mmol, 52% yield, 92% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₅ ) 6 [ppm] = 7.79 (s, 1 H), 7.35 (s, 2H), 6.79 (s, 1 H), 6.73 (s, 1 H), 3.86 (s, 3H), 3.67 (s, 3H), 2.32 (s, 3H), 2.03 (s, 3H).

Intermediate 367 methyl 5-(2-methoxy-4, 6-dimethyl-phenyl) -3-[[1-tert-butoxycarbonylpiperidine-3- carbonyl]amino]pyrazine-2-carboxylate

To a solution of 1-tert-butoxycarbonylpiperidine-3-carboxylic acid (402 mg, 1 .75 mmol, 1 .20 eq) in pyridine (5 mL) was added methyl 3-amino-5-(2-methoxy-4, 6-dimethyl-phenyl) pyrazine-2- carboxylate (420 mg, 1.46 mmol, 1 .00 eq) and phosphorus oxychloride (224 mg, 1.46 mmol, 136 pL, 1 .00 eq). After stirring at 20 °C for 3 h, water (50 mL) was added to the mixture, then extracted with ethyl acetate (50 mL x 3), the combined organic layers was washed with saturated brine (20 mL x 2) and the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated in vacuum to afford residue. The crude product was purified by silica gel column chromatography (S1O ₂ , petroleum ether/ethyl acetate = 1/0 to 4/1) to afford methyl 5-(2-methoxy-4, 6-dimethyl-phenyl) -3-[[rac-(3R) -1- tert-butoxycarbonylpiperidine-3-carbonyl]amino]pyrazine-2-ca rboxylate (650 mg, 1.30 mmol, 89% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm]= 11.05 (s, 1 H), 8.42 (s, 1 H), 6.90-6.69 (m, 2H), 3.97 (s, 2H), 3.78 (s, 3H), 3.69 (s, 3H), 2.80-2.69 (m, 1 H), 2.59 (It, J = 3.6, 10.8 Hz, 1 H), 2.35 (s, 3H), 2.05 (s, 3H),

I .97-1 .90 (m, 2H), 1 .74-1 .67 (m, 1 H), 1 .59 (br d, J = 12.4 Hz, 1 H), 1 .40 (s, 9H), 1 .36-1 .30 (m, 1 H).

Intermediate 368

7-(2-methoxy-4, 6-dimethyl-phenyl) -2-[1-methyl-3-piperidyl]-3H-pyrido[2, 3-d]pyrimidin-4-one To a solution of methyl 5-(2-methoxy-4, 6-dimethyl-phenyl) -3-[[1-tert-butoxycarbonylpiperidine-3- carbonyl]amino]pyrazine-2-carboxylate (650 mg, 1.30 mmol, 1.00 eq) in methanol (5 mL) was added ammonia (7 M in methanol, 13 mL, 70.0 eq). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated in vacuum to afford tert-butyl 3-[7-(2-methoxy-4, 6-dimethyl- phenyl) -4-oxo-3H-pteridin-2-yl]piperidine-1 -carboxylate (600 mg, crude) as a light yellow solid. LC-MS (Method C): Rt = 0.570 min; MS (ESI) m/z = 466.3 [M+H] ⁺ .

Intermediate 369

7-(2-methoxy-4, 6-dimethyl-phenyl) -2-[3-pipendyi]-3H-pteridin-4-one

To a solution of tert-butyl 3- [7- (2- meth oxy-4, 6-dimethyl-phenyl) -4-oxo-3H-pteridin-2-yl]piperidine-1- carboxylate (600 mg, 1 .29 mmol, 1 .00 eq) in methanol (10 mL) was added hydrogen chloride (4 M in methanol, 6 mL, 20.0 eq). The reaction mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated in vacuum to afford 7- (2- meth oxy-4, 6-dimethyl-phenyl) -2-[3-piperidyl]-3H-pteridin- 4-one (510 mg, crude, HCI salt) as a light yellow solid.

Intermediate 370

7-(2-methoxy-4, 6-dimethyl-phenyl) -2-[ 1-methyl-3-piperidyl]-3H-pteridin-4-one

To a solution of 7-(2-methoxy-4, 6-dimethyl-phenyi) -2-[3-piperidyi]-3H-pteridin-4-one (510 mg, 1.27 mmol, 1 eq, HCI salt, EW45058-69) in methanol (20 mL) was added potassium acetate (374 mg, 3.81 mmol, 3.00 eq) and formaldehyde (272 mg, 2.54 mmol, 249 pL, 28% purity, 2.00 eq). The reaction mixture was stirred at 20 °C for 0.5 h, sodium cyanoborohydride (160 mg, 2.54 mmol, 2.00 eq), was added. The reaction mixture was stirred at 20 °C for 1 .5 h. The mixture was concentrated in vacuum. The mixture was further purification by reverse-phase column (column: Cis, 40 g, mobile phase: [water (NH3«H2O)-MeCN];B%: 0% - 26%, 12 min) to give 7-(2-methoxy-4, 6-dimethyl-phenyl) -2-[1- methyl-3-piperidyl]-3H-pteridin-4-one (330 mg, 870 pmol, 68 % yield) as a light yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 6[ppm] = 8.61 (s, 1 H), 6.93-6.72 (m, 2H), 3.68 (s, 3H), 2.95 (br d, J =

I I .6 Hz, 1 H), 2.90-2.83 (m, 1 H), 2.72 (br d, J = 10.4 Hz, 1 H), 2.36 (s, 3H), 2.20 (s, 4H), 2.05 (s, 3H), 2.01-1.87 (m, 2H), 1.79-1.67 (m, 1 H), 1.60-1.46 (m, 2H).

Intermediate 371

7-(2-hydroxy-4, 6-dimethyl-pheny!) -2-[ 1-methy!-3-piperidyl]-3H-pyrido[2, 3-d]pyrimidm-4-one To a solution of 7-(2-methoxy-4, 6-dimethyi-phenyl) -2-[1-methyi-3-piperidyl]-3H-pteridin-4-one (330 mg, 870 pmol, 1.00 eq) in dichioromethane (5 mL) was added boron tribromide (654 mg, 2.61 mmol, 251 pL, 3.00 eq) under -78 °C. Then the mixture warmed to 20 °C and stirred at 20 °C for 2 h. The pH of mixture was adjusted to 7 by ammonia (7 M in methanol), concentrated under reduced pressure to give a residue, the residue was further purification by reverse-phase column (column: C18, 40 g, mobile phase: [water (NHH-hO) - MeCN];B%: 0% - 20%, 12 min) to give 7-(2-hydroxy-4, 6-dimethyl- phenyi) -2-[1-methyl-3-piperidyl]-3H-pteridin-4-one (200 mg, 547 pmol, 62 % yield) as a light yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) b[ppm] = 12.92-12.06 (m, 1 H), 9.90-9.43 (m, 1 H), 8.71 (s, 1 H), 6.64 (d, J = 2.4 Hz, 2H), 2.98-2.87 (m, 2H), 2.72 (d, J = 9.6 Hz, 1 H), 2.26 (s, 4H), 2.21 (s, 3H), 2.08 (s, 3H), 2.01-1.92 (m, 2H), 1.77-1.69 (m, 1 H), 1.59-1.51 (m, 2H).

Compound 164 and 165

7-(2-hydroxy-4, 6-dimethyl-phenyl) -2-[ 1 -methyl-3-pipendyl]-3H-pyndo[2, 3-d]pyi'imidin-4-oiie The reaction was set up for SFC separation. The residue was separated by SFC: (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10um) ;mobile phase: [CCh-ACN/i-PrOH (0.1 % NH ₃ ’H ₂ O) ];B%:45%, isocratic elution mode) to afford Compound 164 7- (2- hydroxy-4, 6-dimethyl-phenyl)-2-[1- methyl-3-piperidyl]-3H-pteridin-4-one(78.4 mg, 215 pmol, 39% yield) as a light yellow solid, and Compound 165 7-(2-hydroxy-4, 6-dimethyl-phenyl)-2-[1 -methyl-3-piperidyl]-3H-pteridin-4-one (88.3 mg, 242 pmol, 44% yield) as a light yellow solid.

Compound 164

NMR (400 MHz, DMSO-cf ₆ ) 6[ppm] = 9.93-9.39 (m, 1 H), 8.69 (s, 1 H), 6.64 (d, J = 4.0 Hz, 2H), 2.97-2.87 (m, 2H), 2.72 (br d, J = 10.4 Hz, 1 H), 2.27-2.23 (m, 4H), 2.21 (s, 3H), 2.08 (s, 3H), 1.99- 1.91 (m, 2H), 1.75-1.70 (m, 1 H), 1.59-1.51 (m, 2H).

LC-MS (Method C): Rt = 0.393 min; MS (ESI) m/z = 366.3 [M+H] ⁺ .

SFC (Rt = 1 .252 min, ee% = 98%).

Compound 165

¹ H NMR (400 MHz, DMSO-d ₅ ) 6[ppm] = 10.1 1-9.29 (m, 1 H), 8.65 (s, 1 H), 6.64 (d, J = 6 Hz, 2H), 2.95 (br d, J = 11.4 Hz, 1 H), 2.91-2.83 (m, 1 H), 2.72 (br d, J = 10.4 Hz, 1 H), 2.26 (s, 4H), 2.24-2.18 (m, 3H), 2.08 (s, 3H), 1 .99-1 .87 (m, 2H), 1 .77-1 .69 (m, 1 H), 1 .63-1 .49 (m, 2H).

LC-MS (Method C): Rt = 0.397 min; MS (ESI) m/z = 366.3 [M+H] ⁺ .

SFC (Rt = 1 .574 min, ee% = 94%).

Intermediate 372

3-hydroxy-N-methoxy-N-methyi-cyclobutanecarboxamide (cis)

To a solution of 3-hydroxycyclobutanecarboxylic acid (cis) (2 g, 17.22 mmol, 1 eq) and N- methoxymethanamine (2.52 g, 25.8 mmol, 1.5 eq, HCI salt) in DCM (20 mL) were added EDCI (4.95 g, 25.8 mmol, 1 ,5eq), DIPEA (6.68 g, 51 .7 mmol, 9.0 mL, 3eq) and HOBt (3.49 g, 25.8 mmol, 1 .5 eq) at 20 °C. After stirring at 20 °C for 3 h, the mixture was diluted with water (20 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 2/1) to give 3-hydroxy-N-methoxy-N-methyi-cyclobutanecarboxamide (cis) (2.40 g, 14.3 mmol, 83% yield, 95% purity) as a light yellow oil.

¹ H NMR (400 MHz, DMSO-d6) 6 = 5.10 (d, J = 7.0 Hz, 1 H), 4.05-3.93 (m, 1 H), 3.62 (s, 3H), 3.08 (s, 3H), 2.91-2.78 (m, 1 H), 2.37-2.24 (m, 2H), 2.01-1.85 (m, 2H).

Intermediate 373

1 -(3-hydroxycyciobiityl)ethanone (cis)

To a solution of 3-hydroxy-N-methoxy-N-methyl-cyclobutanecarboxamide (cis) (2.20 g, 13.8 mmol, 1 eq) in THF (20 mL) was added MeMgBr (3 M in THF, 23.0 ml_, 5 eq) at 0 °C. After stirring at 20 °C for 3 h, the reaction mixture was quenched by saturated ammonium chloride aqueous solution (50 mL) at 0 °C, and then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 1-(3-hydroxycyclobutyl)ethanone (cis) (1 .00 g, 8.32 mmol, 60% yield, 95% purity) as light yellow oil.

¹ H NMR (400 MHz, DMSO-d6) 5 = 5.06 (d, J = 6.8 Hz, 1 H), 4.02 - 3.93 (m, 1 H), 2.75 - 2.64 (m, 1 H), 2.38 - 2.27 (m, 2H), 2.03 (s, 3H), 1 .90 - 1 .78 (m, 2H).

Intermediate 374 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyr!dm-2-yl]cyclobutanol (cis)

To a solution of 2-amino-6-(2-methoxy-4,6-dimethyl-phenyl)pyridine-3-carbalde hyde (0.300 g, 1.17 mmol, 1 eq) and 1 -(3-hydroxycyclobutyl)ethanone (cis) (267 mg, 2.34 mmol, 2 eq) in EtOH (5 mL) was added DBU (535 mg, 3.51 mmol, 529 pL, 3 eq) at 20 °C. After stirring at 50 °C for 24 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SIO ₂ , petroleum ether/ethyl acetate=1/0 to 0/1) to give 3-[7-(2- methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]cyclobutanol (80.0 mg, 215 pmol, 24% yield, 90% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.432 min; MS (ESIpos): m/z = 335.2 [M+H]+.

Compound 166 2-[7-(3-hydroxycyc!obutyi)-1 _! §-naphthyncHn-2-yi]-3,5-dimethyFphenol (cis)

To a solution of 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]cyclobutanol (70.0 mg, 209 pmol, 1 eq) in DCM (5 mL) was added BBra (52.4 mg, 209 pmol, 20.2 pL, 1 eq) at -70 °C. After stirring at 20 °C for 2 h, the reaction was quenched by ammonia (3 mL, 7.0 M in methanol), and the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18, 20 g, mobile phase: [water(FA) - MeCN];B%: 20% - 60%, 10 min) to give 2-[7-(3-hydroxycyclobutyl)-1 ,8-naphthyridin-2-yi]-3,5-dimethyl-phenol (15.0 mg, 45.9 pmol, 22% yield, 98% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) 6 = 9.83 (s, 1 H), 8.37 (t, J = 7.6 Hz, 2H), 7.56-7.51 (m, 2H), 6.62 (d, J = 5.2 Hz, 2H), 5.17 (d, J = 7.2 Hz, 1 H), 4.18-4.09 (m, 1 H), 3.26 (s, 1 H), 2.68-2.62 (m, 2H), 2.35-2.29 (m, 1 H), 2.26 (s, 3H), 2.24-2.20 (m, 1 H), 2.10 (s, 3H).

LC-MS (Method C): Rt = 0.418 min; MS (ESIpos): m/z = 321.1 [M+H]+. intermediate 375

1 -(1 -hydroxycyciopropyl)propan-2-one

To a solution of 1-cyciopropylidenepropan-2-one (3.00 g, 31 .2 mmoi, 1 .00 eq) in dimethylsulfoxide (15.0 mL) and water (15.0 mL) was added oxaiic acid (2.81 g, 31 .2 mmoi, 2.75 mL, 1 .00 eq). After stirring at 25 °C for 12h, the mixture was poured into water (50.00 mL) and extracted with ethyl acetate (50.0 mL x 10). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethylacetate/Petroleum ether gradient @ 80 mL/min) to give 1-(1-hydroxycyclopropyl)propan-2-one (980 mg, 8.59 mmol, 27.51 % yield) as a yellow oil.

¹ H NMR (400 MHz, CDCb) 6 = 2.72 (s, 2H), 2.20 (s, 3H), 0.89-0.82 (m, 2H), 0.46-0.40 (m, 2H).

Intermediate 376

2-am!no-6-(2-hydroxy-4,6-dimethyl-phenyl)pynd!ne-3-carbal dehyde

To a solution of 2-amino-6-(2-methoxy-4,6-dimethyl-phenyl)pyridine-3-carbalde hyde (5.00 g, 19.5 mmol, 1 .00 eq) in dichloromethane (100 mL) was added boron tribromide (9.77 g, 39,02 mmoi, 3.76 mL, 2 eq) dropwise at 0 °C under nitrogen atmosphere. After stirring at 0 °C for 4 h, the reaction mixture was slowly poured into saturated sodium bicarbonate solution (50.0 mL), then extracted with dichloromethane (50.0 mL x 3). The organic phase was washed by brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-15% Ethylacetate/Petroleum ethergradient @ 50 mL/min) to give 2-amino-6-(2- hydroxy-4,6-dimethyl-phenyl)pyridine-3-carbaldehyde (1.00 g, 4.13 mmol, 21 % yield) as a yellow solid.

^! H NMR (400 MHz, DMSO-d ₆ ) 6 = 9.87 (d, J = 8.0 Hz, 2H), 8.01 (d, J = 8.0 Hz, 1 H), 7.62 (s, 2H), 6.73 (d, J = 8.0 Hz, 1 H), 6.55 (d, J = 5.8 Hz, 2H), 2.21 (s, 3H), 2.11 (s, 3H).

Compound 167 2-[7-[(1-hydroxycydopropyi)methyl]-1 ,§-naphthyridin-2-y!]-3,5-dimethyi-phenol A mixture of 1-(1-hydroxycyclopropyl)propan-2-one (141 mg, 1.24 mmol, 2.00 eq), 2-amino-6-(2- hydroxy-4,6-dimethyl-phenyl)pyridine-3-carbaldehyde (150 mg, 0.619 mmol, 1.00 eq) and pyrrolidine (44.0 mg, 0.619 mmol, 1 .00 eq) in methanol (5.00 mL) was stirred at 60°C for 12 h. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:15%- 45% B over 10 min) to give 2-[7-[(1-hydroxycyclopropyl)methyl]-1 ,8-naphthyridin-2-yl]-3,5-dimethyl- phenol (41.0 mg, 0.121 mmol, 19% yield, 95% purity) as an orange solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 = 9.91 (s, 1 H), 8.39 (t, J = 8.0 Hz, 2H), 7.70 (d, J = 8.4 Hz, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 6.63 (d, J = 5.8 Hz, 2H), 5.46 (s, 1 H), 3.17 (s, 2H), 2.26 (s, 3H), 2.11 (s, 3H), 0.69 0.61 (m, 4H).

LC-MS (Method C) Rt = 0.426 min; MS (ESIpos): m/z = 321 .3 [M+H] ⁺ .

Intermediate 377 tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyi)-1 ,8-naphthyridin-2-yl]-4-oxo-piperidine-1 - carboxylate (racemate)

To a solution of 2-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (2.00 g, 4.62 mmol, 1 eq) and tert-butyl 4-oxopiperidine-1 -carboxylate (2.76 g, 13.9 mmol, 3eq) in dioxane (30 mL) were added LiHMDS (1.00 M, 13.8 mL, 3.00eq) and 1 ,3-bis(2,6-diisopropylphenyl)-2H-imidazole;3- chloropyridine;dichloropalladium (314 mg, 462 pmol, 0.1 eg) at 25 °C, the mixture was degassed and purged with N2 for 3 times, after stirring at 100 °C for 16 h, the mixture was filtered and concentrated to a crude. The crude was purified by column chromatography (SiOa, Petroleum ether/Ethyl acetate=10/1 to 1/1) to give tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-4- oxo-piperidine-1 -carboxylate (2.50 g, 3.79 mmol, 82% yield, 70% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d6) 6 = 8.20 (d, J = 8.0 Hz, 1 H), 8.13 (d, J = 9.2 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 1 H), 7.20-7.13 (m, 1 H), 6.81 (s, 1 H), 6.75 (s, 1 H), 4.30 (s, 2H), 3.66 (s, 3H), 3.58 (t, J = 6.0 Hz, 2H), 3.45-3.35 (m, 1 H), 2.42 (t, J = 6.0 Hz, 2H), 2.34 (s, 3H), 2.00 (s, 3H), 1 .43 (s, 9H).

LC-MS (Method C): Rt = 0.604 min; MS (ESIpos): m/z = 462.3 [M+1 ] ⁺ .

Intermediate 378 tert-butyl 4-hydroxy-3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl] piperidine-1 - carboxylate (racemate)

To a solution of tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-4-oxo- piperidine-1 - carboxylate (2.50 g, 3.79 mmol, 1 eg) in THE (100 mL) was added NaBH-i (717 mg, 18.9 mmol, 5 eq) at 0 °C, after stirring at 0 °C for 3 h, the mixture was added saturated NH^CI solution (100 mL) and extracted with ethyl acetate (100 mL x 3), the combined organic phase was concentrated to give a crude. The crude was purified by column chromatography (SiOa, Petroleum ether/Ethyl acetate=10/1 to 1/1) to give tert-butyl 4-hydroxy-3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8- naphthyridin-2-yl] piperidine-1 -carboxylate (900 mg, 1.36 mmol, 36% yield, 70% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.493 min; MS (ESIpos): m/z = 464.1 [M+1 ] ⁺ .

Intermediate 379

3-[7-(2-methoxy-4.6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl] piperidin-4-ol (racemate)

To a solution of tert-butyl 4-hydroxy-3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8- naphthyridin-2- yl]piperidine-1 -carboxylate (900 mg, 1 .36 mmol, 1 eq) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) at 25 °C, after stirring at 25 °C for 2 h, the mixture was concentrated to give 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl] piperidin-4-ol (1.5 g, crude, TFA salt) as yellow oil.

LC-MS (Method C): Rt = 0.412 min; MS (ESIpos): m/z = 364.2 [M+1 ] ⁺ .

Intermediate 380 3-[7-(2-methoxy-4,6-dimethyl-phenyi)-1 ,8-naphthyridin-2-yl]-1-methyl-piperidin-4-ol (racemate) To a solution of 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]piperidin-4-ol (1.40 g, 2.93 mmol, 1 eq, TFA) and (HCHO)n (176 mg, 5.86 mmol, 2eq) in methanol (50 mL) were added KOAc (1.44 g, 14.7 mmol, 5 eq) and NaBFhCN (368 mg, 5.86 mmol, 2eq) at 25 °C. After stirring at 25 °C for 1 hour, the mixture was concentrated to give a crude. The crude was purified by reversed phase reversed-phase column (column: C18, 80 g, mobile phase: [water(FA) - MeCN];B%: 20% - 50%, 10 min) to give 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-methyl-piperidin-4-ol (350 mg, 834 pmol, 28% yield, 90% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.425 min; MS (ESIpos): m/z = 378.3 [M+1 ] ⁺ .

Intermediate 381 3-[7-(2-hydroxy-4 _! 6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-methyl-pipendin-4-ol (racemate) To a solution of 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1 -methyl-piperidin-4-ol (130 mg, 344 pmol, 1 eq) in dichloromethane (10 mL) was added BBrs (2 M, 516 pL, 3eq), after stirring at -78 °C for 2h., the mixture was concentrated to give a crude, the crude was purified by reversed phase reversed-phase column (column: C18, 40 g, mobile phase: [water(FA) - MeCN];B%: 15% - 55%, 7 min) to give 3-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-methyl-piperidin-4-ol (40 mg, 104 pmol, 30% yield, 95% purity) as a yellow oil.

LC-MS (Method C): Rt = 0.394 min; MS (ESIpos): m/z = 364.3 [M+1] ⁺ .

Compound 168 3-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,S-naphthyridin-2-yl]-1 -methyl-piperidin-4-ol (single enantiomers) 3-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1 -methyl-piperidin-4-ol was separated by by SFC :column: DAICEL CHIRALPAK AY-H(250mm • 30mm,10um);mobile phase: [CO ₂ -i-PrOH/ACN];B%:80%, isocratic elution mode to give Compound 168 3-[7-(2-hydroxy-4,6- dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-methyl-piperidin-4-ol (20.0 mg, 54.5 pmol, 25% yield, 99% purity) as a yellow solid, and Compound 168 3-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]-1 -methyl-piperidin-4-ol (5.00 mg, 12.4 pmol, 6% yield, 90% purity) as a yellow solid.

Compound 168

¹ H NMR (400 MHz, DMSO-d _s ) 5 = 9.74 (br s, 1 H), 8.51 - 8.39 (m, 2H), 7.60 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 6.8 Hz, 2H), 5.19 (br s, 1 H), 4.08 - 3.87 (m, 1 H), 3.69 - 3.53 (m, 2H), 3.24 (d, J = 12.0 Hz, 2H), 2.89 - 2.80 (m, 3H), 2.26 (s, 3H), 2.18 (d, J = 12.4 Hz, 2H), 2.09 (s, 3H), 1.89 - 1.82 (m, 1 H). LC-MS (Method C): Rt = 0.391 min; MS (ESIpos): m/z = 364.3 [M+1] ⁺ .

SFC (Rt = 0.981 min, ee% = 99%).

Enantiomer 2

¹ H NMR (400 MHz, DMSO-d ₈ ) 6 = 9.85 (t, J = 10.0 Hz, 1 H), 8.38 - 8.30 (m, 2H), 7.56 (dd, J = 8.4, 11.6 Hz, 2H), 6.63 (d, J = 6.0 Hz, 2H), 4.79 - 4.61 (m, 1 H), 3.92 - 3.82 (m, 1 H), 3.10 - 3.00 (m, 2H), 2.91 - 2.79 (m, 2H), 2.26 (s, 3H), 2.20 (s, 3H), 2.11 - 2.08 (m, 3H), 1 .93 - 1 .87 (m, 1 H), 1 .92 - 1 .85 (m, 1 H), 1.65 - 1.58 (m, 1 H).

LC-MS (Method C): Rt = 0.388 min; MS (ESipos): m/z - 364.3 [M+1 ] ⁺ .

SFC (Rt = 0.987min, ee% = 99%).

Intermediate 382 tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-2,5-dihydropyiTole-1 - carboxylate

To a solution of 2-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (2.00 g, 4.62 mmol, 1 eq) in dioxane (20 mL) and water (2 mL) was added tert-butyl 3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (3.41 g, 11.5 mmol, 2.5 eq), Pd(dppf)Cl2 (337 mg, 461 pmol, 0.1 eq) and K2CO3 (1 .92 g, 13.8 mmol, 3 eq) at 25 °C. After stirring at 80 °C for 16 h, the mixture was filtered and concentrated to a crude. The crude was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/1 to 1/1) to give tert-butyl 3-[7-(2-methoxy-4,6-dimethyl- phenyl)-1 ,8-naphthyridin-2-yl]-2,5-dihydropyrrole-1-carboxylate (3.00 g, 6.40 mmol, 79% yield, 92% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.545 min; MS (ESipos): m/z = 432.3 [M+1] ⁺ .

Intermediate 383 tert-butyl 3-hydroxy-4-[7-(2-methoxy-4,6-d!methyl-phenyl)-1 ,8-naphthyndin-2-yl]pyrrolidine-1- carboxylate (racemate, trans)

To a solution of tert-butyl 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-2,5- dihydropyrroie-1 -carboxylate (3.00 g, 6.40 mmol, 1 eq) in tetrahydrofuran (50 mL) was added BHa-THF (1 .00 M in tetrahydrofuran, 7.68 mL, 1 .2 eq) at 25 °C. After stirring at 25 °C for 2 h, a solution of sodium hydroxide (767 mg, 19.2 mmol, 3 eq) in water (5 mL) and H2O ₂ (4.35 g, 38.4 mmol, 3.69 mL, 30% purity in water, 6 eq) were added to the mixture at 25 °C. After stirring at 80 °C for 16 h, the mixture was quenched with saturated Na ₂ SO3 solution (100 mL) and extracted with ethyl acetate (100 mL x 2), the combined organic phase was concentrated to give a crude. The crude was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/1 to 1/1) to give tert-butyl 3- hydroxy-4-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]pyrrolidine-1 -carboxylate (850 mg, 1 .32 mmol, 21 % yield, 70% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d6) 0 = 8.31 (d, J = 8.0 Hz, 1 H), 8.24 (d, J = 8.0 Hz, 1 H), 7.65-7.60 (m, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 6.76 (s, 1 H), 6.67 (s, 1 H), 5.69 (br s, 1 H), 3.90-3.72 (m, 4H), 3.69 (s, 3H), 2.52-2.43 (m, 1 H), 2.39 (s, 3H), 2.25-2.15 (m, 1 H), 2.13 (s, 3H), 1.47 (s, 9H) LC-MS (Method C): Rt = 0.506 min; MS (ESIpos): m/z = 450.3 [M+1 ] ⁺ . intermediate 384

4-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]pyrrolidin-3-ol (racemate, trans) To a solution of tert-butyi 3-hydroxy-4-[7-(2-methoxy-4, 6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]pyrroiidine-1 -carboxylate (750 mg, 1.17 mmol, 1 eq) in dichloromethane (10 mL) was added TFA (5 mL) at 25 °C. After stirring at 25 °C for 16 h, the mixture was concentrated to give rac-(3S, 4S)-4-[7- (2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]pyrrolidin-3-ol (540 mg, crude, TFA salt) as yellow oil.

LC-MS (Method C): Rt - 0.418 min; MS (ESIpos): m/z = 350.2 [M+1 ] ⁺ .

Intermediate 385 4-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yn-1“methyl-pyrrolidin-3-ol (racemate, trans)

To a solution of 4-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]pyrrolidin-3-ol (540 mg, 1.55 mmol, 1 eq) and potassium acetate (455 mg, 4.64 mmol, 3 eq) in methanol (10 mL) were added NaBFhCN (194 mg, 3.09 mmol, 2 eq) and (HCHO)n (92.7 mg, 3.09 mmol, 2 eq) at 25 °C. After stirring at 25 °C for 1 h, the mixture was concentrated to give a crude. The crude was purified by reversed phase (FA condition) to give 4-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-methyl- pyrrolidin-3-ol (500 mg, 962 pmol, 62% yield, 70% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.425 min; MS (ESIpos): m/z = 364.2 [M+1 ] ⁺ .

Intermediate 386 4-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-methyl-pyrrolidm-3-ol (racemate, trans)

To a solution of 4-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]- 1 -methyl-pyrrolidin-3-ol (450 mg, 866 pmol, 1 eq) in dichloromethane (2 mL) was added BBr?. (2 M in dichloromethane, 1 .30 mL, 3 eq) at 0 °C. After stirring at 25 °C for 4 h, the mixture was added NHs (10 mL, 7 M in methanol) and concentrated to give a crude. The crude was purified by prep_HPLC: column: Phenomenex Luna C18 150*25mm*10um;mobile phase: [water(FA)-MeCN];gradient:5%-35% B over 10 min to give 4-[7- (2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-methyl-pyrrolidin-3-ol (75.0 mg, 212 pmol, 24% yield, 99% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.390 min; MS (ESIpos): m/z - 350.3 [M+1 ] ⁺ .

Compound 170 4-[7-(2-hydroxy-4,6-dimethyi-phenyi)-1 ,8-naphthyridin-2-yi]-1-methyi-pyrrolidin-3-oi (single enantiomers)

4-[7-(2-hydroxy-4, 6-dimethyl-phenyl)-1 , 8-naphthyridin-2-yl]-1-methyl-pyrrolidin-3~ol (racemate, trans) was separated by SFC: The residue was purified by SFC: column: Phenomenex-Cellulose-2 (250 mm*30 mm, 10 pm);mobile phase: [CO ₂ -MeCN/EtOH(0.1 % NH3H2O)];B%:50%, isocratic elution mode to give Compound 170 4-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-methyl- pyrrolidin-3-ol (35.0 mg, 98.1 pmol, 47% yield, 98% purity) as a yellow solid, and Compound 171 4-[7- (2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-methyl-pyrrolidin-3-ol (30 mg, 84.1 pmol, 40% yield, 98% purity) as a yellow solid.

Compound 170 ¹ H NMR (400 MHz, DMSO-d6) 6 = 9.71 (s, 1 H), 8.44 (dd, J = 8.4, 15.9 Hz, 2H), 7.92 (d, J = 8.4 Hz, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 6.63 (d, J = 6.4 Hz, 2H), 5.77 (s, 1 H), 3.11 (d, J = 9.6 Hz, 1 H), 2.90 (q, J = 7.6 Hz, 1 H), 2.81 (d, J = 9.6 Hz, 1 H), 2.70 (dt, J = 5.6, 8.4 Hz, 1 H), 2.65-2.56 (m, 1 H), 2.35 (s, 3H), 2.26 (s, 3H), 2.09-2.03 (m, 4H)

LC-MS (Method C): Rt = 0.399 min; MS (ESIpos): m/z = 350.4 [M+1 ] ⁺ . SFC (Rt = 0.614 min, ee% = 86%).

Enantiomer 2

¹ H NMR (400 MHz, DMSO-d _s ) 5 = 9.86-9.55 (m, 1 H), 8.49 (d, J = 8.4 Hz, 1 H), 8.44 (d, J = 8.0 Hz, 1 H), 8.21 (s, 1 H), 7.94 (d, J = 8.4 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 6.64 (d, J = 6.0 Hz, 2H), 3.23 (d, J = 10.0 Hz, 1 H), 3.01 (d, J = 8.4 Hz, 1 H), 2.92 (d, J = 10.0 Hz, 1 H), 2.86-2.78 (m, 1 H), 2.61 (dd, J = 4.8, 7.2 Hz, 1 H), 2.44 (s, 3H), 2.27 (s, 3H), 2.13-2.06 (m, 4H)

LC-MS (Method C): Rt = 0.393 min; MS (ESIpos): m/z = 350.3 [M+1]* SFC (Rt = 0.806 min, ee% = 85%).

Intermediate 387 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-y0cyclopent-2-en-1 -one

To a solution of 2-bromo-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridine (1.00 g, 2.91 mmol, 1eq) , 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one (909 mg, 4.37 mmol, 1.5eq) , Pd(dppf)Cl2 (213 mg, 291 pmol, 0.1 eq) , cesium carbonate (1.90 g, 5.83 mmol, 2eq) in dioxane (1 OmL) and Water (2mL) was degassed and purged with N2 for 3 times, after stirring at 80 °C for 16h under N2 atmosphere, the mixture concentrated to give a crude. The crude product was purified by column chromatography (SIO ₂ , Petroleum ether/Ethyl acetate=5/1 to 1/1) to give 3-[7-(2- methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]cyclopent-2-en-1-one (600 mg, 1.69 mmol, 58 % yield, 97% purity) as a white solid.

LC-MS (Method C): Rt = 0.493 min; MS (ESIpos): m/z = 345.1 [M+1]*.

Intermediate 388 3-[7-(2-methoxy-4,6-dimethyi-phenyl)-1 _! 8-naphthyridin-2-yl]cyciopentanone (racemate) To a solution of 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]cyclopent-2-en-1-one (600 mg, 1 .74 mmol, 1 eq) in methanol (10 mL) was added Pd/C (1 .85 g, 1 .74 mmol, 10% purity, 1 eq) at 25 °C, after stirring at 25 °C for 1 h under H? (15 psi) atmosphere, the reaction mixture was filtered and the filtrate was concentrated at reduced pressure to give 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8- naphthyridin-2-yl]cyclopentanone (540 mg, 1 .32 mmol, 76% yield, 85% purity) as a yellow solid. LC-MS (Method C): Rt = 0.448 min; MS (ESIpos): m/z = 347.1 [M+1] ⁺ . intermediate 389

3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 _s 8-naphthyndin-2-yl]cyclopentanol (racemate)

To a solution of 3-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]cyclopentanone (590 mg, 1 .70 mmol, 1 eq) in THF (15 mi_) was added NaBI-k (0.22 g, 5.82 mmol, 3.41 eq), after stirring at 25 °C for 1 h, the mixture was quenched with saturated NFUCi solution (50 ml) and extracted with ethyl acetate (20 ml * 3), the combined organic phase was concentrated to give 3-[7-(2-methoxy-4,6- dimethyl-phenyi)-1 ,8-naphthyridin-2-yi]cyclopentanoi (550 mg, 1.42 mmol, 83% yield, 90% purity) as a white solid.

¹ H NMR (400 MHz, DMSO-d _s ) 5 = 8.46 - 8.33 (m, 2H), 7.69 - 7.54 (m, 1 H), 7.48 - 7.40 (m, 1 H), 6.82 (s, 1 H), 6.77 (s, 1 H), 4.96 (d, J = 4.8 Hz, 1 H), 4.31 - 4.23 (m, 1 H), 3.64 (s, 3H), 2.36 (s, 3H), 2.33 - 2.26 (m, 1 H), 2.05 (br d, J = 6.4 Hz, 1 H), 1 .99 (d, J = 3.6 Hz, 4H), 1.91 - 1 .80 (m, 2H), 1 .78 - 1 .68 (m, 1 H)

LC-MS (Method C): Rt = 0.438 min; MS (ESIpos): m/z = 349.3 [M+1] ⁺ .

Intermediate 390

2-(7-(3-hydroxycyclopentyl)-1 ,8-naphthyndin-2-yl)-3,5-dimethylphenol (racemate)

To a solution of 3-(7-(2-methoxy-4,6-dimethylphenyl)-1 ,8-naphthyridin-2-yl)cyclopentan-1-ol (180 mg, 516 pmol, 1 eq) in dichloromethane (15 mL) was added BBrs (388 mg, 1.55 mmol, 149 pL, 3eq), after stirring at 25 °C for 1 h, The mixture was quenched with NHs/MeOH (5ml) and purified by reversed- phase HPLC ( 0.1 % FA condition ) to give 2-(7-(3-hydroxycyclopentyl)-1 ,8-naphthyridin-2-yl)-3,5- dimethylphenoi (80 mg, 227.27 pmol, 43.99% yield, 95% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.419 min; MS (ESIpos): m/z = 335.1 [M+1 ] ⁺ .

Compound 172,173, 174 and 175

2-(7-(3-hydroxycyclopentyl)-1 .8-naphthyridin-2~yl)-3,5-dimethylphenol (single enantiomers) 2-(7-(3-hydroxycyclopentyl)-1 ,8-naphthyridin-2-yl)-3,5-dimethyiphenol (racemate) was separated by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm,10um);mobile phase: [CO ₂ - EtOH(0.1 %NH3H2O)];B%:50%, isocratic elution mode) to give peak 1 (80 mg, 239.23 pmol, 47.06% yield, cis) and peak 2 (60 mg, 179.42 pmol, 35.29% yield, trans), peak 1 (cis) was separated by SFC (column: DAICEL CHIRALCEL OD(250mm*30mm,10um);mobile phase: [CO ₂ -i- PrOH(0.1 %NH3H2O)];B%:40%, isocratic elution mode) to give Compound 172 (12.2 mg, 44.4 pmol, 18.56% yield, 99% purity) as a yellow solid, Compound 173 (13.3 mg, 43.9 pmol, 18.38% yield, 98% purity) as a yellow solid, peak 2 (trans) was separated by SFC (column: Daicel ChiralPak IG (250*30mm, 10um);mobile phase: [CO ₂ -EtOH(0.1 %NHsH2O)];B%:50%, isocratic elution mode) to give compound Compound 174 (4.66 mg, 13.66 pmol, 7.61 % yield, 98% purity) as a yellow solid, and Compound 175 (17.98 mg, 53.23 pmol, 29.67% yield, 99% purity) as a yellow solid.

Compound 172 ¹ H NMR (400 MHz, DMSO-c/6) 6 = 9.81 (s, 1 H), 8.39 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 8.4 Hz, 1 H), 6.62 (d, J = 5.6 Hz, 2H), 4.99 (d, J = 4.4 Hz, 1 H), 4.33 - 4.21 (m, 1 H), 3.45 (t, J = 8.4 Hz, 1 H), 2.40 - 2.30 (m, 1 H), 2.26 (s, 3H), 2.13 - 2.08 (m, 3H), 2.07 - 1 .96 (m, 2H), 1.91 - 1 .79 (m, 2H), 1.77 - 1.66 (m, 1 H)

LC-MS (Method C): Rt = 0.430 min; MS (ESIpos): m/z = 335.2 [M+1]*.

SFC (Rt = 2.125 min, ee% = 99.7%)

Compound 173

¹ H NMR (400 MHz, DMSO-d6) 6 = 9.90 - 9.73 (m, 1 H), 8.43 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 1 H), 7.58 (d, J = 8.0 Hz, 1 H), 6.63 (d, J = 5.6 Hz, 2H), 4.33 - 4.22 (m, 1 H), 3.53 - 3.42 (m, 2H), 2.40 ■ 2.31 (m, 1 H), 2.26 (s, 3H), 2.09 (s, 3H), 2.07 - 1.98 (m, 2H), 1.85 (ddd, J = 5.6, 8.0, 12.8 Hz, 2H), 1.74 (dt, J = 4.4, 8.0 Hz, 1 H)

LC-MS (Method C): Rt = 0.432 min; MS (ESIpos): m/z = 335.2 [M+1 ]*

SFC (Rt = 2.267 min, ee% = 97.8%)

Compound 174

¹ H NMR (400 MHz, DMSO-d6) 5 = 9.81 (s, 1 H), 8.39 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 8.4 Hz, 1 H), 6.62 (d, J = 5.6 Hz, 2H), 5.00 (d, J = 5.2 Hz, 1 H), 4.33 - 4.22 (m, 1 H), 3.48 - 3.43 (m, 1 H), 2.33 (d, J = 4.8 Hz, 2H), 2.26 (s, 3H), 2.09 (s, 3H), 2.05 - 1 .98 (m, 1 H), 1 .85 (br s, 2H), 1 .78 - 1.67 (m, 1 H)

LC-MS (Method C): Rt = 0.425 min; MS (ESIpos): m/z = 335.2 [M+1]*

SFC (Rt = 1 .351 min, ee% = 96%)

Compound 175

¹ H NMR (400 MHz, DMSO-(fe) 6 = 9.81 (br s, 1 H), 8.37 (t, J = 8.4 Hz, 2H), 7.55 (dd, J = 8.4, 14.8 Hz, 2H), 6.62 (d, J = 5.6 Hz, 2H), 4.61 (br s, 1 H), 4.36 (br s, 1 H), 3.75 - 3.62 (m, 1 H), 2.26 (s, 3H), 2.21 (br dd, J = 4.2, 8.6 Hz, 1 H), 2.08 (s, 3H), 2.05 - 1 .96 (m, 3H), 1 .92 - 1 .78 (m, 1 H), 1 .70 - 1 .56 (m, 1 H) LC-MS (Method C): Rt = 0.417 min; MS (ESIpos): m/z = 335.2 [M+1]* SFC (Rt = 1 .803 min, ee% = 98%).

Intermediate 391 benzyl 2H-pyridlne-1 -carboxylate

To a solution of pyridine (10.0 g, 126 mmol, 10 mL, 1 eq) in methanol (100 mL) was added NaBH4 (5.29 g, 139 mmol, 1 eq) at -70 °C in portions under Ns atmosphere. After stirring at -70 °C for 10 min, the CbzCI (23.7 g, 139 mmol, 19 mL, 1 .1 eq) in methanol (10 mL) was added to the mixture. After stirring at -70 °C for 2 h, the mixture was poured into ice-water (200 mL) and extracted with ethyl acetate (150 mL). The combined organic phase was washed with saturated sodium bicarbonate aqueous solution (100 mL) and brine (100 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to to give benzyl 2H-pyridine-1 -carboxylate (22.0 g, 102 mmol, 80% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-cfe) S = 7.39 (d, J = 5.2 Hz, 5H), 6.69 (dd, J = 0.8, 8.0 Hz, 1 H), 5.94-5.79 (m, 1 H), 5.56 (br s, 1 H), 5.19-5.10 (m, 3H), 4.41-4.19 (m, 2H).

Intermediate 392 O ₂ -benzyl O6-methyl 2-azablcyclo[2.2.2]oct-7-ene-2,6-dlcarboxylate (racemate)

A solution of benzyl 2H-pyridine-1 -carboxylate (22.0 g, 102 mmol, 1 eg) and methyl prop-2-enoate (43.9 g, 511 mmol, 46 mL, 5 eq) in acetonitrile was stirring at 80 °C for 16. Then the mixture was poured into water (100 mL) and extracted with ethyl acetate (150 mL). The combined organic phase was washed with brine (80 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue, the residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 5/1) to give O ₂ -benzyl O6-methyl 2-azabicyclo[2.2.2]oct-7-ene- 2,6-dicarboxylate (17.0 g, 45.1 mmol, 44% yield, 80% purity) as a yellow oil.

LC-MS (Method C): Rt = 0.552 min; MS (ESIpos): m/z = 302.3 [M+1 ] ⁺ .

Intermediate 393 2-benzyloxycarbonyl-2-azabicyclo[2.2.2]oct-7-ene-6-carboxyli ic acid (racemate) To a solution of O ₂ -benzyl O6-methyl 2-azabicyclo[2.2.2]oct-7-ene-2,6-dicarboxylate (17.0 g, 56.4 mmol, 1 eq) in tetra hydrofuran (100 mL) was dropwise added Lithium hydroxide hydrate (11 .8 g, 282 mmol, 5 eq) in H2O (20 mL ) at 25 °C. After stirring at 25 °C for 16 hours, the pH of reaction mixture was adjusted to 2 with hydrochloric acid aqueous solution. The mixture was extracted with ethyl acetate (300 mL). The combined organic phase was washed with brine (150 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give 2- benzyloxycarbonyl-2-azabicyclo[2.2.2]oct-7-ene-6-carboxylic acid (15.0 g, 46.9 mmol, 83% yield, 90% purity) as yellow oil.

LC-MS (Method C): Rt = 0.477 min; MS (ESIpos): m/z = 288.2 [M+1 ] ⁺ .

Intermediate 394 benzyl 7-[methoxy(methyl)carbamoyl]-2-azabicyclo[2.2.2]oct-5-ene-2- carboxylate (racemate) To a solution of 2-benzyloxycarbonyl-2-azabicyclo[2.2.2]oct-7-ene-6-carboxyli c acid (15.0 g, 52.2 mmol, 1 eq), HOBt (10.5 g, 78.3 mmol, 1.5 eq) and N-methoxymethanamine; hydrochloride (7.64 g, 78.3 mmol, 1 .5 eq) in dichloromethane (100 mL) were added EDCI (15.0 g, 78.3 mmol, 1 .5 eq) and DIPEA (20.2 g, 156 mmol, 27 mL, 3 eq) at 25 °C. After stirring at 25 °C for 1 h, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give benzyl 7-[methoxy(methyl)carbamoyl]-2-azabicyclo[2.2.2]oct-5- ene-2-carboxylate (13.0 g, 35.4 mmol, 67% yield, 90% purity) as colorless oil.

LC-MS (Method C): Rt = 0.524 min; MS (ESIpos): m/z = 331.3 [M+1 ] ⁺ .

Intermediate 395 benzyl 7-acetyl-2-azabicyclo[2.2.2]oct-5-ene-2 -carboxylate (racemate) To a solution of benzyl 7-[methoxy(methyl)carbamoyl]-2-azabicyclo[2.2.2]oct-5-ene-2- carboxylate (13.0 g, 39.3 mmol, 1 eq) in tetrahydrofuran (100 mL) was dropwise added MeMgBr (3 M in THF, 39 mL, 3 eq) at 0 °C. After stirring at 25 °C for 1 h, the reaction mixture was quenched by addition ammonium chloride saturated solution (200 mL) and then diluted with water (50 mL) and extracted with ethyl acetate (90 mL). The combined organic concentrated under reduced pressure to give benzyl 7-acetyl-2-azabicyclo[2.2.2]oct-5-ene-2-carboxylate (10.0 g, 31.5 mmol, 80% yield, 90% purity) as a white solid.

LC-MS (Method C): Rt = 0.515 min; MS (ESIpos): m/z - 286.2 [M+1 ] ⁺ .

Intermediate 396 benzyl 7-[7-(2-methoxy-4,6-dirnethyl-phenyl)-1 ,8-naphthyridin-2-yl]-2-azabicyclo [2.2.2]oct-5- ene-2-carboxylate (racemate)

To a solution of benzyl 7-acetyl-2-azabicyclo[2.2.2]oct-5-ene-2-carboxylate (5.00 g, 17.5 mmol, 2 eq) and 2-amino-6-(2-methoxy-4,6-dimethyl-phenyl)pyridine-3-carbalde hyde (2.25 g, 8.76 mmol, 1 eq) in methanol (50 mL) was added DBU (4.00 g, 26.28 mmol, 3.96 mL, 3 eq). After stirring at 60 °C for 4 h, the reaction mixture was concentrated to give a crude. The residue was purified by reversed-phase column (column: C18 80 g, mobile phase: [water (FA) - MeCN]; B%: 40% - 90%, 20 min) to give benzyl 7-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-2-azabicyclo [2.2.2]oct-5-ene-2- carboxylate (3.40 g, 6.39 mmol, 72% yield, 95% purity) as yellow oil.

LC-MS (Method C): Rt = 0.536 min; MS (ESIpos): m/z = 506.2 [M+1] ⁺ .

Intermediate 397

2-(2-methoxy-4,6-d!methyl-phenyl)-7-(2-methyl-2-azab!cycl o[2.2.2]octan-6-yl)-1,8-naphthyridine (racemate)

To a solution of benzyl 7-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-2- azabicyclo[2.2.2] oct-5-ene-2-carboxylate (900 mg, 1.78 mmol, 1 eq) in methanol (20 mL) was added Pd/C (189 mg, 178 pmol, 10% purity, 0.1 eq) at 25 °C. After stirring at 25 °C for 1 h under H2 (15 psi) atmosphere, the mixture was filtered and the filtrate was concentrated at reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18 80 g, mobile phase: [water (FA) - MeCN]; B%: 20% - 80%, 12 min) to give 2-(2-methoxy-4,6-dimethyl-phenyl)-7-(2-methyl-2- azabicyclo[2.2.2]octan-6-yl)-1 ,8-naphthyridine (200 mg, 516 pmol, 28% yield) as a yellow solid. LC-MS (Method C): Rt = 0.432 min; MS (ESIpos): m/z = 388.2 [M+1 ] ⁺ .

Intermediate 398

3,5-dimethyb2-[7-(2-methyi-2-azabicyclo[2.2.2]octan-6-y!) -1 _s 8-naphthyridin-2-yi]phenol (racemate)

To a solution of 2-(2-methoxy-4,6-dimethyl-phenyl)-7-(2-methyl-2-azabicyclo[2 .2.2]octan-6-yl)-1 ,8- naphthyridine (200 mg, 516 pmol, 1 eq) in dichloromethane (15 mL) was added BBrs (387 mg, 1.55 mmol, 149 pL, 3 eq) at -70 °C . After stirring at 25 °C for 2hr, the reaction mixture was quenched by addition of 5 mL of methanol, and a clear yellow-brown solution was obtained. The pH was adjusted to around 7 by progressively adding 7.0 M ammonia in methanol. Then the mixture was filtered and the filtrate was concentrated at reduced pressure to give a residue. The residue was purified by column chromatography (column: Welch Ultimate XB-Diol 250*50*10um;mobile phase: [Hexane- EtOH (0.1 % NH3.H2O) ];gradient:15%-55% B over 15 min) to give 3,5-dimethyl-2-[7-(2-methyl-2- azabicyclo[2.2.2]octan-6-yl)-1 ,8-naphthyridin-2-yl]phenol (130 mg, 348 pmol, 67% yield) as yellow oil, LC-MS (Method C): Rt = 0.472 min; MS (ESIpos): m/z = 374.1 [M+1 ] ⁺ .

Compound 177, 178 and 179

3.5-dimethyl-2-[7-(2-methyl-2-azabicyclo[2.2.2]octan-6-yl )-1 ,8-naphthyndin-2-yl]phenol (single enantiomers)

3.5-dimethyl-2-[7-(2-methyl-2-azabicyclo[2.2.2]octan-6-yl )-1 ,8-naphthyridin-2-yl]phenol was separated by SFC (column: DAICEL CHIRALCEL OX (250mm*30mm,10um);mobile phase: [CO ₂ -ACN/i- PrOH(0.1 % NH3H2O)];B%:70%, isocratic elution mode ) to give peak 1 (30 mg ) as a yellow solid and peak 2 (30 mg) as a yellow solid. And then peak 1 was separated by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm,10um);mobile phase: [CO ₂ -ACN/EtOH(0.1% NH3H2O)];B%:50%, isocratic elution mode ) to give Compound 176 (5.16 mg, 13.39 pmol, 2.50% yield) as a white solid, and Compound 177 (6.11 mg, 13.39 pmol, 2.50% yield) as a white solid. And peak 2 was separated by SFC (column: DAICEL CHIRALPAK IC(250mm*30mm,10um);mobile phase: [CO ₂ - ACN/MeOH(0.1 % NH3H2O)];B%:62.5%, isocratic elution mode) to give Compound 178 (2.86 mg, 13.39 pmol, 2.50% yield) as a white solid and Compound 179 (1.74 mg, 13.39 pmol, 2.50% yield) as a white solid.

Diastereomer 1

¹ H NMR (400 MHz, DMSO-d _s ) 6 = 8.42 (dd, J = 2.0, 8.4 Hz, 2H), 7.65 (dd, J = 4.4, 8.4 Hz, 2H), 6.66 (d, J = 16.8 Hz, 2H), 4.67-4.44 (m, 2H), 4.00-3.88 (m, 1 H), 3.71 (br s, 1 H), 3.15 (d, J = 12.0 Hz, 1 H), 2.92 (s, 3H), 2.55 (dd, J = 7.6, 12.8 Hz, 1 H), 2.31 (s, 3H), 2.26-2.20 (m, 1 H), 2.13 (s, 3H), 2.03 (s, 1 H), 2.00-1 .85 (m, 3H), 1 .74-1 .60 (m, 1 H).

LC-MS (Method C): Rt = 0.420 min; MS (ESIpos): m/z = 374.2 [M+1] ⁺ . SFC (Rt = 0.851 min, ee% = 99%)

Compound 177 ¹ H NMR (400 MHz, DMSO-(fe) 6 = 8.39 (dd, J = 5.6, 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 8.4 Hz, 1 H), 6.63 (s, 1 H), 6.62 (s, 1 H), 3.72 ( t, J = 8.8 Hz, 1 H), 3.66-3.59 (m, 1 H), 3.28-3.20 (m, 3H), 2.97-2.88 (m, 2H), 2.58 ( d, J = 9.2 Hz, 1 H), 2.26 (s, 3H), 2.07 (s, 3H), 1 .96-1 .83 (m, 2H), 1 .67-1 .49 (m, 4H).

LC-MS (Method C): Rt = 0.413 min; MS (ESIpos): m/z = 374.2 [M+1 ] ⁺ SFC (Rt = 1 .206 min, ee% - 97%)

Compound 178 ¹ H NMR (400 MHz, DMSO-cfe) S = 8.39 (dd , J = 5.6, 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 8.4 Hz, 1 H), 6.63 (s, 1 H), 6.62 (s, 1 H), 3.72 ( t, J = 8.8 Hz, 1 H), 3.66-3.59 (m, 1 H), 3.28-3.20 (m, 3H), 2.97-2.88 (m, 2H), 2.58 ( d, J = 9.2 Hz, 1 H), 2.26 (s, 3H), 2.07 (s, 3H), 1 .96-1 .83 (m, 2H), 1 .67-1 .49 (m, 4H).

LC-MS (Method C): Rt = 0.413 min; MS (ESIpos): m/z = 374.2 [M+1] ⁺ SFC (Rt = 1 .206 min, ee% = 97%)

Diastereomer 4 ¹ H NMR (400 MHz, DMSO-cfe) 5 = 8.46-8.30 (m, 2H), 7.95 (d, J = 8.4 Hz, 1 H), 7.62 (d, J = 8.4 Hz, 1 H), 6.98 (br s, 1 H), 6.68 (d, J = 17.2 Hz, 2H), 4.69-4.47 (m, 1 H), 3.28-3.13 (m, 1 H), 3.06 (d, J = 7.2 Hz, 2H), 2.75 (s, 3H), 2.50 (d, J = 8.0 Hz, 2H), 2.44-2.37 (m, 1 H), 2.33 (s, 3H), 2.16 (s, 4H), 2.02-1.89 (m, 1 H), 1 .57-1 .41 (m, 1 H).

LC-MS (Method C): Rt = 0.420 min; MS (ESIpos): m/z = 374.2 [M+1 ] ⁺ SFC (Rt = 1 .775 min, ee% = 96%)

Intermediate 399 tert-butyl 6-(methoxy(methyl)carbamoyl)-1 ,4-osrazepane-4-carboxylate (racemate)

To a solution of 4-tert-butoxycarbonyl-1 ,4-oxazepane-6-carboxylic acid (1.70 g, 6.93 mmol, 1.00 eq) and N-methoxymethanamine (1 .01 g, 10.4 mmol, 1 .50 eq, HCI salt) in DCM (20 mL) were added EDCI (1 .99 g, 10.4 mmol, 1 .50 eq), HOBt (1 .40 g, 10.4 mmol, 1 .50 eq) and DIPEA (2.69 g, 20.8 mmol, 3.62 mL, 3.00 eq) at 20 °C, After stirring at 20 °C for 16 h. the mixture was concentrated to dry. The residue was purified by column chromatography (SIOz, petroleum ether/ethyl acetate = 2/1) to give tert-butyl 6-[methoxy(methyl)carbamoyl]-1 ,4-oxazepane-4-carboxylate (2.00 g, crude) as yellow oil.

Intermediate 400 tert-butyl 6-acetyl-1 ,4-oxazepane-4-carboxylate (racemate)

To a solution of tert-butyl 6-[methoxy(methyl)carbamoyl]-1 ,4-oxazepane-4-carboxylate (2.00 g, 6.24 mmol, 1 .00 eq) in THF (20 mL) was added MeMgBr (3 M in THF, 10.4 mL, 5.00 eq) at 0 °C. After stirring at 25 °C for 2 h, the reaction mixture was quenched by saturated ammonium chloride aqueous solution (20 mL) at 0 °C. The solution was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl 6-acetyl-1 ,4-oxazepane-4- carboxylate (1 .50 g, 6.17 mmol, 99% yield) as yellow oil.

Intermediate 401 tert-butyl 6-[7-(2-methoxy-4,6-dimethyi-phenyl)-1 ,8-naphthyridln-2-yl]-1 ,4-oxazepane-4- carboxylate (racemate)

To a solution of 2-amino-6-(2-methoxy-4,6-dimethyl-phenyl)pyridine-3-carbalde hyde (500 mg, 1.95 mmol, 1 .00 eq) and tert-butyl 6-acetyl-1 ,4-oxazepane-4-carboxylate (1 .42 g, 5.85 mmol, 3.00 eq) in EtOH (10 mL) was added DBU (891 mg, 5.85 mmol, 882 pL, 3.00 eq) at 20 °C. After stirring at 60 °C for 24 h, the mixture was concentrated to dry. The residue was purified by reversed phase (column: C18 40 g, mobile phase: [water (FA) - MeCN]; B%: 40%-70%,7 min) to give tert-butyl 6-[7-(2- methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1 ,4-oxazepane-4-carboxylate (200 mg, 406 pmol, 21 % yield, 94% purity) as yellow oil.

LC-MS (Method C): Rt = 0.514 min; MS (ESIpos): m/z = 464.4 [M+H] ⁺ .

Intermediate 402

3.5-dimethyi-2-(7-1 ,4-oxa2epan-6-yi)-1 naphthyridin-2-yl]phenoi (racemate)

To a solution of tert-butyl 6-[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1 ,4- oxazepane- 4-carboxylate (180 mg, 388 pmol, 1.00 eq) in DCM (0.20 mL) was added BBr ₃ (292 mg, 1.16 mmol, 112 pL, 3.00 eq) at -70 °C, After stirring at 25 °C for 0.5 h, the mixture was quenched by NHs • MeOH (7 M) at 20 °C. The pH of mixture was adjusted to 7. Then, filtered, the filtrate was concentrated to dry. The residue was purified by reversed phase (column: C18, 40 g, mobile phase: [water (FA) - MeCN]; B%: 40% - 70%, 5 min) to give 3,5-dimethyl-2-(7-1 ,4-oxazepan-6-yl)-1 ,8- naphthyridin-2- yl]phenol (130 mg, 368 pmol, 95% yield, 99% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.409 min; MS (ESIpos): m/z = 350.4 [M+H] ⁺ .

Compound 180 and 181

3.5-d!methyl-2-(7-1 ,4-oxazepan-6-yl)-1 ,8- naphthyridin-2-ylJphenol (single enantiomers)

3.5-dimethyl-2-(7-1 ,4-oxazepan-6-yl)-1 ,8- naphthyridin-2-yl]phenol was separated by SFC: (column: DAICEL CHIRALPAK AY-H (250 mm x 30 mm, 10 pm); mobile phase: [CO ₂ -i-PrOH (0.1 % NH ₃ *H ₂ O)]; B%:60%, isocratic elution mode) to give Compound 180 (36.0 mg, 102 pmoi, 27% yield, 98% purity) as a yellow solid and Compound 181 (54.5 mg, 147 pmol, 40% yield, 945% purity) as a yellow solid. Compound 180

^! H NMR (400 MHz, DMSO-(fe) 6 = 9.84 (s, 1 H), 8.40 (t, J = 8.0 Hz, 2H), 7.56 (t, J = 7.6 Hz, 2H), 6.64 (s, 1 H), 6.62 (s, 1 H), 3.76 (dd, J = 2.8, 10.8 Hz, 1 H), 3.69-3.67 (m, 1 H), 3.44-3.39 (m, 1 H), 3.38 (s, 1 H), 3.27-3.24 (m, 2H), 3.00-2.96 (m, 2H), 2.83-2.79 (m, 1 H), 2.26 (s, 3H), 2.10 (s, 3H).

LC-MS (Method C): Rt = 0.418 min; MS (ESIpos): m/z = 350.4 [M+H] ⁺

SFC (Rt - 0.900 min, ee% = 99%).

Compound 181

^! H NMR (400 MHz, DMSO-d ₆ ) 5 = 9.80 (s, 1 H), 8.44 (s, 1 H), 8.42 (s, 1 H), 7.62-7.56 (m, 2H), 6.64 (s, 1 H), 6.63 (s, 1 H), 3.90-3.86 (m, 1 H), 3.82-3.75 (m, 1 H), 3.60 (s, 1 H), 3.55-3.52 (m, 1 H), 3.43-3.38 (m, 1 H), 3.12-3.08 (m, 2H), 3.06-3.02 (m, 1 H), 2.98-2.91 (m, 1 H), 2.27 (s, 3H), 2.10 (s, 3H).

LC-MS (Method C): Rt = 0.391 min; MS (ESIpos): m/z = 350.2 [M+H] ⁺ SFC (Rt =1 .713 min, ee% = 90%).

Intermediate 403

4-bromo-2-methoxy-6-methyl-pheno! To a solution of 2-methoxy-6-methyl-phenol (50.0 g, 362 mmol, 1 eq) in AcOH (250 mL) was added NBS (64.4 g, 362 mmol, 1 eq). After stirring at 25 °C for 16 h, the volatiles were removed under reduced pressure. The residue was diluted with water (400 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layer was washed with saturated sodium bicarbonate (300 mL) dried over sodium sulfate filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOz, petroleum ether/ethyl acetate = 20/1) to give 4-bromo- 2-methoxy-6-methyl-phenol (74.0 g, 341 mmol, 94 % yield) as yellow oil.

¹ H NMR (400 MHz, MeOD) 6 = 6.86 (d, J = 2.0 Hz, 1 H), 6.81 (d, J = 2.0 Hz, 1 H), 3.81 (s, 3H), 2.15 (s, 3H).

Intermediate 404 methyl 4-hydroxy-3-methoxy-5-methyl-benzoate

To a solution of 4-bromo-2-methoxy-6-methyl-phenol (10.0 g, 46.1 mmol, 1 eq) in MeOH (200 mL) was added Pd(dppf)Clz (1 .69 g, 2.30 mmol, 0.05 eq) and EtsN (14.0 g, 138 mmol, 19.2 mL, 3 eq) under N? atmosphere. The suspension was degassed and purged with CO for 3 times. After stirring at 80 °C under CO (50 psi.) for 16 h, the mixture was filtered and concentrated to dry. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0) to give methyl 4- hydroxy-3-methoxy-5-methyl-benzoate (11 .0 g, 56.1 mmol, 20 % yield) as yellow oil.

¹ H NMR (400 MHz, CDCb) 6 = 7.53 (s, 1 H), 7.41 (d, J = 1.6 Hz, 1 H), 6.12 (s, 1 H), 3.93 (s, 3H), 3.90- 3.87 (m, 3H), 2.28 (s, 3H).

Intermediate 405 methyl 3-methoxy-5-methyl-4-(trifluoromethylsulfonyloxy)benzoate

To a solution of methyl 4-hydroxy-3-methoxy-5-methyl-benzoate (11.0 g, 56.1 mmol, 1 eq) in dichloromethane (100 mL)was added DIPEA (14.5 g, 112 mmol, 19.5 mL, 2 eq)and Tf2O (23.7 g, 84.1 mmol, 13.8 mL, 1 .5 eq) at 0 °C. After stirring at 25 °C for 2 h, the mixture was concentrated to dry.

The residue was purified by column chromatography (SiCb, Petroleum ether/Ethyl acetate = 1/0) to give methyl 3-methoxy-5-methyl-4-(trifluoromethylsulfonyloxy)benzoate (13.0 g, 39.6 mmol, 70 % yield) as a yellow solid.

^! H NMR (400 MHz, DMSO-d ₆ ) 5 = 7.61 (s, 1 H), 7.58 (d, J = 1.6 Hz, 1 H), 3.94 (s, 3H), 3.88 (s, 3H), 2.36 (s, 3H).

Intermediate 406 methyl 3-methoxy-5-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-clioxaborolan-2-yl)benzoate

To a solution of methyl 3-methoxy-5-methyl-4-(trifluoromethylsulfonyloxy)benzoate (13.0 g, 39.6 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3,2- dioxaborolane (12.1 g, 47.5 mmol, 1.2 eq)in dioxane (200 mL)was added Pd(dppf)Cl2 (2.90 g, 3.96 mmol, 0.1 eq) and KOAc (7.77 g, 79.2 mmol, 2 eq). After stirring at 100 °C for 16 hr, the mixture was filtered and concentrated to dry. The residue was purified by column chromatography (SIO ₂ , Petroleum ether/Ethyl acetate=1/0) to give methyl 3-methoxy-5-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzoate (15.0 g, 39.2 mmol, 98% yield, 80% purity) as a yellow solid ¹ H NMR (400 MHz, DMSO-d ₈ ) 6 = 7.61 (s, 1 H), 7.58 (s, 1 H), 3.94 (s, 3H), 3.88 (s, 3H), 2.36 (s, 3H), 1.16 (s, 12H).

Intermediate 407 benzyl 3-[7-(2-methoxy-4-methoxycarbonyl-6-methyl-phenyl)-1,§-naph thyridin-2-yl]piperidine- 1 -carboxylate (racemate)

To a mixture was benzyl 3-(7-chloro-1 ,8-naphthyridin-2-yl)piperidine-1 -carboxylate (300 mg, 785 pmol, 1 eq), methyl 3-methoxy-5-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (721 mg, 2.36 mmol, 3 eq) and K3PO4 (500 mg, 2.36 mmol, 3 eq) in THF (4 mL) was added XPhos Pd G3 (66.5 mg, 78.5 pmol, 0.1 eq) at 20 °C in one portion. After stirring at 60 °C for 48 h, the reaction mixture was diluted with water (50 ml), and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous Na?SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOz, Petroleum ether/Ethyl acetate = 5/1 to 1/1), and then purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(0.1% FA condition) - MeCN];B%: 35% - 75%, 5 min) to give benzyl 3-[7-(2-methoxy-4-methoxycarbonyl-6-methyl-phenyl)-1 ,8- naphthyridin-2-yl]piperidine-1 -carboxylate (350 mg, 532 pmol, 13 % yield, 80% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.578 min; MS (ESIpos): m/z = 526.3 [M+H] ⁺

Intermediate 408 benzyl 3-[7-(4-carbamoyl-2-methoxy-6-methyl-phenyl)-1 ,8-naphthyridin-2-yl]pipend!ne-1 - carboxylate (racemate)

NH3 was bubbled into MeOH (20 mL) at -70°C for 10 minutes. After the mixture of benzyl 3-[7-(2- methoxy-4-methoxycarbonyl-6-methyl-phenyl)-1 ,8-naphthyridin-2-yl]piperidine-1 -carboxylate (350 mg, 665 pmol, 1 eq) in above solution (10 mL) stirring at 60 °C for 3 days, the reaction mixture was diluted with water (30 ml), and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous NazSOi, filtered and the filtrate was concentrated under reduced pressure to give benzyl 3-[7-(4-carbamoyl-2-methoxy-6-methyl-phenyl)- 1 ,8-naphthyridin-2-yl]piperidine-1 -carboxylate (300 mg, 587 pmol, 88% yield) as a yellow solid.

LC-MS (Method C): Rt = 0.489 min; MS (ESIpos): m/z = 511 .3 [M+H] ⁺

Intermediate 409 3-methoxy-5-methyl-4-[7-(1-methyl-3-piperidyl)-1,8-naphthynd ln-2-yl]benzarmde (racemate)To a solution of benzyl 3-[7-(4-carbamoyl-2-methoxy-6-methyl-phenyl)-1 ,8-naphthyrid in-2-yl]piperidine-1 - carboxylate (300 mg, 587 pmol, 1 eq) and HCHO (176 mg, 1 .76 mmol, 161 pL, 30% purity, 3 eq) in MeOH (10 mL) was added Pd/C (62.5 mg, 58.7 pmol, 10% purity, 0.1 eq) at 20 °C in one portion. After stirring at 20 °C for 1 .5 hr under H2 (15 psi) atmosphere, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(0.1 % FA condition) - MeCN];B%: 35% - 40%, 8 min) to give 3-methoxy-5-methyl-4-[7-(1-methyl-3-piperidyl)-1 ,8-naphthyridin-2- yl]benzamide (90.0 mg, 195 pmol, 33 % yield, 85% purity) as a light yellow solid.

LC-MS (Method C): Rt = 0.372 min; MS (ESIpos): m/z = 391 .3 [M+H] ⁺

Intermediate 410

3-hydroxy-5-methyl-4-[7-(1 -methyl-3-piperidyl)-1 ,8-naphthyridin-2-yl]benzamide (racemate) To a solution of 3-methoxy-5-methyl-4-[7-(1-methyl-3-piperidyl)-1 ,8-naphthyridin-2-yl]benzamide (90.0 mg, 230 pmol, 1 eq) in DMF (1 .5 mL) was added NaSEt (387 mg, 4.61 mmol, 20 eq) at 20 °C in one portion. After stirring at 100 °C for 16 hr, the reaction mixture filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(0.1% NH3 H2O condition) - MeCN]; B%: 25% - 35%, 7 min) to give 3-hydroxy-5-methyl-4-[7-(1-methyl-3-piperidyl)-1 ,8-naphthyridin-2-yl]benzamide (40.0 mg, 100 pmol, 43% yield, 95% purity) as a yellow solid

LC-MS (Method C): Rt = 0.649 min; MS (ESIpos): m/z = 377.3 [M+H] ⁺

Intermediate 411

3-hydroxy-S-methyl-4-[7-(1 -methyl-3-piperidyl)-1 , 8-naphthyridin-2 -yl] benzonitrile (racemate) To a solution of 3-hydroxy-5-methyl-4-[7-(1-methyl-3-piperidyl)-1 ,8-naphthyridin-2-yl]benzamide (60.0 mg, 159 pmol, 1 eq) and TEA (64.5 mg, 637 pmol, 88.7 pL, 4 eq) in dichloromethane (5 mL) was added TFAA (133 mg, 637 pmol, 88.6 pL, 4 eq) at Q°C in one portion. After stirring at 0 °C for 1 hr, the mixture was quenched by MeOH at 0°C. The mixture was concentrated to give a residue. The residue was purified by reversed-phase column (column: Cl 8, 40 g, mobile phase: [water (0.1 % NH3 H2O condition) - MeCN); B%: 40% - 60%, 10 min) to give 3-hydroxy-5-methyl-4-[7-(1-methyl-3-piperidyl)- 1 ,8-naphthyridin-2-y!]benzonitrile (40.0 mg, 106 pmol, 66% yield, 95% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.628 min; MS (ESIpos): m/z = 359.3 [M+H] ⁺

Compound 182 and 183

3-hydroxy-5-methyi-4-[7-(1 -methyi-3-piperidyi)-1 ,8-naphthyridin-2-yl]benzonitrile (single enantiomers)

3-hydroxy-5-methyl-4-[7-(1-methyl-3-piperidyl)-1 ,8-naphthyridin-2-yl]benzonitrile was separated by SFC: ( column: DAICEL CHIRALPAK IG (250mm x 30 mm, 10 pm); mobile phase: [CO ₂ -i-PrOH (0.1 % NHs-HaO)]; B%: 52%, isocratic elution mode) to give compound 19 (9.74 mg, 26.9 pmol, 24% yield, 99% purity) as a yellow solid and compound 20 (14.9 mg, 40.3 pmol, 36 % yield, 97% purity) as an orange solid.

Compound 182

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 = 10.59-10.19 (m, 1 H), 8.46 (d, J = 8.4 Hz, 1 H), 8.42 (d, J = 8.4 Hz, 1 H), 7.65 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.28 (s, 1 H), 7.16 (s, 1 H), 3.19-3.08 (m, 1 H), 3.06-2.99 (m, 1 H), 2.84-2.76 (m, 1 H), 2.24-2.18 (m, 4H), 2.07 (s, 3H), 1.99 (d, J = 10.8 Hz, 1 H), 1 .94- 1.87 (m, 1 H), 1.79-1.74 (m, 1 H), 1.69-1.57 (m, 2H).

LC-MS (Method C): Rt = 0.394 min; MS (ESIpos): m/z = 359.1 [M+H] ⁺ SFC (Rt = 0.976, ee% = 97%)

Compound 183

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 = 10.44-10.21 (m, 1 H), 8.52-8.47 (m, 1 H), 8.46 (d, J = 8.4 Hz, 1 H), 7.67 (d, J = 8.4 Hz, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.30 (s, 1 H), 7.18 (d, J = 0.8 Hz, 1 H), 3.25 (d, J = 6.8 Hz, 2H), 3.04-2.96 (m, 1 H), 2.65-2.51 (m, 1 H), 2.42 (br s, 3H), 2.30-2.21 (m, 1 H), 2.09-2.01 (m, 4H), 1 .86-1 .68 (m, 2H), 1 .66-1 .57 (m, 1 H)

LC-MS (Method C): Rt = 0.397 min; MS (ESIpos): m/z = 359.1 [M+H] ⁺ SFC (Rt = 1 .500, ee% = 97%)

Intermediate 412 4-chioro-7-(2-methoxy-4 _! 6-dimethyl-phenyl)-2-(1 ,2 _! 3,6-tetrahydropyridin-5-yl)-1 ,8-naphthyridine A mixture of tert-butyl 5-[4-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-3,6- dihydro-2H-pyridine-1 -carboxylate (3.40 g, 7.08 mmol, 1 eg), HCI (4 M in dioxane, 40 mL, 23 eg) was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuum to give 4-chloro-7-(2- methoxy-4,6-dimethyi-phenyl)-2-(1 , 2, 3, 6-tetrahydropyridin-5-yl)-1 ,8-naphthyridine (2.95 g, 7.09 mmol, 100% yield, HCI salt) as a yellow solid.

Intermediate 413

4-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-2-(1-methyl-3 _! 6-dihydro-2H-pyridin-5-yl)-1 ,8- naphthyridine

To a solution of 4-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-2-(1 ,2,3,6-tetrahydropyridin-5-yl)-1 ,8- naphthyridine (2.95 g, 7.09 mmol, 1 eq, HCI salt) in MeOH (30 mL) was added HCHO (1 .73 g, 21 .2 mmol, 1 .58 mL, 37% purity, 3 eq) and KOAc (1 .39 g, 14.2 mmol, 2 eq) at 0 °C, then NaBH(OAc)3 (4.51 g, 21 .3 mmol, 3 eq) was added to the mixture at 0 °C. After stirring at 25 °C for 14 h. the mixture was added into ammonium chloride (50 mL) at 0 °C. The pH of the mixture was adjusted to 8-9 with saturated sodium bicarbonate at 0 °C. The mixture was extracted with ethyl acetate (100 mL x 3). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The product was purified by reversed-phase(instrument: 80 g Flash; Column: Welch Ultimate XB__C18 20-40pm; eluent A: water (0.1 % FA), eluent B: acetonitrile; gradient: 0-20 min 0- 30% B, 20-25 min 30% B; flow 80 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give 4-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-2-(1-methyl-3,6-d ihydro-2H-pyridin-5-yl)-1 ,8- naphthyridine (1.3 g, 3.30 mmol, 46.58% yield) as a red solid.

LC-MS (Method C): Rt = 0.483 min; MS (ESI) m/z = 394.2 [M+H] ⁺ .

Intermediate 414 tert-butyl N-[[7-(2-methoxy-4,6-dimethyl-phenyl)-2-(1-methyl-3,6-dihydr o-2H-pyndin-5-yl)-1 ,8- naphthyndin-4-yl]methyl] carbamate

To a solution of 4-chloro-7-(2-methoxy-4,6-dimethyl-phenyl)-2-(1-methyl-3,6-d ihydro-2H-pyridin-5-yl)-

1 .8-naphthyridine (960 mg, 2.44 mmol, 1 eq), potassium;(tert-butoxycarbonylamino)methyl-trifluoro- boranuide (2.89 g, 12.2 mmol, 5 eq) and CS2CO3 (1 .59 g, 4.87 mmol, 2 eq) in H2O (3 mL) and dioxane (10 mL) was added Pd(OAc)2 (54.7 mg, 244 pmol, 0.1 eq) and bis(1-adamantyl)-butyl-phosphane (131 mg, 366 pmol, 0.15 eq) at 25 °C. After stirring at 100 °C for 14 h, the reaction mixture was concentrated in vacuum to give a residue. The product was purified by reversed-phase (instrument: 80 g Flash; Column: Welch Ultimate XB_C18 20-40pm; eluent A: water (0.1 % FA), eluent B: acetonitrile; gradient: 0-10 min 0-25% B, 10-20 min 25% B; flow 80 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give tert-butyl N-[[7-(2-methoxy-4,6-dimethyl-phenyl)-2-(1- methyl-3,6-dihydro-2H-pyridin-5-yl)-1 ,8-naphthyridin-4-yl]methyl] carbamate (580 mg, 1.19 mmol, 49% yield) as a brown solid.

LC-MS (Method C): Rt = 0.537 min; MS (ESI) m/z = 489.4 [M+H] ⁺ .

Intermediate 415 [/-(Z-methoxy^iS-dimethyl-phenyll-Z-CI-methyl-SjS-dihydro^H- pyndin-S-yO-l iS-naphthyridin^- yi] methanamine

A mixture of tert-butyl N-[[7-(2-methoxy-4,6-dimethyl-phenyl)-2-(1 -methyl-3,6-dihydro-2H-pyridin-5-yl)-

1.8-naphthyridin-4-ylJmethyl]carbamate (530 mg, 1.08 mmol, 1 eq), HCI (4 M in dioxane, 10 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated in vacuum to give [7-(2-methoxy-4,6- dimethyl-phenyl)-2-(1 -methyl-3,6-dihydro-2H-pyridin-5-yl)-1 ,8-naphthyridin-4-yn methanamine (461 mg, 1.08 mmol, 100% yield, HCI salt) as a brown solid.

LC-MS (Method C): Rt = 0.424 min; MS (ESI) m/z = 423.5 [M+H] ⁺ .

Intermediate 416

N-[[7-(2-methoxy-4,6-dimetbyLphenyl)~2-(1~methyL3,6-dihyd ro-2H-py!'idin-5-yl)-1.8- naphthyridin-4-yl]methyl]acetamide

To a solution of [7-(2-methoxy-4,6-dimethyl-phenyl)-2-(1-methyl-3,6-dihydro-2 H-pyridin-5-yl)-1 ,8- naphthyridin-4-yl]methanamine (461 mg, 1.08 mmol, 1 eq, HCI salt) in DCM (5 mL) was added EtsN (659 mg, 6.51 mmol, 906 pL, 6 eq) and AC2O (133 mg, 1.30 mmol, 122 pL, 1.2 eq) at 0 °C. After stirring at 25 °C for 14 h, the reaction mixture was concentrated in vacuum to give a residue. The product was purified by reversed-phase (instrument: 80 g Flash; Column: Welch Ultimate XB_C18 20- 40pm; eluent A: water (0.1 % FA), eluent B: acetonitrile; gradient: 0-15 min 0-30% B, 15-20 min 30% B; flow 80 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give N-[[7-(2- methoxy-4,6-dimethyl-phenyl)-2-(1-methyl-3,6-dihydro-2H-pyri din-5-yl)-1 ,8-naphthyridin-4- yl]methyl]acetamide (370 mg, 859 pmol, 79% yield) as a brown solid.

LC-MS (Method C): Rt = 0.429 min; MS (ESI) m/z = 431 .3 [M+HJ*.

Intermediate 417 N-[[7-(2-methoxy-4,6-dimethyl-phenyl)-2-(1-methyl-3-pipendyl )-1 _! 8-naphthyridin-4- yl]methyl]acetamide (racemate)

To a solution of N-[[7-(2-methoxy-4,6-dimethyl-phenyl)-2-(1-methyl-3,6-dihydr o-2H-pyridin-5-yl)-1 ,8- naphthyridin-4-yl]methyl]acetamide (370 mg, 859 pmol, 1 eq) in MeOH (4 mL) was added Pd/C (40 mg, 10% purity) under N2 atmosphere. The suspension was degassed under vacuum and purged with H2 (15 psi) several times. After stirring under H2 (15 psi) at 25 °C for 8 h, the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuum to give a residue. The product was purified by reversed-phase (instrument: 80 g Flash; Column: Welch Ultimate XB_C18 20-40pm; eluent A: water (0.1 % FA), eluent B: acetonitrile; gradient: 0-20 min 0-20% B, 20-25 min 20% B; flow 80 mL/min; temperature: room temperature; Detector: UV 220/254 nm) to give N-[[7-(2-methoxy-4,6- dimethyl-phenyl)-2-(1-methyl-3-piperidyl)-1 ,8-naphthyridin-4-yl]methyl]acetamide (240 mg, 555 pmol, 65% yield) as a yellow solid.

LC-MS (Method C): Rt = 0.764 min; MS (ESI) m/z = 433.3 [M+H] ⁺ .

Intermediate 418

N-[[7-(2-hydroxy-4,6-dimethyl-phenyl)-2-(1-methyl-3-piper idyl)-1 ,8-naphthyndin-4- yljmethyljacetamide (racemate)

To a solution of N-[[7-(2-methoxy-4,6-dimethyl-phenyl)-2-(1-methyl-3-piperidy l)-1 ,8-naphthyridin-4- yl]methyljacetamide (210 mg, 485 pmol, 1 eq) in DCM (2 mL)was added BBrs (365 mg, 1 .46 mmol, 140 pL, 3 eq) at 0 °C. After stirring at 25°C for 4 h, the mixture was added dropwise to ice water (5 mL) at 0 °C. The pH of mixture was adjusted to 8 by saturated sodium bicarbonate aqueous solution and extracted with DCM (15 mL x 3), the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase(instrument: 80 g Flash; Column: Welch Ultimate XB_C18 20-40pm; eluent A: water (0.1 % FA), eluent B: acetonitrile; gradient: 0-5 min 0-10% B,5-10 min 10% B ; flow 80 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give N-[[7-(2-hydroxy-4,6-dimethyi-phenyl)-2-(1-methyl-3-piperidy l)-1 ,8-naphthyridin-4- yl]methyl]acetamide (90 mg, 213 pmol, 44% yield) as a yellow solid, LC-MS (Method C): Rt = 0.410 min; MS (ESI) m/z = 419.2 [M+H] ⁺ .

Compound 184 and 185

N-[[7-(2-hydroxy-4,6-dimethyi-phenyl)-2-(1-methyi-3-piper idyi)-1 ,8-naphthyridin-4- yl]methyi]acetamide (single enantiomers)

N-[[7-(2-hydroxy-4,6-dimethyl-phenyl)-2-(1-methyl-3-piper idyl)-1 ,8-naphthyridin-4-yl]methyl]acetamide was separated by SFC: (column: DAICEL CHIRALPAK IK(250mm*30mm,10 um);mobile phase: [CO ₂ - i-PrOH(0.1 %NH3 ^< 'H2O)]; B%: 50%, isocratic elution mode) to give compound 21 (22.5 mg, 47.2 pmol, 97% purity, FA salt) as brown gum and compound 22 (53.7 mg, 123 pmol, 96% purity) as brown gum.

Compound 184 ¹ H NMR (400 MHz, DMSO-d ₆ ) 6 = 8.56-8.56 (m, 2H), 8.31 (s, 1 H), 8.20 (s, 1 H), 7.57 (d, J = 4.0 Hz 1 H), 7.46 (s, 1 H), 6.62 (d, J = 4.0 Hz 1 H), 4.77-4.76 (m, 2H), 3.21-3.18 (m, 2H), 3.17 (s, 1 H), 2.37 (s, 3H), 2.26 (s, 3H), 2.08-2.02 (m, 1 H), 2.01 (s, 3H),1 .99-1 .94 (m, 4H), 1.79-1.63 (m, 2H).

LC-MS (Method C): Rt = 0.729 min; MS (ESI) m/z = 419.2 [M+H] ⁺ .

SFC (Rt = 1 .767 min, ee% = 99%).

Compound 185

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 = 8.54 (s, 1 H), 8.52 (s, 1 H), 7.55 (d, J = 4.0 Hz, 1 H), 7.45 (s, 1 H), 6.64(s, 1 H), 6.60 (s, 1 H), 4.75 (d, J = 4.0 Hz, 2H), 3.11 -3.10 (m, 1 H), 3.08-3.06 (m, 1 H), 3.02-3.01 (m, 1 H), 2.25 (s, 1 H), 2.22 (s, 3H), 2.19-2.16 (m, 1 H), 2.08 (s, 3H), 1.93-1.75 (m, 4H), 1.64-1.59 (m, 4H). LC-MS (Method C): Rt = 0.734 min; MS (ESI) m/z = 419.2 [M+H] ⁺ .

SFC (Rt = 2.224 min, ee% = 97%).

Intermediate 419 tert-butyl 3-f!uoro-5-[methoxy(methyl)carbamoyl]plperidlne-1 -carboxylate

To a solution of 1-tert-butoxycarbonyl-5-fluoro-piperidine-3-carboxylic acid (1.00 g, 4.04 mmol, 1 eq) and N-methoxymethanamine hydrochloride (788 mg, 8.09 mmol, 2 eq) in dichloromethane (20 mL) was added EDCI (1.16 g, 6.07 mmol, 1.5 eq) , HOBt (819 mg, 6.07 mmol, 1.5 eq) and DIPEA (2.61 g, 20.2 mmol, 3.52 mL, 5 eq) at 25 °C. After stirring at 25 °C for 16 h, the reaction mixture was concentrated in vacuum to give a residue. The residue was purified by column chromatography (S1O ₂ , petroleum ether/ethyl acetate = 10/1 to 2/1) to give a tert-butyl 3-fluoro-5-[methoxy(methyl)carbamoyl]piperidine- 1 -carboxylate (1.10 g, 3,79 mmol, 93% yield) as colorless oil.

¹ H NMR (400 MHz, CDCh) <5 [ppm] = 4.52-4.32 (m, 1 H), 4.31-4.04 (m, 1 H), 3.81 -3.66 (m, 3H), 3.29- 3.10 (m, 3H), 3.01-2.84 (m, 1 H), 2.83-2.43 (m, 2H), 2.40-2.25 (m, 1 H), 1 .97-1 .75 (m, 1 H), 1 .74-1 .54 (m, 1 H), 1.52-1.43 (m, 9H)

Intermediate 420 tert-butyl 3-acetyl-5-fluoro-piperidine-1 -carboxylate

To a solution of tert-butyl 3-fluoro-5-[methoxy(methyl)carbamoyl]piperidine-1-carboxylat e (1.1 g, 3.79 mmol, 1 eq) in tetrahydrofuran (20 mL) was added MeMgBr (3 M in tetrahydrofuran, 3.79 mL, 3 eq) at 0 °C. After stirring at 25 °C for 2 h, the mixture was added saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (15 mL), the combined organic phase were concentrated to give a tert-butyl 3-acetyl-5-fluoro-piperidine-1 -carboxylate (900 mg, 3.67 mmol, 96% yield) as colorless oil.

¹ H NMR (400 MHz, CDCh) 5 [ppm] = 4.68-4.41 (m, 1 H), 4.32-4.02 (m, 2H), 2.59 (s, 1 H), 2.46-2.31 (m, 1 H), 2.22 (s, 3H), 1 .76 ( d, J = 11 .6 Hz, 1 H), 1 .73-1 .58 (m, 2H), 1 .47 (s, 9H)

Intermediate 421 tert-butyl 3-fluoro-5-[7-(2-hydroxy-4,6-dlmethyl-pheny!)-1,8-naphthyrid ln-2-yl]piperldine-1- carboxylate To a solution of tert-butyl 3-acetyl-5-fluoro-piperidine-1 -carboxylate (900 mg, 3.67 mmol, 1 eq) and 2- amino-6-(2-hydroxy-4,6-dimethyl-phenyl)pyridine-3-carbaldehy de (300 mg, 1.24 mmol, 3.37e-1 eq) in methanol (20 mL) was added DBU (1 .68 g, 11 .01 mmol, 1 .66 ml_, 3 eq) at 25 °C. After stirring at 60 °C for 16 h, the mixture was concentrated to give a crude and the crude was purified by column chromatography (SIO ₂ , Petroleum ether/Ethyl acetate=10/1 to 2/1) to give a tert-butyl 3-fluoro-5-[7-(2- hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]piperidine-1-carboxylate (300 mg, 664 pmol, 18% yield) as yellow oil.

LC-MS (Method C): Rt = 0.529 min; MS (ESIpos): m/z - 452.2 [M+1 ] ⁺ .

Intermediate 422

2-[7-(5-fluoro-3-pipendy0-1 _! 8-naphthyndin-2-yl]-3.5-dimethyl-phenol

To a solution of tert-butyl 3-fluoro-5-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2- yl]piperidine-1 -carboxylate (300 mg, 664 pmol, 1 eq) in dichloromethane (15 mL) was added TFA (227 mg, 1 .99 mmol, 148 pL, 3 eq) at 25°C. After stirring at 25 °C for 2 h, the reaction mixture was concentrated in vacuum to give a 2-[7-(5-fluoro-3-piperidyi)-1 ,8-naphthyridin-2-yl]-3,5-dimethyl-phenol (220 mg, 626.04 pmol, 94.23% yield, TFA salt) as yellow oil..

LC-MS (Method C): Rt = 0.387 min; MS (ESIpos): m/z = 352.1 [M+1J*.

Compound 186, 187, 188 and 189

4-[6-(2~hydrGxy~4.6~dimethyi~phenyl)pyi'idG[2.3--b]pyrazi i'i~3-yl]tetrahydrGpyi'an'3~ai

To a solution of 2-[7-(5-fluoro-3-piperidyl)-1 ,8-naphthyridin-2-yl]-3,5-dimethyl-phenol (220 mg, 626 pmol, 1 eq TFA salt) in methanol (15 mL) was added NaBHsCN (59.0 mg, 939 pmol, 1 .5 eq) , potassium acetate (184 mg, 1 .88 mmol, 3 eq) and (HCHO)n (28.1 mg, 939 pmol, 1 .5 eq) at 25 °C. After stirring at 25 °C for 2 h, the mixture was filtrated and the filtrate was purified by reversed-phase column (column: C1820 g, mobile phase: [water (FA) - MeCN]; B%: 20% - 80%, 10 min) to give a 2-[7-(5-fluoro-1-methyl-

3-piperidyl)-1 ,8-naphthyridln-2-yl]-3,5-dimethyl-phenol (150 mg, 410 pmol, 65% yield) as yellow oil as a mixture of 4 diastereoisomers. The residue was separated by SFC (column: The residue was purified by SFC (column: DAICEL CHIRALPAK IC(250mm*30mm,10um);mobile phase: [COz-ACN/i- PrOH(0.1 % NH3HzO)];B%:45%, isocratic elution mode) to give Compound 186 2-[7-[5-fluoro-1-methyl- 3-piperidyl]-1 ,8-naphthyridin-2-yl]-3,5-dimethyl-phenol (12.4 mg, 33.7 pmol, 6% yield, 99% purity) as a white solid; Compound 187 2-[7-[5-fluoro-1-methyl-3-piperidyl]-1 ,8-naphthyridin-2-yl]-3,5-dimethyl- phenol (20.64 mg, 55.91 pmol, 11 .35% yield, 99% purity) as a white solid, and a third fraction (150 mg) as a yellow oil, which was further separated by SFC (column: DAICEL CHIRALPAK AS(250mm*30mm,10um);mobile phase: [CO ₂ -i-PrOH(0.1 %NH3H2O)];B%:25%, isocratic elution mode) to give Compound 188 2-[7-[5-fluoro-1-methyl-3-piperidyl]-1 ,8-naphthyridin-2-yl]-3,5-dimethyl-phenol (46.0 mg, 124 pmol, 25.31 % yield, 99% purity) as a white solid, and Compound 188 2-[7-[5-fluoro-1- methyl-3-piperidyl]-1 ,8-naphthyridin-2-yl]-3,5-dimethyl-phenol (73.2 mg, 174 pmol, 35.41 % yield, 98% purity, FA salt) as a white solid.

Compound 186 ¹ H NMR (400 MHz, DMSO-ofe) 5 [ppm] = 8.41 (dd, J = 6.4, 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 6.62 (d, J = 7.6 Hz, 2H), 5.00-4.62 (m, 1 H), 3.20-3.14 (m, 2H), 3.03 ( d, J = 1 1 .2 Hz, 1 H), 2.43 ( s, 1 H), 2.30 (s, 3H), 2.26 (s, 3H), 2.15 (t, J = 11 .2 Hz, 1 H), 2.08 (s, 3H), 1.99 (dt, J = 5.4, 10.0 Hz, 1 H), 1 .83 (m, J = 11.6 Hz, 1 H)

LC-MS (Method C): Rt = 0.412 min; MS (ESIpos): m/z = 366.2 [M+1] ⁺ .

SFC (Rt = 1 .554 min, ee% = 99%)

Compound 187

¹ H NMR (400 MHz, DMSO-da) 6 [ppm] = 8.41 (dd, J = 6.0, 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 6.62 (d, J = 10.0 Hz, 2H), 5.01-4.65 (m, 1 H), 3.19-3.14 (m, 2H), 3.03 ( d, J = 11.2 Hz, 1 H), 2.45-2.40 (m, 1 H), 2.30 (s, 3H), 2.26 (s, 3H), 2.19-2.12 (m, 1 H), 2.07 (s, 3H), 2.03-1.96 (m, 1 H), 1.87-1.79 (m, 1 H)

LC-MS (Method C): Rt = 0.424 min; MS (ESIpos): m/z = 366.1 [M+1 ] ⁺

SFC (Rt = 1 .693 min, ee% = 97%)

Compound 188

¹ H NMR (400 MHz, DMSO-c/6) 5 [ppm] = 8.39 (dd, J = 4.8, 8.4 Hz, 2H), 7.70-7.51 (m, 2H), 6.60 (d, J = 16.4 Hz, 2H), 5.10-4.91 (m, 1 H), 3.08-2.94 (m, 3H), 2.31-2.26 (m, 1 H), 2.25 (s, 3H), 2.23 (s, 3H), 2.21- 2.10 (m, 2H), 2.08 (s, 3H), 2.06-1.96 (m, 1 H)

LC-MS (Method C): Rt = 0.402 min; MS (ESIpos): m/z = 366.1 [M+1] ⁺

SFC (Rt = 1 .197 min, ee% = 100%)

Compound 189

¹ H NMR (400 MHz, DMSO-cfe) 5 [ppm] = 9.76 (br s, 1 H), 8.42 (dd, J = 7.2, 8.4 Hz, 2H), 7.71-7.63 (m, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 6.63 (d, J = 6.8 Hz, 2H), 5.23-4.94 (m, 1 H), 3.23 (d, J = 10.4 Hz, 3H), 2.59 (s, 1 H), 2.41 (s, 3H), 2.26 (s, 3H), 2.24-2.10 (m, 2H), 2.09-2.06 (m, 3H), 2.05-1 .95 (m, 1 H) LC-MS (Method C): Rt = 0.409 min; MS (ESIpos): m/z = 366.2 [M+1] ⁺ SFC (Rt = 1 .586 min, ee% = 99%)

Intermediate 422

3 _! 5-dimethyl-2-[3-[(3R)-3-pipendyl]pyndo[2,3-b]pyi'azin- 6-yl]phenol

To a solution of tert-butyl (3R)-3-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazi n-3-yl]piperidine- 1-carboxyiate (1 g, 2.30 mmol, 1 eq) in DCM (10 mL) was added TFA (262 mg, 2.30 mmol, 171 pL, 1 eq) at 25°C. After stirring at 25 °C for 1 h , the reaction mixture was concentrated in vacuum to give 3,5-dimethyl-2-[3-[(3R)-3-piperidyi]pyrido[2,3-b]pyrazin-6-y l]phenol (2.1 g, 2.11 mmol, 92% yield, 91 % purity, 5TFA) as black brown oil.

LC-MS (Method C): Rt = 0.419 min; MS (ESIpos): m/z = 335.1 [M+1] ⁺ .

Compound 190

3 _! 5-dimethyl-2-[3-[(3R)-3-pipendyl]pyndo[2,3-b]pyi'azin- 6-yl]phenol 3.5-dimethyl-2-[3-[(3R)-3-piperidyl]pyrido[2,3-b]pyrazin-6-y l]phenol was purification by reversed-phase column (column: C18 80 g, mobile phase: [water (FA) - MeCN]; B%: 30% - 60%, 15 min) to give 3,5- dimethyl-2-[3-[(3R)-3-piperidyl]pyrido[2,3-b]pyrazin-6-yl]ph enol (38.3 mg, 112 pmol, 19% yield, 98% purity) as a orange solid

LC-MS (Method C): Rt = 0.395 min; MS (ESIpos): m/z = 335.1 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₅ ) 6 = 9.58 (s, 1 H), 9.12 (s, 1 H), 8.85 (d, J = 8.4 Hz, 1 H), 8.52 (d, J = 8.8 Hz, 1 H), 7.82 (d, J = 8.8 Hz, 1 H), 6.65 (s, 1 H), 6.63 (s, 1 H), 3.65 (d, J = 12.8 Hz, 1 H)„ 3.58-3.50 (m, 1 H), 3.35-3.29 (m, 2H), 3.08-2.93 (m, 1 H), 2.26 (s, 3H), 2.23 (s, 1 H), 2.07 (s, 3H), 2.00-1.93 (m, 1 H), 1.91-1.84 (m, 1 H), 1.82 (d, J = 9.6 Hz, 1 H).

Intermediate 423

3.5-dimethyl-2-[3-(3~pipe!'idyi)pyi'ido[2 _! 3~b]pyrazin~6-yl]phenoi (racemate)

To a solution of tert-butyl 3-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazin-3-y l]piperidine-1- carboxylate (500 mg, 1.15 mmol, 1 eq) in dioxane (5 mL) was added HCI/dioxane (4 M, 2.88 mL, 10 eq) at 0 °C dropwise. The mixture was stirred at 0 °C for 2 hours. The mixture was concentrated in vacuum to give 3,5-dimethyl-2-[3-(3-piperidyl)pyrido[2,3-b]pyrazin-6-yl]phe nol (400 mg, 1.08 mmol, 93.73% yield, HCI salt) was obtained as a black brown solid

LC-MS (Method C): Rt =0.422; MS (ESI) m/z = 335.2 [M+H] ⁺ .

Compound 191

3.5-dimethyb2-[3-[3-pipendyl]pyddo(2,3-b]pyrazm-S-yt]phen ol

The racemate was separated by SFC (column: DAICEL CHIRALPAK IC(250mm*30mm,10um);mobile phase: [CO ₂ -ACN/i-PrOH(0.1 % NH3*H2O)];B%:50%, isocratic elution mode) to give 3,5-dimethyl-2-[3- [rel-(3R)-3-piperidyl]pyrido[2,3-b]pyrazin-6-yi]phenoi (9.21 mg, 27.27 pmol, 9.12% yield, 99% purity) as a white solid and 3,5-dimethyi-2-[3-[rel-(3R)-3-piperidyl]pyrido[2,3-b]pyrazin -6-yl]phenol (9.21 mg, 27.27 pmol, 9.12% yield, 99% purity) as a white solid.

Compound 190 (stereochemistry assigned from enantiopure synthesis of compound 190)

¹ H NMR (400 MHz, DMSO-d _s ) 5 [ppm] = 9.06 (s, 1 H), 8.48 (d, J = 8.4 Hz, 1 H), 8.33 (s, 1 H), 7.78 (d, J = 8.4 Hz, 1 H), 6.65 (s, 1 H), 6.63 (s, 1 H), 3.40-3.34 (m, 2H), 3.13-3.09 (m, 1 H), 3.06-3.01 (m, 1 H), 2.74- 2.66 (m, 1 H), 2.26 (s, 3H), 2.19-2.11 (m, 1 H), 2.07 (s, 3H), 1.89-1.77 (m, 2H), 1.60 (s, 1 H).

LC-MS (Method C): Rt =0.414; MS (ESI) m/z = 335.2 [M+H] ⁺ .

SFC (Rt = 0.810 min, ee% = 96%)

Compound 191 3 _! 5-dimetbyi-2-[3-[(3S)-3-p!peridyl]pyi'ido[2 _> 3-b]pyrazin-6-yl]pbena^ (stereochemistry assigned as S, from enantiopure synthesis of compound 190)

¹ H NMR (400 MHz, DMSO-d _e ) 5 [ppm] = 8.66 (s, 1 H), 8.09 (d, J = 8.4 Hz, 1 H), 7.94 (s, 1 H), 7.39 (d, J = 8.4 Hz, 1 H), 6.25 (s, 1 H), 6.22 (s, 1 H), 3.04-2.95 (m, 2H), 2.77-2.66 (m, 2H), 2.40-2.29 (m, 1 H), 1.86 (s, 3H), 1 .80-1 .73 (m, 1 H), 1 .67 (s, 3H), 1 .47-1 .37 (m, 2H), 1 .36-1 .25 (m, 1 H).

LC-MS (Method C): Rt =0.412; MS (ESI) m/z = 335.2 [M+H] ⁺ .

SFC (Rt = 1 .474 min, ee% = 84%) Intermediate 424

2-bromo-5-methoxy-3-methyl-phenol

To a mixture of 3-methoxy-5-methyl-phenol (30.0 g, 217 mmol, 1 eq) in CCU (320 mL) was added NBS (38.6 g, 217 mmol, 1 eq) at 0 °C. After stirring at 25 °C for 0.5 h, the mixture was filtered and the filtrate was concentrated at reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=5/1) to give 2-bromo-5-methoxy-3-methyl- phenol (20.0 g, 92.1 mmol, 42% yield) as white solid.

¹ H NMR (400 MHz, CDCh) 6 = 6.47 (d, J = 2.8 Hz, 1 H), 6.43 (d, J = 2.8 Hz, 1 H), 5.60 (s, 1 H), 3.77 (s, 3H), 2.37 (s, 3H).

Intermediate 425

1-benzyloxy-2-bi'omo-5-methoxy-3-methyl-benzene

To a mixture of 2-bromo-5-methoxy-3-methyl-phenol (20.0 g, 92.1 mmol, 1 eq) and K2CO3 (31.8 g, 230 mmol, 2.5 eq) in MeCN (200 mL) was added BnBr (16.1 g, 94.0 mmol, 11 .2 mL, 1 .02 eq) at 25°C. After stirring at 80 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate= 100/1) to give 1-benzyloxy-2-bromo-5-methoxy-3-methyl- benzene (28.0 g, 91 .2 mmol, 98% yield) as a brown solid.

¹ H NMR (400 MHz, CDCh) 6 = 7.51 (d, J = 7.6 Hz, 2H), 7.45 - 7.38 (m, 2H), 7.34 (d, J = 7.2 Hz, 1 H), 6.46 (d, J = 2.8 Hz, 1 H), 6.41 (d, J = 2.4 Hz, 1 H), 5.14 (s, 2H), 3.77 (s, 3H), 2.43 (s, 3H).

Intermediate 426

2-(2-benzyloxy-4~methoxy-6~methyl-phenyl)-4,4,5.5-tet? ^, amethyi~1,3.2-diaxabO!'olane

To a mixture of 1-benzyloxy-2-bromo-5-methoxy-3-methyl-benzene (4.00 g, 13. mmol, 1 eq), 4, 4, 5, 5- tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (6.61 g, 26.0 mmol, 2 eq), KOAc (3.83 g, 39.1 mmol, 3 eq) in dioxane (80 mL) was added Pd(dppf)Cl2 (953 mg, 1.30 mmol, 0.1 eq) at 25 °C. After stirring at 100 °C for 16 h under N2 atmosphere, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOz, petroleum ether/ethyl acetate= 100/1 to 10/1) to give 2-(2-benzyloxy-4-methoxy- 6-methyl-phenyl)-4, 4, 5, 5-tetramethyl-1 ,3,2-dioxaborolane (2.30 g, 5.19 mmol, 10% yield, 80% purity) as colorless oil.

¹ H NMR (400 MHz, CDCh) 6 = 7.48 (d, J = 7.6 Hz, 2H), 7.38-7.32 (m, 2H), 7.30 (d, J = 7.2 Hz, 1 H), 6.32 (d, J = 1 .6 Hz, 1 H), 6.30 (d, J = 2.0 Hz, 1 H), 5.01 (s, 2H), 3.78 (s, 3H), 2.37 (s, 3H), 1 .30 (s, 12H).

Intermediate 427

6-(2-benzyloxy-4-methoxy-6-methybphenyl)pyndine-2,3-diami ne To a mixture of 2-(2-benzyloxy-4-methoxy-6-methyl-phenyi)-4,4,5,5-tetramethy l-1 ,3,2-dioxaborolane (2 g, 5.65 mmol, 1.05 eq), 6-chloropyridine-2,3-diamine (772 mg, 5.38 mmol, 1 eq), CS2CO3 (4.38 g, 13.4 mmol, 2.5 eq) in dioxane (20 mL) and H2O (2 mL) was added XPhos Pd G3 (455 mg, 538 pmol, 0.1 eq) at 25 °C. After stirring at 90 °C for16 hr under N2 atmosphere, the mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 3). The organic phase was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated to give a residue. The residue was purified by reversed phase (column: C18 120 g, mobile phase: [water (FA) - MeCN]; B%: 70% - 90%, 7 min) to give 6-(2-benzyloxy-4-methoxy-6-methyl-phenyl)pyridine-2,3-diamin e (500 mg, 1.48 mmol, 25% yield, 99% purity) as a purple solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 7.33-7.20 (m, 5H), 6.74 (d, J = 7.6 Hz, 1 H), 6.44 (d, J = 2.0 Hz, 1 H), 6.39 (d, J = 2.0 Hz, 1 H), 6.32 (d, J = 7.6 Hz, 1 H), 5.26 (s, 2H), 4.99 (s, 2H), 4.58 (s, 2H), 3.71 (s, 3H), 2.01 (s, 3H)

LC-MS (Method C): Rt = 0.444 min; MS (ESI): m/z = 336.1 [M+H] ⁺ .

Intermediate 428

2-(S,6-diair>ino-2-pyridyl)-5-ir>ethoxy-3-methyl-ph enol

To a solution of 6-(2-benzyloxy-4-methoxy-6-methyl-phenyl)pyridine-2,3-diamin e (500 mg, 1.49 mmol, 1 eq) in THF (10 mL) was added Pd/C (50.0 mg, 47.0 pmol, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 1 h, the reaction mixture was filtered and the filtrate was concentrated to give 2-(5,6- diamino-2-pyridyl)-5-methoxy-3-methyl-phenol (350 mg, 1.43 mmol, 96% yield) as a violet solid.

¹ H NMR (400 MHz, DMSO-d«) 5 [ppm] = 12.2 (s, 1 H), 6.82 (d, J = 8.0 Hz, 1 H), 6.56 (d, J = 8.0 Hz, 1 H), 6.29-6.25 (m, 1 H), 6.22 (d, J = 2.4 Hz, 1 H), 5.77 (s, 2H), 4.84 (s, 2H), 3.69 (s, 3H), 2.30 (s, 3H)

Intermediate 429

A solution of 2-(5,6-diamino-2-pyridyl)-5-methoxy-3-methyl-phenol (350 mg, 1.43 mmol, 1 eq) and tertbutyl (3R)-3-oxaldehydoyipiperidine-1-carboxylate (344 mg, 1.43 mmol, 1 eq) in EtOH (10 mL) was stirred at 60 °C for 1 h. Then the mixture was concentrated to dry. The residue was purified by reversed phase (column: C18 40 g, mobile phase: [water (FA) - MeCN]; B%: 40% - 70%, 7 min) to tert-butyl (3R)-

3-[6-(2-hydroxy-4-methoxy-6-methyl-phenyl)pyrido[2,3-b]py razin-3-yl]piperidine-1 -carboxylate (300 mg, 659 pmol, 46% yield, 99% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 9.92 (s, 1 H), 9.05 (s, 1 H), 8.47 (d, J = 8.4 Hz, 1 H), 7.81 (d, J = 8.4 Hz, 1 H), 6.41 (d, J = 4.4 Hz, 2H), 4.30-4.07 (m, 1 H), 3.95 (d, J = 13.2 Hz, 1 H), 3.76 (s, 3H), 3.20 (s, 2H), 2.90 (t, J = 12.0 Hz, 1 H), 2.19-2.15 (m, 1 H), 2.14 (s, 3H), 1.93-1 .71 (m, 2H), 1.62-1.48 (m, 1 H), 1.38 (s, 9H)

LC-MS (Method C): Rt = 0.589 min; MS (ESI): m/z = 451 .3 [M+H] ⁺ . Intermediate 430

5-methoxy-3-methyl-2-[3-[(3R)-3-pipendyl]pyndo[2 _s 3-b]pyrazin-6-y^phenol

To a solution of tert-butyi (3R)-3-[6-(2-hydroxy-4-methoxy-6-methyl-phenyl)pyrido[2,3-b] pyrazin-3- yl]piperidine-1 -carboxylate (300 mg, 666 pmol, 1 eq) in DCM (10 mL) was added TFA (4.60 g, 40.4 mmol, 3.00 mL, 60.6 eq) at 0 °C. After stirring at 25 °C for 0.5 h, the mixture was concentrated to dry to give 5-methoxy-3-methyl-2-[3-[(3R)-3-piperidyl]pyrido[2,3-b]pyraz in-6-yl]phenol (300 mg, 646 pmol, 97% yield, TFA) as a yellow solid.

Compound 192

5-methoxy-3-methyl-2-[3-[(3R)-1-methyb3-pipendyl]pyndo[2, 3-b]pyrazm-S-yl]phenol

To a solution of 5-methoxy-3-methyl-2-[3-[(3R)-3-piperidyl]pyrido[2,3-b]pyraz in-6-yl]phenol (250 mg, 538 pmol, 1 eq, TFA) in MeOH (5 mL) was added KOAc (158 mg, 1.61 mmol, 3 eq), NaBHsCN (50.7 mg, 807 pmol, 1.5 eq)and (HCHO)n (11.6 mg, 646 pmol, 1.2 eq)at 25 °C unde N2. After stirring at 25 °C for 0.5 h, the mixture was filtered, and the filtrate was concentrated to dry. The residue was purified by reversed phase (column: C18 40 g, mobile phase: [water (FA) - MeCN]; B%: 40% - 70%, 7 min) to give the 5-methoxy-3-methyl-2-[3-[(3R)-1-methyl-3-piperidyl]pyrido[2, 3-b]pyrazin-6-yl]phenol (216 mg, 495 pmol, 92% yield, 94% purity, FA) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 9.05 (s, 1 H), 8.46 (d, J = 8.4 Hz, 1 H), 8.31 (s, 1 H), 7.80 (d, J = 8.4 Hz, 1 H), 6.41 (s, 2H), 3.76 (s, 3H), 3.08-3.03 (m, 1 H), 2.84-2.78 (m, 1 H), 2.34-2.26 (m, 2H), 2.24 (s, 3H), 2.13 (s, 3H), 2.05-1 .96 (m, 2H), 1 .80-1 .74 (m, 1 H), 1 .69-1 .60 (m, 2H)

LC-MS (Method C): Rt = 0.411 min; MS (ESI): m/z = 365.2 [M+H] ⁺ .

SFC (Rt = 1 .688 min, ee% = 99%).

Compound 193

2-[3-[(3R)-1-ethyl-3-piperidyl]pyrido[2,3-b]pyrazin-6-yl] -3,5-dimethyl-phenol

To a mixture of 3,5-dimethyl-2-[3-[(3R)-3-piperidyl]pyrido[2,3-b]pyrazin-6-y l]phenol (300 mg, 331 pmol, 1 eq, 5TFA) , KOAc (325 mg, 3.32 mmol, 10 eq) , and acetaldehyde (14.6 mg, 332 pmol, 18.6 pL, 1 eq) in MeOH (5 mL) was added NaBHsCN (104 mg, 1.66 mmol, 5 eq) at 25 °C, After stirring at 25 °C for 2hr, the mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18 80 g, mobile phase: [water (FA) - MeCN]; B%: 20% - 50%, 10 min) to give 2-[3-[(3R)-1-ethyl-3-piperidyl]pyrido[2,3-b]pyrazin-6-yl]-3, 5-dimethyl-phenol (111 mg, 301 pmol, 91 % yield, 98% purity) as a orange solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 = 9.07 (s, 1 H), 8.47 (d, J = 8.8 Hz, 1 H), 8.40 (s, 3H), 7.77 (d, J = 8.8 Hz, 1 H), 6.66 (s, 1 H), 6.62 (s, 1 H), 3.32-3.26 (m, 2H), 3.14 (s, 1 H), 2.94 (d, J = 8.8 Hz, 1 H), 2.41 (d, J = 7.2 Hz, 2H), 2.35-2.30 (m, 1 H), 2.26 (s, 3H), 2.06 (s, 3H), 1 .98 (s, 1 H), 1 .81-1 .75 (m, 1 H), 1 .68 (t, J = 11 .6 Hz, 2H 2H), 1 .03 (t, J = 7.2 Hz, 3H).

LC-MS (Method C): Rt = 0.437 min; MS (ESIpos): m/z = 363.1 [M+1] ⁺ .

Intermediate 431

6-(2~methoxy~6-methyl-phenyi)pyndine-2,3-diamiiie To a mixture of 6-chloropyridine-2,3-diamine (10.0 g, 69.7 mmol, 1 eq), (2-methoxy-6-methyl- phenyl)boronic acid (17.3 g, 104 mmol, 1 .5 eq), CS2CO3 (56.7 g, 174 mmol, 2.5 eq) in dioxane (200 mL) and H2O (20 mL) was added XPhos Pd G3 (2.95 g, 3.48 mmol, 0.05 eq) at 25°C. After stirring at 80 °C for 16 h under N2 atmosphere, the mixture was diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 3). The organic phase was washed with brine (800 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether/ethyl acetate=100/1 to 0/1) to give 6-(2-methoxy-6-methyl- phenyi)pyridine-2,3-diamine (15.0 g, 62.8 mmol, 90% yield, 96% purity) as black oil.

LC-MS (Method C): Rt = 0.387 min; MS (ESI): m/z = 230.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CHLOROFORM-d) 6 = 7.20 (t, J = 8.0 Hz, 1 H), 6.96 (d, J = 7.6 Hz, 1 H), 6.86 (d, J = 7.6 Hz, 1 H), 6.80 (d, J = 8.0 Hz, 1 H), 6.61 (d, J = 7.6 Hz, 1 H), 4.30 (8s, 2H), 3.72 (s, 3H), 2.10 (s, 3H).

Intermediate 432 tert-butyl (3R)-3-[§-(2-methoxy-6-methyl-pheny!)pyrido[2,3-b]pyrazin-3 -yl]piperidme-1- carboxylate

To a mixture of 6-(2-methoxy-6-methyl-phenyl)pyridine-2,3-diamine (15.0 g, 65.4 mmol, 1 eq) in EtOH (250 mL) was tert-butyl (3R)-3-oxaldehydoylpiperidine-1 -carboxylate (20.0 g, 82.9 mmol, 1.27 eq) at 25°C. After stirring at 60 °C for 0.5 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=100/1 to 3/1) to give tert-butyl (3R)-3-[6-(2-methoxy-6-methyl- phenyl)pyrido[2,3-b]pyrazin-3-yl]piperidine-1 -carboxylate (10.5 g, 23.2 mmol, 35% yield, 96% purity) as a brown solid.

¹ HNMR (400 MHz, CHLOROFORM-d) 5 [ppm] = 8.87 (s, 1 H), 8.45 (d, J = 8.4 Hz, 1 H), 7.70 (d, J = 8.4 Hz, 1 H), 7.30 (t, J = 8.0 Hz, 1 H), 6.92 (d, J = 7.6 Hz, 1 H), 6.85 (d, J = 8.4 Hz, 1 H), 4.38 (m, 1 H), 4.24- 4.13 (m, 1 H), 3.71 (s, 3H), 3.43-3.25 (m, 1 H), 3.23-3.16 (m, 1 H), 2.91-2.71 (m, 1 H), 2.16 (s, 3H), 2.11- 2.05 (m, 1 H), 1.83 (d, J = 13.6 Hz, 1 H), 1.72 (s, 1 H), 1.65 (d, J = 14 Hz, 1 H), 1.47 (s, 9H).

LC-MS (Method C): Rt = 0.609 min; MS (ESI): m/z = 435.2 [M+H] ⁺ .

Intermediate 433

To a solution of tert-butyl (3R)-3-[6-(2-methoxy-6-methyl-phenyl)pyrido[2,3-b]pyrazin-3- yl]piperidine-1- carboxylate (3.00 g, 6.90 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (3.51 g, 13.8 mmol, 2 eq) in THF (100 mL) were added (1Z,5Z)- cycloocta-1 ,5-diene;2,4-dimethyl-BLAHbicyclo[1 .1 ,0]butane (458 mg, 690 pmol, 0.1 eq) and 4-tert- butyl-2-(4-tert-butyl-2-pyridyl)pyridine (371 mg, 1.38 mmol, 0.2 eq). After stirring at 80 °C for 16 h under N2, the mixture was concentrated to give a crude. The residue was purified by prep-HPLC (column: C18 330 g, mobile phase: [water(FA)-MeCN];B%: 70%-75%,20min) to give the solution, which was then lyophilized to give tert-butyl (3R)-3-[6-[2-methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl]pyrido[2,3-b]pyrazin-3-yl]piperidine-1-carboxyla te (2.10 g, 3.67 mmol, 27% yield, 98% purity) as yellow oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 8.54 (d, J = 8.4 Hz, 1 H), 8.14 (d, J = 6.4 Hz, 1 H), 7.74-7.71 (m, 1 H), 7.30 (s, 1 H), 7.19 (s, 1 H), 3.93 (d, J = 12.4 Hz, 1 H), 3.69 (s, 3H), 3.25-3.20 (m, 2H), 2.94-2.89 (m, 1 H), 2.15 (d, J = 11.2 Hz, 1 H), 2.04 (s, 3H), 1.85 (t, J = 10.4 Hz, 3H), 1.55-1 .51 (m, 1 H), 1.37 (s, 9H), 1.34 (s, 12H).

LC-MS (Method C): Rt - 0.680 min; MS (ESIpos): m/z = 561 .3 [M+H] ⁺ .

Intermediate 434

6-(4-bromo-2-methoxy-6-methyl-phenyl)-3-(3-piperidyl)pyri do[2,3-b]pyrazine

To a solution of tert-butyl (3R)-3-[6-[2-methoxy-6-rnethyl-4-(4,4,5,5-teframethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]pyrido[2,3-b]pyrazin-3-yl]piperidine-1 -carboxylate (2.00 g, 3.57 mmol, 1 eq) in MeOH (30 mL) and HzO (15 mL) was added CuBr? (1.99 g, 8.92 mmol, 417.7 pL, 2.5 eq). After stirring at 80 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with aqueous sodium chloride (30 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude was used to next step directly. Compound 6-(4-bromo- 2-methoxy-6-methyl-phenyl)-3-(3-piperidyl)pyrido[2,3-b]pyraz ine (2.5 g, crude) was obtained as brown oil (as a racemate).

Intermediate 435 tert-butyl 3-[S-(4-bromo-2-methoxy-6-methyl-phenyl)pyrido[2,3-b]pyrazin -3-yl]plperidlne-1- carboxylate

To a solution of 6-(4-bromo-2-methoxy-6-methyl-phenyl)-3-(3-piperidyl)pyrido[ 2,3-b]pyrazine (2.50 g, 6.05 mmol, 1 eq) in DCM (20 mL) were added DIPEA (1.56 g, 12.1 mmol, 2.11 mL, 2 eq) and B0C2O (1.58 g, 7.26 mmol, 1.67 mL, 1.2 eq). After stirring at 25 °C for 2 h, the mixture was concentrated to give a crude. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate/Petroleum ether gradient @ 60 mL/min) to give tert-butyl 3-[6-(4-bromo-2-methoxy-6-methyl-phenyl)pyrido[2,3-b]pyrazin -3-yl]piperidine-1 -carboxylate (2.00 3.74 mmol, 62 yield, 96% purity) as yellow oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 9.10 (s, 1 H), 8.55 (d, J = 8.4 Hz, 1 H), 7.76 (d, J = 8.4 Hz, 1 H), 7.22 (d, J = 4.4 Hz, 2H), 4.33-4.1 1 (m, 1 H), 3.95-3.90 (m, 1 H), 3.70 (s, 3H), 3.35 (s, 1 H), 3.26-3.18 (m, 1 H), 2.95-2.86 (m, 1 H), 2.14 (d, J = 11.2 Hz, 1 H), 2.04 (s, 3H), 1.90-1.80 (m, 2H), 1.60-1.49 (m, 1 H), 1.42-1.31 (m, 9H).

LC-MS (Method C): Rt = 0.640 min; MS (ESIpos): m/z = 513.2 [M+H] ⁺ .

Intermediate 436 tert-butyl 3-[6-(4-cyano-2-methoxy-6-methyl-phenyl)pyrido[2,3-b]pyrazin -3-yl]piperidine-1- carboxylate

To a solution of tert-butyl 3-[6-(4-bromo-2-methoxy-6-methyl-phenyl)pyrido[2,3-b]pyrazin -3- yl]piperidine-1 -carboxylate (1.00 g, 1.95 mmol, 1 eq) in dioxane (16 mL) and H2O (4 mL) were added KOAc (573 mg, 5.84 mmol, 3 eq), tetrapotassium;hexacyanoiron(4-);trihydrate (823 mg, 1.95 mmol, 1 eq) and tBuXPhos Pd G3 (77.4 mg, 97.4 pmoi, 0.05 eq). After stirring at 100 °C for 16 h under N2, the reaction mixture was quenched by saturated ammonium chloride aqueous solution (50 mL) at 25 °C, stirred at room temperature for 30 minutes. The solution was extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~35% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give tert-butyl 3-[6-(4-cyano-2- methoxy-6-methyl-phenyl)pyrido[2,3-b]pyrazin-3-yl]piperidine -1-carboxylate (700 mg, 1.48 mmol, 76% yield, 97% purity) as yellow oil.

¹ H NMR (400 MHz, CHLOROFORM-d) 5 [ppm] = 9.10 (s, 1 H), 8.69 (d, J = 8.4 Hz, 1 H), 7.84 (d, J = 8.4 Hz, 1 H), 7.46-7.42 (m, 2H), 4.65-4.48 (m, 1 H), 4.40-4.30 (m, 1 H), 3.92 (s, 3H), 3.42-3.34 (m, 1 H), 3.02 (t, J = 12.0 Hz, 1 H), 2.36 (s, 3H), 2.34 (s, 1 H), 2.02 (d, J = 13.6 Hz, 1 H), 1.90-1.82 (m, 1 H), 1.80 (s, 2H), 1.65 (s, 9H).

LC-MS (Method C): Rt = 0.591 min; MS (ESIpos): m/z = 460.2 [M+H] ⁺ .

Intermediate 437 tert-butyl 3-[6-(4-cyano-2-hydroxy-6-methyl-phenyl)pyrido[2,3-b]pyrazin -3-yl]piperidine-1- carboxylate

To a solution of tert-butyl 3-[6-(4-cyano-2-methoxy-6-methyl-phenyl)pyrido[2,3-b]pyrazin -3- yl]piperidine-1 -carboxylate (650 mg, 1.41 mmol, 1 eq) in DMF (10 mL) was added NaSEt (1.19 g, 14.1 mmol, 10 eq). After stirring at 100 °C for 16 h, the residue was quenched by addition sodium hypochlorite 20 mL at 25°C, stirred at room temperature for 30 minutes, and then extracted with dichloromethane(40 mL *3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate = 10/1 to 1/1) to give tert-butyl 3-[6-(4-cyano-2- hydroxy-6-methyl-phenyl)pyrido[2,3-b]pyrazin-3-yl]piperidine -1-carboxylate (520 mg, 1.05 mmol, 74% yield, 90% purity) as yellow oil.

LC-MS (Method C): Rt = 0.551 min; MS (ESIpos): m/z = 446.2 [M+H] ⁺ .

Intermediate 438

3-hydroxy-5-methy!-4-[3-(3-piperidyl)pyrido[2,3-b]pyrazin -6-yl]benzonitri!e

To a solution oftert-butyl 3-[6-(4-cyano-2-hydroxy-6-methyl-phenyl)pyrido[2,3-b]pyrazin -3-yl]piperidine- 1 -carboxylate (300 mg, 673 pmol, 1 eq) in DCM (6 mL) was added TFA (2 mL). After stirring at 25 °C for 2 h, the mixture was concentrated to give a crude. The crude was used to next step directly. Compound 3-hydroxy-5-methyl-4-[3-(3-piperidyl)pyrido[2,3-b]pyrazin-6- yl]benzonitrile (350 mg, crude, 2TFA salt) was obtained as brown oil. intermediate 439

3-hydroxy-5-methyl-4-[3-(1-methyl-3-pipendyl)pyndo[2,3-b] pyrazin-6-yl]benzonitrbe

To a solution of 3-hydroxy-5-methyl-4-[3-(3-piperidyl)pyrido[2,3-b]pyrazin-6- yl]benzonitrile (350 mg, 762 pmoi, 1 eq, 2TFA salt) in MeOH (8 mL) were added KOAc (1 .12 g, 1 1 .4 mmol, 15 eq), HCHO (114 mg, 3.81 mmol, 105 pL, 5 eq) and NaBHsCN (144 mg, 2.29 mmol, 3 eq). After stirring at 25 °C for 2 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: C18 80 g, mobile phase: [water(FA)-MeCN];B%: 10%-12%,10min) to give the solution, which was then lyophilized to give 3-hydroxy-5-methyl-4-[3-(1-methyl-3- piperidyl)pyrido[2,3-b]pyrazin-6-yl]benzonitrile (192 mg, 534 pmol, 70% yield, 99% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 9.11 (s, 1 H), 8.56 (d, J = 8.4 Hz, 1 H), 8.30 (s, 2H), 7.80 (d, J = 8.4 Hz, 1 H), 7.29-7.20 (m, 2H), 3.38-3.29 (m, 2H), 3.08 (d, J = 10.4 Hz, 1 H), 2.82 (d, J = 10.4 Hz, 1 H), 2.35-2.29 (m, 1 H), 2.25 (s, 3H), 2.08 (s, 3H), 2.05-1 .94 (m, 2H), 1 .81-1 .75 (m, 1 H), 1 .66 (d, J = 9.6 Hz, 1 H).

LC-MS (Method C): Rt = 0.398 min; MS (ESIpos): m/z = 360.2 [M+H] ⁺ .

Compound 194 and 195

3~hydi'oxy~5-methy!~4~[3~[1-methyi~3-pipendyl]pyrido[2.3- b]py!'azin-8--y!]benzGnit!'iie 3-hydroxy-5-methyl-4-[3-(1 -methyl-3-piperidyl)pyrido[2,3-b]pyrazin-6-yl]benzonitrile was separated by SFC column: Chiral Pak IH, 250*50mm, 10um;mobile phase: [CO ₂ -i-PrOH(0.1 % NHsH2O)];B%:25%, isocratic elution mode to give compound 194 3-hydroxy-5-methyl-4-[3-[1-methyl-3-piperidyl]pyrido[2,3- b]pyrazin-6-yl]benzonitrile (55.5 mg, 153 pmol, 58% yield, 99% purity) as a yellow solid and compound 195 3-hydroxy-5-methyl-4-[3-[rel-(3R)-1 -methyl-3-piperidyl]pyrido[2,3-b]pyrazin-6-yl]benzonitrile (81 .4 mg, 221 pmol, 84% yield, 98% purity) as a yellow solid.

Compound 194

¹ H NMR (400 MHz, DMSO-c/ ₆ ) 6 [ppm] = 9.03 (s, 1 H), 8.41 (d, J = 8.4 Hz, 1 H), 7.80 (d, J = 8.4 Hz, 1 H), 6.80 (s, 2H), 3.29 (d, J = 3.6, 7.2, 10.8 Hz, 2H), 3.04 (d, J = 1 1.2 Hz, 1 H), 2.79 (d, J = 10.8 Hz, 1 H), 2.30-2.25 (m, 1 H), 2.23 (s, 3H), 2.05 (s, 3H), 2.00-1.92 (m, 1 H), 1.81-1.74 (m, 1 H), 1.70-1.60 (m, 2H). LC-MS (Method C): Rt = 0.398 min; MS (ESIpos): m/z = 360.1 [M+H] ⁺ .

SFC (Rt = 1 .617 min, ee% - 96%)

Compound 195

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 9.11 (s, 1 H), 8.57 (d, J = 8.4 Hz, 1 H), 7.83-7.77 (m, 1 H), 7.30 (s, 1 H), 7.19 (s, 1 H), 3.30-3.26 (m, 1 H), 3.08 (d, J = 10.4 Hz, 1 H), 2.82 (d, J = 10.8 Hz, 1 H), 2.32 (d, J = 10.8 Hz, 1 H), 2.25 (s, 3H), 2.10-2.07 (m, 3H), 2.06-1.95 (m, 2H), 1.81-1.74 (m, 1 H), 1 .71-1 .61 (m, 2H). LC-MS (Method C): Rt = 0.400 min; MS (ESIpos): m/z = 360.1 [M+H] ⁺ .

SFC (Rt = 1 .783 min, ee% = 85%) intermediate 440

5-(2-methoxy-4,6-dimethylpher!yl)pyrazine-2.,3-diamme

To a solution of (six batches) 5-bromopyrazine-2,3-diamine (500 mg, 2.65 mmol, 1.00 eq) and (2- methoxy-4,6-dimethyl-phenyl)boronic acid (714 mg, 3.97 mmol, 1 .50 eq) in N,N-dimethylformamide (10 mL) and water (2 mL) was added Pd(dppf)Cl2 (193 mg, 264 pmol, 0.1 eq) and potassium carbonate (1 .10 g, 7.94 mmol, 3.0 eq). The mixture was stirred at 90 °C for 16 hr under nitrogen atmosphere. The reaction mixture (six batches) was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (80 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/1 to 1/3) to give 5-(2-methoxy-4,6- dimethylphenyl)pyrazine-2,3-diamine (2.6 g, 10.6 mmol, 67% yield) as yellow solid.

¹ H NMR (400 MHz, DMSO-de) 6 [ppm] = 7.00 (s, 1 H), 6.65 (d, J = 10.0 Hz, 2H), 5.80 (d, J = 8.4 Hz, 4H), 3.60 (s, 3H), 2.28 (s, 3H), 1.98 (s, 3H)

Intermediate 441 tert-butyl (R)-3-(7-(2-methoxy-4,6-diriiethylphenyl)pyrazino[2,3-b]pyra zin-2-yl)p!peridine-1- carboxylate

To a solution of 5-(2-methoxy-4,6-dimethyl-phenyl)pyrazine-2,3-diamine (2.6 g, 10.6 mmol, 1.00 eq) in ethyl alcohol (30 mL) was added tert-butyl (3R)-3-oxaldehydoylpiperidine-1-carboxylate (5.14 g, 21.3 mmol, 2.00 eq, EW45064-34). The mixture was stirred at 60 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash reverse phase (instrument: 60 g Flash; Column: Welch Ultimate XB_C18 20-40pm; eluent A: water (0.1 % FA), eluent B: acetonitrile; gradient: 60% B; flow 50 ml/min) to give a mixture of tert-butyl (3R)-3-[6-(2-methoxy-4,6- dimethyl-phenyl)pyrazino[2,3-b]pyrazin-2-yl]piperidine-1 -carboxylate and tert-butyl (3R)-3-[6-(2- methoxy-4,6-dimethyl-phenyl)pyrazino[2,3-b]pyrazin-3-yl]pipe ridine-1 -carboxylate (3.2 g, 7.12 mmol, 66.88% yield) as yellow solid.

Intermediate 442

(R)-2-(2-methoxy-4,8-d!methylphenyl)-7-(p!peridiri-3-yl)p yrazmo[2,3-b]pyrazine To a solution of intermediate 441 (1 .50 g, 3.34 mmol, 1 .00 eq) in dichloromethane (15 mL) was added 2,2,2-trifluoroacetate (5 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The pH of the residue was adjusted to 7 with sat aq sodium hydrogen carbonate. The residue was extracted with dichloromethane (30mL x 2). The combined organic layers were washed with brine (30mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a mixture of 6-(2-methoxy-4,6- dimethyl-phenyl)-2-[(3R)-3-piperidyl]pyrazino[2,3-b]pyrazine and 6-(2-methoxy-4,6-dimethyl-phenyl)-3- [(3R)-3-piperidyl]pyrazino[2,3-b]pyrazine (1.00 g, 2.86 mmol, 85% yield) was obtained as red solid.

Intermediate 443

(R)-2~(2-methoxy-4,6-dimethylphenyi)-7~(1-methylpipe!'idm -3~yi)pyi'azinQ[2,3-b]pyi'azine

To a solution of intermediate 442 (1.00 g, 2.86 mmol, 1 .00 eq) in methanol (15 mL) was added potassium acetate (842 mg, 8.59 mmol, 3.00 eq), formaldehyde (613 mg, 5.72 mmol, 563 pL, 28% purity, 2.00 eq) and sodium cyanoboranuide (359 mg, 5.72 mmol, 2.00 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash reverse phase (instrument: 30 g Flash; Column: Welch Ultimate XB_C18 20-40pm; eluent A: water (0.1 % FA), eluent B: acetonitrile; gradient: 24% B; flow 30 ml/min) to give mixture product (900 mg). The mixture product (500 mg) was purified by SFC (column: DAICEL CHIRALPAK IC(250mm ⁱ 30mm,10um);mobile phase: [CO ₂ -ACN/MeOH(0.1% NH3H2O)];B%:55%, isocratic elution mode) to give (R)-2-(2-methoxy-4,6-dimethylphenyl)-7-(1-methylpiperidin-3- yl)pyrazino[2,3-bjpyrazine (220 mg, 605 pmol, 21 % yield) as red gum

¹ H NMR (400 MHz, DMSO-ds) 6 [ppm] = 9.24 (s, 1 H), 9.07 (s, 1 H), 6.91 (s, 1 H), 6.84 (s, 1 H), 4.35 (s, 1 H), 3.71 (s, 3H), 3.48 - 3.40 (m, 2H), 3.10 - 3.03 (m, 1 H), 2.84 - 2.76 (m, 1 H), 2.38 (s, 3H), 2.31 - 2.27 (m, 1 H), 2.24 (s, 3H), 2.13 (s, 3H), 2.09 - 2.02 (m, 1 H), 2.01 - 1.93 (m, 1 H), 1.80 - 1.75 (m, 1 H), 1.71 - 1 .62 (m, 2H)

Intermediate 444

(R)-3,5-dimethyl-2-(7-(1-methylp!peridin-3-yl)pyrazino[2, 3-b]pyrazin-2-yl)phenol

To a solution of 6-(2-methoxy-4,6-dimethyl-phenyl)-3-[(3R)-1-methyl-3-piperid yl]pyrazino[2,3- b]pyrazine (270 mg, 742 pmol, 1.00 eq) in dichloromethane (5 mL) was added boron tribromide (558 mg, 2.23 mmol, 214 pL, 3.00 eq) at -70 °C. The mixture was warmed to 25 °C and stirred for 2 hr. The pH of the reaction mixture was adjusted to 7 with ammonia (7 M in methanol). The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash reverse phase (instrument: 30 g Flash; Column: Welch Ultimate XB__C18 20-40pm; eluent A: water (0.1 % FA), eluent B: acetonitrile; gradient: 15%B; flow 30 ml/min) to give crude product (40 mg) and (R)-4-bromo-3,5- dimethyl-2-(7-(1-methylpiperidin-3-yl)pyrazino[2,3-b]pyrazin -2-yl)phenol (150 mg, 316 pmol, 42% yield, FA) as yellow solid. The crude product (40 mg) was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um;mobile phase: [water(FA)-ACN];gradient:1 %-30% B over 10 min) to give (R)-3,5- dimethyl-2-(7-(1-methylpiperidin-3-yl)pyrazino[2,3-b]pyrazin -2-yl)phenol (7.00 mg, 17.7 pmol, 2% yield, 100% purity, FA) as yellow gum. Intermediate 445

(R)~3,5~d!methyl~2‘(7~(1~methylpiperidin~3~yi)pyraz!no[ 2 _! 3‘b]py!’az!n-2~y!)phenol

To a solution of 4-bromo-3,5-dimethyl-2-[3-[1-methyl-3-piperidyl]pyrazino[2,3 -b]pyrazin-6-yl]phenol (110 mg, 256 pmol, 1.00 eq) in methanol (3 mL) was added palladium on carbon (30 mg, 10% purity) under nitrogen atmosphere. The mixture was degassed and purged with hydrogen for 3 times, and then the mixture was stirred at 25 °C for 3 hr under hydrogen (15 psi) atmosphere. The mixture was stirred at 25 °C for 3 hr under hydrogen (15 psi) atmosphere. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash reverse phase (instrument: 12 g Flash; Column: Welch Ultimate XB_C18 20-40pm; eluent A: water (0.1 % FA), eluent B: acetonitrile; gradient: 14% B; flow 20 ml/min) to give a product. The product was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um;mobile phase: [water(FA)-ACN];gradient:3%-33% B over 10 min) to give (R)-3,5-dimethyl-2-(7-(1-methylpiperidin-3- yl)pyrazino[2,3-b]pyrazin-2-yl)phenol (12.0 mg, 29.4 pmol, 11 % yield, 97.0% purity, FA) was obtained as yellow gum.

Compound 196 (R)-3,5-dimethyl-2-(7-(1-methyipipendin-3-y!)pyrazino[2 _! 3-b]pyrazin-2-yi)phenol Intermediates 444 and 445 were combined to give (R)-3,5-dimethyl-2-(7-(1-methylpiperidin-3- yl)pyrazino[2,3-b]pyrazin-2-yl)phenol (15.5 mg, 39,3 pmol, 81 % yield, FA)

NMR (400 MHz, DMSO-d6) 6 [ppm] = 9.85 (s, 1 H), 9.25 (s, 1 H), 9.15 (s, 1 H), 8.14 (s, 1 H), 6.70 (s, 1 H), 6.69 (s, 1 H), 3.68 - 3.54 (m, 3H), 2.85 - 2.68 (m, 4H), 2.28 (s, 3H), 2.25 - 2.18 (m, 1 H), 2.17 (s, 3H), 2.03 - 1 .82 (m, 3H), 1 .77 - 1 .62 (m, 1 H)

LC-MS (Method K): Rt = 0.402 min; MS (ESIpos) m/z = 350.1 [M+H] ⁺ .

Intermediate 446

5-chloro-2-iodo-1-methoxy-3-methyl-benzene

To a solution of 5-chloro-2-iodo-3-methyl-phenol (8.00 g, 29.8 mmol, 1 eq) in MeCN (80 mL) were added Mel (21.2 g, 149 mmol, 9.28 mL, 5 eq) and K2CO3 (12.4 g, 89.4 mmol, 3 eq). After stirring at 25 °C for 16 h, the mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (100 mL x 1), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuum. The crude was used to next step directly. Compound 5-chloro-2-iodo-1-methoxy-3-methyl-benzene (8.40 g, 29.7 mmol, 100% yield) was obtained as a brown solid.

¹ H NMR (400 MHz, DMSO-c/ ₆ ) 5 [ppm] = 7.06 (d, J = 2.0 Hz, 1 H), 6.90 (d, J = 2.0 Hz, 1 H), 3.84 (s, 3H), 2.38 (s, 3H).

Intermediate 447

(4-chioro-2-methoxy-6-rnethyl-pheny0boi'onic acid To a solution of 5-chloro-2-iodo-1-methoxy-3-methyl-benzene (5.40 g, 19.1 mmol, 1 eq) in THF (60 mL)was added i-PrMgCl-LiCI (1.30 M, 29.4 mL, 2 eq)at 0 °C, the reaction mixture was stirred at 0 °C for 0.5 hour foliwed by triisopropyl borate (7.19 g, 38.2 mmol, 8.79 mL, 2 eq'jwas added. After stirring at 25 °C for 2 h, the reaction mixture was quenched by addition saturated ammonium chloride solution 100 mL, and then extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with aqueous sodium chloride (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude. The residue was purified by column chromatography (SiOa, Petroleum ether/Ethyl acetate = 1/0 to 5/1) to give (4-chloro-2-methoxy-6- methyl-phenyl)boronic acid (3.10 g, 14.7 mmol, 77% yield, 95% purity) as a yellow solid.

¹ HNMR (400 MHz, DMSO-d6) 5 [ppm] = 8.07 (s, 2H), 6.79 (d, J = 5.6 Hz, 2H), 3.71 (s, 3H), 2.21 (s, 3H).

Intermediate 448

To a solution of (4-chloro-2-methoxy-6-methyl-phenyl)boronic acid (1.03 g, 5.16 mmol, 1.8 eq) and tertbutyl (3R)-3-(6-chloropyrido[2,3-b]pyrazin-3-yl)piperidine-1-carbo xylate (1 .00 g, 2.87 mmol, 1 eq) in dioxane (15 mL) were added Pd(dppf)Cl2 (105 mg, 143 pmol, 0.05 eq) and NazCOs (608 mg, 5.73 mmol, 2 eq) in H2O (3 mL). After stirring at 80 °C for 16 h under N2, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with aqueous sodium chloride (20 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOz, Petroleum ether/Ethyl acetate = 1/0 to 2/1) to give tert-butyl (3R)-3-[6-(4-chloro-2-methoxy-6-methyl-phenyl)pyrido[2,3-b]p yrazin-3- yl]piperidine-1 -carboxylate (950 mg, 1.86 mmol, 65% yield, 92% purity) as yellow oil.

¹ H NMR (400 MHz, DMSO-d _s ) 5 [ppm] = 9.10 (s, 1 H), 8.55 (d, J = 8.4 Hz, 1 H), 7.76 (d, J = 8.4 Hz, 1 H), 7.12-7.07 (m, 2H), 3.97-3.90 (m, 1 H), 3.70 (s, 3H), 3.37-3.33 (m, 1 H), 3.28-3.16 (m, 2H), 2.96-2.87 (m, 1 H), 2.15 (d, J = 11 .2 Hz, 1 H), 2.04 (s, 3H), 1 .90-1 .82 (m, 2H), 1 .57-1 .50 (m, 1 H), 1 .38 (d, J = 4.8 Hz, 9H).

LC-MS (Method C): R _t = 0.634 min; MS (ESIpos): m/z = 469.1 [M+H] ⁺ .

Intermediate 449 tert-butyl (3R)-3-[6-[2-niethoxy-6-snethyl-4-(4 _> 4,5,5-tetram&thyl-1,3,2-dlQxaborolan-2- yl)phenyl]pyrido[2,3-b]pyrazln-3-yl]piperidme-1 -carboxylate

To a solution of tert-butyl (3R)-3-[6-(4-chloro-2-methoxy-6-methyi-phenyi)pyrido[2,3-b]p yrazin-3- yl]piperidine-1 -carboxylate (850 mg, 1.81 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 ,3,2-dioxaboroiane (690 mg, 2.72 mmol, 1.5 eq) in dioxane (15 mL) were added Pd2(dba)s (83.0 mg, 90.6 pmol, 0.05 eq), XPhos (86.4 mg, 181 pmol, 0.1 eq) and KOAc (356 mg, 3.62 mmol, 2 eq). After stirring at 100 °C for 16 h under N2, the mixture was concentrated to give a crude. The residue was purified by column chromatography (SIO ₂ , Petroleum ether/Ethyl acetate = 1/0 to 1/1) to give tert-butyl (3R)-3-[6-[2-methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]pyrido[2,3-b]pyrazin-3-yl]piperidine-1 -carboxylate (1.00 g, 1.43 mmol, 79% yield, 80% purity) as yellow oil.

LC-MS (Method C): Rt = 0.666 min; MS (ESIpos): m/z = 561 .3 [M+H] ⁺ .

Intermediate 450

6-(4~brGmG-2-m&thaxy-6-methyi-ph&nyl)~3-(3~pipend yl)pyddG[2,3~b]pyi'azm&

To a solution of tert-butyl (3R)-3-[6-[2-methoxy-6-methyl-4-(4,4,5,5-tetramethyi-1 ,3,2-dioxaborolan-2- yl)phenyl]pyrido[2,3-b]pyrazin-3-yl]piperidine-1-carboxylate (800 mg, 1.43 mmol, 1 eq) in MeOH (6 mL) and H2O (6 mL) was added CuBr2 (797 mg, 3.57 mmol, 167 pL, 2.5 eq). After stirring at 80 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with aqueous sodium chloride (30 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOa, DCM: MeOH = 10/1 to 3/1) to give 6-(4-bromo-2-methoxy-6-methyl-phenyl)-3-(3-piperidyl)pyrido[ 2,3- b]pyrazine (220 mg, 468 pmol, 33% yield, 88% purity) as a brown solid.

LC-MS (Method C): Rt = 0.453 min; MS (ESIpos): m/z = 413.0 [M+H] ⁺ .

Intermediate 451

8d4~bromO'2~methoxy~6~methybphenyl)~3d1~methyb3-pipendy!) pyrido[2.3~b]pyrazine

To a solution of 6-(4-bromo-2-methoxy-6-methyl-phenyl)-3-(3-piperidyl)pyrido[ 2,3-bjpyrazine (200 mg, 484 pmol, 1 eq) in MeOH (8 mL) were added HCHO (72.7 mg, 2.42 mmol, 66.7 pL, 5 eq) and NaBHsCN (91 .2 mg, 1 .45 mmol, 3 eq). After stirring at 25 °C for 2 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: C18 40 g, mobile phase: [water(FA)-MeCN];B%: 19%-30%,1 Omin) to give the solution, which was then lyophilized to give 6-(4-bromo-2-methoxy-6-methyl-phenyl)-3-(1-methyl-3-piperidy l)pyrido[2,3-b]pyrazine (130 mg, 274 pmol, 57% yield, 90% purity) as a brown solid.

LC-MS (Method C): Rt = 0.452 min; MS (ESIpos): m/z = 427.0 [M+H] ⁺ .

Intermediate 452

5-bromo-3-methyl-2-[3-(1-methyl-3-p!pendyl)pyndo[2,3-b]py raz!ii-6-y!]phenol

To a solution of 6-(4-bromo-2-methoxy-6-methyl-phenyl)-3-(1-methyl-3-piperidy l)pyrido[2,3-b]pyrazine (50.0 mg, 117 pmol, 1 eq) in DCM (4 mL) was added BBrs (87.9 mg, 351 pmol, 33.8 pL, 3 eq). After stirring at -70 °C for 2 h, the reaction was quenched by addition of 10 mL of methanol at 25 °C. After the addition, it was stirred for 20 min, and then heated for reflux for 20 min, and a clear yellow-brown solution was obtained. The pH was adjusted to around 7 by progressively adding 7.0 M ammonia in methanol. The residue was purified by prep-HPLC (column: C18 40 g, mobile phase: [water(FA)- MeCN];B%: 20%-30%,1 Omin) to give the solution, which was then lyophilized to give 5-bromo-3-methyl- 2-[3-(1-methyl-3-piperidyl)pyrido[2,3-b]pyrazin-6-yl]phenol (45.0 mg, 107 pmol, 91 % yield, 98% purity) as a brown solid. LC-MS (Method C): Rt = 0.446 min; MS (ESIpos): m/z = 413.1 [M+H] ⁺ .

Compounds 197 and 198 5-bromo-3-methyl-2-[3-[1-metbyl-3-pipendyl]pyndo[2,3-b]pyraz in-6-yl]phenol intermediate 452 was separated by SFC coiumn: column: DAICEL CHIRALPAK IC(250mm*30mm,10um);mobile phase: [CO ₂ -EtOH(Q.1 %NH3p2O)];B%:40%, isocratic elution mode to give 5-bromo-3-methyl-2-[3-[rel-(3R)-1-methyl-3-piperidyl]pyrido[ 2,3-b]pyrazin-6-yl]phenol (7.99 mg, 18.6 pmoi, 34% yield, 96% purity) as a yellow solid, and 5-bromo-3-methyl-2-[3-[rel-(3R)-1-methyl-3- piperidyi]pyrido[2,3-b]pyrazin-6-yl]phenol (3.87 mg, 9.27 pmoi, 17% yield, 99% purity) as a yellow solid.

Compound 197

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 9.10 (s, 1 H), 8.53 (d, J = 8.8 Hz, 1 H), 8.16 (s, 1 H), 7.80 (d, J = 8.8 Hz, 1 H), 7.03 (d, J = 3.6 Hz, 2H), 3.25 (d, J = 10.4 Hz, 2H), 3.00-2.96 (m, 1 H), 2.64-2.56 (m, 1 H), 2.41 (s, 3H), 2.29-2.21 (m, 1 H), 2.10 (d, J = 3.6 Hz, 1 H), 2.06 (s, 3H), 1.87-1.80 (m, 1 H), 1.78-1.71 (m, 1 H), 1.69-1.60 (m, 1 H).

LC-MS (Method C): Rt = 0.440 min; MS (ESIpos): m/z = 413.0 [M+H] ⁺ .

SFC (Rt = 1 .325 min, ee% = 95%)

Compound 198

NMR (400 MHz, DMSO-c/ ₆ ) 6 [ppm] = 9.11 (s, 1 H), 8.57 (d, J = 8.4 Hz, 1 H), 7.83-7.77 (m, 1 H), 7.30 (s, 1 H), 7.19 (s, 1 H), 3.30-3.26 (m, 1 H), 3.08 (d, J = 10.4 Hz, 1 H), 2.82 (d, J = 10.8 Hz, 1 H), 2.32 (d, J = 10.8 Hz, 1 H), 2.25 (s, 3H), 2.10-2.07 (m, 3H), 2.06-1.95 (m, 2H), 1.81-1.74 (m, 1 H), 1 .71-1 .61 (m, 2H).

LC-MS (Method C): Rt = 0.435 min; MS (ESIpos): m/z = 415.0 [M+H] ⁺ .

SFC (Rt = 1 .616 min, ee% = 13%)

Intermediate 453

2-bromo-1-m&thoxy-3-methyl-5-(tnfluoromethoxy)benz&am p;n&

A mixture of 2,6-dibromo-4-(trifluoromethoxy)aniline (25.0 g, 44.9 mmol, 1 eq) , Pd(dppf)Cl2 (2.62 g, 3.58 mmol, 0.08 eq), 2,4,6-trimethyl-1 ,3,5,2,4,6-trioxatriborinane (3.5 M, 12.8 mL, 1 eq) and K2CO3 (12.38 g, 89.5 mmol, 2 eq) in dioxane (200 mL)/H2O (10 mL) was degassed and purged with N2 for 3 times. After stirring at 90 °C for 12 hr under N2 atmosphere, the mixture was concentrated to give a residue. The residue and was purified by column chromatography (SiCh, petroleum ether/ethyl acetate = 10/1 to 5/1) to give 2-bromo-6-methyl-4-(trifluoromethoxy)aniline (14.2 g, 38.6 mmol, 86% yield, 73% purity) as yellow oil.

¹ H NMR (400 MHz, DMSO-ds) 6 = 7.27(t, J = 15.6 Hz, 1 H), 6.92(s, 1 H), 4.14(s, 2H), 2.22(s, 3H)

Intermediate 454

2-bi’omo-6-methyl-4-(tnfluoi'omethoxy)aniline A mixture of 2-bromo-6-methyl-4-(trifluoromethoxy)aniline (6.00 g, 22.2 mmol, 1 eq) , Cui (4.23 g, 22.2 mmol, 1 eq) , sodium methanolate (40.0 g, 222 mmol, 30% purity, 10 eq) in DMSO (60 mL) was degassed and purged with N2 for 3 times. After stirring at 100 °C for 12hr under N2 atmosphere, the reaction was poured into water, extracted with ethyl acetate(50 Ml x 3), the organic layers dried with Na ₂ SO4, filtered .concentrated to afford the residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 8/1) to give 2-methoxy-6-methyl-4- (trifluoromethoxy)aniline (4.80 g, 20.1 mmol, 90 % yield, 92% purity) as yellow oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 = 6.69 (d, J = 2.0 Hz, 1 H), 6.62 (s, 1 H), 4.59 (s, 2H), 3.78 (s, 3H), 2.10 (s, 3H))

Intermediate 455

2-bromo- 1 ■methoxy-3-methyl-5-(trifluoromethoxy)benzene

To a mixture of 2-methoxy-6-methyl-4-(trif!uoromethoxy)aniline (2.50 g, 11.3 mmol, 1 eq) ,CuBr (2.43 g, 16.9 mmol, 516 pL, 1.5 eq) and CuBr ₂ (3.79 g, 16.9 mmol, 793 pL, 1 .5 eq) in MeCN (50.0 mL) was added t-BuONO (5.83 g, 56.5 mmol, 6.72 mL, 5 eq) at 0 °C in one portion. After stirring at 0°C for 4 hr, the reaction mixture was diluted with NH3 H2O (30 ml), and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by twice column chromatography (S1O ₂ , petroleum ether/ethyl acetate = 1/0 to 1/0) to give 2- bromo-1-methoxy-3-methyl-5-(trifluoromethoxy)benzene (1.00 g, 3.51 mmol, 31 % yield) as light yellow oil.

¹ H NMR (400 MHz, DMSO-cfe) 6 = 6.77(s, 1 H), 6.61 (d, J = 2.0 Hz, 1 H), 3.90(s, 3H), 2.43(s, 3H).

Intermediate 456

2-[2-methoxy-&-methyl-4-(trifluoromethoxy)phenyl]-4^ _! 5,5d:etramethyM _! 3,2<Moxaborolarie

To a mixture of -bromo-1-methoxy-3-methyl-5-(trifluoromethoxy)benzene (1.1 g, 3.86 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (1 .47 g, 5.79 mmol, 1 .5 eq) and KOAc (946 mg, 9.65 mmol, 2.5 eq) in dioxane (30 mL) was added Pd(dppf)Cl2 (282 mg, 385 pmol, 0.1 eq) 5 °C in one portion. After stirring at 90 °C for 16 hr under N ₂ atmosphere, the reaction mixture was diluted with water (60 mL), and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous Na ₂ SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 20/1) to give 2-[2-methoxy-6- methyl-4-(trifluoromethoxy)phenyl]-4, 4, 5, 5-tetramethyl-1 ,3,2-dioxaborolane (580 mg, 1.75 mmol, 45 % yield) as a light green solid.

¹ H NMR (400 MHz, DMSO-ds) 6 = 6.66(s, 1 H), 6.62(s, 1 H), 3.76(s, 3H), 2.33(s, 3H), 1.37(s, 12H)

Intermediate 457

6-[2~methoxy-6-methyl-4~(ti-ifiuoi'oinethoxy)phenyl]pyi-i diiie-2 _! 3-diamme To a mixture of 2-[2-methoxy-6-methyl-4-(trifluoromethoxy)phenyl]-4,4,5,5-te tramethyl-1 ,3,2- dioxaborolane (530 mg, 1.60 mmol, 1 eq) , 6-chloropyridine-2,3-diamine (274 mg, 1.91 mmol, 1.2 eq) and CS2CO3 (1.30 g, 3.99 mmol, 2.5 eq) in dioxane (10 mL) and H2O (3 mL) was added XPhos Pd G3 (135 mg, 159 pmol, 0.1 eq) at 25 °C in one portion. After stirring at 90°C for 16 hr. the reaction mixture was diluted with water (30 ml), and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(0.1 %FA condition) - MeCN];B%: 35% - 75%, 10 min) to give 6-[2-methoxy-6-methyl-4-(trifiuoromethoxy)phenyl]pyridine-2, 3-diamine (280 mg, 813 pmol, 50 % yield, 91 % purity) as a black solid.

¹ H NMR (400 MHz, DMSO-cfe) 5 = 8.31 (s, 1 H), 6.98(d, J = 7.6 Hz, 1 H), 6.74(s, 1 H), 6.62(d, J = 5.2 Hz, 1 H), 6.48(d, J = 7.6 Hz, 1 H), 3.74(s, 3H), 2.16(s, 3H).

LC-MS (Method C): Rt = 0.451 min; MS (ESI): m/z = 314.1 [M+H] ⁺ .

Intermediate 458

2-[2-methoxy-6-methyl-4-(trlfluoromethoxy)phenyl]-4,4,5 _! 5-tetramethyl-1.3 _! 2-dioxaborolane

To a solution of 6-[2-methoxy-6-methyl-4-(trifluoromethoxy)phenyl]pyridine-2, 3-diamine (250 mg, 798 pmol, 1 eq) in dichloromethane (20 mL) was added BBra (999 mg, 3.99 mmol, 384 pL, 5 eq) at -70°C dropwise. After stirring at 25°C for 3 hr, the reaction mixture was quenched by ice-water (20 mL), the pH of the mixture was adjust to 8-9 by 30% ammonium hydroxide, then extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na ₂ SO4, filtered and the filtrate was concentrated under reduced pressure to give to 2-(5,6-diamino-2- pyridyl)-3-methyl-5-(trifluoromethoxy)phenoi (220 mg, 661 pmol, 82 % yield, 90% purity) as a black solid.

LC-MS (Method C): Rt = 0.423 min; MS (ESI): m/z = 300.1 [M+H] ⁺ .

Intermediate 459

To a solution of 2-(5,6-diamino-2-pyridyl)-3-methyl-5-(trifluoromethoxy)pheno l (200 mg, 668 pmol, 1 eq) in EtOH (15 mL) was added tert-butyl (3R)-3-oxaldehydoylpiperidine-1-carboxylate (564 mg, 2.34 mmol, 3.5 eq) at 25°C in one portion. After stirring at 60 °C for 1 hr, the mixture concentrated to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(0.1 % FA condition) - MeCN];B%: 75% - 80%, 5 min) to give tert-butyl (3R)-3-[6-[2-hydroxy-6- methyl-4-(trifluoromethoxy)phenyljpyrido[2,3-b]pyrazin-3-yl] piperidine-1 -carboxylate (230 mg, 433 pmol, 64% yield, 95% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.619 min; MS (ESI): m/z = 449.2 [M+H] ⁺ .

Intermediate 460

2-[2-rnethoxy-3-methyl-4-(trifluoromethoxy)pheriyl]-4,4 _! 5,5-tetramethyl-1,3,2-dioxaboro!aiie To a solution of 2-(5,6-diamino-2-pyridyl)-3-methyl-5-(trifluoromethoxy)pheno l (200 mg, 668 pmol, 1 eq) in ethyi alcohol (15 mL) was added tert-butyl (3R)-3-oxaldehydoylpiperidine-1 -carboxylate (564.41 mg, 2.34 mmol, 3.5 eq) at 25°C in one portion. After stirring at 60 °C for 1 hr, the mixture concentrated to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(0.1 % FA condition) - MeCN];B%: 35% - 55%, 6 min) to give tert-butyl (3R)-3-[6-[2-hydroxy-6- methyl-4-(trifluoromethoxy)phenyl]pyrido[2,3-b]pyrazin-3-yl] piperidine-1 -carboxylate (230 mg, 433 pmol, 64% yield, 95% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.450 min; MS (ESI): m/z = 405.2 [M+H] ⁺ .

Compound 199

3-met/?y/-2-£3-ff3/?J-f-met/?y/-3-p/per/dy/7pyndo£2 _; 3-£Vpyrazm-S-y/7-5-(tnf/j/orometf)oxyJpf)eno/

To a solution of 3-methyl-2-[3-[(3R)-3-piperidyl]pyrido[2,3-b]pyrazin-6-yl]-5 -(trif!uoromethoxy)phenol (88.0mg, 217 pmol, 1 eq) in methyl alcohol (4 mL) was added KOAc (106 mg, 1.09 mmol, 5 eq) at 25°C.The mixture was stirred at 10 min. Then the mixture was added (HCHO)n (32.6 mg, 1 .09 mmol, 5 eq) and NaBFhCN (41.0 mg, 652 pmol, 3 eq) at 25°C. After stirring at 25°C for 0.5 h, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous NazSCh, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(0.1% FA) - MeCN];B%: 35% - 45%, 8 min) to give 3-methyl-2-[3-[(3R)-

1-methyl-3-piperidyl]pyrido[2,3-b]pyrazin-6-yl]-5-(triflu oromethoxy)phenol (57.7 mg, 135 pmol, 62% yield, 98% purity) was obtained as a yellow solid.

¹ H NMR (400 MHz, DMSO-ds) 5 = 9.09 (s, 1 H), 8.53 (d, J = 8.4 Hz, 1 H), 8.29 (s, 1 H), 7.81 (d, J = 8.4 Hz, 1 H), 6.82 (s, 1 H), 6.80 (s, 1 H), 3.37-3.29 (m, 2H), 3.12-3.05 (m, 1 H), 2.82 (br d, J = 11.2 Hz, 1 H), 2.26 (s, 3H), 2.10 (s, 3H), 2.05-1.96 (m, 2H), 1 .81-1.75 (m, 1 H), 1.71-1.61 (m, 2H) LC-MS (Method C): Rt = 0.444 min; MS (ESI): m/z = 419.0 [M+H] ⁺ .

SFC (Rt = 1 .253 min, ee% = 90%)

Intermediate 461

2-[3-[(3R)-1-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-3-pip eridyl]pyrido[2,3-b]pyrazin-6-yl]-3,5- dimethyi-pheno!

To a solution of 3,5-dimethyl-2-[3-[(3R)-3-piperidyl]pyrido[2,3-b]pyrazin-6-y l]phenol (0.300 g, 897 pmol, 1 eq) and 2,2-dimethyl-1 ,3-dioxane-5-carbaldehyde (129 mg, 897 pmol, 1 eq) in MeOH (5 mL) were added sodium;cyanoboranuide (169 mg, 2.69 mmol, 3 eq) and KOAc (880 mg, 8.97 mmol, 10 eq) at 20 °C. After stirring at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase (column: C18,40 g, mobile phase: [water(FA)-MeCN];B%: 40%-70%, 7min) to give 2-[3-[(3R)-1-[(2,2-dimethyl-1 ,3-dioxan-5-yl)methyl]-3- piperidyl]pyrido[2,3-b]pyrazin-6-yl]-3,5-dimethyl-phenol (250 mg, 486 pmol, 54% yield, 90% purity) as a yellow solid.

LC-MS (Method C) Rt = 0.432 min; MS (ESIpos): m/z = 463.2 [M+H] ⁺ . Compound 200

2-[[(3R)-3-[6-(2-hydroxy-4,§-dimethyl-phenyi)pyrido[2,3- b]pyrazin-3-yi]-1- piperidyl]methyl]propane- 1, 3-diol

To a solution of 2-[3-[(3R)-1-[(2,2-dimethyl-1 ,3-dioxan-5-yl)methyl]-3-piperidyl]pyrido[2,3-b]pyrazin-6- yl]-3,5-dimethyl-phenol (0.250 g, 540 pmol, 1 eq) in DCM (4 mL) was added TFA (6.16 g, 54.0 mmol, 4.01 mL, 100 eq) at 0 °C. After stirring at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase (column: C18, 80 g, mobile phase: [water(FA)-MeCN];B%: 20% - 70%, 8 min) to give 2-[[(3R)-3-[6-(2-hydroxy-4,6-dimethyl- phenyl)pyrido[2,3-b]pyrazin-3-yl]-1-piperidyl]methyl]propane -1 , 3-diol (0.035 g, 62.0 pmol, 11 % yield, 95% purity, TFA salt) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 = 9.58 (s, 1 H), 9.11 (s, 1 H), 8.53 (d, J = 8.5 Hz, 1 H), 7.83 (d, J = 8.5 Hz, 1 H), 6.64 (d, J = 6.6 Hz, 2H), 4.92-4.88 (m, 1 H), 3.97-3.89 (m, 1 H), 3.67-3.61 (m, 2H), 3.54-3.50 (m, 2H), 3.43 (s, 2H), 3.21 (d, J = 1.1 Hz, 2H), 3.12-3.04 (m, 1 H), 2.26 (s, 3H), 2.24-2.10 (m, 3H), 2.07 (s, 3H), 2.04-1.94 (m, 2H).

LC-MS (Method C) Rt = 0.413 min; MS (ESIpos): m/z = 423.3 [M+H] ⁺ .

SFC (Rt = 1 .897 min, ee% = 99%).

Intermediate 462

O1 -tert-butyl O4-ethyl 3-hydroxypiperidir!e-1,4-dicarboxylate

To a solution of methyl O1 -tert-butyl O4-ethyl 3-oxopiperidine-1 ,4-dicarboxylate (5.00 g, 18.4 mmol, 1 eq) in THF (50 mL) was added NaBH4 (699 mg, 18.4 mmol, 1 eq) at 0 °C under N2 atmosphere. After stirring at 0 °C for 1 h, the mixture was quenched with hydrochloric acid solution (100 mL, 1 M) at 0 °C and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give O1 -tert-butyl O4-ethyl 3- hydroxypiperidine-1 ,4-dicarboxylate (5.00 g, 18.3 mmol, 99% yield) as colorless oil.

Intermediate 463

O1 -tert-butyl O4-ethyl 3-[tert-butyl(dipbenyl)silyl]oxypiperidine-1 ,4-dicarboxylate

To a solution of O1 -tert-butyl O4-ethyl 3-hydroxypiperidine-1 ,4-dicarboxylate (5.00 g, 18.3 mmol, 1 eq) and imidazole (3.74 g, 54.9 mmol, 3 eq) in DCM (50 mL) was added tert-butyl-chloro-diphenylsilane (6.03 g, 21.9 mmol, 1.2 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SIOz, petroleum ether/ethyl acetate=10/1 to 1/1) to give O1 -tert-butyl O4-ethyl 3-[tert-butyl(diphenyl)silyl]oxypiperidine-1 ,4- dicarboxylate (10.0 g, 15.6 mmol, 85% yield) as colorless oil.

Intermediate 464

1-tert-butoxycarbonyl-3-[tert-buty!(dipheriy!)sily!]oxy-p iperidirie-4-carboxy!ic acid

To a solution of O1 -tert-butyl O4-ethyl 3-[tert-butyl(diphenyl)silyl]oxypiperidine-1 ,4-dicarboxylate (10.0 g, 15.6 mmol, 1 eq) in EtOH (100 mL) and H2O (20 mL) was added LiOH.HzO (1.97 g, 46.9 mmol, 3 eq) at 25 °C. After stirring at 25 °C for 16 h, the reaction mixture was concentrated to remove EtOH. The crude was adjusted to PH to 4-5 by hydrochloric acid solution (1 M) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-tert-butoxycarbonyl-3-[tert-butyl(diphenyl)silyi]oxy- piperidine-4-carboxylic acid (9.00 g, crude) as colorless oil.

Intermediate 465 tert-butyl 3-[tert-butyl(diphenyl)silyl]oxy-4-[methoxy(methyl)carbarnoy l]piperidine-1- carboxylate

To a solution of 1-tert-butoxycarbonyl-3-[tert-butyl(diphenyl)silyl]oxy-piper idine-4-carboxylic acid (9.00 g, 14.9 mmol, 1 eq) and N-methoxymethanamine (2.18 g, 22.3 mmol, 1.5 eq, HCI salt) in DCM (100 mL) were added HOBt (3.02 g, 22.3 mmol, 1 .5 eq), EDCI (4.28 g, 22.3 mmol, 1 .5 eq) and DIPEA (9.62 g, 74.4 mmol, 5 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was concentrated to give a residue. The residue was purified by column chromatography (S1O ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to give tert-butyl 3-[tert-butyl(diphenyl)silyl]oxy-4-[methoxy(methyl)carbamoyl ]piperidine-1- carboxylate (4.60 g, 8.73 mmol, 59% yield) as colorless oil.

¹ H NMR (400 MHz, CDCb) 6 = 7.70-7.66 (m, 4H), 7.45-7.35 (m, 6H), 4.08-4.05 (m, 1 H), 3.95-3.90 (m, 1 H), 3.73 (s, 3H), 3.50-3.45 (m, 1 H), 3.16 (s, 3H), 3.06-3.03 (m, 1 H), 2.68-2.65 (m, 1 H), 1.80-1.70 (m, 1 H), 1 .62-1 .58 (m, 1 H), 1 .34-1 .32 (m, 1 H), 1 .06-1 ,02(m, 18H).

Intermediate 466 tert-butyl 4-acetyl-3-(tert-butyl (diphenyl) silyl] oxy-piperidine-1 -carboxylate

To a solution of tert-butyl 3-[tert-butyl(diphenyl)silyl]oxy-4-[methoxy(methyl)carbamoyl jpiperidine-1- carboxylate (4.60 g, 8.73 mmol, 1 eq) in THF (40 mL) was added methyl magnesium bromide (3 M, 8.73 mL, 3 eq) at 0 °C. After stirring at 25 °C for 2 h, the mixture was quenched with saturated ammonium chloride solution (100 mL) at 0 °C and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 4-acetyl-3-[tert-butyl(diphenyl)silyl]oxy-piperidine-1 -carboxylate (4.2 g, 8.72 mmol, crude) as colorless oil.

Intermediate 467 tert-butyl 3-[tert-butyl (diphenyl) silyl] oxy-4-oxaldehydoyl-piperidine-1-carboxylate

To a solution of tert-butyl 4-acetyl-3-[tert-butyl(diphenyl)silyl]oxy-piperidine-1-carbo xylate (1.5 g, 3.11 mmol, 1 eq) in dioxane (20 mL) was added SeCh (1.73 g, 15.6 mmol, 5 eq) at 25 °C. After stirring at 100 °C for 2 h, the reaction mixture was filtrated and the filtrate was concentrated to give tert-butyl 3- [tert-butyl(diphenyl)silyl]oxy-4-oxaldehydoyl-piperidine-1-c arboxylate (1.5 g, crude) as yellow oil.

Intermediate 468 tert-butyl 3-[tert-buty!(diphenyl)silyl]oxy-4-[6-(2-hydroxy-4,6-dirneth y!-phenyl)pyrido[2.3- b]pyrazin-3-y!]piperidine-1 -carboxylate To a solution of tert-butyl 3-[tert-butyl(diphenyl)sily0oxy-4-oxaldehydoyl-piperidine-1 -carboxylate (1 .5 g, 3.30 mmol, 1 eq) in EtOH (30 mL) was added 2-(5, 6-diamino-2-pyridyl)-3, 5-dimethyl-phenol (0.69 g, 3.03 mmol, 1 eq) at 25 °C. After stirring at 60 °C for 4 h, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether/ethyl acetate=10/1 to 1/1) to tert-butyl 3-[tert-butyl(diphenyl)silyl]oxy-4-[6-(2-hydroxy-4,6-dimethy l-phenyl)pyrido[2,3-b]pyrazin-3- yl]piperidine-1-carboxylate (800 mg, 696 pmol, 23% yield, 60% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.768 min; MS (ESI): m/z = 689.3 [M+H] ⁺ .

Intermediate 469

2-[3~[3-[ted~butyl(diphfjriyl)sihyl]oxy~4-pipe,ddyl]pydda [2,3-b]py!azhii-6~yl]~3,5-dhrifjthybphenoi To a solution of tert-butyl 3-[tert-butyl(diphenyl)silyl]oxy-4-[6-(2-hydroxy-4,6-dimethy l-phenyl)pyrido[2,3- b]pyrazin-3-yl]piperidine-1 -carboxylate (709 mg, 609 pmol, 1 eq) in DCM (5 mL) was added TFA (208 mg, 1.83 mmol, 3 eq) at 25 °C. After stirring at 25 °C for 2 h, the mixture was concentrated under reduced pressure to give 2-[3-[3-[tert-butyl(diphenyl)silyl]oxy-4-piperidyl]pyrido[2, 3-b]pyrazin-6-yl]-3,5- dimethyl-phenol (500 mg, crude, TFA salt) as a yellow solid.

Intermediate 470

To a solution of 2-[3-[3-[tert-butyl(diphenyl)silyl]oxy-4-piperidyl]pyrido[2, 3-b]pyrazin-6-yl]-3,5-dimethyl- phenol (500 mg, 849 pmol, 1 eq) and TEA (172 mg, 1 .70 mmol, 2 eq) in DCM (5 mL) was added Ac2O (78.0 mg, 764 pmol, 0,9 eq) at 0 °C. After stirring at 25 °C for 2 h, the reaction mixture was concentrated under reduced pressure to give a crude. The crude product was purified by reversed flash (Instrument: 40g Flash; Column: Welch Ultimate XB_C18 20-40pm; Eluent A: water (0.1 % NH3 H2O), eluent B: acetonitrile; gradient: 0-10 min 20-80% B; flow 60 ml/min; temperature: room temperature; Detector: UV220/254 nm) to give 1-[3-[tert-butyl(diphenyl)silyl]oxy-4-[6-(2-hydroxy-4,6-dime thyl- phenyl)pyrido[2,3-b]pyrazin-3-y0-1-piperidyl]ethanone (500 mg, 555 pmol, 65% yield, 70% purity) as yellow oil.

LC-MS (Method C): Rt = 0.799 min; MS (ESI): m/z = 631 .4 [M+H] ⁺ .

Intermediate 471

To a solution of 1-[3-[tert-butyl(diphenyl)silyl]oxy-4-[6-(2-hydroxy-4,6-dime thyl-phenyl)pyrido[2,3- b]pyrazin-3-yl]-1-piperidyl]ethanone (500 mg, 555 pmol, 1 eq) in DMF (10 mL) was added cesium fluoride (168 mg, 1 .1 1 mmol, 2 eq) at 25 °C. After stirring at 50 °C for 4 h, the mixture was added water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude. The crude product was purified by reversed flash (Instrument: 40g Flash; Column: Welch Ultimate XB_C18 20- 40pm; Eluent A: water (0.1 % NH3 H2O), eluent B: acetonitrile; gradient: 0-10 min 0-40% B; flow 60 ml/min; temperature: room temperature; Detector: UV220/254 nm) to give 1-[3-hydroxy-4-[6-(2- hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazin-3-yl]-1-pip eridyl]ethanone (100 mg, 252 pmol, 45% yield, 99% purity) as yellow oil.

LC-MS (Method C): Rt = 0.4805 min; MS (ESI): m/z = 393.2 [M+H] ⁺ .

Compounds 201 and 202

The reaction was set up for SFC separation. The residue was purified by SFC: (column: DAICEL CHIRALCEL OJ(250mm*30mm,10um);mobile phase: [CO ₂ -i-PrOH(0.1%NH ₃ H ₂ O)];B%:40%, isocratic elution mode) to give peak A (40 mg) and peak B (30 mg) as yellow solid. Peak A was separated by SFC: (column: DAICEL CHIRALPAK IG (250mm*30mm,10um);mobile phase: [CO ₂ -ACN/i-PrOH(0.1% NH3H2O)];B%:60%, isocratic elution mode) to give compound 201 1-[3-hydroxy-4-[6-(2-hydroxy-4,6- dimethyl-phenyl)pyrido[2,3-b]pyrazin-3-yl]-1-piperidyl]ethan one (17.2 mg, 43.4 pmol, 17% yield, 99% purity, peak 1 , Rt = 0.524 min) as a yellow solid; diastereoisomer 1 1-[3-hydroxy-4-[6-(2-hydroxy-4,6- dimethyl-phenyl)pyrido[2,3-b]pyrazin-3-yl]-1-piperidyl]ethan one (17.5 mg, 44.1 pmol, 16% yield, 99% purity, peak 2, Rt = 0.839 min) as a yellow solid. Peak B was separated by SFC: (column: DAICEL CHIRALPAK IG (250mm*30mm,10um);mobile phase: [CO ₂ -ACN/i-PrOH(0.1 % NH ₃ H ₂ O)];B%:73%, isocratic elution mode) to give compound 202 1-[3-hydroxy-4-[6-(2-hydroxy-4,6-dimethyl- phenyl)pyrido[2,3-b]pyrazin-3-yl]-1-piperidyl]ethanone (9.34 mg, 23.5 pmol, 9% yield, 99% purity, peak 3, Rt = 1.106 min) as a yellow solid, and diastereoisomer 2 1-[3-hydroxy-4-[6-(2-hydroxy-4,6-dimethyl- phenyl)pyrido[2,3-b]pyrazin-3-yl]-1-piperidyl]ethanone (13.6 mg, 34.3 pmol, 14% yield, 95% purity, peak 4, Rt = 1 .683 min) as a yellow solid.

Compounds 201

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 = 8.97 (d, J = 1 .2 Hz, 1 H), 8.52 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 8.4 Hz, 1 H), 6.68 (s, 1 H), 6.64 (s, 1 H), 4.83-4.78 (m, 2H), 4.20-4.10 (m, 1 H), 4.05-3.90 (m, 1 H), 3.28-3.10 (m, 2H), 2.85-2.60 (m, 1 H), 2.30 (s, 3H), 2.18 (d, J = 6.4 Hz, 3H),2.15 (s, 3H), 2.10-1.95 (m, 2H).

LC-MS (Method C): Rt = 0.431 min; MS (ESIpos): m/z = 393.1 [M+1 ] ⁺ .

SFC (Rt = 0.524 min, ee% = 99%); diastereoisomer 1

¹ H NMR (400 MHz, DMSO- d ₆ ) 5 = 8.97 (d, J = 1 .2 Hz, 1 H), 8.52 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 8.4 Hz, 1 H), 6.68 (s, 1 H), 6.64 (s, 1 H), 4.83-4.78 (m, 2H), 4.20-4.10 (m, 1 H), 4.05-3.90 (m, 1 H), 3.28-3.10 (m, 2H), 2.85-2.60 (m, 1 H), 2.30 (s, 3H), 2.18 (d, J = 6.4 Hz, 3H),2.15 (s, 3H), 2.10-1.95 (m, 2H). LC-MS (Method C): Rt = 0.430 min; MS (ESIpos): m/z = 393.1 [M+1 ] ⁺ .

SFC (Rt = 0.839 min, ee% = 99%):

Compounds 202 ¹ H NMR (400 MHz, DMSO-d _s ) 5 = 9.07-9.02 (m, 1 H), 8.53 (d, J = 8.4 Hz, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 6.69 (s, 1 H), 6.64 (s, 1 H), 4.80-4.65 (m, 2H), 4.43 (s, 1 H), 4.23-4.05 (m, 1 H), 3.55-3.45 (m, 2H), 3.10- 2.80 (m, 1 H), 2.60-2.40 (m, 1 H), 2.31 (s, 3H), 2.18 (d, J = 13.2 Hz, 3H),2.15 (s , 3H), 2.08-1 .96 (m, 1 H). LC-MS (Method C): Rt = 0.429 min; MS (ESIpos): m/z = 393.1 [M+1] ⁺ .

SFC (Rt = 1 .106 min, ee% = 97%) diastereoisomer 2

¹ H NMR (400 MHz, DMSO-d _s ) 6 = 9.07-9.02 (m, 1 H), 8.52 (d, J = 8.4 Hz, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 6.67 (s, 1 H), 6.64 (s, 1 H), 4.80-4.65 (m, 2H), 4.42 (s, 1 H), 4.23-4.05 (m, 1 H), 3.55-3.45 (m, 2H), 3.10- 2.80 (m, 1 H), 2.60-2.40 (m, 1 H), 2.30 (s, 3H), 2.18 (d, J = 13.2 Hz, 3H),2.14 (s, 3H), 2.08-1.96 (m, 1 H). LC-MS (Method C): Rt = 0.430 min; MS (ESIpos): m/z = 393.2 [M+1 ] ⁺ .

SFC (Rt = 1 .683 min, ee% = 99%)

Intermediate 472

1-[[(3R)-3-[6-(2-hydroxy-4,6-dimethyl-phQnyl)pyndo[2,3-b] pyrazin-3-yl]-1- piperidy!]methyl]cyciopropaiiecaiboxylate

To a solution of 3,5-dimethyl-2-[3-[(3R)-3-piperidyl]pyrido[2,3-b]pyrazin-6-y l]phenol (500 mg, 1 .50 mmol, 1 eq) in MeOH (5 mL) was added NaBHsCN (282 mg, 4.49 mmol, 3 eq), methyl 1- formylcyclopropanecarboxylate (575 mg, 4.49 mmol, 3 eq) and AcOK (440 mg, 4,49 mmol, 3 eq) at 25 °C under N2. After stirring at 25 °C for 2 h, the mixture was filtered, and the filtrate was concentrated to dry. The residue was purified by reversed phase (column: C18 120 g, mobile phase: [water (FA) - MeCN]; B%: 40% - 70%, 10 min) to give methyl 1-[[(3R)-3-[6-(2-hydroxy-4,6-dimethyl- phenyl)pyrido[2,3-bjpyrazin-3-yl]-1-piperidyljmethyl]cyclopr opanecarboxylate (300 mg, 638 pmol, 43% yield, 95% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) <5 [ppm] = 10.15 (s, 1 H), 9.60 (s, 1 H), 9.09 (s, 1 H), 8.50 (d, J = 8.4 Hz, 1 H), 7.81 (d , J = 8.4 Hz, 1 H), 6.69 (d, J = 6.4 Hz, 1 H), 6.65 (s, 1 H), 6.63 (s, 1 H), 4.76 (d, J = 6.4 Hz, 1 H), 3.64 (s, 2H), 3.62 (s, 3H), 2.26 (s, 3H), 2.15 (s, 1 H), 2.08 (s, 3H), 1.92-1 .63 (m, 4H), 1.24-1.20 (m, 3H), 1 .17-1 .10 (m, 2H), 1 .08-1 .00 (m, 2H).

LC-MS (Method C): Rt = 0.448 min; MS (ESI): m/z = 447.3 [M+H] ⁺ .

Intermediate 473

1-[[3-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyra zin-3-yl]-1- piperidyl]methyl]cyc!opropanecarboxy!ic acid

To a solution of methyl 1-[[(3R)-3-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]py razin-3-yl]-1- piperidyl]methyl]cyclopropanecarboxylate (300 mg, 665 pmol, 1 eq) in MeOH (0.3 mL), THF (0.3 mL) and H2O (0.3 mL) was added LIOH H2O (83.7 mg, 2.00 mmol, 3 eq) at 25 °C. After stirring at 25 °C for 1 h, the mixture was concentrated to remove some solvent. The residue was purified by reversed phase (column: C18 25 g, mobile phase: [water (FA) - MeCN]; B%: 40% - 70%, 7 min) to give 1-[[3-[6-(2- hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazin-3-yl]-1-pip eridyl]methyl]cyclopropanecarboxylic acid (200 mg, 458 pmol, 69% yield, 99% purity) as a yellow solid. LC-MS (Method C): Rt = 0.435 min; MS (ESI): m/z = 433.3 [M+H] ⁺ .

Compounds 203 and 204

1-[[3-[6-(2-hydroxy-4 _! 6-dinielhybphenys)pyr!do[2,3-b]pyraz!n-3-y!]-1- piperidyljmethyljcycloproparsecarboxylic acid 1-[[3-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazin -3-yi]-1-piperidyl]methyl]cyclopropane- carboxylic acid (220 mg, 504 pmol, 1 eq) was separated by chiral SFC (column: DAICEL CHIRALCEL OX (250 mm x 30 mm, 10 pm); mobile phase: [COz- MeCN/EtOH (0.1 % NH3 H2O)]; B%: 72%, isocratic elution mode) to give Compounds 203 1-[[3-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazin -3- yl]-1-piperidyl]methyl]cyclopropanecarboxylic acid (162 mg, 370 pmol, 74% yield, 99% purity) (peak 1) as a yellow solid and Compounds 204 1-[[3-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazin -3- yl]-1-piperidyl]methyl]cyclopropanecarboxylic acid (41 .7 mg, 95.0 pmol, 19% yield, 99% purity) (peak 2) as yellow solid.

Compounds 203

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 9.97 (s, 1 H), 9.53 (s, 1 H), 8.92 (d, J = 8.4 Hz, 1 H), 8.22 (d, J = 8.4 Hz, 1 H), 7.06 (d, J = 6.0 Hz, 2H), 3.88-3.84 (m, 2H), 3.66-3.62 (m, 1 H), 3.28 - 3.15 (m, 3H), 2.88- 2.77 (m, 1 H), 2.69 (s, 3H), 2.59-2.53 (m, 1 H), 2.50 (s, 3H), 2.33 (s, 1 H), 2.21-2.09 (m, 2H), 1.50 (s, 2H), 1.18-1.08 (m, 2H)

LC-MS (Method C): Rt = 0.431 min; MS (ESIpos): m/z = 433.2 [M+H] ⁺ SFC (Rt = 0.752 min, ee% = 99%).

Compounds 204

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 9.07 (s, 1 H), 8.54 (s, 1 H), 8.47 (d, J = 8.4 Hz, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 6.67 (s, 1 H), 6.62 (s, 1 H), 3.22-3.13 (m, 2H), 2.98-2.89 (m, 1 H), 2.67 (s, 2H), 2.45-2.39 (m, 1 H), 2.26 (s, 3H), 2.20-2.11 (m, 1 H), 2.08 (s, 3H), 2.03-1.97 (m, 1 H), 1.77-1.62 (m, 3H), 0.89-0.85 (m, 2H), 0.52-0.42 (m, 2H)

LC-MS (Method C): Rt = 0.430 min; MS (ESIpos): m/z = 433.2 [M+H] ⁺ SFC (Rt =1 .228 min, ee% = 95%).

Intermediate 474 tert-butyl (3R)-3-[methoxy(methyl}carbamoyl]piperidine-1 -carboxylate

To a solution of 3R)-1-tert-butoxycarbonylpiperidine-3-carboxylic acid (100 g, 436 mmol, 1 eq) , N- methoxymethanamine hydrochloride (63.8 g, 654 mmol, 1.5 eq) and DIPEA (169 g, 1.31 mol, 227 mL, 3 eq) in dichloromethane (1000 mL) were added EDCI (125 g, 654 mmol, 1.5 eq) and HOBt (88.4 g, 654 mmol, 1 .5 eq) at 0 °C. After stirring at 20 °C for 16 h, the mixture was poured into ice-water (1000 mL) and extracted with dichloromethane (500 mL x 2). The combined organic phase was washed with brine (500 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiOz, Petroleum ether/Ethyl acetate = 10/1 to 3/1) to give tert-butyl (3R)-3-[methoxy(methyl)carbamoyl]piperidine-1 -carboxylate (110 g, 403 mmol, 92% yield) as yellow oil ¹ H NMR (400 MHz, CDCh) 5 [ppm] = 4.21-4.05 (m, 2H), 3.73 (s, 3H), 3.19 (s, 3H), 2.92-2.64 (m, 3H), 1.97-1.90 (m, 1 H), 1.75-1.60 (m, 3H), 1.46 (s, 9H).

Intermediate 475 tert-butyl (3R)-3-acetylpiperidine-1 -carboxylate

To a solution of tert-butyl (3R)-3-[methoxy(methyl)carbamoyl]piperidine-1 -carboxylate (105 g, 385 mmol, 1 eq) in THF (1000 mL) was added MeMgBr (3.00 M in diethyl ether, 385 mL, 3 eq) at 0 °C dropwise. After stirring at 0 °C for 1 h, the mixture was quenched by ice-water (1500 mL) and extracted with ethyl acetate (1000 mL x 2). The combined organic phase was washed with brine (1000 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 4/1) to give tertbutyl (3R)-3-acetyipiperidine-1 -carboxylate (80.0 g, 351 mmol, 91 % yield) as yellow oil.

¹ H NMR (400 MHz, CDCh) 5 [ppm] = 4.15-4.09 (m, 1 H), 3.96-3.84 (m, 1 H), 2.98-2.87 (m, 1 H), 2.84- 2.74 (m, 1 H), 2.55-2.46 (m, 1 H), 2.18 (s, 3H), 2.01-1.95 (m, 1 H), 1.73-1.67 (m, 1 H), 1.62-1.49 (m, 2H), 1.45 (s, 9H).

Intermediate 476 tert-butyl (3R)-3-oxaldehydoy!piperidme-1 -carboxylate

To a solution of tert-butyl (3R)-3-acetylpiperidine-1-carboxylate (10.0 g, 43.9 mmol, 1 eq) in dioxane (100 mL) was added SeO ₂ (14.6 g, 138 mmol, 14.36 mL, 3 eq) at 20 °C in one portion. After stirring at 80 °C for 16 h, the mixture was filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SIO ₂ , Petroleum ether/Ethyl acetate = 0/1) to give tertbutyl (3R)-3-oxaldehydoylpiperidine-1-carboxylate (10.0 g, 41.4 mmol, 94.20% yield) as yellow oil.

Intermediate 477 tert-butyl (3R)-3-[6-(2-hydroxy-4,8-dimetbyl-phenyl)pyrido[2,3-b]pyrazi n-3-yl]piperidine-1- carboxylate

To a solution of tert-butyl (3R)-3-oxaldehydoylpiperidine-1-carboxylate (9.00 g, 37.3 mmol, 1 eq, EW28562-1024) in EtOH (10 mL) was added 2-(5,6-diamino-2-pyridyl)-3,5-dimethyl-phenol (3.42 g, 14.9 mmol, 0.4 eq, EW29564-1258) at 20 °C in one portion. After stirring at 60 °C for 1 h, the mixture was filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiOz, Petroleum ether/Ethyl acetate = 10/1 to 3/1) to give tert-butyl (3R)-3- [6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazin-3-yl] piperidine-1 -carboxylate (9.00 g, 20.5 mmol, 54% yield, 99% purity) as a yellow solid.

¹ H NMR (400 MHz, CDCh) 6 [ppm] = 8.87 (s, 1 H), 8.49 (d, J = 8.8 Hz, 1 H), 7.97 (d, J = 9.2 Hz, 1 H), 6.81 (s, 1 H), 6.72 (s, 1 H), 4.49-4.32 (m, 1 H), 4.27-4.11 (m, 1 H), 3.45-3.13 (m, 2H), 2.97-2.82 (m, 1 H), 2.55 (s, 3H), 2.35 (s, 3H), 2.24-2.14 (m, 1 H), 2.10-2.00 (m, 1 H), 1.92-1.83 (m, 1 H), 1.74-1.65 (m, 1 H), 1.49 (s, 9H).

LC-MS (Method C): Rt = 0.608; MS (ESI) m/z = 435.2 [M+H] ⁺ . Intermediate 478

3.5-dimethyl-2-[3-[(3R)-3-pipendyl]pyndo[2,3-b]pyrazm-6-y i]phenol

To a solution of tert-butyl (3R)-3-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazi n-3-yl]piperidine- 1 -carboxylate (3.50 g, , 8.05 mmol, 1 eq) in dichloromethane (15 mL) was added TFA (7.68 g, 67.3 mmol, 5 mL, 8 eq) at 0 °C. After stirring at 20 °C for 1 h, the mixture was concentrated in vacuum to give 3,5-dimethyl-2-[3-[(3R)-3-piperidyl]pyrido[2,3-b]pyrazin-6-y l]phenol (4 g, crude) as black brown oil. LC-MS (Method C): Rt = 0.406; MS (ESI) m/z = 335.2 [M+H] ⁺ .

Intermediate 478 methyl 3-[(3R)-3-[6-(2-hydroxy-4 _> 6-d!methyi-phenyl}pyrido[2 _! 3-b]pyrszin-3-yl]-1-pipeddyl]-2 _! 2- dimethyl-propanoate

To a solution of 3,5-dimethyl-2-[3-[(3R)-3-piperidyl]pyrido[2,3-b]pyrazin-6-y l]phenol (500 mg, 1 .50 mmol, 1 eq) and potassium acetate (1.64 g, 14.9 mmol, 10 eq) in methanol (8 mL) was added methyl

2.2-dimethyl-3-oxo-propanoate (972 mg, 7.48 mmol, 5 eq) and NaBHsCN (281 mg, 4.49 mmol, 3 eq) at 20 °C in one portion. After stirring at 20 °C for 2 h, the mixture was filtered and filtrate was concentrated in vacuum to give a residue The residue was purified by reversed-phase HPLC(column: C18 80 g, mobile phase: [water (FA) - MeCN]; B%: 20% - 35%, 13 min) to give methyl 3-[(3R)-3-[6-(2-hydroxy-

4.6-dimethyl-phenyl)pyrido[2,3-b]pyrazin-3-yl]-1-piperidy l]-2,2-dimethyl-propanoate (100 mg, 209 pmol, 14% yield, 94% purity) as a yellow solid.

LC-MS (Method C): Rt =0.456; MS (ESI) m/z = 449.2 [M+HJ*.

Compounds 205 and 206

To a solution of methyl 3-[(3R)-3-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyr azin-3-yl]-1- piperidyl]-2,2-dimethyl-propanoate (100 mg, 222 pmol, 1 eq) in THF (2 mL) were added LiOH’HzO (46.7 mg, 1.11 mmol, 5 eq) in H2O (0.5 mL) at 20 °C dropwsie. After stirring at 40 °C for 5 h, the mixture was filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by reversed- phase HPLC (column: C18 80 g, mobile phase: [water (FA) - MeCN]; B%: 25% - 35%, 13 min) to give a racemate. The racemate was separated by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [CO ₂ -MeCN/EtOH(0.1 % NH3‘H2O)];B%:50%, isocratic elution mode) to give Compounds 205 2,2-dimethyl-3-[3-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2 ,3- b]pyrazin-3-yl]-1 -piperidyljpropanoic acid (30.0 mg, 68.3 pmol, 30% yield, 99% purity, FA salt) as a yellow solid and Compounds 206 2,2-dimethyl-3-[3-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2 ,3- b]pyrazin-3-yl]-1 -piperidyljpropanoic acid (5.00 mg, 10.5 pmol, 4% yield, 92% purity, FA salt) as a yellow solid.

Compounds 205

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 9.68-9.51 (m, 1 H), 9.05 (s, 1 H), 8.48 (d, J = 8.8 Hz, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 6.65 (s, 1 H), 6.63 (s, 1 H), 3.13-3.09 (m, 1 H), 2.90-2.85 (m, 1 H), 2.68-2.52 (m, 4H), 2.34-2.27 (m, 1 H), 2.26 (s, 3H), 2.07 (s, 3H), 2.05-2.00 (m, 1 H), 1.77-1.60 (m, 3H), 1.09 (s, 6H). LC-MS (Method C): Rt = 0.437; MS (ESQ m/z = 435.3 [M+H] ⁺ .

SFC (Rt =0.984, ee% = 80%)

Compounds 206

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 9.05 (s, 1 H), 8.48-8.45 (m, 2H), 7.77 (d, J = 8.4 Hz, 1 H), 6.66

(s, 1 H), 6.61 (s, 1 H), 3.14-3.09 (m, 1 H), 2.89-2.84 (m, 1 H), 2.65-2.53 (m, 4H), 2.34-2.28 (m, 1 H), 2.26

(s, 3H), 2.06 (s, 3H), 2.04-1 .99 (m, 1 H), 1 .75-1 .61 (m, 3H), 1 .08 (s, 6H)

LC-MS (Method C): Rt = 0.440; MS (ESI) m/z = 435.3 [M+H] ⁺ .

SFC (Rt = 0.201 min, ee% = 94%)

Intermediate 479 methyl 1 -formylcyclohexanecarboxylate

To a solution of methyl 1-(hydroxymethyl)cyclohexanecarboxylate (0.500 g, 2.90 mmol, 1 eq) in DCM (10 mL) was added Dess-Martin (1.85 g, 4.35 mmol, 1.35 mL, 1.5 eq) at 20 °C. After stirring at 20 °C for 1 h, the reaction mixture was quenched by saturated sodium bicarbonate aqueous solution (10 mL) and saturated sodium sulfite (10 mL) aqueous solution at 0 °C, and then extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SIO?, petroleum ether/ethyl acetate = 3/1) to give methyl 1 -formylcyclohexanecarboxylate (0.350 g, 1.85 mmol, 64% yield, 90% purity) as colorless oil. 9.52 (s, 1 H), 3.75 (s, 3H), 2.04-1 .96 (m, 2H), 1 .93-1 .83 (m, 2H), 1 .56- 1.48 (m, 4H), 1.47-1.39 (m, 2H).

Intermediate 480 methyl 1 -[[(3R)~3-[6~(2-hydroxy-4.S-dimethyl-phenyl)pyrido[2,3-b]pyr azin-3-yl]-1 - pipendyl]methyl]cyclohexanecarboxylate

To a solution of 3,5-dimethyl-2-[3-[(3R)-3-piperidyl]pyrido[2,3-b]pyrazin-6-y l]phenol (0.200 g, 598 pmol, 1 eq) and methyl 1 -formylcyclohexanecarboxylate (102 mg, 598 pmol, 1 eq) in MeOH (5 mL) were added sodium;cyanoboranuide (113 mg, 1.79 mmol, 3 eq) and KOAc (587 mg, 5.98 mmol, 10 eq) at 20 °C. After stirring at 20 °C for 16 h, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase (column: C18,80 g, mobile phase: [water(FA)- MeCN]; B%: 50%-70%,15 min) to give methyl 1-[[(3R)-3-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3- b]pyrazin-3-yl]-1-piperidyl]methyl]cyclohexanecarboxylate (70.0 mg, 129 pmol, 22% yield, 90% purity) as a light yellow solid.

LC-MS (Method C) Rt = 0.513 min; MS (ESIpos): m/z = 489.3 [M+H] ⁺ .

Intermediate 481 1-((3-(6-(2-hydroxy-4,6-dimethylphenyl)pyndo[2,3-b]pyrazin-3 -yl)pipendin-1- yl)methyl)cyclohexane-1 -carboxylic acid

To a solution of methyl 1-[[(3R)-3-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]py razin-3-yl]-1- piperidynmethyl]cyclohexanecarboxylate (50.0 mg, 71 .6 pmol, 1 eq) in EtOH (1 .5 mL) and H2O (1 .5 mL) was added NaOH (28.7 mg, 716 pmol, 10 eq) at 20 °C. After stirring at 60 °C for 24 h, the mixture was filtered and the filtrate was concentrated at reduced pressure to give a residue. The residue was purified by reversed-phase (column: C18.40 g, mobile phase: [water(FA)-MeCN];B%: 40% - 70%, 7 min) to give 1-((3-(6-(2-hydroxy-4,6-dimethylphenyl)pyrido[2,3-b]pyrazin- 3-yl)piperidin-1-yl)methyl)cyclohexane-1- carboxylic acid (0.030 g, 60.0 pmol, 84% yield, 95% purity) as a light yellow solid.

LC-MS (Method C) Rt = 0.478 min; MS (ESIpos): m/z = 475.3 [M+H] ⁺ .

Compounds 207 and 208

1-[[3-[6-(2-hydroxy-4 _! 6-dimethyl-phenyl)pyrido[2,3-b]pyrazin-3-yl]-1- piperidyl]methyl]cyclohexanecarboxylic acid

The reaction was set up for SFC separation. The residue was separated by SFC: (column: DAICEL CHIRALCEL OX (250 mm*30 mm, 10 um);mobile phase: [CO ₂ -MeCN/EtOH(0.1 % NH ₃ «H ₂ O)];B%:50%, isocratic elution mode) to give Compound 207 1-[[3-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3- b]pyrazin-3-yl]-1-piperidyl]methyl]cyclohexanecarboxylic acid (4.81 mg, 9.53 pmol, 15% yield, 94% purity) as a light yellow solid and Compound 208 1-[[3-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3- b]pyrazin-3-yl]-1-piperidyl}methyl]cyclohexanecarboxylic acid (6.35 mg, 12.8 pmol, 20% yield, 96% purity) as a light yellow solid.

Compounds 207

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 = 9.05 (s, 1 H), 8.48 (s, 1 H), 7.76 (d, J = 8.5 Hz, 1 H), 6.98 (s, 1 H), 6.66 (s, 1 H), 6.61 (s, 1 H), 3.09-3.04 (m, 2H), 2.85-2.80 (m, 1 H), 2.61-2.56 (m, 1 H), 2.27-2.26 (m, 3H), 2.25- 2.22 (m, 2H), 2.06 (s, 3H), 2.02-1.99 (m, 1 H), 1.94-1.88 (m, 2H), 1.72-1.62 (m, 3H), 1.48-1.46 (m, 2H), 1.37-1.30 (m, 2H), 1.28-1.18 (m, 5H)

LC-MS (Method C) Rt = 0.478 min; MS (ESIpos): m/z = 475.3 [M+H] ⁺ .

SFC (Rt = 0.971 min, ee% = 95%).

Compounds 208

^! H NMR (400 MHz, DMSO-d ₆ ) 5 = 9.05 (s, 1 H), 8.48 (d, J = 8.4 Hz, 1 H), 8.37-8.31 (m, 1 H), 7.77 (d, J = 8.5 Hz, 1 H), 6.64 (d, J = 9.0 Hz, 2H), 3.69 (s, 2H), 3.09 (s, 2H), 3.05 (d, J = 1 .4 Hz, 1 H), 2.84 ■ 2.80 (m, 1 H), 2.26 (s, 3H), 2.07 (s, 3H), 2.04-1 .97 (m, 1 H), 1 .91 (d, J = 10.6 Hz, 2H), 1 .74-1 .58 (m, 4H), 1 .53-1 .44 (m, 3H), 1 .40-1 .37 (m, 5H)

LC-MS (Method C) Rt = 0.480 min; MS (ESIpos): m/z = 475.2 [M+H] ⁺ .

SFC (Rt = 1 .313 min, ee% = 90%).

Intermediate 482 methyl 4-hydroxytetrahydrofuran-3-carboxylate To a solution of methyl 4-oxotetrahydrofuran-3-carboxylate (5.00 g, 34.7 mmol, 1 eq) in THF (50 mL) was added NaBFk (1 .97 g, 52.1 mmol, 1 .5 eq) at 0 °C under N2 atmosphere. After stirring at 0 °C for 1 h, the mixture was quenched with hydrochloric acid solution (100 mL, 1 M) at 0 °C and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl 4-hydroxytetrahydrofuran-3- carboxylate (2.50 g, 17.1 mmol, 49% yield) as colorless liquid.

Intermediate 483 methyl 4-[tert-butyl (diphenyl) silyl] oxytetrahydrofisran-3-carboxylate

To a solution of methyl 4-hydroxytetrahydrofuran-3-carboxylate (2.50 g, 17.1 mmol, 1 eq) and imidazole (3.49 g, 51.3 mmol, 3 eq) in DCM (50 mL) was added tert-butyl-chloro-diphenylsilane (5.64 g, 20.5 mmol, 1 .2 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to give methyl 4-[tert-butyl (diphenyl) silyl] oxytetrahydrofuran-3-carboxylate (5.00 g, 13.0 mmol, 76% yield) as colorless oil.

¹ H NMR (400 MHz, CDCb) 6 = 7.75-7.72 (m, 2H), 7.67-7.63 (m, 3H), 7.42-7.38 (m, 5H), 4.71-4.67 (m, 1 H), 4.20-4.15 (m, 1 H), 3.95-3.90 (m, 1 H), 3.74-3.70 (m, 2H), 3.55 (s, 3H), 3.10-3.05 (m, 1 H), 1.08 (s, 9H).

Intermediate 484

4-[tert~butyl (diphenyl) silyl] oxytetrahydrofuran-3-carboxylic acid

To a solution of methyl methyl 4-[tert-butyl (diphenyl) silyl] oxytetrahydrofuran-3-carboxylate (5.00 g, 13.0 mmol, 1 eq) in MeOH (100 mL) and H2O (20 mL) was added LiOH.HzO (1 .64 g, 39.0 mmol, 3 eq) at 25 °C. After stirring at 25 °C for 16 h, the reaction mixture was concentrated to remove MeOH. The crude was adjusted to PH to 4-5 by hydrochloric acid solution (1 M) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-[tert-butyl(diphenyl)silyl]oxytetrahydrofuran-3- carboxylic acid (5.00 g, crude) as colorless oil.

Intermediate 485

4-[tert-butyl (diphenyl) silyl] oxy-N-methoxy-N-methyl-tetrahydrofnran-3-carboxamide

To a solution of 4-[tert-butyl(diphenyl)silyl]oxytetrahydrofuran-3-carboxylic acid (5.00 g, 13.5 mmol, 1 eq) and N-methoxymethanamine (2.63 g, 27.0 mmol, 2 eq, HCI salt) in DCM (100 mL) were added HOBt (2.74 g, 20.2 mmol, 1 .5 eq), EDCI (3.88 g, 20.2 mmol, 1 .5 eq) and DIPEA (8.72 g, 67.5 mmol, 5 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiOz, petroleum ether/ethyl acetate=10/1 to 1/1) to give 4- [tert-butyl (diphenyl) silyl] oxy-N-methoxy-N-methyl-tetrahydrofuran-3-carboxamide (2.50 g, 6.04 mmol, 45% yield) as colorless oil.

¹ H NMR (400 MHz, CDCb) 5 = 7.70-7.60 (m, 4H), 7.45-7.35 (m, 6H), 4.82-4.78 (m, 1 H), 4.26 (t, d, J = 8.4 Hz, 1 H), 3.80-3.70 (m, 3H), 3.50 (s, 3H), 3.45-3.40 (m, 1 H), 3.08 (s, 3H), 1.08 (s, 9H). Intermediate 486

1-[4-[tert-butyl (diphenyl) silyl] oxytetrahydrofuran-3-yl] ethanone

To a solution of 4-[tert-butyl (diphenyl) silyl] oxy-N-methoxy-N-methyl-tetrahydrofuran-3-carboxamide (2.50 g, 6.04 mmol, 1 eq) in THF (40 mL) was added methyl magnesium bromide (3 M, 6.04 mL, 3 eq) at 0 °C. After stirring at 25 °C for 2 h, the mixture was quenched with saturated ammonium chloride solution (100 mL) at 0 °C and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1- [4-[tert-butyl(diphenyl)silyl]oxytetrahydrofuran-3-yl]ethano ne (2.20 g, crude) as colorless oil.

Intermediate 487

2-[4-[tert- butyl (diphenyl) silyl] oxytet!-ahydrofuran-3-y!]-2-oxo-acetaldehyde

To a solution of 1-[4-[tert-butyl (diphenyl) silyl] oxytetrahydrofuran-3-yl] ethanone (2.10 g, 5.70 mmol, 1 eq) in dioxane (20 mL) was added SeOz (1 .90 g, 17.1 mmol, 3 eq) at 25 °C. After stirring at 90 °C for 16 h, the reaction mixture was filtrated and the filtrate was concentrated to give 2-[4-[tert- butyl(diphenyl)silyl]oxytetrahydrofuran-3-yl]-2-oxo-acetalde hyde (2.20 g, crude) as a yellow solid.

Intermediate 488

2-[3-]4-[tert-butyi(dipheny!)silyi]oxytetrahydrofuran-3-y !]pyrido[2,3-b]pyrazin-6~yl]-3,5-difnethyl- phenol

To a solution of 2-[4-[tert-butyl (diphenyl) silyl] oxytetrahydrofuran-3-yl]-2-oxo-acetaldehyde (2.20 g, 5.75 mmol, 1 eq) in EtOH (30 mL) was added 2-(5, 6-diamino-2-pyridyl)-3, 5-dimethyl-phenol (1.19 g, 5.18 mmol, 0.9 eq, EW29564-1261) at 25 °C. After stirring at 60 °C for 4 h, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SIO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to 2-[3-[4-[tert-butyl(diphenyl)silyl]oxytetrahydrofuran-3-yl]p yrido[2,3-b]pyrazin-6- yi]-3, 5-dimethyl-phenol (2.50 g, 3.04 mmol, 53% yield, 70% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.725 min; MS (ESI): m/z = 576.3 [M+H] ⁺ .

Intermediate 489

4-[6-(2-hydroxy-4, 6-dimethyl-phenyi) pyrido [2, 3-b] pyrazin-3-yi] tetrahydrofuran-3-ol ■

To a solution of 2-[3-[4-[tert-butyl(diphenyl)silyl]oxytetrahydrofuran-3-yl]p yrido[2,3-b]pyrazin-6-yl]-3,5- dimethyl-phenol (1.50 g, 1.82 mmol, 1 eq) in DMF (20 mL) was added cesium fluoride (554 mg, 3.65 mmol, 2 eq) at 25 °C. After stirring at 25 °C for 2 h, the mixture was added water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude. The crude product was purified by reversed flash (Instrument: 40g Flash; Column: Welch Ultimate XB_C18 20-40pm; Eluent A: water (0.1 % NHo H2O), eluent B: acetonitrile; gradient: 0-10 min 0-40% B; flow 60 ml/min; temperature: room temperature; Detector: UV220/254 nm) to give 4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3- b]pyrazin-3-yl]tetrahydrofuran-3-ol (330 mg, 968 pmol, 53% yield, 99% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.455 min; MS (ESI): m/z = 337.9 [M+H] ⁺ . Compounds 209, 210, 211 and 212

4-[6-(2-hydroxy-4, 6-dimethyl-phenyl) pyrido [2, 3-b] pyrazin-3-yl] tetrahydrofuran-3-ol

The reaction was set up for SFC separation. The residue was purified by SFC: (column: DAICEL CHIRALPAK IC (250mm*30mm, 10um); mobile phase: [CO ₂ -MeCN/i-PrOH (0.1 % NH3H2O)]; B%:55%, isocratic elution mode) to give peak A (230 mg) and peak B (90 mg) as yellow solid. Peak A was separated by SFC: (column: DAICEL CHIRALPAK IG (250mm*30mm,10um); mobile phase: [CO ₂ - ACN/EtOH(0.1 % NH3H2O)];B%:45%, isocratic elution mode) to give Compound 209 4-[6-(2-hydroxy- 4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazin-3-yl]tetrahydrofura n-3-ol (108 mg, 317 pmol, 33% yield, 99% purity, peak 1 , Rt = 1.122 min) as a yellow solid and Compound 210 4-[6-(2-hydroxy-4,6-dimethyl- phenyl)pyrido[2,3-b]pyrazin-3-yl]tetrahydrofuran-3-ol (102 mg, 301 pmol, 33% yield, 99% purity, peak 2, Rt = 1.514 min) as a yellow solid. Peak B was separated by SFC (column: DAICEL CHIRALPAK IC(250mm*30mm,10um);mobile phase: [CO ₂ -EtOH(0.1 %NH3H2O)];B%:35%, isocratic elution mode) to give Compound 21 1 4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazin-3-y l]tetrahydrofuran-3-ol (36.1 mg, 105 pmol, 11 % yield, 99% purity, peak 3, Rt = 1.751 min) as a yellow solid and Compound 212 4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazin-3-y l]tetrahydrofuran-3-ol (42.8 mg, 120 pmol, 12% yield, 95% purity, peak 4, Rt = 2.024 min) as a yellow solid.

Compound 209 9.02 (s, 1 H), 8.49 (d, J = 8.4 Hz, 1 H), 7.79 (d, J = 8.8 Hz, 1 H), 6.64 (s, 1 H), 6.62 (s, 1 H), 5.80-5.20 (m, 1 H), 4.68-4.60 (m, 1 H), 4.32 (t, J = 8.4 Hz, 1 H), 4.10-4.00 (m, 2H), 3.80-3.74 (m, 1 H), 3.70-3.64 (m, 1 H), 2.26 (s, 3H), 2.07 (s, 3H).

LC-MS (Method C): Rt = 0.445 min; MS (ESIpos): m/z = 338.1 [M+1] ⁺ .

SFC (Rt = 1 .122 min, ee% = 95%)

Compound 210

¹ H NMR (400 MHz, DMSO- d ₆ ) 6 = 9.01 (s, 1 H), 8.49 (d, J = 8.4 Hz, 1 H), 7.78 (d, J = 8.4 Hz, 1 H), 6.64 (s, 1 H), 6.62 (s, 1 H), 5.57 (s, 1 H), 4.68-4.60 (m, 1 H), 4.31 (t, J = 8.0 Hz, 1 H), 4.10-4.00 (m, 2H), 3.80- 3.74 (m, 1 H), 3.70-3.64 (m, 1 H), 2.25 (s, 3H), 2.06 (s, 3H).

LC-MS (Method C): Rt = 0.455 min; MS (ESIpos): m/z = 338.1 [M+1 ] ⁺ .

SFC (Rt = 1 .514 min, ee% = 98%)

Compound 211

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 = 9.02 (s, 1 H), 8.50-8.45 (m, 1 H), 7.80-7.75 (m, 1 H), 6.64 (s, 1 H), 6.59 (s, 1 H), 4.80-4.60 (m, 1 H), 4.45-4.30 (m, 1 H), 4.22 (t, J = 8.0 Hz, 1 H), 4.10-4.00 (m, 2H), 3.95-3.85 (m, 1 H), 3.80-3.75 (m, 1 H), 2.25 (s, 3H), 2.07 (s, 3H).

LC-MS (Method C): Rt = 0.445 min; MS (ESIpos): m/z = 338.1 [M+1 ] ⁺ .

SFC (Rt = 1 .751 min, ee% = 80%)

Compound 212 ¹ H NMR (400 MHz, DMSO-c/ _e ) 6 = 9.02 (s, 1 H), 8.50-8.45 (m, 1 H), 7.80-7.75 (m, 1 H), 6.63 (s, 1 H), 6.60 (s, 1 H), 4.80-4.60 (m, 1 H), 4.45-4.30 (m, 1 H), 4.22 (t, J = 8.4 Hz, 1 H), 4.10-4.00 (m, 2H), 3.95-3.85 (m, 1 H), 3.80-3.75 (m, 1 H), 2.25 (s, 3H), 2.07 (s, 3H).

LC-MS (Method C): Rt = 0.442 min; MS (ESIpos): m/z = 338.1 [M+1] ⁺ .

SFC (Rt = 2.024 min, ee% = 89%)

Intermediate 490

[3-[[tert-butyl (diphenyl) silyl] oxymethyl] oxetan-3-yl] methanol

To a solution of [3-(hydroxymethyl)oxetan-3-yl]methanol (2.00 g, 16.9 mmol, 1 eq) and imidazole (1.38 g, 20.3 mmol, 1.2 eq) In DCM (20 mL) was added tert-butyl-chloro-diphenylsilane (5.12 g, 18.6 mmol, 1.1 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiOz, petroleum ether/ethyl acetate=10/1 to 1/1) to give [3-[[tert-butyl(diphenyl)silyl]oxymethyl]oxetan-3-yl]methano l (2.40 g, 6.73 mmol, 40% yield) as colorless oil.

¹ H NMR (400 MHz, CDCb) 6 = 7.70-7.65 (m, 4H), 7.50-7.40 (m, 6H), 4.50-4.45 (m, 2H), 4.41-4.38 (m, 2H), 3.97 (s, 4H), 2.13-2.08 (m, 1 H), 1.08 (s, 9H).

Intermediate 491

3-[[tert-butyl(dipheny!)silyl]oxymethyl]oxetane-3-carbald ehyde

To a solution of [3-[[tert-butyl(diphenyl)silyl]oxymethyl]oxetan-3-yl]methano l (2.40 g, 6.73 mmol, 1 eq) in DCM (30 mL) was added Dess-Martin (5.71 g, 13.5 mmol, 2 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was filtrated and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to give 3-[[tert- butyl(diphenyl)silyl]oxymethyl]oxetane-3-carbaldehyde (1.30 g, 3.67 mmol, 54% yield) as colorless oil.

Intermediate 492

1-[3-[[tert-butyl(diphenyl)silyl]oxymethyl]oxetan-3-yl]et hanol

To a solution of 3-[[tert-butyl(diphenyl)silyl]oxymethyl]oxetane-3-carbaidehy de (1 .30 g, 3.67 mmol, 1 eq) in THF (10 mL) was added methyl magnesium bromide (3 M, 2.44 mL, 2 eq) at 0 °C. After stirring at 20 °C for 2 h, the mixture was quenched with saturated ammonium chloride solution (50 mL) at 0 °C and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-[3-[[tert- butyl(diphenyl)silyl]oxymethyl]oxetan-3-yl]ethanol (1.40 g, 3.78 mmol, crude) as colorless oil.

Intermediate 493

1-[3-[[tert-butyl(diphenyl)silyl]oxymethyl]oxetan-3-yl]et hanone

To a solution of 1-[3-[[tert-butyl(diphenyl)silyl]oxymethyl]oxetan-3-yl]ethan ol (1.40 g, 3.78 mmol, 1 eq) in DCM (20 mL) was added Dess-Martin (2.40 g, 5.67 mmol, 1 .5 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was filtrated and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to give 1-[3-[[tert- butyl(diphenyl)silyl]oxymethyl]oxetan-3-yl]ethanone (1.10 g, 2.98 mmol, 79% yield) as colorless oil.

¹ H NMR (400 MHz, CDCb) 6 = 7.65-7.60 (m, 4H), 7.48-7.40 (m, 6H), 4.82 (d, J = 6.4 Hz, 2H), 4.46 (d, J = 6.4 Hz, 2H), 4.10 (s, 2H), 2.23 (s, 3H), 1 .06 (s, 9H). intermediate 494

2-[3-[[tert-butyl(diphenyl)silyl]oxymethy!]oxetan-3-yl]-2 -oxo-aceta!dehyd

To a solution of 1-[3-[[tert-butyl(diphenyl)silyl]oxymethyl]oxetan-3-yl]ethan one (1 .00 g, 2.71 mmol, 1 eq) in dioxane (20 mL) was added SeCh (1 .51 g, 13.6 mmol, 5 eq) at 25 °C. After stirring at 100 °C for 16 h, the reaction mixture was filtrated and the filtrate was concentrated to give 2-[3-[[tert- butyl(diphenyl)silyl]oxymethyl]oxetan-3-yl]-2-oxo-acetaldehy de (1.00 g, crude) as yellow oil.

Intermediate 495

2-[3-[3-[[tert-butyi(diphenynsilyl]oxymethyl]oxetan-3-yl] pyrido[2,3-h]pyrazin-6-yl]-3 _! 5-dimethyl- phenol

To a solution of 2-[3-[[tert-butyl(diphenyl)silyl]oxymethyl]oxetan-3-yl]-2-ox o-acetaldehyde (1.00 g, 2.61 mmol, 1 eq) in EtOH (30 mL) was added 2-(5, 6-diamino-2-pyridyl)-3, 5-dimethyl-phenol (0.54 g, 2.35 mmol, 0.9 eq) at 25 °C. After stirring at 60 °C for 4 h, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether/ethyl acetate=10/1 to 1/1) to 2-[3-[3-[[tert-butyl(diphenyl)silyl]oxymethyl]oxetan-3-ylJpy rido[2,3-bJpyrazin-6-yl]-3,5-dimethyl- phenol (700 mg, 1.02 mmol, 39% yield, 81 % purity) as a yellow solid.

LC-MS (Method C): Rt = 0.716 min; MS (ESI): m/z = 576.2 [M+H] ⁺ .

Compound 213

2-[3-[3-(hydroxymethyl)oxetan-3-yl]pyndo[2,3-h]pyrazin-6- yl]-3, 5-dimethyl-phenol

To a solution of 2-[3-[3-[[tert-butyl(diphenyl)silyl]oxymethyl]oxetan-3-yl]py rido[2,3-b]pyrazin-6-yl]-3,5- dimethyl-phenol (300 mg, 438 pmol, 1 eq) in DMF (2 mL) was added cesium fluoride (199 mg, 1.31 mmol, 3 eq) at 25 °C. After stirring at 25 °C for 1 h, the mixture was added water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude. The crude product was purified by reversed flash (Instrument: 40g Flash; Column: Welch Ultimate XB_C18 20-40pm; Eluent A: water (0.1 % NH3 H2O), eluent B: acetonitrile; gradient: 0-10 min 10-50% B; flow 60 ml/min; temperature: room temperature; Detector: UV220/254 nm) to give 2-[3-[3-(hydroxymethyl)oxetan-3-yl]pyrido[2,3-b]pyrazin- 6-yl]-3, 5-dimethyl-phenol (73.2 mg, 214 pmol, 49% yield, 99% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d _e ) 6 = 8.97 (s, 1 H), 8.51 (d, J = 8.8 Hz, 1 H), 7.82 (d, J = 8.8 Hz, 1 H), 6.64 (s, 1 H), 6.60 (s, 1 H), 5.06 (d, J = 6.0 Hz, 2H), 4.77 (d, J = 6.0 Hz, 2H), 4.09 (s, 2H), 2.25 (s, 3H), 2.08 (s, 3H).

LC-MS (Method C): Rt = 0.453 min; MS (ESIpos): m/z = 338.2 [M+1 ] ⁺ .

Intermediate 496 2-chloro-5-cyclopropyM,3-dimethyl-benzene

To a solution of 5-bromo-2-chloro-1 ,3-dimethyl-benzene (5.00 g, 22.7 mmol, 1 eq), cyclopropylboronic acid (7.83 g, 91.1 mmol, 4 eq) and CS2CO3 (22.2 g, 68.3 mmol, 3 eq) in dioxane (80 mL) and H2O (20 mL) was added Pd(dppf)Cl2 (1 .67 g, 2.28 mmol, 0.1 eq) at 20 °C in one portion. After stirring at 90 °C for 16 h under nitrogen atmosphere, the mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine (80 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiOa, Petroleum ether/Ethyl acetate = 1/0 ) to give 2- chloro-5-cyclopropyl-1 ,3-dimethyl-benzene (4.00 g, 22.1 mmol, 97% yield) as yellow oil.

¹ H NMR (400 MHz, CDCh) 5 [ppm] = 6.80 (s, 2H), 2.35 (s, 6H), 1 .86-1 .76 (m, 1 H), 0.98-0.91 (m, 2H), 0.69-0.63 (m, 2H)

Intermediate 497

2-(4<;yc!opropyl-2, 6-dimethybphenyl)-4, 4,5, 54etramethyl-1 ,3,2-dioxaborolane

To a solution of 2-chloro-5-cyclopropyl-1 ,3-dimethyl-benzene (3.00 g, 16.6 mmol, 1 eq) , 4,4,5,5- tetramethyl-2-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (8.43 g, 33.2 mmol, 2 eq) and potassium acetate (4.89 g, 49.8 mmol, 3 eq) in dioxane (30 mL) were added Pdz(dba)3 (1.52 g, 1 .66 mmol, 0.1 eq) and XPhos (1 .58 g, 3.32 mmol, 0.2 eq) at 20 °C in one portion. After stirring at 90 °C for 16 h under nitrogen atmosphere, the mixture was poured into water (80 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (S1O ₂ , Petroleum ether/Ethyl acetate = 1/0 to 100/1) to give 2-(4-cyclopropyl-2,6-dimethyl-phenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (2.50 g, 9.18 mmol, 55% yield) as yellow oil.

¹ H NMR (400 MHz, CDCh) 5 [ppm] = 6.67 (s, 2H), 2.38 (s, 6H), 1 .84-1 .76 (m, 1 H), 1 .38 (s, 12H), 0.94- 0.88 (m, 2H), 0.70-0.65 (m, 2H)

Intermediate 498

6-(4-cyclopropyl-2,6-dimethyl-phenyl)pyridine-2,3-diamine

To a solution of 6-chloropyridine-2,3-diamine (400 mg, 2.79 mmol, 1 eq), 2-(4-cyclopropyl-2,6-dimethyl- phenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (909 mg, 3.34 mmol, 1 .2 eq) and CS2CO3 (2.72 g, 8.36 mmol, 3 eq) in dioxane (8 mL) and H2O (2 mL) was added XPhos Pd G3 (235 mg, 278 pmol, 0.1 eq) at 20 °C in one portion. After stirring at 90 °C for 16 h under nitrogen atmosphere, the mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine (40 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiOz, Petroleum ether/Ethyl acetate = 5/1 to 1/1) to give 6-(4-cyclopropyl-2,6-dimethyl-phenyl)pyridine-2,3-diamine (640 mg, 2.37 mmol, 85% yield, 94% purity) as brown oil.

LC-MS (Method C): Rt =0.444; MS (ESI) m/z = 254.1 [M+H] ⁺ . Intermediate 499

To a solution of tert-butyl (3R)-3-oxaldehydoylpiperidine-1-carboxylate (1.22 g, 5.05 mmol, 2 eq) in ethanol (10 mL) was added 6-(4-cyclopropyl-2,6-dimethyl-phenyl)pyridine-2,3-diamine (640 mg, 2.53 mmol, 1 eq) at 20 °C in one portion. After stirring at 60 °C for 2 h, the mixture was poured into water (20 mL) extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (30 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate - 10/1 to 3/1) to give tert-butyl (3R)-3-[6-(4-cyclopropyl-2,6-dimethyl-phenyl)pyrido[2,3-b]py razin-3- yl]piperidine-1 -carboxylate (670 mg, 1.31 mmol, 52% yield, 90% purity) as yellow oil.

LC-MS (Method C): Rt =0.664; MS (ESI) m/z = 459.3 [M+H] ⁺ .

Intermediate 500

@-(4-cyclopropyl-2,6-dimethy!-phenyl)-3-[(3R)-3-piperidyl ]pyrldo[2.3-b]pyrazlrie

To a solution of tert-butyl (3R)-3-[6-(4-cyclopropyl-2,6-dimethyl-phenyl)pyrido[2,3-b]py razin-3- yl]piperidine-1-carboxylate (670 mg, 1 .46 mmol, 1 eq) in dichloromethane (6 mL) was added TFA (1 .54 g, 13.4 mmol, 1 mL, 9.21 eq) at 20 °C dropwise. After stirring at 20 °C for 1 h, the mixture was concentrated in vacuum to give 6-(4-cyclopropyl-2,6-dimethyl-phenyl)-3-[(3R)-3-piperidyl]py rido[2,3- b]pyrazine (500 mg, 1.39 mmol, 95% yield) as black brown oil.

Intermediate 501

6-(4-cyclopropyl-2,8-dimethyl-phenyl)-3-(1-methyl-3-plper idyl)pyrido[2,3-b]pyrazine

To a solution of 6-(4-cyclopropyl-2,6-dimethyl-phenyl)-3-[(3R)-3-piperidyl]py rido[2,3-b]pyrazine (250 mg, 697.39 pmol, 1 eq) and potassium acetate (684 mg, 6.97 mmol, 10 eq) in methanol (3 mL) were added paraformaldehyde (104 mg, 3.49 mmol, 5 eq) and NaBHsCN (131 mg, 2.09 mmol, 3 eq) at 20 °C in one portion. After stirring at 20 °C for 1 h, the mixture was filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(FA) - MeCN];B%: 35% - 75%, 10 min) to give 6-(4-cyclopropyl-2,6-dimethyl- phenyl)-3-(1-methyl-3-piperidyl)pyrido[2,3-b]pyrazine (150 mg, 394 pmol, 56% yield, 98% purity) as a yellow solid.

LC-MS (Method C): Rt =0.470; MS (ESI) m/z = 373.3 [M+H] ⁺ .

Compound 214

6-(4-cyc!opropyl-2 _! 6-dimethyl-phenyl)-3-[1-methy!-3-plperidy!]pyridG[2,3- b]pyi'azin&

The racemate was separated by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm,10um);mobile phase: [CO ₂ -EtOH(0.1 % NHs-FhO)]; B%: 42%, isocratic elution mode) to give Compound 214 6-(4-cyclopropyl-2,6-dimethyl-phenyl)-3-[1-methyl-3-piperidy l]pyrido[2,3-b]pyrazine (81 .38 mg, 205 pmol, 51.00% yield, 94% purity) as a yellow solid and enantiomer X 6-(4-cyclopropyl-2,6-dimethyl- phenyl)-3-[rel-(3R)-1-methyl-3-piperidyl]pyrido[2,3-b]pyrazi ne (4.83 mg, 12.8 pmol, 3% yield, 99% purity) as a yellow solid.

Compound 214

¹ H NMR (400 MHz, DMSO-d _e ) 5 [ppm] = 9.10 (s, 1 H), 8.56 (d, J = 8.4 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 6.90 (s, 2H), 3.10-3.04 (m, 1 H), 2.84-2.78 (m, 1 H), 2.31-2.26 (m, 1 H), 2.24 (s, 3H), 2.08-2.02 (m, 1 H), 1.98 (s, 6H), 1.97-1.89 (m, 3H), 1.81-1.75 (m, 1 H), 1.70-1.62 (m, 2H), 1 .00-0.94 (m, 2H), 0.76-0.71 (m, 2H)

LC-MS (Method C): R _t = 0.450; MS (ESI) m/z = 373.2 [M+H] ⁺ .

SFC (Rt =1 .680, ee% = 99%) enantiomer 1

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 9.15 (s, 1 H), 8.52 (d, J = 8.4 Hz, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 6.89 (s, 2H), 3.10-3.04 (m, 1 H), 2.87-2.79 (m, 1 H), 2.34-2.30 (m, 1 H), 2.26 (s, 3H), 2.07-2.00 (m, 2H), 1.97 (s, 6H), 1.95-1.86 (m, 2H), 1.81-1.76 (m, 1 H), 1.72-1.61 (m, 2H), 0.99-0.94 (m, 2H), 0.75-0.69 (m, 2H)

LC-MS (Method C): Rt = 0.459; MS (ESI) m/z = 373.1 [M+H] ⁺ .

SFC (Rt = 1 .893 min, ee% = 95%)

Intermediate 502

6-(4-ch/ort3-2 ₅ 6-d/mefhy/-pheny/)pyr/d?ne-2,3-d/am/ne

To a solution of 6-chloropyridine-2,3-diamine (2.50 g, 17.4 mmol, 1 eq) in dioxane (50 mL) and water (10 mL) were added (4-chloro-2,6-dimethyl-phenyl)boronic acid (5.00 g, 27.1 mmol, 1.56 eq), Pd(dppf)Cl2 (1.27 g, 1.74 mmol, 0.1 eq) and CS2CO3 (17.0 g, 52.2 mmol, 3 eq)at 20 °C in one portion. After stirring at 80 °C for 16 h, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The residue was purified by reversed phase (column: C18 40 g, mobile phase: [water (FA) - MeCN]; B%: 6%- 20%, 7 min) to give 6-(4- chloro-2,6-dimethyl-phenyl)pyridine-2,3-diamine (600 mg, 2.42 mmol, 14% yield) as a yellow solid.

Intermediate 503

A mixture of 6-(4-chloro-2,6-dimethyl-phenyl)pyridine-2,3-diamine (600 mg, 2.42 mmol, 1 eq) and tertbutyl (3R)-3-oxaldehydoylpiperidine-1 -carboxylate (584 mg, 2.42 mmol, 1 eq) in EtOH (10 mL) were stirred at 60 °C for 1 h. Then the mixture was concentrated to dry. The residue was purified by reversed phase (column: C18, 40 g, mobile phase: [water (FA) - MeCN]; B%: 40% - 70%, 7 min) to give tert-butyl (3R)-3-[6-(4-chloro-2,6-dimethyi-phenyi)pyrido[2,3-b]pyrazin -3-yl]piperidine-1 -carboxylate (400 mg, 830.07 pmol, 34.27% yield, 94% purity) was obtained as a yellow solid.

LC-MS (Method C) Rt = 0.667 min; MS (ESIpos): m/z = 397.0 [M-55H] ⁺ .

Intermediate 504 tert-butyl (3R)-3-[ 6-[2, 6-dimethyl-4-(4,4, 5, 5-tetramethyl- 1,3, 2-dioxaboralan-2- yl)phenyl]pyrido[2,3-b]pyrazin-3-yl]plperidlne-1 -carboxylate

To a solution of tert-butyl (R)-3-(6-(4-chloro-2,6-dimethylphenyl)pyrido[2,3-b]pyrazin-3 -yl)piperidine-1- carboxylate (0.4.00 g, 883 pmol, 1 eq) in dioxane (10 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3,2-dioxaboroiane (448 mg, 1.77 mmol, 2 eq), Pdztdba).? (80.9 mg, 88.3 pmol, 0.1 eq), XPhos (42.1 mg, 88.3 pmol, 0.1 eq) and KOAc (260 mg, 2.65 mmol, 3 eq) at 25 °C under nitrogen atmosphere. After stirring at 100 °C for 16 h. The mixture was filtered and the filtrate was concentrated at reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether/ethyl acetate - 2/1) to give tert-butyl (3R)-3-[6-[2,6-dimethyl-4- (4,4,5,5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)phenyl]pyrido[2,3-b]pyrazin-3-yl]piperid ine-1 -carboxylate (0.5 g, crude) as light yellow oil.

LC-MS (Method C) Rt = 0.678 min; MS (ESIpos): m/z = 545.3 [M+H] ⁺ .

Intermediate 505

6-(4-bromo-2,6-dimethyl-phenyl)-3-[(3R)-3-piperidyl]pyrid o[2,3-b]pyrazine

To a solution of tert-butyl (3R)-3-[6-[2,6-dimethyl-4-(4, 4, 5, 5-tetramethyl- 1 ,3,2-dioxaborolan-2- yl)phenyl]pyrido[2,3-b]pyrazin-3-yl]piperidine-1 -carboxylate (500 mg, 918 pmol, 1eq) in MeOH (5 mL) and HaO (5 mL) was added CuBrz (615 mg, 2.75 mmol, 129 pL, 3 eq) at 20 °C. The mixture was stirred at 80 °C for 16 h. The mixture was filtered and the filtrate was concentrated at reduced pressure to give a residue. The residue was purified by reversed-phase (column: C18, 40 g, mobile phase: [water(FA)- MeCN];B%: 35%-60%, 10 min) to give 6-(4-bromo-2,6-dimethyl-phenyl)-3-[rac-(3R)-3- piperidynpyrido[2,3-b]pyrazine (0.200 g, 478 pmol, 52% yield, 95% purity) as light yellow oil.

¹ H NMR (400 MHz, DMSO-d _e ) 5 = 9.13 (s, 1 H), 8.63 (d, J = 8.4 Hz, 1 H), 7.81 (d, J = 8.4 Hz, 1 H), 7.45 (s, 2H), 2.84-2.71 (m, 2H), 2.57 (d, J = 4.0 Hz, 2H), 2.27-2.12 (m, 1 H), 2.01 (s, 7H), 1 .90-1 .76 (m, 2H), 1.74 - 1.58 (m, 1 H).

LC-MS (Method C) Rt = 0.458 min; MS (ESIpos): m/z = 397.1 [M+H] ⁺ .

Intermediate 506

6-(4-bromo-2,6-dimetbyl-phenyl)-3-[(3R)-1-methyl-3-plperi dyl]pyrldo[2,3-b]pyrazlne

To a solution of 6-(4-bromo-2,6-dimethyl-phenyl)-3-[(3R)-3-piperidyl]pyrido[2 ,3-b]pyrazine (80.0 mg, 201 pmol, 1 eq) and potassium acetate (98.8 mg, 1.01 mmol, 5 eq) in methanol (1 mL) were added paraformaldehyde (30.2 mg, 1 .01 mmol, 5 eq) and NaBHsCN (37.9 mg, 604 pmol, 3 eq) at 20 °C in one portion. After stirring at 20 °C for 1 h, the mixture was filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C1840 g, mobile phase: [water (FA) - MeCN]; B%: 15%- 25%, 7 min) to give 6-(4-bromo-2,6-dimethyl-phenyl)-3-[(3R)-1-methyl- 3-piperidyl]pyrido[2,3-b]pyrazine (50 mg, 1 17.91 pmol, 58.56% yield, 97% purity) as a yellow solid. LC-MS (Method C) Rt = 0.476 min; MS (ESIpos): m/z = 411.3 [M+H] ⁺ .

SFC (Rt = 0.732 min, ee% = 75%).

Compound 215 6-(4~bromij-2 _f 6-dimethys~phefiyl)-3-[(3R)-1-inielhyb3-piperidyl]pydd o[2.3-b]pyrazine

The racemate was separated by SFC (column: Phenomenex-Cellulose-2 (250mm*30mm,10um);mobile phase: [CO ₂ -MeCN/EtOH(0.1 % NH3*H2O)];B%:40%, isocratic elution mode) to give 6-(4-bromo-2,6- dimethyl-phenyl)-3-[(3R)-1-methyl-3-piperidyl]pyrido[2,3-b]p yrazine (30.0 mg, 70.74 pmol, 58.20% yield, 97% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d _e ) 5 [ppm] = 9.12 (s, 1 H), 8.61 (d, J = 8.0 Hz, 1 H), 7.79 (d, J = 8.4 Hz, 1 H), 7.45 (s, 2H), 3.11-3.04 (m, 1 H), 2.83-2.77 (m, 1 H), 2.34-2.26 (m, 1 H), 2.24 (s, 3H), 2.11-2.01 (m, 2H), 2.00 (s, 6H), 1.98-1.92 (m, 1 H), 1.81-1.75 (m, 1 H), 1.71-1.60 (m, 2H)

LC-MS (Method C): Rt = 0.465; MS (ESI) m/z = 411.1 [M+H] ⁺ .

SFC (Rt = 0.735 min, ee% = 99%)

Intermediate 507

2-chloi’o-4-cyclopi'opyb§-methyl-aniline

To a solution of 4-bromo-2-chloro-6-methyl-aniline (4.00 g, 18.1 mmol, 1 eq), cyclopropylboronic acid (4.67 g, 54.4 mmol, 3 eq) and CS2CO3 (11.8 g, 36.2 mmol, 2 eq) in dioxane (40 mL) and H2O (10 mL) was added Pd(dppf)Cl2 (663 mg, 907 pmol, 0.05 eq) at 20 °C in one portion . After stirring at 100 °C for 16 h under nitrogen atmosphere, the mixture was poured into water (100 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic phase was washed with brine (100 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate = 10/1) to give 2- chloro-4-cyclopropyl-6-methyl-aniline (1 .80 g, 9.91 mmol, 54% yield) as light yellow oil.

¹ H NMR (400 MHz, CDCb) 6 [ppm] = 6.89 (d, J = 1 .6 Hz, 1 H), 6.74 (s, 1 H), 4.09-3.57 (m, 2H), 2.18 (s, 3H), 1.81-1.74 (m, 1 H), 0.89-0.85 (m, 2H), 0.61-0.56 (m, 2H).

Intermediate 508

2-bromo-1-chloro-5-cyclopropyl-3-methyl-benzene

To a solution of 2-chloro-4-cyclopropyl-6-methyl-aniline (1.80 g, 9.91 mmol, 1 eq) and CuBr2 (2.66 g, 11 .8 mmol, 556 pL, 1 .2 eq) in acetonitrile (25 mL) were added tert-butyl nitrite (1 .53 g, 14.8 mmol, 1 .77 mL, 1 .5 eq) in acetonitrile (5 mL) at 0 °C dropwise. After stirring at 50 °C for 1 h, the mixture was poured into ice-water (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine (30 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate - 1/0) to give 2-bromo-1-chloro-5-cyclopropyl-3-methyl-benzene (1.80 g, 7.33 mmol, 73% yield) as colorless oil.

¹ H NMR (400 MHz, CDCb) 5 [ppm] = 7.00 (d, J = 2.0 Hz, 1 H), 6.85 (d, J = 2.0 Hz, 1 H), 2.41 (s, 3H), 1.83-1.78 (m, 1 H), 1.01-0.95 (m, 2H), 0.71-0.64 (m, 2H)

Intermediate 509

2-(2-chloi'o-4-cyclopi'opyl-6-methyl-pheny0-4,4.5 _! 5-teti'amethyl-1,3,2-dioxaborolane To a solution of 2-bromo-1-chloro-5-cyclopropyl-3-methyl-benzene (1.80 g, 7.33 mmol, 1 eq), 4, 4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3-dioxolan-2-yl)-1 ,3,2-dioxaborolane (5.63 g, 21 .9 mmol, 3 eq) and potassium acetate (2.16 g, 21.9 mmol, 3 eq) in dioxane (20 mL) was added Pd(dppf)Cl2 (536.39 mg, 733.07 pmol, 0.1 eq) at 20 °C in one portion. After stirring at 100 °C for 16 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine (30 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SIOz, Petroleum ether/Ethyl acetate = 1/0) to give 2-(2-chloro-4-cyclopropyl-6-methyl-phenyl)-4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolane (1 .40 g, 4.78 mmol, 65% yield) was obtained as yellow oil.

¹ H NMR (400 MHz, CDCh) 6 [ppm] = 6.82 (s, 1 H), 6.73 (s, 1 H), 2.34 (s, 3H), 1.84-1.79 (m, 1 H), 1.40 (s, 12H), 0.97-0.93 (m, 2H), 0.69-0.66 (m, 2H)

Intermediate 510

6-(2-chloro-4-cyclopropyl-6-methyl-phenyl)pyndine-2,3-dia mine

To a solution of 2-(2-chloro-4-cyclopropyl-6-methyl-phenyl)-4, 4, 5, 5-tetra methyl- 1 ,3,2-dioxaborolane (1 .40 g, 4.78 mmol, 1 eq), 6-chloropyridine-2,3-diamine (893 mg, 6.22 mmol, 1 .3 eq) and CS2CO3 (4.68 g, 14.3 mmol, 3 eq) in dioxane (15 mL) and H2O (5 mL) was added Pd(dppf)Cl2 (350 mg, 478 pmol, 0.1 eq) at 20 °C in one portion under nitrogen atmosphere. After stiring at 90 °C for 16 hours, the mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to giv a residue. The residue was purified by reversed-phase column (column: C18 80 g, mobile phase: [water (FA) - MeCN]; B%: 20% - 30%, 8 min) to give 6-(2-chloro-4-cyclopropyl- 6-methyl-phenyl)pyridine-2,3-diamine (500 mg, 1 .64 mmol, 34% yield, 90% purity) as yellow oil.

LC-MS (Method C): Rt = 0.453; MS (ESI) m/z = 274.3 [M+HJ*.

Intermediate 511 tert-butyl (3R)-3-[6-(2-chloro-4-cyclopropyl-6-methyl-phenyl)pyrldo[2,3 -b]pyrazln-3- yl]plperidlne-1 -carboxylate

To a solution of 6-(2-chloro-4-cyclopropyl-6-methyl-phenyl)pyridine-2,3-diami ne (400 mg, 1.46 mmol, 1 eq) in EtOH (10 mL) was added tert-butyl (3R)-3-oxaldehydoylpiperidine-1-carboxylate (705 mg, 2.92 mmol, 2 eq) at 20 °C. After stirring at 60 °C for 2 h, the mixture was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 10/1 to 3/1) to give tert-butyl (3R)-3-[6-(2-chloro-4-cyclopropyl-6-methyl-phenyl)pyrido[2,3 -b]pyrazin-3- yl]piperidine-1 -carboxylate (470 mg, 892 pmol, 61.11 % yield, 91 % purity) as yellow oil.

LC-MS (Method C): Rt = 0.672; MS (ESI) m/z = 479.2 [M+H] ⁺ .

Intermediate 512

6-(2-chloro-4-cyclopropyl-§-methyl-phenyl)-3-[(3R)-3-pip eridyl]pyrido[2,3-b]pyrazine

To a solution of tert-butyl (3R)-3-[6-(2-chloro-4-cyclopropyl-6-methyl-phenyl)pyrido[2,3 -b]pyrazin-3- yl]piperidine-1 -carboxylate (470 mg, 981.19 pmol, 1 eq) in dichloromethane (5 mL) was added TFA (3.07 g, 26.9 mmol, 2 mL, 27 eq) at 0 °C in one portion. After stirring at 20 °C for 1 h, the mixture was concentrated in vacuum to give 6-(2-chloro-4-cyclopropyl-6-methyl-phenyl)-3-[(3R)-3- piperidyl]pyrido[2,3-b]pyrazine (350 mg, 923 pmol, 94% yield) as brown oil.

Compound 216 6-(2-chloro-4-cyclopropyl-6-methyl-phenyl)-3-[(3R)-1-methyl- 3-piperidyl]pyndo[2,3-b]pyrazme To a solution of 6-(2-chloro-4-cyclopropyl-6-methyl-phenyl)-3-[(3R)-3-piperid yl]pyrido[2,3-b]pyrazine (350 mg, 923.73 pmol, 1 eq) and potassium acetate (453 mg, 4.62 mmol, 5 eq) in methanol (10 ml) were added paraformaldehyde (138 mg, 4.62 mmol, 5 eq) and NaBHsCN (174 mg, 2.77 mmol, 3 eq) in one portion. After stirring at 20 °C for 2 h, the mixture was filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18 80 g, mobile phase: [water (FA) - MeCN]; B%: 22% - 30%, 9 min) to give 6-(2-chloro-4-cyclopropyl-6-methyl- phenyl)-3-[(3R)-1-methyl-3-piperidyl]pyrido[2,3-b]pyrazine (130 mg, 317 pmol, 34% yield, 96% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 9.13 (s, 1 H), 8.61 (d, J = 8.4 Hz, 1 H), 7.80 (d, J = 8.4 Hz, 1 H), 7.17 (s, 1 H), 7.08 (s, 1 H), 3.38-3.32 (m, 1 H), 3.15-3.09 (m, 1 H), 2.89-2.83 (m, 1 H), 2.41-2.36 (m, 1 H), 2.29 (s, 3H), 2.10-2.04 (m, 2H), 2.02 (s, 3H), 2.01-1.97 (m, 1 H), 1.79-1.61 (m, 3H), 1.05-0.99 (m, 2H), 0.82-0.77 (m, 2H)

LC-MS (Method C): Rt = 0.478; MS (ESI) m/z = 393.1 [M+H] ⁺ .

SFC (Rt = 1.717 min, ee% = 80%)

Intermediate 513

5~ch!oro~3~methyl~2-(4.4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)phenol

To a solution of 5-chloro-2-iodo-3-methyl-phenol (12.0 g, 44.7 mmol, 1 eq), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (17.0 g, 67.0 mmol, 1.5 eq) and potassium acetate (8.77 g, 89.3 mmol, 2 eq) in dioxane (200 mL) was added Pd(dppf)Cl2 (1.64 g, 2.23 mmol, 0.05 eq) at 20 °C in one portion. After stirring at 60 °C for 16 h under nitrogen atmosphere, the reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (150 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOa, Petroleum ether/Ethyl acetate = 20/1 to 10/1) to give 5- chloro-3-methyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (7.00 g, 26.0 mmol, 58.32% yield) as light yellow oil.

¹ H NMR (400 MHz, CDCfe) 5 [ppm] = 6.80 (d, J = 2.0 Hz, 1 H), 6.67 (d, J = 2.4 Hz, 1 H), 2.40 (s, 3H), 1.25 (s, 12H)

Intermediate 514 benzyl 3-[7-(4-chloro-2-hydroxy-@-methy!-pheny!)-1.8-naphthyridln-2 -yl]plperidine-1- carboxylate To a solution of mixture of benzyl 3-(7-chloro-1 ,8-naphthyridin-2-yl)piperidine-1 -carboxylate (1.00 g, 2.62 mmol, 1 eq), 5-chloro-3-methyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (1.05 g, 3.93 mmol, 1.5 eq) and CS2CO3 (2.56 g, 7.86 mmol, 3 eq) in dimethyl tetrahydrofuran (30 mL) was added XPhos Pd G3 (221 mg, 261 pmol, 0.1 eq) at 20 °C in one portion under nitrogen atmosphere. After stirring at 80 °C for 16 h, the reaction mixture was diluted with water (150 ml) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SIOs, Petroleum ether/Ethyl acetate - 10/1 to 2/1) to give benzyl 3-[7-(4-chloro-2-hydroxy-6-methyl-phenyl)-1 ,8-naphthyridin-2-yl]piperidine- 1 -carboxylate (800 mg, 1 .38 mmol, 13% yield, 84% purity) as light yellow oil.

LC-MS (Method C): Rt = 0.645 min; MS (ESIpos): m/z = 488.2 [M+H] ⁺

Intermediate 515 benzyl 3-[7-[2-hydroxy-4-(hydi'oxymethyl)-S-methyl-phenyl]-1 _! 8-naphthyndin-2-yl]pipendine-1- carboxylate

To a solution of benzyl 3-[7-(4-chloro-2-hydroxy-6-methyl-phenyl)-1 ,8-naphthyridin-2-yl]piperidine-1- carboxylate (600 mg, 1 .23 mmol, 1 eq) and tributylstannylmethanol (1 .97 g, 6.15 mmol, 5 eq) in toluene (2 mL) was added XPhos Pd G3 (520 mg, 614 pmol, 0.5 eq) at 20 °C in one portion. After stirring at 100 °C for 16 h, the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate = 5/1 to 1/1) to give benzyl 3-[7-[2-hydroxy-4- (hydroxymethyl)-6-methyl-phenyl]-1 ,8-naphthyridin-2-yl]piperidine-1-carboxylate (510 mg, 896 pmol, 72% yield, 85% purity) as a yellow gum.

LC-MS (Method C): Rt = 0.552 min; MS (ESIpos): m/z = 484.3 [M+H] ⁺

Intermediate 516

5-(hydroxymethyl)-3-methyl-2-[7-(3-piperidyl)-1,8-naphthy ridln-2-yl]phenol

To a solution of benzyl 3-[7-[2-hydroxy-4-(hydroxymethyl)-6-methyl-phenyl]-1 ,8-naphthyridin-2-yl] piperidine-1 -carboxylate (400 mg, 827 pmol, 1 eq) in dichloromethane (4 mL) was added H2SO4 (405 mg, 4.14 mmol, 220 pL, 5 eq) at 0 °C in one portion. After stirring at 0 °C for 1 h, the mixture was quenched by water (0.5 mL).The pH was adjusted to 9-10 with ammonium hydroxide. The mixture was filtered and filtrate was concentrated in vacuum to give 5-(hydroxymethyl)-3-methyl-2-[7-(3-piperidyl)- 1 ,8-naphthyridin-2-yl]phenol (200 mg, crude) was obtained as a yellow oil.

LC-MS (Method C): Rt = 0.408 min; MS (ESIpos): m/z = 350.2 [M+1 ] ⁺ .

Compound 217

5-(hydroxymethyl)-3-methyl-2-[7-(1-methyl-3-piperidyl)-1, §-naphthyridln-2-yl]phenol

To a solution of 5-(hydroxymethyl)-3-methyl-2-[7-(3-piperidyl)-1 ,8-naphthyridin-2-yl]phenol (200 mg, 572 pmol, 1 eq), paraformaldehyde (171 mg, 5.72 mmol, 10 eq) and AcOK (112 mg, 1.14 mmol, 2 eq) in methanol (3 mL) was added NaBHsCN (107.91 mg, 1.72 mmol, 3 eq) at 20 °C in one portion. After stirring at 20 °C for 1 h, the mixture was filtered and filtrate was concentrated in vacuum to give 5- (hydroxymethyl)-3-methyl-2-[7-(1-methyl-3-piperidyl)-1 ,8-naphthyridin-2-yl]phenol (1.26 mg, 5.17 pmol, 94% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-ds) 6 = 8.48 (d, J = 8.4 Hz, 1 H), 8.41 (d, J = 8.4 Hz, 1 H), 7.52 (d, J = 8.4 Hz, 1 H), 7.37 (d, J = 8.8 Hz, 1 H), 7.12-7.08 (m, 1 H), 6.99-6.92 (m, 1 H), 5.37-5.28 (m, 1 H), 4.81-4.49 (m, 2H), 3.32-3.17 (m, 2H), 2.76-2.62 (m, 3H), 2.52 (s, 3H), 2.39-2.33 (m, 3H), 2.08-1 .98 (m, 1 H), 1 .94-1 .83 (m, 2H), 1 .64-1 .49 (m, 1 H)

LC-MS (Method C): Rt = 0.422 min; MS (ESIpos): m/z - 364.2 [M+1 ] ⁺ .

Intermediate 517

1-cyclopmpylidenepropan-2~one

A mixture of (l-ethoxycyclopropoxy)-trimethyl-silane (5.00 g, 28.7 mmol, 1.00 eq), 1-(triphenyl- phosphanylidene)propan-2-one (11.9 g, 37.3 mmol, 1 .30 eq) and p-toluenesulfonic acid monohydrate (546 mg, 2.87 mmol, 0.100 eq) in 1 ,2-dichlorobenzene (40.0 mL) was stirred at 100 °C for 16 h. The mixture was concentrated at vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-20% ethyl acetate / petroleum ether gradient @ 150 mL/min) to afford 1-cyclopropylidenepropan-2-one (1 .10 g, 11 .4 mmol, 39.9% yield) as yellow oil.

¹ H NMR (400 MHz, CDCb) 5 = 6.38 (s, 1 H), 2.27 (s, 3H), 0.88-0.81 (m, 2H), 0.55-0.48 (m, 2H).

Intermediate 518

1-acetonylcyclopropanecarbonitrile

To a solution of tetrabutylammonium fluoride (1.00 M in tetrahydrofuran, 21.9 mL, 1.50 eq) in tetrahydrofuran (5.00 mL) was added trimethylsilyl nitrile (2.17 g, 21.9 mmol, 1.50 eq) at 0 °C. After stirring at 20 °C for 0.5 h, then a solution of 1-cyclopropylidenepropan-2-one (1 .40 g, 14.6 mmol, 1 .00 eq) in tetrahydrofuran (5.00 mL) was added dropwise at 0 °C. After stirring at 20 °C for 16 h. The mixture was concentrated at vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40.0 g SepaFlash® Silica Flash Column, Eluent of 10-30% ethyl acetate / petroleum ether gradient @ 100 mL/min) to afford 1 -acetonylcyclopropanecarbonitrile (650 mg, 4.75 mmol, 32.6% yield, 90% purity) as yellow oil.

^! H NMR (400 MHz, CDCb) 5 = 2.61 (s, 2H), 2.22 (s, 3H), 1.40-1.33 (m, 2H), 0.90-0.84 (m, 2H).

Intermediate 519

1-[[7-(2-methoxy-4, 8-dlmethyl-phenyO-l , §-naphthyridm-2-yi] methyl] cyciopropanecarbonitrile To a mixture of 1-acetonylcyclopropanecarbonitrile (206 mg, 1.67 mmol, 1.30 eq) and 2-amino-6-(2- methoxy-4,6-dimethyl-phenyl)pyridine-3-carbaldehyde (330 mg, 1.29 mmol, 1.00 eq) in methanol (10.0 mL) was added pyrrolidine (45.8 mg, 644 pmol, 0.500 eq), the mixture was stirred at 60 °C for 16 h. The mixture was diluted with saturated ammonium chloride (20.0 mL) aqueous solution and extracted with ethyl acetate (20.0 mL x 2), washed with brine (20.0 mL x 2), and dried over anhydrous sodium sulfate, filtered and concentrated, to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 50 ~ 70% ethyl acetate / petroleum ether gradient @ 100 mL/min) to afford 1-[[7-(2-methoxy-4, 6-dimethyl-phenyl)-1 , 8- naphthyridin-2-yl] methyl] cyclopropanecarbonitrile (250 mg, 728 pmol, 56.5% yield) as yellow oil.

¹ H NMR (400 MHz, DMSO-d ₅ ) 6 = 8.49 (d, J = 8.4 Hz, 1 H), 8.43 (d, J = 8.4 Hz, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.50 (d, J = 8.0 Hz, 1 H), 6.83 (s, 1 H), 6.77 (s, 1 H), 3.66 (s, 3H), 3.20 (s, 2H), 2.36 (s, 3H), 2.01 (s, 3H), 1.37-1.32 (m, 2H), 1.27-1.21 (m, 2H).

LC-MS (Method Q) Ri = 0.468 min; MS (ESIpos): m/z = 344.2 [M+H] ⁺ .

Intermediate 520

1 -[[7-(2-methoxy-4, §-dimethyi-pheny!)-1 , 8-naphthyridin-2-yl] methyl] cyclopropanecarboxylic acid

To a solution of 1-[[7-(2-methoxy-4, 6-dimethyl-phenyl)-1 , 8-naphthyridin-2-yl] methyl] cyclopropanecarbonitrile (200 mg, 582 pmol, 1 .00 eq) in ethanol (5.00 mL) was added sodium hydroxide (2.00 M in water, 5.00 mL). After stirring at 90 °C for 16 h. The mixture was diluted with water (20.0 mL). The aqueous phase was extracted with ethyl acetate (20.0 mL), then the aqueous was adjusted to pH-3 with hydrochloric acid (2.00 M in water). The mixture was extracted with ethyl acetate (20.0 mL x 2) and the combined organic phase was washed with brine (15.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford 1-[[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8- naphthyridin-2-yl]methyl]cyclopropanecarboxylic acid (120 mg, 298 pmol, 51 .2% yield, 90.0% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d _s ) 6 = 8.37 (dd, J = 4.0, 8.4 Hz, 2H), 7.63 (d, J = 8.0 Hz, 1 H) , 7.43 (d, J = 8.0 Hz, 1 H), 6.82 (s, 1 H), 6.76 (s, 1 H), 3.64 (s, 3H), 3.23 (s, 2H), 2.36 (s, 3H), 1.99(s, 3H), 1.23-1.18 (m, 2H), 1 .00-0.93 (m, 2H).

LC-MS (Method Q) Rt = 0.443 min; MS (ESIpos): m/z = 363.1 [M+H] ⁺ .

Intermediate 521

1-[[7-(2-methoxy-4, 6 -dimethyl-phenyl)-1 , 8-naphthyridin-2-yl] methyl]-N-methyl- cyclopropanecarboxamide

To a solution of 1-[[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridln-2- yl]methyl]cyclopropanecarboxylic acid (120 mg, 331 pmol, 1.00 eq) and methanamine hydrochloride (33.5 mg, 497 pmol, 1.50 eq) in /V,/V-dimethylformamide (3.00 mL) was added N,N- diisopropylethylamine (214 mg, 1.66 mmol, 5.00 eq) and 0-(7-azabenzotriazol-1-yl)-/V, N, N, N- tetramethyluroniumhexafluorophosphate (189 mg, 497 pmol, 1.50 eq). After stirring at 20 °C for 16 h. The mixture was diluted with saturated ammonium chloride (10.0 mL) aqueous solution and extracted with ethyl acetate (20.0 mL x 2), washed with brine (15.0 mL), and dried over anhydrous sodium sulfate, filtered and concentrated to give a residue, to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 50~100% ethyl acetate / petroleum ether gradient @ 50 mL/min) to afford 1-[[7-(2-methoxy-4,6-dimethyl-phenyl)-1 ,8- naphthyridin-2-yl]methyl]-A/-methyl-cyclopropanecarboxamide (80.0 mg, 202 pmol, 61.1 % yield, 95.0% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 = 8.40 (dd, J = 4.8, 8.0 Hz, 2H), 7.59 (d, J = 8.4 Hz, 1 H), 7.48 (d, J = 8.4 Hz, 1 H), 6.83 (s, 1 H), 6.78 (s, 1 H), 3.66 (s, 3H), 3.28 (s, 2H), 2.55 (d, J = 4.4 Hz, 3H), 2.36 (s, 3H), 2.02 (s, 3H), 1.11-1.06 (m, 2H), 0.88-0.82 (m, 2H)

Compound 218

1-[[7-(2-hydroxy-4„ S-dimethyl-phenyl)-1. §-naphthyridm-2-yl] methyl]-N-methyl- cyclopropanecarboxamide

To a solution of 1-[[7-(2-methoxy-4, 6-dimethyl-phenyl)-1 , 8-naphthyridin-2-yl] methyl]-/V-methyl- cyclopropanecarboxamide (80.0 mg, 213 pmol, 1.00 eq) in dichloromethane (2.00 mL) was added tribromoborane (160 mg, 639 pmol, 3.00 eq) at -70 °C. After stirring at 20 °C for 1 h. The mixture quenched by methanol (2.00 mL) at 0 °C under nitrogen, the mixture was concentrated at vacuum, to give a residue. The residue was purified by prep-HPLC (column: C18 150x30 mm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 25%-55% B over 7 min) to afford 1-[[7-(2-hydroxy-4, 6-dimethyl- phenyl)-1 , 8-naphthyrid in-2-yl] methyl]-/V-methyl-cyclopropanecarboxamide (39.6 mg, 105 pmol, 75.8% yield, 95.8% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 = 9.86 (s, 1 H), 8.41 (dd, J = 2.4, 8.4 Hz, 2H), 8.12-8.04 (m, 1 H), 7.59 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 6.0 Hz, 2H), 3.29 (s, 2H), 2.56 (d, J = 4.8 Hz, 3H), 2.26 (s, 3H), 2.11 (s, 3H), 1.12-1.05 (m, 2H), 0.88-0.80 (m, 2H).

LC-MS (Method Q) Rt = 0.876 min; MS (ESIpos): m/z = 362.1 [M+H] ⁺ .

HPLC (Method AJ) Rs = 0.991 min; Purity = 95.8%

Intermediate 522

1-(3-hydroxybutyl)cyclopropanol

To a solution of 5-methyltetrahydrofuran-2-one (10.0 g, 99.8 mmol, 9.46 mL, 1 .00 eq) in tetrahydrofuran (100 mL) was added titanium(IV) isopropoxide (34.0 g, 119 mmol, 35.3 mL, 1.20 eq) at -60 °C under nitrogen atmosphere. After 0.5 h, ethylmagnesium bromide (3.00 M, 99.8 mL, 3.00 eq) was added dropwise at -60 °C under N2 atmosphere. The mixture was stirred at -60 °C for 0.5 h, then poured into saturated ammonium chloride (150 mL) aqueous, extracted with ethyl acetate (50.0 mL x 3). The combined organic phases was dried over anhydrous sodium sulfate and filtered. After filtration, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 20-30% Ethyl acetate/Petroleum ether gradient @ 80 mL/min) to give 1-(3-hydroxybutyl)cyclopropanol (3.00 g, 20.7 mmol, 54% yield, 90% purity) as yellow oil.

¹ H NMR (400 MHz, CDCb) 6 = 3.99-3.86 (m, 1 H), 1.81-1.57 (m, 4H), 1.29-1.22 (m, 4H), 0.80-0.71 (m, 2H), 0.50-0.36 (m, 2H).

Intermediate 523

4-(1~hydmxycycl(}propyl)butaii-2~one A mixture of 1-(3-hydroxybutyl)cyclopropanol (400 mg, 3.07 mmoi, 1 .00 eq), dimethylsulfoxide (600 mg, 7.68 mmoi, 2.50 eq), N,N-diisopropyiethyiamine (1.59 g, 12.3 mmol, 2.14 mL, 4.00 eq) and sulfur trioxide pyridine (1.22 g, 7.68 mmol, 2.50 eq) in dichloromethane (20.0 mL) was stirred at 0°C for 1 h. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (60.0 mL x 5). The organic phase was concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ethergradient @ 60 mL/min) to give 4-(1-hydroxycyclopropyl)butan-2-one (200 mg, 1 .40 mmol, 45% yield, 90% purity) as a colorless oil.

¹ H NMR (400 MHz, CDCb) 6 = 2.73 (t, J = 6.6 Hz, 2H), 2.21 (s, 3H), 1 .84 (t, J = 6.6 Hz, 2H), 0.84-0.69 (m, 2H), 0.55-0.37 (m, 2H).

Compound 219

2-[7-[2~(1~hydi'oxycycJQpropyi)ethyl]~1 _! 8~naphthyndiii-2~yl]-3.S-dimethyi-phenol

A mixture of 2-amino-6-(2-hydroxy-4,6-dimethyl-phenyl)pyridine-3-carbalde hyde (100 mg, 0.412 mmol, 1.00 eq), 4-(1-hydroxycyclopropyl)butan-2-one (52.9 mg, 0.412 mmol, 1.00 eq) and pyrrolidine (29.3 mg, 0.412 mmol, 1 .00 eq) in methanol (2.00 mL) was stirred at 60°C for 12 h. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC(column: C18 150x30mm;mobile phase: [water(FA)-ACN];gradient:22%-52% B over 7 min) to give a crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate/Petroleum ethergradient @ 60 mL/min) to give 2-[7-[2- (1-hydroxycyclopropyl)ethyl]-1 ,8-naphthyridin-2-yl]-3,5-dimethyl-phenol (29.1 mg, 0.084 mmol, 20% yield, 96% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d _e ) 5 = 9.90 (s, 1 H), 8.39 (d, J = 8.4 Hz, 1 H), 8.36 (d, J = 8.4 Hz, 1 H), 7.57 (d, J = 4.8 Hz, 1 H), 7.55 (d, J = 4.8 Hz, 1 H), 6.63 (s, 1 H), 6.62 (s, 1 H), 5.32 (s, 1 H), 3.21-3.12 (m, 2H), 2.26 (s, 3H), 2.11 (s, 3H), 1 .99-1.93 (m, 2H), 0.60-0.55 (m, 2H), 0.43-0.35 (m, 2H).

LC-MS (Method Q) Rt = 0.442 min; MS (ESIpos): m/z = 335.3 [M+H] ⁺ .

Intermediate 524 tert-butyl (3R)-3-[methoxy(methyl)carbamoyl]pyrrolldlne-1 -carboxylate

To a solution of (3R)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (5.00 g, 23.2 mmol, 1 eq) and N-methoxymethanamine (4.53 g, 46.5 mmol, 2 eq, HCI salt) in DCM (60 mL) were added EDCI (6.68 g, 34.8 mmol, 1.5 eq), HOBt (4.71 g, 34.8 mmol, 1.5 eq) and DIPEA (9.01 g, 69.7 mmol, 12.1 mL, 3 eq). After stirring at 25 °C for 16 h, the mixture was concentrated to give a crude. The residue was purified by column chromatography (SiCb, Petroleum ether/Ethyl acetate=10/1 to 2/1) to give tert-butyl (3R)-3-[methoxy(methyl)carbamoyl]pyrrolidine-1 -carboxylate (6.00 g, 23.2 mmol, 100% yield) as colourless oil.

¹ H NMR (400 MHz, CHLOROFORM-d) 5 [ppm] = 3.70 (s, 3H), 3.57 (br s, 2H), 3.44-3.28 (m, 3H), 3.18 (s, 3H), 2.22-1.98 (m, 2H), 1.44 (s, 9H).

Intermediate 525 tert-butyl (3R)-3-acetylpyrrolidine-1-carboxylate

To a solution of tert-butyl (3R)-3-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate (6.00 g, 23.2 mmol, 1 eq) in THF (100 mL) was added MeMgBr (3 M, 15.5 mL, 2 eq) at 0 °C. After stirring at 20 °C for 1 h under N2, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was quenched by addition saturated ammonium chloride solution 200mL at 25°C, and then extracted with ethyl acetate (100mL *3). The combined organic layers were washed with aqueous sodium chloride (100mL * 3), dried over sodium chloride, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOa, Petroleum ether/Ethyl acetate=15/1 to 3/1) to give tert-butyl (3R)-3-acetylpyrrolidine-1-carboxylate (4.40 g, 20.6 mmol, 89% yield) was obtained as colourless oil.

¹ H NMR (400 MHz, CHLOROFORM-d) 5 [ppm] = 3.65-3.30 (m, 4H), 3.12 (br d, J = 7.2 Hz, 1 H), 2.19 (s, 3H), 2.1 1-1 .97 (m, 2H), 1 .45 (s, 9H).

Intermediate 526 tert-butyl (3 R)-3-oxaidehydoyl pyrrolidine- 1 -carboxylate

To a solution of tert-butyl (3R)-3-acetylpyrrolidine-1 -carboxylate (1.00 g, 4.69 mmol, 1 eq) in dioxane (10 mL) was added SeOa (1 .56 g, 14.1 mmol, 1 .53 mL, 3 eq). After stirring at 80 °C for 16 h, the mixture was concentrated to give a crude. The crude was used to next step directly. Compound tert-butyl (3R)- 3-oxaldehydoylpyrrolidine-1-carboxylate (1.1 g, crude) was obtained as brown oil.

Intermediate 527

To a solution of tert-butyl (3R)-3-oxaldehydoylpyrrolidine-1-carboxylate (1.10 g, 4.84 mmol, 1 eq) in EtOH (15 mL) was added 2-(5,6-diamino-2-pyridyl)-3,5-dimethyl-phenol (999 mg, 4.36 mmol, 0.9 eq). After stirring at 60 °C for 16 h, the mixture was concentrated to give a crude. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 90-100% Ethyl acetate/Petroleum ether gradient @ 80 mL/min)to give tert-butyl (3R)-3-[6-(2-hydroxy-4,6- dimethyl-phenyl)pyrido[2,3-b]pyrazin-3-yl]pyrrolidine-1-carb oxylate (960 mg, 1.51 mmol, 31 % yield, 66% purity) as brown oil.

LC-MS (Method C): R _t = 0.567 min; MS (ESIpos): m/z = 421 .2 [M+H] ⁺ .

Intermediate 528

3 _! 5-dimethyi-2-[3-[(3R)-pyrroiidin-3-yi]pyrido[2,3-b]pyr azm-6-yi]ph&noi

To a solution of tert-butyl (3R)-3-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazi n-3- yl]pyrrolidine-1 -carboxylate (560 mg, 1.33 mmol, 1 eq) in DCM (6 mL) was added TFA (2 mL). After stirring at 25 °C for 1 h, the mixture was concentrated to give a crude. The crude was used to next step directly. Compound 3,5-dimethyl-2-[3-[(3R)-pyrrolidin-3-yl]pyrido[2,3-b]pyrazin -6-yl]phenol (600 mg, crude, TFA salt) was obtained as brown oil. Compound 220

1-[(3R)-3~[8-(2-hydroxy-4 _! 6-dlmethyl-phenyl)pyrido[2,3-b]pyrazin-3-yl]pyrrolidln ~1-yrjethanone

To a solution of 3,5-dimethyl-2-[3-[(3R)-pyrrolidin-3-yl]pyrido[2,3-b]pyrazin -6-yl]phenol (600 mg, 1.38 mmol, 1 eq, TFA salt) in DCM (10 mL) were added AC2O (282 mg, 2.76 mmol, 259 pL, 2 eq) and DiPEA (714 mg, 5.52 mmol, 962 pL, 4 eq). After stirring at 0 °C for 1 h, the residue was quenched by addition saturated ammonium chloride solution 40mL at 0°C, and then extracted with dichloromethane (40 mL *3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: C18 80 g, mobile phase: [water(FA)-MeCN];B%: 50%-55%,1 Omin) to give the solution, which was then lyophilized to give 1-[(3R)-3-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyr azin-3-yl]pyrrolidin-1-yl]ethanone (160 mg, 429 pmol, 31 % yield, 97% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 9.70-9.51 (m, 1 H), 9.08 (d, J = 6.8 Hz, 1 H), 8.50 (dd, J = 3.2, 8.5 Hz, 1 H), 7.80 (dd, J = 1.6, 8.6 Hz, 1 H), 6.64 (d, J = 8.2 Hz, 2H), 4.06-3.98 (m, 1 H), 3.96-3.88 (m, 1 H), 3.76-3.58 (m, 2H), 2.49-2.39 (m, 1 H), 2.38-2.28 (m, 1 H), 2.26 (s, 3H), 2.24-2.10 (m, 1 H), 2.07 (s, 3H), 1.99 (d, J = 5.4 Hz, 3H).

LC-MS (Method C): Rt = 0.465 min; MS (ESIpos): m/z = 363.1 [M+H] ⁺ .

SFC: Rt = 1 .772

Intermediate 529 tert-butyl (3S)-3-[methaxy(methyl)carbamoyl]pyrraiidine'1 -carboxylate

To a solution of (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (5.00 g, 23.2 mmol, 1 eq) and N-methoxymethanamine (3.40 g, 34.8 mmol, 1.5 eq, HCI) in DCM (100 mL) were added EDCI (6.68 g, 34.8 mmol, 1.5 eq) , HOBt (4.71 g, 34.8 mmol, 1.5 eq) and DIPEA (9.01 g, 69.7 mmol, 12.1 mL, 3 eq) at 20 °C. After stirring at 20 °C for 16 h, the mixture was filtered under reduced pressure. The residue was purified by column chromatography (SIO ₂ , petroleum ether/ethyl acetate = 1/0 to 2/1), to give tertbutyl (3S)-3-[methoxy(methyl)carbamoyl]pyrrolidine-1 -carboxylate (6.00 g, 23.2 mmol, 99% yield) as yellow oil.

¹ H NMR (400 MHz, CHLOROFORM-d) 6 = 3.68 (s, 3H), 3.55 (s, 1 H), 3.45-3.26 (m, 5H), 3.17 (s, 3H), 2.17-2.01 (m, 2H), 1.42 (s, 9H)

Intermediate 530 tert-butyl (3S}-3-acetylpyrrolidme-1 -carboxylate

To a solution of tert-butyl (3S)-3-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate (6.00 g, 23.2 mmol, 1 eq) in THF (60 mL) was added MeMgBr (3 M, 19.4 mL, 2.5 eq) at 0 °C dropwise under N2 atmosphere. After stirring at 25 °C for 0.5 h, the mixture was quenched by saturated ammonium chloride solution (50 mL) at 0 °C for 0.5 h. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether/ethyl acetate=1/1) to give tert-butyl (3S)-3-acetylpyrrolidine-1- carboxylate (4.50 g, 21 .1 mmol, 90% yield) as yellow oil. ¹ HNMR (400 MHz, CHLOROFORM-d) 6 [ppm] = 3.67-3.32 (m, 4H), 3.20-3.07 (m, 1 H), 2.21 (s, 3H), 2.15-1.99 (m, 2H), 1.46 (s, 9H)

Intermediate 531 tert-butyl (3S)-3-oxaldehydoylpyrrolldine-1 -carboxylate

To a solution of tert-butyl (3S)-3-acetylpyrrolidine-1-carboxylate (1.00 g, 4.69 mmol, 1 eq) in dioxane (10 mL) was added SeCh (1 .56 g, 14.1 mmol, 1 .53 mL, 3 eq) at 20 °C in one portion. After stirring at 80 °C for 16 h, the mixture was filtered and filtrate was concentrated in vacuum to give tert-butyl (3S)-3- oxaldehydoylpyrrolidine-1-carboxylate (1.00 g, 4.40 mmol, 94% yield) as yellow oil.

Intermediate 532

^-fZ-methoxy-^S-dlmethyl-phenyOpyridirie-Z^-diamirie

To a mixture of 6-chloropyridine-2,3-diamine (30.0 g, 209 mmol, 1 eq), (2-methoxy-4,6-dimethyl- phenyl)boronic acid (56.4 g, 313 mmol, 1.5 eq) , CS2CO3 (170 g, 522 mmol, 2.5 eq) in dioxane (1200 mL) and H2O (300 mL) was added XPhos Rd G3 (3.54 g, 4.18 mmol, 0.02 eq) at 25 °C and purged with N2 for 3 times. After stirring at 90 °C for 16 h under N2 atmosphere, the reaction mixture was concentrated under reduced pressure to remove most solvent. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with (petroleum ether/ methanol = 30/1 , 400 mL) 25 °C for 16 h to give 6-(2-methoxy-4,6-dimethyl-phenyl)pyridine-2,3-diamine (80.0 g, 312 mmol, 75% yield, 95% purity) as a brown solid.

LC-MS (Method C): Rt = 0.399 min; MS (ESI): m/z = 244.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) 6 = 6.72 (d, J = 7.6 Hz, 1 H), 6.61 (d, J = 10.4 Hz, 2H), 6.21 (d, J = 7.6 Hz, 1 H), 5.25 (s, 2H), 4.57 (s, 2H), 3.58 (s, 3H), 2.27 (s, 3H), 1.94 (s, 3H)

Intermediate 533

2-(5, 6-diamiuo-2-py!idyl)-3, 5-dimethyl-phenol

To a solution of 6-(2-methoxy-4,6-dimethyl-phenyl)pyridine-2,3-diamine (50.0 g, 206 mmol, 1 eq) in DCM (2500 mL) was dropwise BBrs (154 g, 617 mmol, 59.4 mL, 3 eq) at -60 °C. After stirring at 25 °C for 16 h, the mixture was quenched by water (4000 mL) at 0 °C, the aqueous phase was adjust to pH = 9 with ammonium hydroxide. The mixture was extracted with dichloromethane (4000 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The crude product was triturated with (methanol 50 mL) at 25 °C for 16 h to give 2-(5,6- diamino-2-pyridyl)-3, 5-dimethyl-phenol (57.0 g, crude) as a brown solid.

LC-MS (Method C): Rt = 0.380 min; MS (ESI): m/z = 230.0 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) 6 = 11.76 (s, 1 H), 6.83 (d, J = 8.0 Hz, 1 H), 6.58 (d, J = 8.0 Hz, 1 H), 6.49 (s, 1 H), 6.47 (s, 1 H), 5.77 (s, 2H), 4.87 (s, 2H), 2.28 (s, 3H), 2.18 (s, 3H)

Intermediate 534 tert-butyl (3S)-3-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazi n-3-yl]pyrrolidine-1- carboxylate

To a solutin of tert-butyl (3S)-3-oxaldehydoylpyrrolidine-1-carboxylate (1.0 g, 4.40 mmol, 1 eq) in EtOH (10 mL) was added 2-(5,6-diamino-2-pyridyl)-3,5-dimethyl-phenol (807 mg, 3.52 mmol, 0.8 eq) at 20 °C in one portion. After stirring at 60 °C for 1 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOz, petroleum ether/ethyl acetate=1/0 to 3/1) to give tert-butyl (3S)-3-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3- b]pyrazin-3-yl]pyrrolidine-1-carboxylate (950 mg, 2.17 mmol, 45% yield, 96% purity) as a yellow solid. LC-MS (Method C): R _t = 0.575 min; MS (ESI): m/z = 421 .2 [M+H] ⁺ .

¹ H NMR (400 MHz, CHLOROFORM-d) 6 = 12.19-11.41 (m, 1 H), 8.86 (s, 1 H), 8.50 (d, J = 8.8 Hz, 1 H), 7.98 (d, J = 8.8 Hz, 1 H), 6.81 (s, 1 H), 6.72 (s, 1 H), 4.08-3.92 (m, 1 H), 3.90-3.78 (m, 2H), 3.77-3.68 (m, 1 H), 3.63-3.45 (m, 1 H), 2.55 (s, 3H), 2.51-2.40 (m, 2H), 2.35 (s, 3H), 1.57-1.53 (m, 2H), 1.50 (s, 9H)

Intermediate 535

3.5-dimethyl-2-[3-[(3S)-pyrrolidin-3-yl]pyndo[2,3-b]pyraz in-6-yl]phenol

To a mixture of tert-butyl (3S)-3-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazi n-3-yl]pyrrolidine- 1 -carboxylate (200 mg, 475 pmol, 1 eq) in DCM (4 mL) was added TFA (271 mg, 2.38 mmol, 177 pL, 5 eq) at 0°C. After stirring at 25 °C for 0.5 h, the reaction mixture was concentrated in vacuum to give

3.5-dimethyl-2-[3-[(3S)-pyrrolidin-3-yl]pyrido[2,3-b]pyra zin-6-yl]phenol (150 mg, 468 pmol, 98% yield) as brown oil.

LC-MS (Method C): Rt = 0.409 min; MS (ESIpos): m/z = 321.1 [M+H] ⁺ .

Compound 221

1-[(3S)-3~[6-(2-hydroxy‘4 _! 6‘dimethyl-pheny!)pyrido[2 _: ,3~b]pyrazm‘3-y!]pyrrolidin-1~yrjethanarie

To a mixture of 3,5-dimethyl-2-[3-[(3S)-pyrrolidin-3-yl]pyrido[2,3-b]pyrazin -6-yl]phenol (150 mg, 468 pmol, 1 eq) and DIPEA (302 mg, 2.34 mmol, 408 pL, 5 eq) in DCM (2 mL) was added AC2O (71.7 mg, 702 pmol, 66 pL, 1 .5 eq) at 0°C. After stirring at 25°C for 0.5 h, the mixture was quenched by addition saturated ammonium chloride aqueous solution 40 mL at 0°C, and then extracted with dichloromethane (40 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: C18 80 g, mobile phase: [water(FA) - MeCN];B%: 20%-55%,10min) to give 1 -[(3S)-3-[6-(2- hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazin-3-yl]pyrrol idin-1-yl]ethanone (66.5 mg, 182 pmol, 39% yield, 99% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-cfe) 5 [ppm] = 9.55 (d, J = 3.2 Hz, 1 H), 9.08 (d, J = 6.8 Hz, 1 H), 8.50 (d, J = 3.5, 8.5 Hz, 1 H), 7.80 (dd, J = 1 .5, 8.6 Hz, 1 H), 6.64 (d, J = 6.2 Hz, 2H), 4.06-3.99 (m, 1 H), 3.96-3.89 (m, 1 H), 3.77-3.57 (m, 2H), 2.46-2.40 (m, 1 H), 2.38-2.31 (m, 1 H), 2.26 (s, 3H), 2.23-2.14 (m, 1 H), 2.19- 2.12 (m, 1 H), 2.07 (s, 3H), 1.99 (d, J = 5.4 Hz, 3H)

LC-MS (Method C): Rt = 0.477 min; MS (ESIpos): m/z = 363.3 [M+H] ⁺ .

SFC (Rt = 1 .702 min, ee% = 82%) Intermediate 536 tert-butyl (2R)-2-[methoxy(methyl)carbamoyl]morpholine-4-carboxylate

To a solution of (2R)-4-tert-butoxycarbonylmorpholine-2-carboxylic acid (5.00 g, 21.6 mmol, 1 eq) and N-methoxymethanamine hydrochloride (4.22 g, 43.2 mmol, 2 eq) in dichloromethane (50 mL) was added HOBt (4.38 g, 32.4 mmol, 1 .5 eq) and EDCI (6.22 g, 32.4 mmol, 1 .5 eq) and DIPEA (13.9 g, 108 mmol, 18 mL, 5 eq) at 0 °C. After stirring at 25 °C for 16 h, the reaction mixture was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiCb, petroleum ether/ethyl acetate = 10/1 to 2/1) to give a tert-butyl (2R)-2-[methoxy(methyl)carbamoyl]morpholine-4- carboxylate (5.50 g, 20.0 mmol, 92% yield) as colorless oil.

¹ H NMR (400 MHz, CDCb) 5 [ppm] = 4.42-4.26 (m, 1 H), 4.00 (dd, J = 2.0, 11 .6 Hz, 2H), 3.94-3.80 (m, 1 H), 3.75 (s, 3H), 3.63-3.52 (m, 1 H), 3.21 (s, 3H), 3.04 (d, J = 8.8 Hz, 2H), 1.46 (s, 9H)

Intermediate 537 tert-butyl (2R)-2-acetylmorpholine-4-carboxylate

To a solution of tert-butyl (2R)-2-[methoxy(methyl)carbamoyl]morpholine-4-carboxylate (5.50 g, 20.0 mmol, 1 eq) in tetrahydrofuran (50 mL) was added MeMgBr (3 M in tetrahydrofuran, 20.0 mL, 3 eq) at 0 °C. After stirring at 25 °C for 2 h, the mixture was added saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (150 mL), the combined organic phases were concentrated to give a tert-butyl (2R)-2-acetylmorpholine-4-carboxylate (4.00 g, 17.4 mmol, 87% yield) as colorless oil.

NMR (400 MHz, CDCb) 5 [ppm] = 4.28-4.05 (m, 1 H), 3.96 (dd, J = 1.6, 11.6 Hz, 1 H), 3.91-3.72 (m, 2H), 3.56 (dt, J = 2.8, 11 .2 Hz, 1 H), 3.06-2.89 (m, 1 H), 2.80 (t, J = 11 .6 Hz, 1 H), 2.23 (s, 3H), 1 .46 (s, 9H)

Intermediate 538 tert-butyl (2R)-2-oxaldehydoylmorpbolme-4-carboxylate

To a solution of tert-butyl (2R)-2-acetylmorpholine-4-carboxylate (500 mg, 2.18 mmol, 1 eq) in dioxane (15 mL) was added SeO ₂ (725 mg, 6.54 mmol, 711 pL, 3 eq). After stirring at 90 °C for 16 h, The mixture was filtrated and the filtrate was concentrated to give a tert-butyl (2R)-2- oxaldehydoylmorpholine-4-carboxylate (500 mg, 2.06 mmol, 94% yield) as yellow oil.

¹ H NMR (400 MHz, CDCb) 6 [ppm] = 4.40-4.07 (m, 1 H), 4.04-3.93 (m, 1 H), 3.91 -3.79 (m, 1 H), 3.66- 3.44 (m, 1 H), 3.27-2.69 (m, 2H), 2.24 (s, 1 H), 1.65-1.40 (m, 9H)

Intermediate 539 tert-butyl (2R)-2-[6-(2-hydroxy-4,8-dlmethyl-pheriyl)pyrido[2.3-b]pyraz m-3-yl]morpholme-4- carboxylate

To a solution of tert-butyl (2R)-2-oxaldehydoylmorpholine-4-carboxylate (500 mg, 2.06 mmol, 1 eq) in ethyl alcohol (10 mL) was added 2-(5,6-diamino-2-pyridyl)-3,5-dimethyl-phenol (424 mg, 1.85 mmol, 0.9 eq). After stirring at 60 °C for 4 h, the reaction mixture was concentrated to give a crude and the crude was purified by column chromatography (SiO?, Petroleum ether/Ethyl acetate=10/1 to 3/1) to give a tert-butyl (2R)-2-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazi n-3-yl]morpholine-4- carboxylate (350 mg, 801 pmol, 39% yield) as a yellow solid.

LC-MS (Method C): Rt = 0.585 min; MS (ESIpos): m/z =437.2 [M+1 ] ⁺ .

Compound 222

3,5-dimethyl-2-[3-[(2R)-morphQlin-2-yl]pyrido[2,3-b]pyraz in-6-yl]phenol

To a solution of tert-butyl (2R)-2-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazi n-3- yl]morpholine-4-carboxylate (350 mg, 801 pmol, 1 eq) in dichloromethane (20 mL) was added TFA (91 .4 mg, 801 pmol, 59 pL, 1 eq). After stirring at 25 °C for 2 h, the mixture was concentrated to give a crude and the crude was purified by reversed-phase column (column: C18 10 g, mobile phase: [water (NH ₃ ’H ₂ O) - MeCN]; B%: 20% - 80%, 12 min) to give a 3,5-dimethyl-2-[3-[(2R)-morpholin-2- yl]pyrido[2,3-b]pyrazin-6-yl]phenol (85.8 mg, 244 pmol, 30% yield, 96% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-da) 5 [ppm] = 9.62-9.55 (m, 1 H), 9.15 (s, 1 H), 8.54 (d, J = 8.4 Hz, 1 H), 7.91- 7.80 (m, 1 H), 6.64 (d, J = 6.0 Hz, 2H), 5.03 (dd, J = 2.8, 10.4 Hz, 1 H), 4.22-4.08 (m, 1 H), 3.96-3.84 (m, 1 H), 3.54 (d, J = 12.4 Hz, 2H), 3.16-3.10 (m, 2H), 3.04 (dd, J = 3.2, 12.0 Hz, 1 H), 2.26 (s, 3H), 2.08 (s, 3H)

LC-MS (Method C): Rt = 0.413 min; MS (ESIpos): m/z = 337.1 [M+1] ⁺ .

SFC (Rt = 1 .569 min, ee% = 90%)

Intermediate 540 tert-butyl (2S)~2-[methoxy(methyl)carbamoyl]morpholine-4-carboxylate

To a solution of (2S)-4-tert-butoxycarbonylmorpholine-2-carboxylic acid (5.00 g, 21.6 mmol, 1 eq) and N-methoxymethanamine hydrochloride (4.22 g, 43.2 mmol, 2 eq) in dichloromethane (50 mL) was added HOBt (4.38 g, 32.4 mmol, 1 .5 eq) and EDCI (6.22 g, 32.4 mmol, 1 .5 eq) and DIPEA (13.9 g, 108 mmol, 18 mL, 5 eq) at 0 °C. After stirring at 25 °C for 16 h, the reaction mixture was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SIO ₂ , petroleum ether/ethyl acetate = 10/1 to 2/1) to give a tert-butyl (2S)-2-[methoxy(methyi)carbamoyl]morphoiine-4- carboxylate (5.50 g, 20.0 mmol, 92% yield) as colorless oil.

¹ H NMR (400 MHz, CDCb) 5 [ppm] = 4.34 (d, J = 0.8 Hz, 1 H), 4.18-3.95 (m, 2H), 3.94-3.81 (m, 1 H), 3.75 (s, 3H), 3.66-3.47 (m, 1 H), 3.21 (s, 3H), 3.05 (s, 2H), 1.46 (s, 9H)

Intermediate 541 tert-butyl (2S}-2-acety!morpholine-4-carboxy!ate

To a solution of tert-butyl (2S)-2-[methoxy(methyl)carbamoyl]morpholine-4-carboxylate (5.50 g, 20.0 mmol, 1 eq) in tetrahydrofuran (50 mL) was added MeMgBr (3 M in tetrahydrofuran, 20.0 mL, 3 eq) at 0 °C. After stirring at 25 °C for 2 h, the mixture was added saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (150 mL), the combined organic phase were concentrated to give a tert-butyl (2S)-2-acetylmorpholine-4-carboxylate (3.70 g, 16.1 mmol, 80% yield) as colorless oil.

¹ H NMR (400 MHz, CDCb) 6 [ppm] = 4.15 (d, J = 2.0 Hz, 1 H), 4.02-3.93 (m, 1 H), 3.86 (d, J = 8.4 Hz, 2H), 3.66-3.45 (m, 1 H), 2.96 (t, J = 10.4 Hz, 1 H), 2.81 (t, J = 11 .6 Hz, 1 H), 2.23 (s, 3H), 1 .47 (s, 9H) Intermediate 542 tert-butyl (2S)-2-oxaldehydoylmorpholine-4-carboxylate

To a solution of tert-butyl (2S)-2-acetylmorpholine-4-carboxylate (500 mg, 2.18 mmol, 1 eq) in dioxane (15 mL) was added SeO ₂ (725 mg, 6.54 mmol, 711 pL, 3 eq). After stirring at 90 °C for 16 h, The mixture was filtrated and the filtrate was concentrated to give a tert-butyl tert-butyl (2S)-2- oxaldehydoylmorpholine-4-carboxylate (500 mg, 2.06 mmol, 94% yield) as yellow oil.

¹ H NMR (400 MHz, CDCh) 5 [ppm] = 4.36-4.05 (m, 1 H), 4.04-3.77 (m, 2H), 3.75-3.63 (m, 2H), 3.56- 3.46 (m, 2H), 1.47 (s, 9H)

Intermediate 543 tert-butyl (2S)-2-[6-(2-hydroxy-4.6-dimethy!-pherryl)pyrldo[2 _! 3-b]pyrazln-3-yl]morpholme-4- carboxylate

To a solution of tert-butyl (2S)-2-oxaldehydoylmorpholine-4-carboxylate (500 mg, 2.06 mmol, 1 eq) in ethyl alcohol (10 mL) was added 2-(5,6-diamino-2-pyridyl)-3,5-dimethyl-phenol (424 mg, 1.85 mmol, 0.9 eq). After stirring at 60 °C for 4 h, the reaction mixture was concentrated to give a crude and the crude was purified by column chromatography (SIO ₂ , Petroleum ether/Ethyl acetate=10/1 to 3/1) to give a tert-butyl (2S)-2-[6-(2-hydroxy-4,6-dimethyi-phenyl)pyrido[2,3-b]pyrazi n-3-yl]morpholine-4- carboxylate (300 mg, 687 pmol, 33% yield) as a yellow solid.

LC-MS (Method C): Rt = 0.563 min; MS (ESIpos): m/z =437.2 [M+1 ] ⁺ .

Compound 223

3 _; 5-dimethyl-2-[3-[(2S)-morpholin-2-yl]pyrido[2,3-b]pyra ziu-S-yl]phenol

To a solution of tert-butyl (2S)-2-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazi n-3- yl]morpholine-4-carboxylate (300.00 mg, 687.28 pmol, 1 eq) in dichloromethane (20 mL) was added TFA (235 mg, 2.06 mmol, 153 pL, 3 eq). After stirring at 25 °C for 2 h, the mixture was concentrated to give a crude and the crude was purified by reversed-phase column (column: C18 10 g, mobile phase: [water (NH^HsQ) - MeCN]; B%: 20% - 80%, 12 min) to give a 3,5-dimethyl-2-[3-[(2S)-morpholin-2- yl]pyrido[2,3-b]pyrazin-6-yl]phenol (23.8 mg, 70.2 pmol, 10% yield, 99% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-cfe) 5 [ppm] = 9.58 ( J = 1.2 Hz, 1 H), 9.17-9.09 (m, 1 H), 8.57-8.45 (m, 1 H), 7.90-7.78 (m, 1 H), 6.64 (d, J = 6.4 Hz, 2H), 4.79 (dd, J = 2.8, 10.0 Hz, 1 H), 3.99 (d, J = 11 .2 Hz, 1 H), 3.77-3.68 (m, 1 H), 3.24 (dd, J = 2.8, 12.8 Hz, 1 H), 2.85-2.82 (m, 1 H), 2.82-2.77 (m, 2H), 2.27 (s, 3H), 2.08 (s, 3H)

LC-MS (Method C): Rt - 0.488 min; MS (ESIpos): m/z = 337.2 [M+1] ⁺ .

SFC (Rt - 1 .852 min, ee% = 90%)

Intermediate 544 tert-butyl 5-( 6-amlno-5-formyl-pyrazin-2-yl)-3, 6-dihydro-2H-pyridine- 1 -carboxylate

To a solution of 3-amino-5-chloro-pyrazine-2-carbaldehyde (3.00 g, 19.0 mmol, 1 eq) and tert-butyl 5- (4,4,5,5-tetramethyl-1 , 3, 2-dioxaboroian-2-yl)-3,6-dihydro-2H-pyridine-1 -carboxylate (11 .8 g, 38.1 mmol, 2 eq) in dioxane (90 mL) and H2O (20 mL) were added Pd(dppf)Cl2 (1.39 g, 1.90 mmol, 0.1 eq) and CS2CO3 (18.6 g, 57.1 mmol, 3 eq) at 25 °C under N2 atmosphere. After stirring at 80 °C for 16 h, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/1) to give tert-butyl 5-(6-amino-5-formyl- pyrazin-2-yl)-3,6-dihydro-2H-pyridine-1 -carboxylate (6.00 g, 17.7 mmol, 93% yield, 90% purity) as a yellow solid. intermediate 545 tert-butyl 5-(7 -fluoro-6-hydroxy-pyrido[2,3-b]pyrazin-3-yl)-3, 6-dlhydro-2H-pyridlne- 1 ■ carboxylate

To a solution of tert-butyl 5-(6-amino-5-formyl-pyrazin-2-yl)-3,6-dihydro-2H-pyridine-1 -carboxylate (6.00 g, 19.7 mmol, 1 eq) and ethyl 2-diethoxyphosphoryl-2-fluoro-acetate (7.16 g, 29.6 mmol, 6.00 mL, 1 .5 eq) in MeCN (100 mL) were added DBU (4.50 g, 29.6 mmol, 4.46 mL, 1 .5 eq) and LiCI (1 .25 g, 29.6 mmol, 606 pL, 1 .5 eq) at 25 °C. After stirring at 30 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOz, petroleum ether/ethyl acetate=2/1), and then the product was triturated with petroleum ether/ethyl acetate = 5/1 (10 mL) at 25 °C for 0.5 h to give tert-butyl 5-(7-fluoro-6-hydroxy-pyrido[2,3-b]pyrazin-3- yl)-3,6-dihydro-2H-pyridine-1 -carboxylate (3.50 g, 9.50 mmol, 48% yield, 94% purity) as a light yellow solid,

¹ H NMR (400 MHz, DMSO-cfe) 5 [ppm] = 13.0 (s, 1 H), 8.89 (s, 1 H), 7.95 (d, J = 10.0 Hz, 1 H), 7.12 (t, J = 4.0 Hz, 1 H), 4.36 (d, J = 1 .6 Hz, 2H), 3.50 (t, J = 5.6 Hz, 2H), 2.37 (d, J = 4.0 Hz, 2H), 1 .43 (s, 9H). LC-MS (Method C): Rt = 0.511 min; MS (ESI): m/z = 291 .0 [M+H] ⁺ -

Intermediate 546 tert-butyl 3-(7-fluoro-6-hydroxy-pyrido[2,3-b]pyrazin-3-yl)piperidine-1 -carboxylate

To a solution of tert-butyl 5-(7-fluoro-6-hydroxy-pyrido[2,3-b]pyrazin-3-yl)-3,6-dihydro -2H-pyridine-1- carboxylate (3.50 g, 10.1 mmol, 1 eq, EW28561-627) in MeOH (100 mL) was added Pd/C (325 mg, 306 pmol, 10% purity, 3.03e-2 eq) under N2. The suspension was degassed under vacuum and purged with H2 several times. After stirring under H2 (15 psi) at 25 °C for 1 h, the mixture was filtered, and the filtrate was concentrated to give tert-butyl 3-(7-fluoro-6-hydroxy-pyrido[2,3-b]pyrazin-3-yl)piperidine-1 - carboxylate (3.50 g, 10.0 mmol, 99% yield) as a green solid.

¹ H NMR (400 MHz, DMSO-cfe) 5 [ppm] = 13.2-12.8 (m, 1 H), 8.57 (s, 1 H), 7.94 (d, J = 10.0 Hz, 1 H), 4.19-4.04 (m, 1 H), 3.94 (d, J = 12.8 Hz, 1 H), 2.96 (d, J = 10.0 Hz, 1 H), 2.88-2.76 (m, 1 H), 2.02 (d, J = 10.0 Hz, 1 H), 1 .81-1 .71 (m, 2H), 1.55-1.46 (m, 1 H), 1 .39 (s, 9H), 1.27-1.20 (m, 1 H)

Intermediate 547 tert-butyl 3-[7-f!uoro-@-(p-to!ylsu!foriyloxy)pyrido[2,3-b]pyraziri-3-y l]plperidme-1 -carboxylate To a solution of tert-butyl 3-(7-fluoro-6-hydroxy-pyrido[2,3-b]pyrazin-3-yl)piperidine-1 -carboxylate (2.00 g, 5.74 mmol, 1 eq) in DCM (20 mL) were added DIPEA (2.23 g, 17.2 mmol, 3.00 mL, 3 eq) and TosCI (1 .64 g, 8.61 mmol, 1 .5 eq) at 0 °C. After stirring at 0 °C for 1 h, the mixture was diluted with water (10 mL) and extracted with DCM (50 mL x 3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether/ethyl acetate=3/1) to give tert-butyl 3- [7-fluoro-6-(p-tolylsulfonyloxy)pyrido[2,3-b]pyrazin-3-yl]pi peridine-1 -carboxylate (2.50 g, 4.58 mmol, 80% yield, 92% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-da) 5 [ppm] = 9.12 (s, 1 H), 8.73 (d, J = 9.2 Hz, 1 H), 8.03 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 4.20-4.1 1 (m, 1 H), 3.91 (d, J = 12.4 Hz, 1 H), 3.24-3.16 (m, 1 H), 2.98-2.88 (m, 1 H), 2.46 (s, 3H), 2.11 (d, J = 10.4 Hz, 1 H), 1 .89-1 .75 (m, 2H), 1 .64-1 .44 (m, 2H), 1 .36 (s, 9H))

Intermediate 548 tert-butyl 3-[7-fluoro-§-(2-methoxy-4,6-dimethyl-pheny!)pyrido[2,3-b]p yrazin-3-yl]piperidme-1- carboxylate

To a solution of tert-butyl 3-[7-fluoro-6-(p-tolylsulfonyloxy)pyrido[2,3-b]pyrazin-3-yl] piperidine-1- carboxylate (1.00 g, 1.99 mmol, 1 eq) in dioxane (10 mL) were added (2-methoxy-4,6-dimethyl- phenyl)boronic acid (537 mg, 2.98 mmol, 1.5 eq), Pd(dppf)Cl2 (146 mg, 199 pmol, 0.1 eq) and NazCCh (633 mg, 5.97 mmol, 3 eq) at 25 °C. After stirring at 90 °C for 4 h, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3), The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The residue was purified by reversed phase (column: C18 80 g, mobile phase: [water (FA) - MeCN]; B%: 40%-70%, 7 min) to give tert-butyl 3-[7-fluoro-6-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3- b]pyrazin-3-yl]piperidine-1 -carboxylate (450 mg, 965 pmol, 48% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO-ofe) 5 [ppm] = 9.11 (s, 1 H), 8.48 (d, J = 8.4 Hz, 1 H), 6.86 (s, 1 H), 6.82 (s, 1 H), 4.26-4.13 (m, 1 H), 3.98-3.86 (m, 1 H), 3.66 (s, 3H), 3.21 (d, J = 3.1 Hz, 1 H), 2.94-2.85 (m, 1 H), 2.38 (s, 3H), 2.22-2.10 (m, 1 H), 2.02 (d, J = 2.0 Hz, 3H), 1 .89-1 .77 (m, 2H), 1 .59-1 .46 (m, 2H), 1 .36 (s, 9H)

Intermediate 549

7-fluoro-6-(2-methoxy-4,§-dimethyl-phenyl)-3-[3-piper!dy l]pyrido[2.3-b]pyrazme

To a solution of tert-butyl 3-[7-fluoro-6-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3-b]py razin-3- yl]piperidine-1 -carboxylate (300 mg, 643 pmol, 1 eq) in DCM (10 mL) was added TFA (3.07 g, 26.9 mmol, 2.00 mL, 41 .8 eq) at 0 °C. After stirring at 25 °C for 0.5 h, the mixture was concentrated to dry to give 7-fluoro-6-(2-methoxy-4,6-dimethyl-phenyl)-3-[rac-(3S)-3-pip eridyl]pyrido[2,3-b]pyrazine (200 mg, 546 pmol, 85% yield) as yellow oil.

Intermediate 550

7-f!uoro-6-(2-rnethoxy-4 _! t)-dimethyl-pheriy!)-3-[1-methyl-3-piperidyl]pyrido[2. 3-b]pyrazirie To a solution of 7-fluoro-6-(2-methoxy-4,6-dimethyl-phenyl)-3-[rac-(3S)-3-pip eridyl]pyrido[2,3- b]pyrazine (200 mg, 546 pmol, 1 eq) in MeOH (5 mL) was added KOAc (161 mg, 1.64 mmol, 3 eq), (HCHO)n (7.37 mg, 409 pmol, 0.75 eq) and NaBHsCN (103 mg, 1.64 mmol, 3 eq) at 25 °C. After stirring at 25 °C for 1 h, the mixture was filtered, and the filtrate was concentrated to dry. The residue was purified by reversed phase (column: C18 40 g, mobile phase: [water (FA) - MeCN]; B%: 40% - 70%, 7 min) to give 7-fluoro-6-(2-methoxy-4,6-dimethyl-phenyl)-3-[rac-(3S)-1 -methyl-3-piperidyl]pyrido[2,3- bjpyrazine (150 mg, 390 pmol, 72% yield, 99% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-cfe) <5 [ppm] = 9.11 (s, 1 H), 8.47 (d, J = 8.8 Hz, 1 H), 6.86 (s, 1 H), 6.82 (s, 1 H), 3.66 (s, 3H), 3.33-3.30 (m, 1 H), 3.08-3.00 (m, 1 H), 2.84-2.75 (m, 1 H), 2.38 (s, 3H), 2.28 (s, 1 H),

2.23 (d, J = 0.8 Hz, 3H), 2.15-2.04 (m, 1 H), 2.01 (s, 3H), 1.96 (s, 1 H), 1.80-1.74 (m, 1 H), 1.71-1.61 (m, 2H)

LC-MS (Method C): Rt = 0.681 min; MS (ESIpos): m/z = 381.2 [M+H] ⁺ .

Intermediate 551

2-[7-fluoro-3-[1-methyl-3-pipendyl]pyndo[2 _! 3-b]pyrazm-6-yl]-3,5-dimethyl-phenol

To a solution of 7-fluoro-6-(2-methoxy-4,6-dimethyl-phenyl)-3-[rac-(3S)-1-met hyl-3-piperidyl]pyrido[2,3- b]pyrazine (150 mg, 394 pmol, 1 eq) in DCM (5 mL) was added BBrs (296 mg, 1.18 mmol, 1 14 pL, 3 eq) at -70 °C. After stirring at -70 °C for 0.5 h, the mixture was quenched by NH3H2O (10 mL) at 25 °C. After stirring at 25 °C for 0.5 h, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The residue was purified by reversed phase (column: C18 25 g, mobile phase: [water (FA) - MeCN]; B%: 40% - 70%, 7 min) to give 2-[7-fluoro-3-[rac-(3S)-1-methyl-3- piperidyl]pyrido[2,3-b]pyrazin-6-yl]-3,5-dimethyl-phenol (140 mg, 378 pmol, 96% yield, 99% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.406 min; MS (ESIpos): m/z = 367.2 [M+H] ⁺ .

Compounds 224 and 225

2-[7-fluoro-3-[1-methyl-3-pipendyl]pyndo[2,3-b]pyrazin-6- yl]-3,5-dimethyl-phenol 2-[7-Fluoro-3-[1-methyl-3-piperidyl]pyrido[2,3-b]pyrazin-6-y l]-3,5-dimethyl-phenol (140 mg, 382 pmol, 1 eq) was separated by by SFC(column: ChiralPak IH, 250 x 50 mm, 10 pm; mobile phase: [COs-MeCN/i- PrOH (0.1 % NH3H2O)]; B%:45%, isocratic elution mode) to give Compound 224 2-[7-fluoro-3-[(1-methyl-3-piperidyl]pyrido[2,3-b]pyrazin-6- yl]-3,5-dimethyl-phenol (47.3 mg, 128 pmol, 33% yield, 99% purity) as a yellow solid, and Compound 225 2-[7-fluoro-3-[(1-methyl-3-piperidyl]pyrido[2,3-b]pyrazin-6- yl]-3,5-dimethyl-phenol (46.9 mg, 127 pmol, 33% yield, 99% purity) as a yellow solid.

Compound 224

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 9.52 (s, 1 H), 9.10 (s, 1 H), 8.44 (d, J = 8.8 Hz, 1 H), 6.65 (s, 1 H), 6.63 (s, 1 H), 3.28 (s, 1 H), 3.06 (d, J = 11 .2 Hz, 1 H), 2.80 (d, J = 11 .2 Hz, 1 H), 2.33-2.26 (m, 4H),

2.24 (s, 3H), 2.07-1.93 (m, 5H), 1.83-1.72 (m, 1 H), 1.71-1.59 (m, 2H) LC-MS (Method C): Rt = 0.427 min; MS (ESIpos): m/z = 367.1 [M+H] ⁺ SFC (Rt = 1 .50 min, ee% = 99%).

Compound 225

¹ H NMR (400 MHz, DMSO-cfe) 6 [ppm] = 9.68-9.41 (m, 1 H), 9.10 (s, 1 H), 8.44 (d, J = 8.8 Hz, 1 H), 6.64 (d, J = 4.0 Hz, 2H), 3.29 (d, J = 3.6 Hz, 1 H), 3.06 (d, J = 10.4 Hz, 1 H), 2.80 (d, J = 11 .2 Hz, 1 H), 2.30- 2.25 (m, 7H), 2.05-1.92 (m, 5H), 1.81-1.73 (m, 1 H), 1.72-1.60 (m, 2H) LC-MS (Method C): R _t = 0.428 min; MS (ESipos): m/z = 367.1 [M+H] ⁺

SFC (Rt =2.07 min, ee% = 96%).

Intermediate 552

To a solution of 3-bromo-6-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazi ne (450 mg, 1.31 mmol, 1.00 eq), tert-butyl 1 ,2,3,3a,4,5,7,7a-octahydropyrrolo[2,3-c]pyridine-6-carboxyla te (296 mg, 1.31 mmol, 1 .00 eq) in acetonitrile (10.0 ml_) was added potassium carbonate (542 mg, 3.92 mmol, 1 .00 eq). After stirring at 80 °C for 12 h under nitrogen atmosphere. The mixture was poured into water (20 mL) and extracted with ethyl acetate (50.0 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g Sepa Flash® Silica Flash Column, Eluent of 0-100% ethyl acetate / petroleum ether gradient @ 60 mL/min) to give tert- butyl 1-[6-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazin-3-y l]-3, 3a, 4,5,7, 7a-hexahydro-2H- pyrrolo[2,3-c]pyridine-6-carboxylate (380 mg, 760 pmol, 58% yield, 98% purity) as brown oil.

¹ H NMR (400 MHz, DMSO-de) 6 = 8.54 (s, 1 H), 8.20 (d, J = 8.4 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 1 H), 6.83- 6.71 (m, 2H), 4.29-4.17 (m, 1 H), 3.70-3.90 (m, 2H), 3.64 (s, 4H), 3.41-3.32 (m, 2H), 3.17 (d, J = 5.2 Hz, 1 H), 2.99-2.71 (m, 1 H)2.34 (s, 3H), 2.22-2.08 (m, 1 H), 2.01-2.09 (m, 1 H), 1 .97 (s, 3H), 1.78-1.88 (m, 1 H), 1 .72-1 .58 (m, 1 H), 1 .48-1 .06 (m, 9H).

LC-MS (Method Q) Rt = 0.531 min; MS (ESipos): m/z = 490.4 [M+H] ⁺ .

Intermediate 553

To a solution of te/Y-butyi 1-[6-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3-b]pyrazin-3-y l]-3,3a,4,5,7,7a- hexahydro-2H-pyrrolo[2,3-c]pyridine-6-carboxylate (380 mg, 776 pmol, 1.00 eq) in dichloromethane (1.00 mL) was added dropwise tribromoborane (224 pL„ 2.33 mmol, 3.00 eq) at -70 °C, the mixture was stirred at 20 °C for 12 h under nitrogen atmosphere. The mixture was quenched by methanol (20 mL) and concentrated at vacuum to give 2-[3-(2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-e]pyridin-1- yl)pyrido[2,3-b]pyrazin-6-yl]-3,5-dimethyl-phenol (260 mg, 692 pmol, 92% yield) as a yellow solid. LC-MS (Method C) Rt = 0.367 min; MS (ESipos): m/z = 376.2 [M+H] ⁺ .

Compound 226

To a solution of 2-[3-(2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridin-1-yl) pyrido[2,3-b]pyrazin-6-yl]-

3.5-dimethyl-phenol (260 mg, 692 pmol, 1.00 eq) in methanol (8.00 mL) was added sodium cyanoborohydride (52.2 mg, 831 pmol, 1.20 eq) and paraformaldehyde (258 pL, 3.46 mmol, 37.0% purity, 5.00 eq) and potassium acetate (340 mg, 3.46 mmol, 5.00 eq) .The mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into saturated sodium bicarbonate aqueous solution (10.0 mL) and extracted with ethyl acetate (30.0 mL x 2). The organic phase was concentrated in vacuum to give a residue. The residue was purified by reversed-phase flash chromatography (instrument: 40 g Flash; Column: Welch Ultimate XB__C18 20-40 pm; eluent A: water (0.1% formic acid), eluent B: acetonitrile; gradient: 0-10 min 0-60% B; flow 85 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give the product. The product was purified by SFC (column: DAICEL CHIRALPAK IC (250mm*30mm, 10pm) mobile phase: [CO ₂ - acetonitrile / ethanol (0.1 % ammonium hydroxide)]; B%:50%, isocratic elution mode) to afford Diastereoisomer X, 3,5-dimethyl-2-[3-[6-methyl- 3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyrido [2,3-f)]pyrazin-6-yl]phenol (23.17 mg, 51 .9 pmol, 8% yield, 98% purity, formate) as a yellow solid, and Compound 226 3,5-dimethyl-2-[3-[6-methyl- 3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyrido [2,3-f)]pyrazin-6-yl]phenol (29.2 mg, 65.8 pmol, 10% yield, 98% purity, formate) as a yellow solid.

Diastereoisomer 1

¹ H NMR (400 MHz, DMSO-d _e ) 6 = 10.1 1-9.74 (m, 1 H), 8.67-8.40 (m, 1 H), 8.28 (s, 1 H), 8.18 (d, J = 8.4 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 6.60 (d, J = 6.0 Hz, 2H), 4.32-4.49 (m, 1 H), 3.91 -3.59 (m, 3H), 3.17- 3.11 (m, 1 H), 2.60-2.53 (m, 1 H), 2.45-2.34 (m, 1 H), 2.25 (s, 3H), 2.18 (s, 3H), 2.08 (s, 3H), 2.02-2.07 (m, 1 H), 2.00-1 .87 (m, 2H), 1 .81 (t, J = 10.4 Hz, 1 H), 1 .74-1 .66 (m, 1 H).

LCMS (Method C): Rt = 0.398 min; MS (ESI) m/z = 390.4 [M+H] ⁺ .

SFC (Rt = 1 .361 min, ee% = 99%).

Compound 226

^! H NMR (400 MHz, DMSO-de) 6 = 8.64-8.44 (m, 1 H), 8.27-8.21 (m, 1 H), 8.19 (d, J = 8.4 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 6.60 (d, J = 7.2 Hz, 2H), 4.44-4.35 (m, 1 H), 3.87-3.75 (m, 3H), 3.21-3.13 (m, 1 H), 2.61-2.53 (m, 1 H), 2.44-2.30 (m, 1 H), 2.25 (s, 3H), 2.19 (s, 3H), 2.11-2.03 (m, 4H), 2.02-1.91 (m, 2H), 1 .83 ( t, J = 10.0 Hz, 1 H), 1 .71 (d, J = 13.6 Hz, 1 H).

LCMS (Method C): Rt = 0.389 min; MS (ESI) m/z = 390.3 [M+H] ⁺ .

SFC (Rt - 1 .651 min, ee% = 99%).

Intermediate 554

N-methoxy-N-methyl-2-(3-oxocyclobutyl) acetamide

To a solution of 2-(3-hydroxycyclobutyl)-N-methoxy-N-methyl-acetamide (1.00 g, 6.73 mmol, 1 eq) in DCM (10 mL) was added Dess-Martin (2.69 g, 6.35 mmol, 1.1 eq) at 25 °C. After stirring at 25 °C for 2 h, the mixture was filtrated and concentrated to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether/ethyl acetate=10/1 to 1/1) to give N-methoxy-N-methyl-2-(3- oxocyclobutyl)acetamide (900 mg, 5.26 mmol, 91 % yield) as colorless oil.

¹ H NMR (400 MHz, CDCb) 0 = 3.70 (s, 3H), 3.32-3.25 (m, 2H), 3.18 (s, 3H), 2.85-2.80 (m, 2H), 2.78- 2.75 (m, 2H), 2.63-2.57 (m, 1 H).

Intermediate 555

1-(3-hydroxy-3-methyl-cyclobutyi)propan-2-one

To a solution of N-methoxy-N-methyl-2-(3-oxocyclobutyl)acetamide (900 mg, 5.26 mmol, 1 eq) in THF (10 mL) was added methyl magnesium bromide (3 M, 5.26 mL, 3 eq) at 0 °C. After stirring at 20 °C for 1 h, the mixture was quenched with saturated ammonium chloride solution (50 mL) at 0 °C and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-(3-hydroxy-3-methyl-cyclobutyl)propan-2- one (600 mg, 4.57 mmol, crude) as colorless oil.

¹ H NMR (400 MHz, CDCb) 6 = 2.60-2.55 (m, 2H), 2.30-2.25 (m, 2H), 2.20-2.15 (m, 1 H), 2.11 (s, 3H), 1 .78-1 .70 (m, 2H), 1 .38 (s, 2H), 1 .18 (s, 1 H).

Intermediate 556

3-(3-hydi'oxy-3-methybcyclobutyl)-2-oxo-pi'opanal

To a solution of 1-(3-hydroxy-3-methyl-cyclobutyl)propan-2-one (400 mg, 2.81 mmol, 1 eq) in dioxane (10 mL) was added SeCh (936 mg, 8.44 mmol, 3 eq) at 25 °C. After stirring at 90 °C for 2 h, the reaction mixture was filtrated and the filtrate was concentrated to give 3-(3-hydroxy-3-methyl-cyclobutyl)-2-oxo- propanal (450 mg, crude) as yellow oil.

Intermediate 557

2-[3-[(3-hydroxy-3-methyl-cyclobutyl)methyl]pyrido[2,3-b] pyrazin-6-yl]-3, 5-dimethyl-phenol

To a solution of 3-(3-hydroxy-3-methyl-cyclobutyl)-2-oxo-propana (450 mg, 2.88 mmol, 1 eq) in EtOH (10 mL) was added 2-(5, 6-diamino-2-pyridyl)-3, 5-dimethyl-phenol (594 mg, 2.59 mmol, 0.9 eq) at 25 °C. After stirring at 60 °C for 16 h, the mixture was concentrated to give a residue. The residue was purified by reversed flash (Instrument: 40g Flash; Column: Welch Ultimate XB_C18 20-40pm; Eluent A: water (0.1 % NH3 H2O), eluent B: acetonitrile; gradient: 0-10 min 5-40% B; flow 60 ml/min; temperature: room temperature; Detector: UV220/254 nm) to give 2-[3-[(3-hydroxy-3-methyl- cyclobutyl)methyl]pyrido[2,3-b]pyrazin-6-yl]-3, 5-dimethyl-phenol (80.0 mg, 217 pmol, 8% yield, 95% purity) as a yellow solid.

LC-MS (Method C): Rt = 0.478 min; MS (ESI): m/z = 350.1 [M+H] ⁺ .

Compounds 227 and 228 2-[3-[(3-hydroxy-3-methyl-cyclobutyl)methyl]pyrido[2,3-b]pyr azin-6-yl]-3, 5-dimethyl-phenol The reaction was set up for SFC separation. The residue was purified by SFC: (column: Daicel ChiralPak IG (250*30mm, 10um);mobile phase: [CO ₂ -EtOH(0.1 %NH3H2O)];B%:73%, isocratic elution mode) to give Compound 227 2-[3-[(3-hydroxy-3-methyl-cyclobutyl)methyl]pyrido[2,3-b]pyr azin-6-yl]- 3,5-dimethyl-phenol (19.0 mg, 52.6 pmol, 24% yield, 97% purity, peak 1 , Rt = 1.033 min) as a yellow solid, and Compound 228 2-[3-[(3-hydroxy-3-methyl-cyclobutyl)methyl]pyrido[2,3-b]pyr azin-6-yl]-3,5- dimethyl-phenol (18.8 mg, 50.8 pmol, 23% yield, 95% purity, peak 2, Rt = 1 .779 min) as a ye How solid.

Compound 227

¹ H NMR (400 MHz, CD ₃ OD) 0 = 8.84 (s, 1 H), 8.41 (d, J = 8.4 Hz, 1 H), 7.89 (d, J = 8.4 Hz, 1 H), 6.56 (s, 1 H), 6.44 (s, 1 H), 3.21 (d, J = 7.2 Hz, 2H), 2.50-2.40 (m, 1 H), 2.24 (s, 3H), 2.23-2.15 (m, 2H), 2.11 (s, 3H), 2.00-1.90 (m, 2H), 1.32 (s, 3H), 0.92-0.85 (m, 1 H).

LC-MS (Method C): Rt = 0.496 min; MS (ESIpos): m/z - 350.1 [M+1 ] ⁺ .

SFC (Rt = 1 .033 min, ee% = 99%)

Compound 228

¹ H NMR (400 MHz, CD3OD) 6 = 8.83 (s, 1 H), 8.38 (d, J = 8.4 Hz, 1 H), 7.91 (d, J = 8.4 Hz, 1 H), 6.53 (s, 1 H), 6.35 (s, 1 H), 3.21 (d, J = 7.6 Hz, 2H), 3.05-2.95 (m, 1 H), 2.28-2.18 (m, 5H), 2.09 (s, 3H), 2.00-1.93 (m, 2H), 1 .36 (s, 3H), 1 .33-1 .27 (m, 1 H).

LC-MS (Method C): Rt = 0.483 min; MS (ESIpos): m/z = 350.1 [M+1 ] ⁺ .

SFC (Rt = 1 .779 min, ee% = 99%)

Intermediate 558

2~bromG~1-(difiuoromethyi)~3~methGxy~berizene

To a solution of 2-bromo-3-methoxy-benzaldehyde (8.00 g, 37.2 mmol, 1 eq) in EtOH (171 mg, 3,72 mmol, 0.1 eq) and DCM (100 mL) was added DAST (12.0 g, 74.4 mmol, 9.83 mL, 2 eq) at 0 °C. After stirred at 25 °C for 2 h, the reaction mixture was poured into saturated sodium bicarbonate aqueous solution (300 mL) at 0 °C. And the mixture was stirred at 25 °C for 1 h. The solution was extracted with DCM (300 mLx3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOz, petroleum ether/ethyl acetate=1/0) to give 2-bromo-1-(difluoromethyl)-3-methoxy-benzene (8.00 g, 33.8 mmol, 91% yield) as yellow oil.

Intermediate 559

Z-p-fdifluoromethyO-S-methoxy-phenylJ-^.^S-tetramethyl-l^ ^-dioxaborolane

A mixture of 2-bromo-1-(difluoromethyl)-3-methoxy-benzene (8.00 g, 33.8 mmol, 1 eq), 4, 4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (12.9 g, 50.6 mmol, 1 .5 eq), Pd(dppf)Cl2 (2.47 g, 3.37 mmol, 0.1 eq) and KOAc (9.94 g, 101 mmol, 3 eq) in dioxane (150 mL) was stirred at 100 °C for 15 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL * 3). The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (S1O ₂ , petroleum ether/ethyl acetate=100/1) to give 2-[2-(difluoromethyl)-6-methoxy- phenyl]-4, 4, 5, 5-tetramethyl-1 ,3,2-dioxaborolane (10 g, 28.2 mmol, 83% yield, 80% purity) as a green solid. ¹ H NMR (400 MHz, CDCb) 5 [ppm] = 7.40 (t, J = 8.0 Hz, 1 H), 7.14 (d, J = 8.0 Hz, 1 H), 6.99-6.56 (m, 2H), 3.82 (s, 3H), 1.39 (s, 12H).

Intermediate 560

6-[2-(difluoromethyl)-6-methoxy-phenyl]pyrldine-2,3-dlaml ne

To a solution of 6-chloropyridine-2,3-diamine (4.00 g, 27.9 mmol, 1 eq) in dioxane (100 mL) and water (20 mL) was added 2-[2-(difluoromethyl)-6-methoxy-phenyl]-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane (10.0 g, 28.2 mmol, 1 .01 eq), XPhos Pd G3 (2.36 g, 2.79 mmol, 0.1 eq) and CS2CO3 (27.2 g, 83.6 mmol, 3 eq) at 20 °C in one portion. After stirring at 90 °C for 16 hours, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The residue was purified by reversed phase (column: C18 40 g, mobile phase: [water (FA) - MeCN]; B%: 40% - 70%, 7 min) to give 6-[2-(difluoromethyl)-6-methoxy-phenyl]pyridine-2,3-diamine (4.70 g, 17.7 mmol, 64% yield) as yellow oil.

¹ H NMR (400 MHz, CDCb) 6 [ppm] = 7.46-7.40 (m, 1 H), 7.38-7.33 (m, 1 H), 7.05 (dd, J = 0.8, 8.2 Hz, 1 H), 6.97 (d, J = 7.8 Hz, 1 H), 6.72 (d, J = 7.6 Hz, 1 H), 6.56 (t, J = 56.0 Hz,1 H), 4.30 (s, 2H), 3.77 (s, 3H).

¹ F NMR (400 MHz, CDCb) 5 [ppm] = -110.

Intermediate 561

A solution of 6-[2-(difluoromethyl)-6-methoxy-phenyl]pyridine-2,3-diamine (4.70 g, 17.7 mmol, 1 eq) and tert-butyl (3R)-3-oxaldehydoylpiperidine-1-carboxylate (6.41 g, 26.6 mmol, 1 .5 eq) in EtOH (100 mL) was stirred at 60 °C for 2 h. Then, the mixture was filtered, and the filtrate was concentrated to dry. The residue was purified by reversed phase (column: C18 330 g, mobile phase: [water (FA) - MeCN]; B%: 40% - 70%, 7 min) to give the solution, which was then lyophilized to give tert-butyl (3R)-3-[6-[2- (difluoromethyl)-6-methoxy-phenyl]pyrido[2,3-b]pyrazin-3-yl] piperidine-1 -carboxylate (3.70 g, 7.08 mmol, 40% yield, 90% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 9.12 (s, 1 H), 8.56 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 8.4 Hz, 1 H), 7.69-7.64 (m, 1 H), 7.39 (t, J = 8.8 Hz, 2H), 6.99-6.65 (m, 1 H), 4.28-4.16 (m, 1 H), 3.94 (d, J = 12.8 Hz, 1 H), 3.76 (s, 3H), 3.24-3.14 (m, 2H), 2.96-2.84 (m, 1 H), 2.20-2.10 (m, 1 H), 1.85 (t, J = 10.4 Hz, 2H), 1 .55 (d, J = 3.8 Hz, 1 H), 1 .38 (s, 9H)

LC-MS (Method C): R _t = 0.578; MS (ESI) m/z = 471 .0 [M+H] ⁺ .

Intermediate 562 tert-butyl (SRJ-S-lB-^-fdifluoromethyQ-S-methoxy-^f^^S.S-tetramethyl-l^ ^-dioxaborolan^- ylJpherrylJpyrido&S-blpyrazln-S-ylJpiperidirie-l -carboxylate

To a solution of tert-butyl (3R)-3-[6-[2-(difluoromethyl)-6-methoxy-phenyl]pyrido[2,3-b] pyrazin-3- yl]piperidine-1 -carboxylate (3.00 g, 5.93 mmol, 1 eq) in THF (60 mL) were added 4,4,5,5-tetramethyl- 2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (3.01 g, 11.9 mmol, 2 eq), (1Z,5Z)- cycloocta-1 ,5-diene;2,4-dimethyl-BLAHbicyclo[1.1.0]butane (393 mg, 593 pmol, 0.1 eq) and dtbbpy (318 mg, 1.19 mmol, 0.2 eq) at 25 °C under nitrogen atmosphere. After stirring at 80 °C for 16 h, the mixture was concentrated to dry. The residue was purified by reversed phase (column: C18 40 g, mobile phase: [water (FA) - MeCN]; B%: 40% - 70%, 7 min) to give the solution, which was then lyophilized to give tert-butyl (3R)-3-[6-[2-(difluoromethyl)-6-methoxy-4-(4,4,5,5-tetrameth yl-1 ,3,2-dioxaborolan-2- yl)phenyl]pyrido[2,3-b]pyrazin-3-yl]piperidine-1 -carboxylate (900 mg, 1 .51 mmol, 25% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO-cfe) 5 [ppm] = 9.13 (s, 1 H), 8.58 (d, J = 8.4 Hz, 1 H), 7.85 (d, J = 8.5 Hz, 1 H), 7.66 (s, 1 H), 7.52 (s, 1 H), 7.05-6.70 (m, 1 H), 4.29-4.12 (m, 1 H), 3.96 (d, J = 2.5 Hz, 1 H), 3.78 (s, 3H), 3.28-3.20 (m, 2H), 2.97-2.85 (m, 1 H), 2.20-2.10 (m, 1 H), 1.93-1.76 (m, 2H), 1.54 (d, J = 12.4 Hz, 1 H), 1.36 (s, 9H), 1.07 (s, 12H).

Intermediate 563

6-[4-bromo-2-(difluoromethyl)-6-methoxy-phenyl]-3-[(3R)-3 -piperldyl]pyrldo[2,3-b]pyrazlne

To a solution of tert-butyl (3R)-3-[6-[2-(difluoromethyl)-6-methoxy-4-(4,4,5,5-tetrameth yl-1 ,3,2- dioxaborolan-2-yl)phenyl]pyrido[2,3-b]pyrazin-3-yl]piperidin e-1-carboxylate (850 mg, 1.43 mmol, 1 eq) in MeOH (20 mL) and water (10 mL) was added CuBr? (796 mg, 3.56 mmol, 167 pL, 2.5 eq). After stirring at 80 °C for16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6-[4-bromo-2-(difluoromethyl)-6-methoxy-phenyl]-3-[(3R)-3- piperidyl]pyrido[2,3-b]pyrazine (700 mg, crude) as yellow oil.

Intermediate 564

To a solution of 6-[4-bromo-2-(difluoromethyl)-6-methoxy-phenyl]-3-[(3R)-3-pi peridyl]pyrido[2,3- b]pyrazine (700 mg, 1 .56 mmol, 1 eq) in DCM (10 mL) were added B0C2O (408 mg, 1 .87 mmol, 430 pL, 1 .2 eq) and DIPEA (403 mg, 3.12 mmol, 543 pL, 2 eq). After stirring at 25 °C for 0.5 h, the mixture was diluted with 15% citric acid (20 mL) and extracted with DCM (20 mL x 3). The organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give tert-butyl (3R)-3-[6-[4-bromo-2-(difluoromethyl)-6-methoxy-phenyl]pyrid o[2,3- b]pyrazin-3-yl]piperidine-1-carboxylate (700 mg, 1.27 mmol, 82% yield) as yellow oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 9.12 (s, 1 H), 8.57 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 8.4 Hz, 1 H), 7.61 (s, 1 H), 7.51 (s, 1 H), 7.05-6.67 (m, 1 H), 4.26-4.15 (m, 1 H), 3.92-3.89 (m, 1 H), 3.78 (s, 3H), 3.29 (d, J = 2.0 Hz, 2H), 2.95-2.84 (m, 1 H), 2.19-2.08 (m, 1 H), 1 .85-1 .81 (m, 2H), 1 .58-1 .47 (m, 1 H), 1 .36 (s, 9H).

Intermediate 565

To a solution of tert-butyl (3R)-3-[6-[4-bromo-2-(difluoromethyl)-6-methoxy-phenyl]pyrid o[2,3-b]pyrazin- 3-yl]piperidine-1 -carboxylate (300 mg, 546 pmol, 1 eq) in dioxane (3 mL) and water (0.5 mL) were added 2,4,6-trimethyl-1 ,3,5,2,4,6-trioxatriborinane (411 mg, 1 .64 mmol, 458 pL, 3 eq), Pd(dppf)Cl2 (40.0 mg, 54.6 pmol, 0.1 eq) and NazCOs (174 mg, 1.64 mmol, 3 eq) at 25 °C. After stirring at 90 °C for 1 h, the mixture was filtered, and the filtrate was concentrated to dry. The residue was purified by reversed phase (column: C18 40 g, mobile phase: [water (FA) - MeCN]; B%: 40% - 70%, 7 min) to give tert-butyl (3R)-3-[6-[2-(difluoromethyl)-6-methoxy-4-methyl-phenyl]pyri do[2,3-b]pyrazin-3-yl]piperidine-1- carboxylate (180 mg, 371 pmol, 68% yield) as yellow oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 9.11 (s, 1 H), 8.54 (d, J = 8.4 Hz, 1 H), 7.84 (d, J = 8.4 Hz, 1 H), 7.59-7.44 (m, 2H), 7.01-6.66 (m, 1 H), 4.26-4.14 (m, 1 H), 4.01-3.89 (m, 1 H), 3.74 (s, 3H), 3.26-3.21 (m, 2H), 2.93-2.86 (m, 1 H), 2.30 (s, 3H), 2.18-2.14 (m, 1 H), 1.89-1.79 (m, 2H), 1.57-1.49 (m, 1 H), 1.37 (s, 10H).

Intermediate 566

6-[2-(dif!uoromethyl)~&-methoxy-4-methy!-phenyl]~3-[3 ~piperidyl]pyrido[2 _! 3~b]pyrazine

To a solution of tert-butyl (3R)-3-[6-[2-(difluoromethyl)-6-methoxy-4-methyl-phenyl]pyri do[2,3- b]pyrazin-3-yl]piperidine-1-carboxylate (200 mg, 413 pmol, 1 eq) in DCM (1 mL) was added TFA (1.84 g, 16.2 mmol, 1 .20 mL) at 20 °C dropwise. After stirring at 20 °C for 1 h, the mixture was concentrated in vacuum to give 6-[2-(difluoromethyl)-6-methoxy-4-methyl-phenyl]-3-[3-piperi dyl]pyrido[2,3- b]pyrazine (150 mg, 355 pmol, 86% yield, 91 % purity) as black brown oil.

LC-MS (Method C): Rt = 0.439; MS (ESI) m/z = 385.1 [M+HJ*.

Intermediate 567

6-[2-(difluoromethyl)-6-methoxy-4-methyl-phenyl]-3-[1-met byl-3-plperidyl]pyrido[2,3- b]pyrazme

To a solution of 6-[2-(difluoromethyl)-6-methoxy-4-methyl-phenyl]-3-[(3R)-3-p iperidyl]pyrido[2,3- b]pyrazine (150 mg, 390 pmol, 1 eq) and potassium acetate (191 mg, 1.95 mmol, 5 eq) in methanol (4 mL) were added paraformaldehyde (58.5 mg, 1 .95 mmol, 5 eq) and NaBHsCN (73.6 mg, 1 .17 mmol, 3 eq) at 20 °C. After stirring at 20 °C for 1 h, the mixture was poured into water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine (5 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiOa, petroleum ether/ethyl acetate = 0/1 to dichloromethane /methanol ”10/1) to give 6-[2-(difluoromethyl)-6-methoxy-4-methyl-phenyl]-3-[(3R)-1- methyl-3-piperidyl]pyrido[2,3-b]pyrazine (150 mg, 331 pmol, 85% yield, 88% purity) as a brown solid. LC-MS (Method C): Rt = 0.449; MS (ESI) m/z = 399.1 [M+H] ⁺ .

Intermediate 568

3-(dif!uoromethyl)-5-methyl-2-[3-[1-methy!-3-piperidy!]py rido[2,3-b]pyrazin-6-yl]pheno! To a solution of To a solution of 6-[2-(difluoromethyl)-6-methoxy-4-methyl-phenyl]-3-[1-methyl -3- piperidyl]pyrido[2,3-b]pyrazine (140 mg, 351 pmol, 1 eq) in DMF (1 mL) was added NaSEt (296 mg, 3.51 mmol, 10 eq) at 20 °C in one portion. After stirring at 100 °C for 16 h, the mixture was filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by reversed-phase HPLC (0.1 % FA condition) to give 3-(difluoromethyl)-5-methyl-2-[3-[1-methyl-3-piperidyl]pyrid o[2,3- b]pyrazin-6-yl]phenol (40.0 mg, 102 pmol, 29% yield, 98% purity) as a brown solid.

LC-MS (Method C): R _t = 0.416; MS (ESI) m/z = 385.1 [M+H] ⁺ .

Compounds 229 and 230

3-(difiuoromethyl)-5-methyi-2-[3-[1 -methyl-3-pipendyl]pyrido[2,3-b]pyrazm-6-yl]phenol

The mixture was purified by SFC (column: ChiralPak IH, 250 x 50mm, 10 pm; mobile phase: [COz-i- PrOH (0.1 % NH3H2O)]; B%:30%, isocratic elution mode ) to give Compound 229 3-(difluoromethyl)-5- methyl-2-[3-[1-methyl-3-piperidyl]pyrido[2,3-b]pyrazin-6-yl] phenol (21.2 mg, 53.9 pmol, 52% yield, 98% purity) as a white solid, and Compound 230 3-(difluoromethyl)-5-methyl-2-[3-[1-methyl-3- piperidyl]pyrido[2,3-b]pyrazin-6-yl]phenol (21.2 mg, 53.6 pmol, 51 % yield, 97% purity) as a white solid.

Compound 229

¹ H NMR (400 MHz, DMSO-d _e ) 5 [ppm] = 10.09 (s, 1 H), 9.11 (s, 1 H), 8.53 (d, J = 8.4 Hz, 1 H), 7.91 (d, J = 8.4 Hz, 1 H), 7.13-6.81 (m, 3H), 3.21-3.04 (m, 4H), 2.57 (s, 3H), 2.53-2.52 (m, 1 H), 2.37 (s, 3H), 2.18- 2.12 (m, 1 H), 1.93-1.80 (m, 2H), 1.72-1.64 (m, 1 H)

LC-MS (Method C): Rt = 0.408; MS (ESI) m/z = 385.2 [M+H] ⁺ .

SFC (Rt = 1 .414, ee% = 97%)

Compound 230

¹ H NMR (400 MHz, DMSO-d _s ) 5 [ppm] = 9.09 (s, 1 H), 8.52 (d, J = 8.8 Hz, 1 H), 8.21 (s, 1 H), 7.88 (d, J = 8.8 Hz, 1 H), 7.10-6.80 (m, 3H), 3.36-3.32 (m, 1 H), 3.13-3.07 (m, 1 H), 2.88-2.81 (m, 1 H), 2.38 (s, 3H), 2.36-2.31 (m, 1 H), 2.28 (s, 3H), 2.07-2.00 (m, 2H), 1.83-1.75 (m, 1 H), 1.73-1.59 (m, 2H)

LC-MS (Method C): Rt = 0.418; MS (ESI) m/z = 385.2 [M+H] ⁺ .

SFC (Rt = 1 .632, ee% = 89%)

Intermediate 569 benzyl (3R}-3-(hydrazinecarbonyl)piperidine-1 -carboxylate

To a solution of (3R)-1-benzyloxycarbonylpiperidine-3-carboxylic acid (10.0 g, 37.9 mmol, 1 eq), hydrazine hydrochloride (3.90 g, 56.9 mmol, 1 .5 eq) and DIPEA (14.7 g, 113 mmol, 19.8 mL, 3 eq) in dichloromethane (100 mL) were added EDCI (10.9 g, 56.9 mmol, 1 .5 eq) and HOBt (7.70 g, 56.7 mmol, 1 .5 eq) at 20 °C in one portion. After stirring at 20 °C for 2 h, the mixture was poured into water (200 mL) and extracted with dichloromethane (100 mL x 2). The combined organic phase was washed with brine (80 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiOz, Petroleum ether/Ethyl acetate = 3/1 to 0/1) to give benzyl (3R)-3-(hydrazinecarbonyl)piperidine-1-carboxylate (4.00 g, 14.4 mmol, 37% yield) as a white solid.

¹ H NMR (400 MHz, CDCI ₃ ) 6 [ppm] = 7.41-7.29 (m, 5H), 5.20-5.07 (m, 2H), 4.19-3.77 (m, 2H), 3.34- 2.76 (m, 2H), 2.53-2.31 (m, 1 H), 2.00-1.69 (m, 3H), 1.57-1.40 (m, 1 H).

Intermediate 570 benzyl 3~[6-(2-m&thoxy~4,6-dbnrithyl~ph&nyl)pyrido[2,3~ri][ 1 _! 2 _l 4]tdazln-3-yl]pip&ridine~1- carboxylate

To a solution of 3-chioro-6-(2-methoxy-4,6-dimethyi-phenyi)pyridin-2-amine (1 g*3, 3.81 mmol, 1 eq), benzyl (3R)-3-(hydrazinecarbonyl)piperidine-1-carboxylate (1 .58 g, 5.71 mmol, 1 .5 eq) and CS2CO3 (3.72 g, 11 .4 mmol, 3 eq) in 2-methylbutan-2-ol (15 mL) was added tBuXPhos Pd G ₃ (302 mg, 380 pmol, 0.1 eq) at 20 °C in one portion. After stirring at 130 °C for 16 h, the mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase were washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SIO ₂ , Petroleum ether/Ethyl acetate = 10/1 to 5/1) to give benzyl 3-[6-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3-e][1 ,2,4]triazin-3- yl]piperidine-1 -carboxylate (260 mg, 510 pmol, 4% yield, 95% purity) as yellow oil LC-MS (Method C): Rt = 0.620; MS (ESI) m/z = 484.3 [M+H] ⁺ .

Intermediate 571

6-(2-fnethoxy-4,6-dlmethyl~phenyl)~3-[3~piperldyl]pyrido[ 2,3~e][1,2,4]tnazine

To a solution of benzyl 3-[6-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3-e][1 ,2,4]triazin-3-yi]piperidine- 1 -carboxylate (150 mg, 310 pmol, 1 eq) in dichloromethane (3 mL) was added TMSI (186 mg, 930 pmol, 126 pL, 3 eq) at 0 °C in one portion. After stirring at 20 °C for 1 h, the mixture was quenched by methanol (2 mL) and filtered to give a mother liquor. The mother liquor was purified by reversed-phase column (column: C18 80 g, mobile phase: [water (FA) - MeCN]; B%: 15% - 25%, 7 min) to give 6-(2-methoxy- 4,6-dimethyl-phenyl)-3-[3-piperidyl]pyrido[2,3-e][1 ,2,4]triazine (110 mg, 308 pmol, 99.45% yield, 98% purity) as yellow oil.

LC-MS (Method C): Rt = 0.432; MS (ESI) m/z = 350.1 [M+H] ⁺ .

Intermediate 572

6-(2-m&thoxy-4 _! 6-dln'ietbyl-ph&nyl)-3-[1-mefhyb3-.piperldyl]pyrld o[2,3-e][1,2,4]trlazme

To a solution of 6-(2-methoxy-4,6-dimethyl-phenyl)-3-[3-piperidyl]pyrido[2,3- e][1 ,2,4]triazine (110 mg, 314 pmol, 1 eq) and potassium acetate (308 mg, 3.15 mmol, 10 eq) in methanol (2 mL) were added paraformaldehyde (47.2 mg, 1 .57 mmol, 5 eq) and NaBH ₃ CN (59.3 mg, 944 pmol, 3 eq) at 20 °C. After stirring at 20 °C for 1 h, the mixture was poured into water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine (5 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18 80 g, mobile phase: [water (FA) - MeCN]; B%: 15% - 25%, 7 min) to give 6-(2-methoxy-4,6-dimethyl-phenyl)-3-[1-methyl-3-piperidyl]py rido[2,3-e][1 ,2,4]triazine (80 mg, 217.91 pmol, 69.22% yield, 99% purity) was obtained as a brown oil.

LC-MS (Method C): Rt = 0.441 ; MS (ESI) m/z = 364.2 [M+H] ⁺ .

Compound 231

3,5-dimethyl-2-[3-[1-methyl-3-piperidyl]pyrido[2 _; 3-e][1,2,4]tnazin-6-yl]phenol

To a solution of 6-(2-methoxy-4,6-dimethyl-phenyl)-3-[(3R)-1-methyl-3-piperid yl]pyrido[2,3- e][1 ,2,4]triazine (60 mg, 165 pmol, 1 eg) in dichloromethane (2 mL) was added BBrs (413 mg, 1.65 mmol, 159 pL, 10 eq) at -70 °C in one portin. After stirring at -70 °C for 2 h, the mixture was quenched by methanol (3 mL) at -70 °C for 0.5 hour. The mixture was concentrated in vacuum to give a residue. The residue was purified by reversed-phase column (column: C18 80 g, mobile phase: [water (FA) - MeCN]; B%: 20% - 30%, 6 min) to give 3,5-dimethyl-2-[3-[1-methyl-3-piperidyl]pyrido[2,3- e][1 ,2,4]triazin-6-yl]phenol (3.02 mg, 8.47 pmol, 5.13% yield, 98% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 [ppm] = 9.79 (s, 1 H), 8.94 (d, J = 8.8 Hz, 1 H), 8.01 (d, J = 8.8 Hz, 1 H), 6.68 (s, 1 H), 6.66 (s, 1 H), 3.84-3.75 (m, 1 H), 3.67-3.52 (m, 3H), 2.68-2.66 (m, 1 H), 2.63 (s, 3H), 2.31- 2.29 (m, 1 H), 2.27 (s, 3H), 2.13 (s, 3H), 1.98-1.93 (m, 1 H), 1.90-1.80 (m, 2H) LC-MS (Method C): Rt = 0.408; MS (ESI) m/z = 350.1 [M+H] ⁺ .

Intermediate 573

8~chioro~4'Vinyi~pyridii'ie~2 ₎ 3~diamine

To a solution of 4,6-dichloropyridine-2,3-diamine (3.00 g, 16.9 mmol, 1 eq) in dioxane (50 mL) and H2O (3 mL) was added potassium trifluoro(vinyl)boranuide (2.93 g, 21.9 mmol, 1 ,3 eq), [2-(2- aminophenyl)phenyl]palladium(1 +);dicyclohexyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane;methanesulfonate (1.43 g, 1 .69 mmol, 0.1 eq) and CS2CO3 (11.0 g, 33.7 mmol, 2 eq) under nitrogen atmosphere. After stirring at 90°C for 2 h, the mixture was filtered and the filtrate was concentrated at reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether/ethyl acetate = 1/1) to give 6-chloro-4-vinyl-pyridine- 2,3-diamine (2.30 g, 12.2 mmol, 72% yield, 90% purity) as a gray solid.

LC-MS (Method C): Rt = 0.386 min; MS (ESI): m/z = 170.0 [M+H] ⁺ .

Intermediate 574 tert-butyl (R)-3-(6-chloro-8-vmylpyrido[2.3-b]pyrazm-3-yl)piperidine-1 -carboxylate

To a solution of 6-chloro-4-vinyl-pyridine-2,3-diamine (2.20 g, 13.0 mmol, 1 eq) in EtOH (80 mL) was added tert-butyl (3R)-3-oxaldehydoylpiperidine-1 -carboxylate (3.00 g, 12.4 mmol, 1 eq, EW40567-283) at 25 °C. After stirring at 60 °C for 1 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO?, petroleum ether/ethyl acetate = 2/1). tert-butyl (R)-3-(6-chloro-8-vinylpyrido[2,3-b]pyrazin-3-yl)piperidine- 1-carboxyiate (2.00 g, 4.80 mmol, 37% yield, 90% purity) as a yellow oil.

Intermediate 575

To a solution of tert-butyl (3R)-3-(6-chloro-8-vinyl-pyrido[2,3-b]pyrazin-3-yl)piperidin e-1 -carboxylate (2.00 g, 5.34 mmol, 1 eq) and (2-methoxy-4,6-dlmethyl-phenyl)boronic acid (1.92 g, 10.7 mmol, 2 eq) in dioxane (30 mL) and H2O (5 mL) were added Pd(dppf)Cl2 (390 mg, 533 pmol, 0.1 eq) and CS2CO3 (5.21 g, 16.0 mmol, 3 eq) at 25 °C under N2 atmosphere. After stirring at 80 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate - 2/1) to give tert-butyl-(3R)-3-[6-(2- methoxy-4,6-dimethyl-phenyl)-8-vinyl-pyrido[2,3-b]pyrazin-3- yl]piperidine-1 -carboxylate (2.01 g, 3.81 mmol, 71 % yield, 90% purity) as yellow oil.

¹ H NMR (400 MHz, CDCb) 6 = 8.85 (s, 1 H), 7.94-7.84 (m, 1 H), 7.80 (s, 1 H), 6.76 (s, 1 H), 6.67 (s, 1 H), 6.28-6.15 (m, 1 H), 5.81-5.64 (m, 1 H), 4.47-4.33 (m, 1 H), 4.23-4.20 (m, 1 H), 3.71 (s, 3H), 3.40-3.25 (m, 1 H), 3.20-3.15 (m, 1 H), 2.89-2.77 (m, 1 H), 2.40 (s, 3H), 2.17-2.14 (m, 4H), 1 .88-1 .79 (m, 1 H), 1 .69-1 .62 (m, 2H), 1 .48 (s, 9H).

LC-MS (Method C): Rt = 0.644 min; MS (ESIpos): m/z = 475.2 [M+1J*.

Intermediate 576

Ozone was bubbled into a solution of tert-butyl 3-[6-(2-methoxy-4,6-dimethyl-phenyl)-8-vinyl-pyrido[2,3- b]pyrazin-3-yl]piperidine-1-carboxylate (1.50 g, 3.16 mmol, 1 eq) in THF (20 mL) at -70 °C for 30 minutes. After excess O3 was purged by N2, the mixture quenched by sodium hypochlorite solution (60 mL) at 0 °C and stirred at 25 °C for 30 min. Then was extracted with ethyl acetate extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The reaction mixture was concentrated under reduced pressure to give the crude product tertbutyl (3R)-3-[8-formyl-6-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3 -b]pyrazin-3-yl]piperidine-1- carboxylate (1 .50 g, 1 .26 mmol, 40% yield, 40% purity) as yellow oil and the cude product was used to the next step without purification.

LC-MS (Method C): Rt = 0.636 min; MS (ESIpos): m/z = 477.2 [M+1 ] ⁺ .

Intermediate 577 tert-butyl (3R)-3-[8-(hydroxyniethyi)-6-(2-methoxy-4 _> 6-d!niethyi-ph&oyl}pyddo[2,3-b]pyrazm-3- yl]piperidme-1 -carboxylate

The mxiture of tert-butyl (3R)-3-[8-formyl-6-(2-methoxy-4,6-dimethyl-phenyl)pyrido[2,3 -b]pyrazin-3-yl] piperidine-1 -carboxylate (1.50 g, 3.15 mmol, 1 eq) in MeOH (40 mL) was added NaBH4 (595 mg, 15.7 mmol, 5 eq) at 0°C. After stirring at 0°C for 0.5 h, the mixture was quenched by water (50 mL) at 0°C, then the mixture was stirred at 25 °C for 0.5 h. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC(column: C18 80 g, mobile phase: [water (FA) - MeCN]; B%: 35% - 55%, 15 min) to give tert-butyl (3R)-3-[8-(hydroxymethyl)-6-(2-methoxy-4,6-dimethyl-phenyl)p yrido [2,3-b]pyrazin-3-yl]piperidine-1-carboxylate (160 mg, 314 pmol, 10% yield, 94% purity) as a biack solid. LC-MS (Method C): Rt = 0.575 min; MS (ESIpos): m/z = 479.4 [M+1] ⁺ . intermediate 578

[6-(2-methoxy-4,§-d!methy!-pheny!)-3-[(3R)-3-p!pendy!]py ndo[2.3-b]pyrazin-8-y!]methano!

To a solution of tert-butyl (3R)-3-[8-(hydroxymethyl)-6-(2-methoxy-4,6-dimethyl-phenyl)p yrido [2,3- bjpyrazin-3-yl]piperidine-1-carboxylate (0.150 g, 313 pmol, 1 eq) in DCM (3 mL) was added TFA (357 mg, 3.13 mmol, 232 pL, 10 eq) at 25 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated under reduced pressure to give [6-(2-methoxy-4,6-dimethyl-phenyl)-3-[(3R)-3- piperidyl]pyrido[2,3-b]pyrazin-8-yl]methanol (150 mg, 213 pmol, 68% yield, 70% purity, TFA salt) as red oil.

LC-MS (Method C): Rt = 0.411 min; MS (ESIpos): m/z = 379.1 [M+1] ⁺ .

Intermediate 579

(R)-(8-(2-methoxy-4,6-dimethy!phenyl)-3-(1-methy!pipendin -3-y!)pyndo[2,3-b]pyi'azin-8- y!)methanol

To a solution of [6-(2-methoxy-4,6-dimethyl-phenyl)-3-[(3R)-3-piperidyl]pyrid o[2,3-b] pyrazin-8- yljmethanol (150 mg, 304 pmol, 1 eq, TFA) in MeOH (3 mL) were added KOAc (150 mg, 1.52 mmol, 5 eq) , NaBFkCN (38.3 mg, 609 pmol, 2 eq) and (HCHO)n (27.4 mg, 914 pmol, 3 eq) at 25 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(FA)- MeCN];B%: 25%-60%, 3 min) to give (R)-(6-(2-methoxy-4,6-dimethylphenyl)-3- (1-methylpiperidin-3- yl)pyrido[2,3-b]pyrazin-8-yl)methanol (100 mg, 229 pmol, 75% yield, 90% purity) as a light yellow solid. LC-MS (Method C): Rt = 0.404 min; MS (ESIpos): m/z = 393.1 [M+1 ] ⁺ .

Compound 232

To a solution of [6-(2-methoxy-4,6-dimethyl-phenyl)-3-[(3R)-1-methyl-3-piperi dyl]pyrido[2,3-b] pyrazin- 8-yljmethanol (50.0 mg, 127 pmol, 1 eq) in DCM (10 mL) was dropwise BBrs (2 M, 191 pL, 3 eq) at - 70°C .After stirring at 25 °C for 0.5h, the mixture was quenched by methanol (10 mL) at 0 °C, the aqueous phase was adjust to pH = 9 with ammonium hydroxide. The mixture was stirred at 25 °C for 0.5 h. The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The residue was purified by reversed-phase HPLC(column: C18, 40 g, mobile phase: [water(FA)-MeCN];B%: 35%-60%, 10 min) to give 2-[8-(hydroxymethyl)-3-[(3R)- 1- methyl-3- piperidyl]pyrido[2,3-b]pyrazin-6-yl]-3,5-dimethyl-phenol (27.6 mg, 70.6 pmol, 55% yield, 97% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d _s ) 6 = 9.00 (s, 1 H), 8.48 (s, 2H), 7.77 (s, 1 H), 6.69 (s, 1 H), 6.59 (s, 1 H), 5.21 (s, 2H), 3.32-3.26 (m, 2H), 3.06-3.00 (m, 1 H), 2.80 (d, J = 11 .6 Hz, 1 H), 2.54 (s, 1 H), 2.26 (s, 3H), 2.23 (s, 3H), 2.05 (s, 3H), 1 .95-1.93 (m, 1 H), 1 .81-1.72 (m, 1 H), 1.69-1.61 (m, 2H).

LC-MS (Method C): Rt = 0.499 min; MS (ESIpos): m/z = 379.2 [M+1] ⁺ .

SFC (Rt = 2.088 min, ee% = 93%).

Intermediate 580

2-(4-fluoro-3, 5-dimethyl-phenyl)-4,4.5, 5-tetramethyl- 1, 3, 2-dioxaborolane

To a solution of 5-bromo-2-fluoro-1 ,3-dimethyl-benzene (10.0 g, 49.2 mmol, 1 eq) , 4,4,5,5-tetramethyl- 2-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (15.0 g, 59.1 mmol, 1.2 eq) and potassium acetate (12.0 g, 123 mmol, 2.5 eq) in dioxane (200 mL) was added Pd(dppf)Cl2 (720 mg, 984 pmol, 0.02 eq) at 20 °C in one portion. After stirring at 90 °C for 16 h under nitrogen atmosphere, the mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine (100 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiOz, Petroleum ether/Ethyl acetate = 20/1) to give 2-(4-fluoro-3,5-dimethyl-phenyl)- 4, 4, 5, 5-tetra methyl- 1 ,3,2-dioxaborolane (12.0 g, 47.9 mmol, 97% yield) as a yellow oil.

¹ H NMR (400 MHz, CDCb) 6 = 7.49 (s, 1 H), 7.47 (s, 1 H), 2.26 (d, J = 2.0 Hz, 6H), 1 .35 (s, 12H).

Intermediate 581

4-fluoro-3, 5-dimethyl-pheriGl

To a solution of 2-(4-fluoro-3,5-dimethyl-phenyl)-4, 4,5, 5-tetramethyl-1 ,3,2-dioxaborolane (6.00 g, 23.9 mmol, 1 eq) in THF (60 mL) were added H2O ₂ (8.16 g, 71.9 mmol, 6.92 mL, 30% purity, 3 eq) and NaOH (1 .92 g, 47.9 mmol, 2 eq) in water (10 mL) at 0 °C dropwise. After stirring at 20 °C for 2 h, the mixture was poured into water (50 mL). The pH was adjusted to around 7 by progressively adding I N hydrochloric acid aqueous solution at 0 °C. The mixture was extracted with ethyl acetate (40 mL x 2). The combined organic phase was washed with brine (40 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SIOz, Petroleum ether/Ethyl acetate = 10/1) to give 4-fiuoro-3,5-dimethyl-phenol (3.00 g, 21 .4 mmol, 89% yield) as a yellow solid.

^! H NMR (400 MHz, CDCb) 5 = 6.48 (s, 1 H), 6.46 (s, 1 H), 4.77-4.70 (m, 1 H), 2.21 (d, J = 2.0 Hz, 6H).

Intermediate 582

2-fluoro-5-methoxy-1,3-dimethyl-benzene

To a solution of 4-fluoro-3,5-dimethyl-phenol (3.00 g, 21 .4 mmol, 1 eq) in THF (30 mL) was added NaH (1.11 g, 27.8 mmol, 60% purity, 1.3 eq) at 0 °C in portions under nitrogen atmosphere. After stirring at 0 °C for 0.5 h, Mel (15.1 g, 107 mmol, 6.66 mL, 5 eq) was added to the reaction mixture. After stirring at 20 °C for 2 h, the mixture was quenched by ice-water (30 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 10/1) to give 2-fluoro-5-methoxy-1 ,3- dimethyl-benzene (3.20 g, 20.7 mmol, 96% yield) as yellow oil.

¹ H NMR (400 MHz, CDCb) 6 = 6.54 (s, 1 H), 6.52 (s, 1 H), 3.75 (s, 3H), 2.24 (d, J = 2.4 Hz, 6H) intermediate 583

(3-fluoro-6-methoxy-2,4-dimethyl-phenyl)boronic acid

To a solution of 2-fluoro-5-methoxy-1 ,3-dimethyl-benzene (3.20 g, 20.7 mmol, 1 eq) and TMEDA (5.31 g, 45.6 mmol, 6.89 mL, 2.2 eq) in THF (40 mL) was added n-BuLi (2.50 M in hexane, 18.2 mL, 2.2 eq) at 0 °C dropwise under nitrogen atmosphere. After stirring at 20 °C for 1 h, B(OMe)3 (3.02 g, 29.0 mmol, 3.28 mL, 1 .4 eq) was added to the reaction mixture at -70 °C dropwise. After stirring at 20 °C for 1 h, the mixture was quenched by saturated ammonium chloride solution (50 mL) at 0 °C for 0.5 h, The pH was adjusted to around 3 by progressively adding 4N hydrochloric acid aqueous solution. The mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was triturated with toluene (30 mL) at 20 °C for 30 min to give (3-fluoro-6-methoxy- 2,4-dimethyl-phenyl)boronic acid (2.50 g, 12.6 mmol, 60% yield) as a white solid.

¹ H NMR (400 MHz, CDCb) 6 = 6.57 (d, J = 5.6 Hz, 1 H), 6.00 (s, 2H), 3.85 (s, 3H), 2.46 (d, J = 3.2 Hz, 3H), 2.29 (d, J = 2.0 Hz, 3H)

Intermediate 584

8~(341uara~6~methaxy-2,4-dimethyl~pheny!)pyridine~2 _! 3~diamii'ie

To a solution of (3-fluoro-6-methoxy-2,4-dimethyl-phenyl)boronic acid (2.00 g, 10.1 mmol, 1 eq), 6- chloropyridine-2,3-diamine (1.89 g, 13.1 mmol, 1 .3 eq) in CS2CO3 (6.58 g, 20.2 mmol, 2 eq) in dioxane (20 mL) and H2O (5 mL) was added Pd(dppf)Cl2 (369 mg, 505 pmol, 0.05 eq) at 20 °C in one portion under nitrogen atmosphere. After stirring at 90 °C for 16 h, the mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine (30 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 2/1 to 1/1) to give 6-(3-fluoro-6-methoxy-2,4-dimethyl-phenyl)pyridine-2,3-diami ne (320 mg, 991 pmol, 9.82% yield, 81 % purity) as a black brown solid.

^! H NMR (400 MHz, CDCb) 6 = 6.97 (d, J = 8.0 Hz, 1 H), 6.62-6.58 (m, 2H), 4.35-4.25 (m, 2H), 3.68 (s, 3H), 3.44-3.17 (m, 2H), 2.29 (d, J = 2.0 Hz, 3H), 2.01 (d, J = 2.8 Hz, 3H) LC-MS (Method C): R _t = 0.434; MS (ESI) m/z = 262.3 [M+H] ⁺ .

Intermediate 585

2-(5, S-diamino-2-pyndyl)-4-f!uoro-3, 5-dimethyl-phenol

To a solution of 6-(3-f!uoro-6-methoxy-2,4-dimethyl-phenyl)pyridine-2,3-diami ne (300 mg, 1.15 mmol, 1 eq) in dichloromethane (5 mL) was added BBrs (1.44 g, 5.74 mmol, 553 pL, 5 eq) at -70 °C under nitrogen atmosphene. After stirring at 20 °C for 1 h, the mixture was quenched by methanol (5 mL) at - 70 °C for 0.5 h, the pH was adjusted to around 9 by progressively adding NH3.H2O. The mixture was poured into water (10 mL) and extracted with dichioromethane (10 mL x 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous sodium suifate, filtered and filtrate was concentrated in vacuum to give 2-(5,6-diamino-2-pyridyl)-4-t1uoro-3,5-dimethyi-phenol (280 mg, crude) as a yellow solid.

Intermediate 586

To a solution of 2-(5,6-diamino-2-pyridyl)-4-fluoro-3,5-dimethyl-phenol (280 mg, 1.13 mmol, 1 eq) in ethanol (5 mL) was added tert-butyl (3R)-3-oxaldehydoylpiperidine-1-carboxylate (409 mg, 1.70 mmol, 1 .5 eq) at 20 °C in one portion. After stirring at 60 °C for 1 h, the mixture was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SIO ₂ , Petroleum ether/Ethyl acetate = 10/1 to 3/1) to give tert-butyl (3R)-3-[6-(3-f!uoro-6-hydroxy-2,4-dimethyl-phenyl)pyrido[2,3 - b]pyrazin-3-yl]piperidine-1 -carboxylate (220 mg, 393 pmol, 34% yield, 81 % purity) as a yellow solid. LC-MS (Method C): Rt = 0.603; MS (ESI) m/z = 453.2 [M+H] ⁺ .

Intermediate 587

4~fliJoro-3,5-diinetbyl-2'[3-[(3R)'3-pipeddyi]pyrido[2 _; 3-b]pyrazin-6-yl]phenol

To a solution of tert-butyl (3R)-3-[6-(3-fluoro-6-hydroxy-2,4-dimethyl-phenyl)pyrido[2,3 -b]pyrazin-3- yl]piperidine-1 -carboxylate (220 mg, 486 pmol, 1 eq) in dichioromethane (3 mL) was added TFA (767 mg, 6.73 mmol, 0,5 mL, 13 eq) at 20 °C in one portion. After stirring at 20 °C for 1 h, the mixture was concentrated in vacuum to give 4-fluoro-3,5-dimethyl-2-[3-[(3R)-3-piperidyl]pyrido[2,3-b]py razin-6- yl]phenol (170 mg, crude) as yellow oil.

LC-MS (Method C): Rt = 0.416; MS (ESI) m/z = 353.1 [M+HJ*.

Compound 233

4-fluoro-3 _! 5-dimethyl-2-[3-[(3R)-1-methyl-3-piperidyl]pyrido[2,3- b]pyrazin-6-yl]phenol

To a solution of 4-fluoro-3,5-dimethyi-2-[3-[(3R)-3-piperidyl]pyrido[2,3-b]py razin-6-yi]phenol (170 mg, 482 pmol, 1 eq) and potassium acetate (473 mg, 4.82 mmol, 10 eq) in MeOH (3 mL) was added paraformaldehyde (72.3 mg, 2.41 mmol, 5 eq) and NaBHsCN (90.9 mg, 1.45 mmol, 3 eq) at 20 °C in one portion. After stirring at 20 °C for 0.5 hour. The mixture was poured into ice-water (10 mL) and extracted with dichioromethane (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried with anhydrous sodium sulfate, filtered and filtrate was concentrated in vacuum to give a residue. The residue was purified by reversed-phase HPLC(0.1 % FA condition) to give 4-fluoro-3,5- dimethyl-2-[3-[(3R)-1-methyl-3-piperidyl]pyrido[2,3-b]pyrazi n-6-yl]phenol (75.77 mg, 200.58 pmol, 41 .58% yield, 97% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 6 [ppm] = 9.08 (s, 1 H), 8.51 (d, J = 8.4 Hz, 1 H), 8.23-8.16 (m, 1 H), 7.79 (d, J = 8.8 Hz, 1 H), 6.70 (d, J = 6.4 Hz, 1 H), 3.10-3.05 (m, 1 H), 2.85-2.80 (m, 1 H), 2.35-2.26 (m, 2H), 2.25 (s, 3H), 2.23 (s, 3H), 2.08-2.00 (m, 2H), 1.99 (d, J = 2.4 Hz, 3H), 1.80-1.73 (m, 1 H), 1.71-1.61 (m, 2H) LC-MS (Method C): Rt = 0.409; MS (ESQ m/z = 367.1 [M+H] ⁺ .

SFC (Rt = 1 .447, ee% = 80%)

Example 3 - Biological results

NLRP3 HTRF assay

The experiment was performed using the foilowing assay buffer: 50mM HEPES, 150mM NaCI, 5mM MgCI2, 0.5mM TCEP, 0.05% Tween, 0.1 mg/ mL BSA, 100uM ADP, pH 7.5. 5uL of the His tagged NLRP3 NACHT domain (1 ,25nM final concentration in the assay) was dispensed in a ProxiPlate-384 Plus (Perkin Elmer, ref 6008289), containing 30nL of inhibitors in 100% DMSO (0.3 % final DMSO in the assay). After a 1 min centrifugation at 1000 rpm, the plate was incubated 30min at room temperature, before addition of a 5uL mix containing a terbium labelled anti His tag antibody (Cisbio, ref 61 HI2TLB, 0.8 nM final concentration in the assay) and the HTRF probe (150nM final concentration in the assay). After a 1 min centrifugation at 1000 rpm, the plate was then incubated overnight at 4C, before reading on a plate reader Envision 2105 (Perkin Elmer). HTRF signals were measured with an excitation filter at 320 nm and fluorescence wavelength measurement at 615 and 665 nm, an integration delay of 60 ps and an integration time of 400 ps. Results were analysed with a two-wavelengths signal ratio: [intensity (665 nm)/intensity (615 nm)]*104.

Table 2: Biochemical data for representative compounds of the disclosure. EC50 refers to the concentration of compound required to achieve 50% of its maximal effect, in this case inhibition of speck/inflammasome formation.

The data has been binned in a category of A to C as indicated below dependent on the measured value.

For NLRP3 pEC50 assay: A means a measured pEC50 of >7.0;

B means a measured pEC50 of between 6 and 7;

C means active with a measured pEC50 of <6;

Modifications may be made to the above examples without departing from the scope of the present invention as defined in the accompanying claims.