CORONAVIRUS NON-STRUCTURAL PROTEIN 3 DEGRADING COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application 63/253,038 filed October 6, 2021, and U.S. Provisional Application 63/392,062 filed July 25, 2022, the entirety of each of which is incorporated by reference for all purposes. FIELD OF THE INVENTION This invention provides advantageous compounds that degrade a coronavirus non- structural protein 3 (NSP3), for example SARS-CoV-2 NSP3 for the treatment of a coronavirus in a host in need thereof. BACKGROUND In late 2019, a number of patients in Wuhan, China fell ill with symptoms similar to the SARS-CoV-1 outbreak of 2002-2003. In early 2020 the virus was identified as a novel coronavirus and was subsequently named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the resulting illness coronavirus disease 2019 (COVID-19). SARS-CoV-2 quickly spread across the world and on March 11, 2020, the World Health Organization (WHO) declared COVID-19 a global pandemic. SARS-CoV-2 can cause a wide range of symptoms ranging from mild, cold-like symptoms to severe hospitalization, ventilation, and even death. The virus may cause long-term damage to the lungs, heart, and brain. To date over six million lives have been claimed by COVID-19 and far more patients have been hospitalized. The high virulence of SARS-CoV-2, potentially fatal or permanent symptoms, and lack of effective treatments brought the world’s infrastructure to the point of high stress. The pandemic has now lasted for almost three years and new variants continue to develop and spread rapidly. Coronaviruses are enveloped viruses with a single-strand, positive-sense RNA genome. The genome of SARS-CoV-2 is among the largest known RNA viruses in the world and includes approximately 30 kilobases. SARS-CoV-2 is a coronavirus (CoV), which is in the order Nidovirales, family Coronaviridae, subfamily Coronavirinae. Related coronaviruses include: Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Bat SARS-like coronavirus WIV1 (Bat SL-CoV-WIVl), alpha coronaviruses 229E (HCoV-229E), New Haven coronavirus NL63 (HCoV-NL63), beta coronaviruses OC43 (HCoV-OC43), coronavirus HKIJ I (HCoV-HKU 1 ), and Middle East Respiratory Syndrome coronavirus (MERS-CoV). Compared to SARS-CoV and MERS-CoV, SARS-CoV-2 exhibits a faster human-to-human transmission rate (Huang et al., Lancet 2020, 395, 497), making it particularly dangerous and challenging to contain. CoVs are often enzootic, crossing the animal-human species barrier (Lau et al., PNAS 2005, 102, 14040-5; Rest et al., Infect Genet Evol. 2003, 3, 219-25). Cross-species barrier jumps are responsible for CoVs such as the SARS CoV and the Middle Eastern respiratory syndrome CoV (MERS) to manifest as virulent human viruses (Schoeman and Fielding, Virology 2019, 16, 69). Genome sequencing has revealed that SARS-CoV-2 is approximately 96% identical at the whole-genome level to a bat coronavirus (Zhou et al. Nature 2020, 579, 270) and therefore most likely originated in bats.

SARS-CoV-2 enters cells through endocytosis or fusion with the cell membrane by binding to angiotensin converting enzyme 2 (ACE2) receptors. Spike glycoproteins on the surface of the virus envelope then bind to the ACE2 receptor. The human transmembrane protease serine 2 cleaves and activates the spike protein (Luan et al. Biochem. Biophys. Res. Commun. 2020: 527, 165; Hoffman, M. et al. Cell, 2020, 181, 271; Yang et al. Int. J. Biol. Sci. 2020, 16, 1724). Once in the host’s cells SARS-CoV-2 replicates and spreads rapidly.

Dana-Farber Cancer Institute, Inc. filed a patent application published as WO 2022/081827 which describes the use of protein degraders to treat viral disorders including SARS-CoV-2. Kymera Therapeutics, Inc. has also described degraders for the treatment of SARS-CoV-2 in a patent application published as WO 2021/231778.

The University of Illinois and the University of Arizona published new NSP3 inhibitors in a paper titled “Design of SARS-CoV-2 PLpro Inhibitors for COVID-19 Antiviral Therapy Leveraging Binding Cooperativity” J. Med. Chem., CO VID-19 Special Issue October 19, 2021. These inhibitors and a few protein degradation compounds containing these inhibitors are described in WO 2022/169891, claiming priority to USSN 63/146,871 filed on February 8, 2021.

Patent applications filed by C4 Therapeutics, Inc., that describe compounds capable of binding to an E3 ubiquitin ligase and a target protein for degradation include: WO 2022/032026 titled “Advantageous Therapies For Disorders Mediated By Ikaros or Aiolos”; WO 2022/081925 titled “Tricyclic Ligands for Degradation of IKZF2 or IKZF4”; WO 2022/081927 titled “Tricyclic Compounds to Degrade Neosubstrates for Medical Use”; WO 2022/081928 titled “Tricyclic Heterobifunctional Compounds for Degradation of Targeted Proteins”; WO 2021/255212 titled “BRAF Degraders”; WO 2021/255213 titled “Heterobifunctional Compounds as Degraders of BRAF”; WO 2021/178920 titled “Compounds for Targeted Degradation of BRD9”; WO 2021/127561 titled “Isoindolinone And Indazole Compounds For The Degradation Of EGFR”; WO 2021/086785 titled “Bifunctional Compounds”; WO 2021/083949 titled “Bifunctional Compounds for the Treatment of Cancer”; WO 2020/210630 titled “Tricyclic Degraders of Ikaros and Aiolos”; WO 2020/181232 titled “Heterocyclic Compounds for Medical Treatment”; WO 2020/132561 titled “Targeted Protein Degradation”; WO 2019/236483 titled “Spirocyclic Compounds”; WO 2020/051235 titled “Compounds for the degradation of BRD9 or MTH1”; WO 2019/191112 titled “Cereblon binders for the Degradation of Ikaros”; WO 2019/204354 titled “Spirocyclic Compounds”; WO 2019/099868 titled “Degraders and Degrons for Targeted Protein Degradation”; WO 2018/237026 titled “N/O-Linked Degrons and Degronimers for Protein Degradation”; WO 2017/197051 titled “Amine-Linked C ₃ -Glutarimide Degronimers for Target Protein Degradation”; WO 2017/197055 titled “Heterocyclic Degronimers for Target Protein Degradation”; WO 2017/197036 titled “Spirocyclic Degronimers for Target Protein Degradation”; WO 2017/197046 titled “C ₃ -Carbon Linked Glutarimide Degronimers for Target Protein Degradation”; and WO 2017/197056 titled “Bromodomain Targeting Degronimers for Target Protein Degradation.”

Other patent applications that describe protein degrading compounds include:

WO 2015/160845; WO 2016/105518; WO 2016/118666; WO 2016/149668; WO 2016/197032;

WO 2016/197114; WO 2017/007612; WO 2017/011371; WO 2017/011590; WO 2017/030814;

WO 2017/046036; WO 2017/176708; WO 2017/176957; WO 2017/180417; WO 2018/053354;

WO 2018/071606; WO 2018/102067; WO 2018/102725; WO 2018/118598; WO 2018/119357;

WO 2018/119441; WO 2018/119448; WO 2018/140809; WO2018/144649; WO 2018/119448; WO 2018/226542; WO 2019/023553; WO 2019/195201; WO2019/199816; WO 2019/099926; WO 2019/195609; WO 2020/041331; WO 2020/051564; WO 2020/023851; W02020/200291; and WO2021/011634.

In light of the serious and potentially pandemic effect of coronaviruses it is an important health care goal to provide new therapeutic agents for their treatment. SUMMARY OF THE INVENTION

The present invention provides compounds and their compositions, uses and manufacture that cause degradation of a coronavirus non- structural protein 3 (NSP3) for example SARS-CoV- 2 NSP3. By degrading NSP3 a compound of the present invention can be administered in an effective amount to treat a patient with a coronavirus for example SARS-CoV-2 (also known as COVID19). In addition, compounds of the present invention exhibit antiviral activity.

It has been discovered that NSP3 is a useful protein target for the treatment of coronaviruses via targeted protein degradation. NSP3 is a key component for coronavirus replication. It is composed of various domains, the organization of which differs by genus. Despite its structural complexity, eight domains of the NSP3 complex are conserved between the various CoVs: the ubiquitin-like domain 1 (Ubll), the Glu-rich acidic domain (also called "hypervariable region"), a macrodomain (also named "X domain"), the ubiquitin-like domain 2 (Ubl2), the papainlike protease (PLpro), the NSP3 ectodomain (3Ecto, also called "zinc-finger domain"), as well as the domains Y1 and CoV-Y of unknown functions. Neuman, Antiviral Research, 135, 97-107, 2016.

NSP3 is essential to viral survival, displays evidence of multiple functions or scaffolding roles in the virus that can amplify the impact of NSP3 degrader action, the targeted domain of NSP3 diverges from human paralogs that might impact selectivity profiles, and there is structural evidence of conserved functional or surface-exposed binding sites for ligand discovery. Baez- Santos YM et al., Antiviral Research, 2015, 115, 21-38; O'Donoghue SI et al., Mol Syst Biol., 2021, 17(9); Lei J et al., Antiviral Research, 2018, 149, 58-74; and Shan H et al., Cell Chem Biol., 2021, 28(6), 855-865.

Ligands have been developed for the PLpro domain of NSP3. This domain includes a cysteine protease that mediates viral replication by processing of viral polyproteins, in addition to being an essential protease in the formation of the replicase transcriptase complex (RTC). PLpro also functions as a deubiquitinase and a delSGylase, acting as a major antagonist to host immune response by interfering with IRF3/NF-kB activation and IFN antiviral signaling via de- ubiquitination (DUB). Specifically, PLpro cleaves the isopeptide bond that ligates ubiquitin (Ub) and ubiquitin-like proteins (UbL) such as interferon-stimulated gene product 15 (ISG15) to lysine sidechains of host proteins Barretto et. al. Journal of Virology, 79(24), 15189-98, 2005. Non- limiting examples of NSP3 ligands include those described in Shen et al. “Potent, Novel SARS- CoV-2 PLpro Inhibitors Block Viral Replication in Monkey and Human Cell Cultures” preprint doi.org/10.1101/2021.02.13.431008. Additional NSP3 ligands are described in Santos et al., J. Med. Chem., 2014, 57, 2393-2412.

It has been discovered that compounds that contain a selected E3 Ligase Ligand linked through a linking moiety to a NSP3 Targeting Ligand can degrade NSP3 and stop viral replication. By degrading NSP3 instead of simply inhibiting it, the compounds of the present invention can act catalytically on NSP3 and thus offer advantages in the treatment of SARS-CoV-2 (COVID19) compared to treatment with an NSP3 inhibitor by itself. Further, because the PLpro domain of NSP3 is partially conserved throughout coronaviruses the degradation of NSP3 by targeting PLpro may provide robust treatment of SARS-CoV-2 variants, other coronaviruses, or future coronaviruses that have not yet been discovered.

In certain embodiments a compound of the present invention is used to treat a coronavirus variant for example a SARS-CoV-2 variants selected from alpha, beta, gamma, delta, epsilon, eta, iota, kappa, mu, omicron, and zeta. Non limiting examples of SARS-CoV-2 alpha variants include B.1.1.7 and Q.1-Q.8. Non limiting examples of SARS-CoV-2 beta variants include B.1.351, B.1.351.2, and B.1.351.3. Non limiting examples of SARS-CoV-2 gamma variants include P.l, P.1.1, and P.1.2. Non limiting examples of SARS-CoV-2 delta variants include B.1.617.2 and AY.1. Non limiting examples of SARS-CoV-2 epsilon variants include B.1.427 and B.1.429. Non limiting examples of SARS-CoV-2 eta variants include B. 1.525. Non limiting examples of SARS- CoV-2 iota variants include B.1.526. Non limiting examples of SARS-CoV-2 kappa variants include B.1.617.1. Non limiting examples of SARS-CoV-2 mu variants include B.1.621 and B.1.621.1. Non limiting examples of SARS-CoV-2 zeta variants include P.2. Non limiting examples of SARs-CoV2 omicron variants include B.1.1.529 and sub-lineage variants BA.l, BA.2, BA.2.12.1, BA.2.75, BA.3, BA.4, and BA.5.

In certain embodiments a compound of the present invention is used to treat a coronavirus other than SARS-CoV-2. Additional examples of coronaviruses include: Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Bat SARS-like coronavirus WIV1 (Bat SL-CoV-WIVl), alpha coronaviruses 229E (HCoV-229E), New Haven coronavirus NL63 (HCoV-NL63), beta coronaviruses OC43 (HCoV-OC43), coronavirus HKIJ I (HCoV-HKU 1), and Middle East Respiratory Syndrome coronavirus (MERS-CoV). In certain embodiments a compound of the present invention is used to treat a new coronavirus that has not yet been discovered or has not infected an appreciable number of people.

The compounds of the present invention include a NSP3 Targeting Ligand, a heterocyclic moiety, and a Linker that links them. More specifically a compound of Formula A is provided: or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition; wherein:

Heterocyclic Moiety is selected from: , or S;

X ³ , X ⁴ , X ⁵ , and X ⁶ are independently selected from N, CH, and CR ⁵ , wherein one of X ³ , X ⁴ , X ⁵ , and X ⁶ is a carbon atom that is attached to Linker; R ¹ , R ³ , R ⁴ , and R ⁶ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R ³ and R ⁴ together with the carbon to which they are bound form a 3-, 4-, 5-, or 6- membered spirocarbocycle, a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N, O, and S, or an oxo group; or R ¹ and R ⁶ are combine together to form a 1 or 2-carbon bridge; for example or R ¹ and R ³ are combine together to form a 3-6 membered fused ring; for example each R ² is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and -C(O)R ⁹ , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ ; each R ⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR ⁷ R ⁸ , -OR ⁷ , -SR ⁷ , -C(O)R ⁹ , -C(S)R ⁹ , -S(O)R ⁹ , -S(O) ₂ R ⁹ , -OC(O)R ⁹ , -OC(S)R ⁹ , -OS(O)R ⁹ , -OS(O) ₂ R ⁹ , -SC(O)R ⁹ , -OS(O) ₂ R ⁹ ,

-NR ⁷ C(O)R ⁹ , -NR ⁷ C(S)R ⁹ , -NR ⁷ S(O)R ⁹ , -NR ⁷ S(O) ₂ R ⁹ , -P(O)(R ⁹ ) ₂ , -SP(O)(R ⁹ ) ₂ , -NR ⁷ P(O)(R ⁹ ) ₂ , and -OP(O)(R ⁹ ) ₂ ; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ ;

independently selected from R ⁵ ; independently selected from R ⁵ ; and each of which R ¹⁸ is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁵ ; for example includes but does not include

Cycle is a fused aryl or heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁵ and substituted with one R ¹² substituent;

Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1,

2, 3, or 4 substituents independently selected from R ⁵ and substituted with one R ¹² substituent;

R ¹² is the attachment point to Linker;

R ⁷ and R ⁸ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R ¹⁴ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ ; each R ⁹ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR ⁷ R ⁸ , -OR ⁷ , and -SR ⁷ each of which is optionally substituted with 1, 2,

3, or 4 substituents independently selected from R ¹⁰ ; each R ¹⁰ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR ¹¹ R ¹³ , -OR ¹¹ , -SR ¹¹ , -C(O)R ¹⁴ , -C(S)R ¹⁴ , -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -OC(O)R ¹⁴ , -OC(S)R ¹⁴ , -OS(O)R ¹⁴ , -OS(O) ₂ R ¹⁴ , -NR ¹¹ C(O)R ¹⁴ , -NR ¹¹ C(S)R ¹⁴ , -NR ¹¹ S(O)R ¹⁴ , -NR ¹¹ S(O) ₂ R ¹⁴ , -P(O)(R ¹⁴ ) ₂ , -NR ¹¹ P(O)(R ¹⁴ ) ₂ , and -OP(O)(R ¹⁴ ) ₂ ; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁵ ;

R ¹¹ and R ¹³ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R ¹⁴ , -C(S)R ¹⁴ , -S(O)R ¹⁴ ,

-S(O) ₂ R ¹⁴ , and -P(O)(R ¹⁴ ) ₂ ; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁵ ; each R ¹⁴ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)2 each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁵ ; each R ¹⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)2;

Linker is a bivalent chemical group;

NSP3 Targeting Ligand is selected from:

y is 0 or 1;

Fused Cycle is a fused aryl, heteroaryl, cycloalkyl, or heterocycle group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁵ ;

X ¹⁶ is selected from

X ¹⁷ is selected from CR ³³ R ³⁴ , C(O), C(S), S(O), and S(O) ₂ ;

X ¹⁸ is selected from CR ³⁰ , CH, and N; each x is independently 0, 1, 2, 3, or 4;

X ⁸ , X ⁹ , X ¹⁰ , X ¹¹ , X ¹² , X ¹³ , X ¹⁴ , and X ¹⁵ are independently selected from N, CH, and CR ²⁸ ; or X ⁸ , X ⁹ , X ¹⁰ , X ¹¹ , X ¹² , X ¹³ , X ¹⁴ , and X ¹⁵ are independently selected from N, CH, and CR ²⁸ wherein no more than three of X ⁸ , X ⁹ , X ¹⁰ , X ¹¹ , X ¹² , X ¹³ , X ¹⁴ , and X ¹⁵ are N; in certain embodiments no more than two of X ⁸ , X ⁹ , X ¹⁰ , X ¹¹ , X ¹² , X ¹³ , X ¹⁴ , and X ¹⁵ are N; in certain embodiments only one of X ⁸ , X ⁹ , X ¹⁰ , X ¹¹ , X ¹² , X ¹³ , X ¹⁴ , and X ¹⁵ are N;

R ²⁷ is selected from , and , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²⁹ ; each R ²⁸ , R ²⁹ , and R ³⁰ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR ⁷ R ⁸ , -OR ⁷ , -SR ⁷ , -C(O)R ⁹ , - C(S)R ⁹ , -S(O)R ⁹ , -S(O) ₂ R ⁹ , -OC(O)R ⁹ , -OC(S)R ⁹ , -OS(O)R ⁹ , -OS(O) ₂ R ⁹ , -SC(O)R ⁹ , -OS(O) ₂ R ⁹ , -NR ⁷ C(O)R ⁹ , -NR ⁷ C(S)R ⁹ , -NR ⁷ S(O)R ⁹ , -NR ⁷ S(O) ₂ R ⁹ , -P(O)(R ⁹ ) ₂ , -SP(O)(R ⁹ ) ₂ , -NR ⁷ P(O)(R ⁹ ) ₂ , and -OP(O)(R ⁹ ) ₂ ; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ ; each R ³¹ , R ³² , R ³³ , and R ³⁴ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -C(O)R ⁹ , -C(S)R ⁹ , -S(O)R ⁹ , -S(O) ₂ R ⁹ , -OC(O)R ⁹ , -OC(S)R ⁹ , -OS(O)R ⁹ , -OS(O) ₂ R ⁹ , -SC(O)R ⁹ ,

-OS(O) ₂ R ⁹ , -NR ⁷ C(O)R ⁹ , -NR ⁷ C(S)R ⁹ , -NR ⁷ S(O)R ⁹ , -NR ⁷ S(O) ₂ R ⁹ , -P(O)(R ⁹ ) ₂ , -SP(O)(R ⁹ ) ₂ , -NR ⁷ P(O)(R ⁹ ) ₂ , and -OP(O)(R ⁹ ) ₂ ; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents indep

In certain embodiments Linker is selected from wherein: X ¹ and X ² are independently at each occurrence selected from bond, heterocycle, NR ² , C(R ² ) ₂ , O, C(O), and S;

R ²⁰ , R ²¹ , R ²² , R ²³ , and R ²⁴ are independently at each occurrence selected from the group consisting of bivalent moieties selected from bond alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR ² -, -NR ² C(O)-, -O-, -S-, -NR ² -, -C(R ⁴⁰ R ⁴⁰ )-, -P(O)(OR ²⁶ )O-,

-P(O)(OR ²⁶ )-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ ;

R ²⁶ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; and

R ⁴⁰ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl)2, -NHSO2(aliphatic, including alkyl), -N(aliphatic, including alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocycle), -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSChalkenyl, -N(alkyl)SO2alkenyl, -NHSChalkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, and cycloalkyl.

In certain embodiments the NSP3 Targeting Ligand is selected from:

In certain embodiments the NSP3 Targeting Ligand is selected from: In certain aspects a compound of Formula B is provided: or a pharmaceutically acceptable salt, N-oxide , isotopic derivative, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition; wherein: Heterocyclic Moiety is In certain embodiments NSP3 Targeting Ligand ^B is selected from:

In certain aspects a compound of Formula C or Formula D is provided:

or a pharmaceutically acceptable salt, N-oxide , isotopic derivative, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition; wherein: NSP3 Targeting Ligand ^c is selected from:

In certain embodiments, the compound of the present invention provides multiple advantages over traditional antiviral treatment of a coronavirus for example SARS CoV-2. For example a NSP3 degrading compound of the present invention may a) overcome resistance in certain cases; b) prolong the kinetics of drug effect by destroying the protein, thus requiring resynthesis of the protein even after the compound has been metabolized; c) target all functions of the protein at once rather than a specific catalytic activity or binding event; d) require a smaller dose; e) require less frequent dosing; f) require a shorter dosing period; g) cause fewer side effects; and/or h) have increased potency compared to traditional antiviral agents due to the possibility of the compound of the present invention acting catalytically.

In one aspect, a compound of the present invention includes a NSP3 Targeting Ligand that reversibly, non-covalently binds with moderate potency (Kd < 1 pM).

Variables within the formulas described herein are selected such that the resulting compound is sufficiently stable for example stable enough to maintain a shelf life of at least two, three, four, or five months under ambient conditions. One of ordinary skill in the art is well aware of the stability of chemical moieties and can avoid those that are not stable or are too reactive under appropriate conditions. Also, all R groups, with or without optional substituents, should be interpreted in a manner that does not include redundancy (i.e., as known in the art, alkyl substituted with alkyl is redundant; however, for example, alkoxy substituted with alkoxy is not redundant and aryl substituted with aryl is also not redundant).

A compound of the present invention or its pharmaceutically acceptable salt and/or its pharmaceutically acceptable composition thereof can be used to treat a coronavirus, for example SARS CoV-2. Therefore, in some embodiments a method to treat a host with SARS CoV-2 is provided that includes administering an effective amount of the compound of the present invention or its pharmaceutically acceptable salt to a patient in need thereof, typically a human, optionally in a pharmaceutically acceptable composition.

In certain embodiments, a compound of the present invention has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. In one embodiment, the compound of the present invention includes a deuterium or multiple deuterium atoms.

Compounds of the present invention may offer important clinical benefits to patients, in particular for the rapid treatment of SARS CoV-2 infection.

Other features and advantages of the present application will be apparent from the following detailed description and claims.

The present invention thus includes at least the following features:

(a) A compound of the present invention, or a pharmaceutically acceptable salt, isotopic derivative (including a deuterated derivative), or prodrug thereof;

(b) A compound of the present invention, or a pharmaceutically acceptable salt, isotopic derivative (including a deuterated derivative), or prodrug thereof for the treatment of a coronavirus;

(c) A method of treating a coronavirus comprising administering an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, isotopic derivative (including a deuterated derivative), or prodrug thereof to a patient in need thereof;

(d) Use of a compound of the present invention in an effective amount in the treatment of a patient, typically a human, with a coronavirus;

(e) Use of a compound of the present invention in an effective amount in the manufacture of a medicament to treat of a patient, typically a human, with a coronavirus;

(f) A pharmaceutical composition comprising an effective host-treating amount of a compound of the present invention, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof together and a pharmaceutically acceptable carrier;

(g) A compound of the present invention as a mixture of enantiomers or diastereomers (as relevant), including as a racemate; (h) A compound of the present invention in an enantiomerically or diastereomerically (as relevant) enriched form, including an isolated enantiomer or diastereomer (i.e., greater than 85, 90, 95, 97, or 99% pure); and

(i) A process for the preparation of a therapeutic product that contains an effective amount of a compound of the present invention.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 is a line graph showing the degradation of NSP3 in cereblon positive and cereblon negative HEK293 cell lines. The cells were incubated with varying concentrations of Compound 5. The HEK293 cells were incubated for 6 hours. The x-axis is concentration measured in nanomolarity and the y-axis is % response. The experimental procedure is provided in Example 216.

FIG. 2A and FIG. 2B are line graphs showing cell viability in the presence of Compound 5 in cereblon positive and cereblon negative HEK293 cell lines. The cells were incubated with varying concentrations of Compound 5. The HEK293 cells were incubated for 6 or 24 hours. The x-axis is concentration measured in nanomolarity and the y-axis is % response. The experimental procedure is provided in Example 217.

FIG. 3 is a line graph showing the proportion of NSP3 in a ternary complex with cereblon and Compound 5. The cells were incubated with varying concentrations of Compound 5. The x- axis is concentration measured in nanomolarity and the y-axis is fraction of ternary complex formed. The experimental procedure is provided in Example 218.

FIG. 4 is a line graph showing the degradation of NSP3 by Compound 24 in NSP3 UBL2_PLpro-HA HiBiT 293T cell lines. The cells were incubated with varying concentrations of Compound 24 for 6 hours and 24 hours. The x-axis is concentration measured in micromolarity and the y-axis is % response (Emax). The experimental procedure is provided in Example 216.

FIG. 5 is a line graph showing mean plasma concentrations versus time (hours) profile of Compound 92 after IV (1 mg/kg) and PO (10 mg/kg) administration in male ICR-CD1 mice. The experimental procedure and related results are provided in Example 219.

FIG. 6 is a line graph showing mean plasma concentrations versus time (hours) profile of Compound 93 after IV (1 mg/kg) and PO (10 mg/kg) administration in male ICR-CD1 mice. The experimental procedure and related results are provided in Example 219. FIG. 7 depicts Formula A of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

I. DEFINITIONS

Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

The compounds in any of the Formulas described herein may be in the form of a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, A-oxide, isomer; such as rotamer, as if each is specifically described unless specifically excluded by context.

The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term “or” means “and/or”. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed.

The present invention includes a compound of the present invention with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.

Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ¹⁸ F ³¹ P, ³² P, ³⁵ S, ³⁶ C1, and ¹²⁵ I respectively. In one nonlimiting embodiment, isotopically labelled compounds can be used in metabolic studies (with, for example ¹⁴ C), reaction kinetic studies (with, for example ² H or ³ H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an ¹⁸ F labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. In certain embodiments the isotopic substitution occurs on one or more variables selected from Heterocyclic Moiety, Linker, NSP3 Targeting Ligand, Cycle, Fused Cycle, Spirocycle, Q, X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁸ , X ⁹ , X ¹⁰ , X ¹¹ , X ¹² , X ¹³ , X ¹⁴ , X ¹⁵ , X ¹⁶ , X ¹⁷ , X ¹⁸ R ⁴ R ² R ³ R ⁴ R ⁵ R ⁶ R ⁷ R ⁸ R ⁹ R ⁴⁰ R ⁴⁴ R ⁴² R ⁴³ R ⁴⁴ R ⁴⁵ R ⁴⁶ R ⁴⁷ R ⁴⁸ R ²⁰ R ²⁴ R ²² R ²³ R ²⁴ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³⁴ , R ³² , R ³³ , R ³⁴ , R ³⁶ , and R ⁴⁰ .

Isotopic substitutions, for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain embodiments, the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In one non-limiting embodiment, deuterium is 90, 95 or 99% enriched at a desired location.

In one non-limiting embodiment, the substitution of a hydrogen atom for a deuterium atom can be provided in any compound of the present invention. In one non-limiting embodiment, the substitution of a hydrogen atom for a deuterium atom occurs within one or more groups selected from any of R’s or variables described herein, Linker, and NSP3 Targeting Ligand. For example, when any of the groups are, or contain for example through substitution, methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3 etc ). In certain other embodiments, when two substituents are combined to form a cycle the unsubstituted carbons may be deuterated.

The compound of the present invention may form a solvate with a solvent (including water). Therefore, in one non-limiting embodiment, the invention includes a solvated form of the compound. The term "solvate" refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a compound of the invention and water. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent may be isotopically substituted, e.g. D ₂ O, de-acetone, de-DMSO (dimethyl sulfoxide). A solvate can be in a liquid or solid form.

A dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(C=O)NH2 is attached through carbon of the carbonyl (C=O) group.

“Alkyl” is a branched or straight chain saturated aliphatic hydrocarbon group. In one nonlimiting embodiment, the alkyl group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one non-limiting embodiment, the alkyl contains from 1 to about 8 carbon atoms. In certain embodiments, the alkyl is C ₁ -C ₂ , C ₁ -C ₃ , C ₁ -C ₄ , C ₁ -C ₅ , or C ₁ -C ₆ . The specified ranges as used herein indicate an alkyl group having each member of the range described as an independent species. For example, the term C ₁ - G> alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species and therefore each subset is considered separately disclosed. For example, the term C ₁ -C ₄ alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t- butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3 -methylpentane, 2,2- dimethylbutane, and 2,3-dimethylbutane. In an alternative embodiment, the alkyl group is optionally substituted. The term “alkyl” also encompasses cycloalkyl or carbocyclic groups. For example, when a term is used that includes “alk” then “cycloalkyl” or “carbocyclic” can be considered part of the definition, unless unambiguously excluded by the context. For example, and without limitation, the terms alkyl, alkoxy, haloalkyl, etc., can all be considered to include the cyclic forms of alkyl, unless unambiguously excluded by context.

In one embodiment “alkyl” is a C ₁ -C ₁₀ alkyl, C ₁ -C ₉ alkyl, C ₁ -C ₈ alkyl, C ₁ -C ₇ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₅ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₃ alkyl, or C ₁ -C ₂ alkyl.

In one embodiment “alkyl” has one carbon.

In one embodiment “alkyl” has two carbons.

In one embodiment “alkyl” has three carbons.

In one embodiment “alkyl” has four carbons.

In one embodiment “alkyl” has five carbons. In one embodiment “alkyl” has six carbons.

Non-limiting examples of “alkyl” include: methyl, ethyl, propyl, butyl, pentyl, and hexyl.

Additional non-limiting examples of “alkyl” include: isopropyl, isobutyl, isopentyl, and isohexyl.

Additional non-limiting examples of “alkyl” include: sec-butyl, sec-pentyl, and sec-hexyl.

Additional non-limiting examples of “alkyl” include: tert-butyl, tert-pentyl, and tert-hexyl.

Additional non-limiting examples of “alkyl” include: neopentyl, 3 -pentyl, and active pentyl.

In an alternative embodiment “alkyl” is “optionally substituted” with 1, 2, 3, or 4 substituents.

In one embodiment “cycloalkyl” is a Cs-C ₈ cycloalkyl, C ₃ -C ₇ cycloalkyl, Cs-C ₆ cycloalkyl, Cs-C ₅ cycloalkyl, C ₃ -C ₄ cycloalkyl, Cx-Cxcycloalkyl, C ₅ -C ₈ cycloalkyl, or C ₆ -C ₈ cycloalkyl.

In one embodiment “cycloalkyl” has three carbons.

In one embodiment “cycloalkyl” has four carbons.

In one embodiment “cycloalkyl” has five carbons.

In one embodiment “cycloalkyl” has six carbons.

In one embodiment “cycloalkyl” has seven carbons.

In one embodiment “cycloalkyl” has eight carbons.

In one embodiment “cycloalkyl” has nine carbons.

In one embodiment “cycloalkyl” has ten carbons.

Non-limiting examples of “cycloalkyl” include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

Additional non-limiting examples of “cycloalkyl” include dihydro-indene and tetrahydronaphthalene wherein the point of attachment for each group is on the cycloalkyl ring.

For example: s an “cycloalkyl” group.

However, group. In an alternative embodiment “cycloalkyl” is a “optionally substituted” with 1, 2, 3, or 4 substituents.

“Alkenyl” is a linear or branched aliphatic hydrocarbon groups having one or more carboncarbon double bonds that may occur at a stable point along the chain. The specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkenyl radicals include, but are not limited to ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The term “alkenyl” also embodies “cis” and “trans” alkenyl geometry, or alternatively, “E” and “Z” alkenyl geometry. In an alternative embodiment, the alkenyl group is optionally substituted. The term “Alkenyl” also encompasses cycloalkyl or cycloalkyl groups possessing at least one point of unsaturation. In an alternative embodiment “alkenyl” is “optionally substituted” with 1, 2, 3, or 4 substituents.

“Alkynyl” is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain. The specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1 -pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. In an alternative embodiment, the alkynyl group is optionally substituted. The term “Alkynyl” also encompasses cycloalkyl or cycloalkyl groups possessing at least one triple bond. In an alternative embodiment “alkynyl” is “optionally substituted” with 1, 2, 3, or 4 substituents.

“Alkylene” is a bivalent saturated hydrocarbon. Alkylenes, for example, can be a 1, 2, 3, 4, 5, 6, 7 to 8 carbon moiety, 1 to 6-carbon moiety, or an indicated number of carbon atoms, for example C ₁ -C ₂ alkylene, C ₁ -C ₃ alkylene, C ₁ -C ₄ alkylene, C ₁ -C ₅ alkylene, or C ₁ -C ₆ alkylene.

“Alkenylene” is a bivalent hydrocarbon having at least one carbon-carbon double bond. Alkenylenes, for example, can be a 2 to 8 carbon moiety, 2 to 6-carbon moiety, or an indicated number of carbon atoms, for example C ₂ -C ₄ alkenylene.

“Alkynylene” is a bivalent hydrocarbon having at least one carbon-carbon triple bond. Alkynylenes, for example, can be a 2 to 8 carbon moiety, a 2 to 6-carbon moiety, or an indicated number of carbon atoms, for example C ₂ -C ₄ alkynylene.

“Halo” and “Halogen” refers independently to fluorine, chlorine, bromine or iodine. “Haloalkyl” is a branched or straight-chain alkyl groups substituted with 1 or more halo atoms described above, up to the maximum allowable number of halogen atoms. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and di chloropropyl. “Perhaloalkyl” means an alkyl group having all hydrogen atoms replaced with halogen atoms. Examples include but are not limited to, trifluoromethyl and pentafluoroethyl.

In one embodiment “haloalkyl” is a C ₁ -C ₁₀ haloalkyl, C ₁ -C ₉ haloalkyl, C ₁ -C ₈ haloalkyl, C ₁ - C ₇ haloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₅ haloalkyl, C ₁ -C ₄ haloalkyl, C ₁ -Cshaloalkyl, and C ₁ - C ₂ haloalkyl.

In one embodiment “haloalkyl” has one carbon.

In one embodiment “haloalkyl” has one carbon and one halogen.

In one embodiment “haloalkyl” has one carbon and two halogens.

In one embodiment “haloalkyl” has one carbon and three halogens.

In one embodiment “haloalkyl” has two carbons.

In one embodiment “haloalkyl” has three carbons.

In one embodiment “haloalkyl” has four carbons.

In one embodiment “haloalkyl” has five carbons.

In one embodiment “haloalkyl” has six carbons.

Non-limiting examples of “haloalkyl” include:

Additional non-limiting examples of “haloalkyl” include:

Additional non-limiting examples of “haloalkyl” include: an

Additional non-limiting examples of “haloalkyl” include:

2 , and “Chain” indicates a linear chain to which ah other chains, long or short or both, may be regarded as being pendant. Where two or more chains could equally be considered to be the main chain, “chain” refers to the one which leads to the simplest representation of the molecule.

“Haloalkoxy” indicates a haloalkyl group as described herein attached through an oxygen bridge (oxygen of an alcohol radical).

“Heterocycloalkyl” is an alkyl group as described herein substituted with a heterocyclo group as described herein.

“Arylalkyl” is an alkyl group as described herein substituted with an aryl group as described herein.

Non-limiting examples of “arylalkyl” include:

In one embodiment the “arylalkyl” refers to a 2-carbon alkyl group substituted with an aryl group.

Non-limiting examples of “arylalkyl” include:

In one embodiment the “arylalkyl” refers to a 3 -carbon alkyl group substituted with an aryl group.

“Heteroarylalkyl” is an alkyl group as described herein substituted with a heteroaryl group as described herein.

As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g, bicyclic or tricyclic) 4n+2 aromatic ring system (e.g, having 6, π0, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C ₆ -14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C ₆ aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C ₁₀ aryl”; e.g., naphthyl such as 1- naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“Ci4 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocycle groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. The one or more fused carbocyclyl or heterocycle groups can be 4 to 7 or 5 to 7-membered saturated or partially unsaturated carbocyclyl or heterocycle groups that optionally contain 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron, to form, for example, a 3,4- methylenedioxyphenyl group. In one non-limiting embodiment, aryl groups are pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In an alternative embodiment, the aryl group is optionally substituted as described above. In certain embodiments, the aryl group is an unsubstituted C ₆ -14 aryl. In certain embodiments, the aryl group is a substituted C ₆ -i4 aryl. An aryl group may be optionally substituted with one or more functional groups that include but are not limited to, halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and heterocyclo.

In one embodiment “aryl” is a 6-carbon aromatic group (phenyl).

In one embodiment “aryl” is a 10-carbon aromatic group (napthyl).

In one embodiment “aryl” is a 6-carbon aromatic group fused to a heterocycle wherein the point of attachment is the aryl ring. Non-limiting examples of “aryl” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the aromatic ring.

For example, is an “aryl” group.

However, i _{s a} “heterocycle” group.

In one embodiment “aryl” is a 6-carbon aromatic group fused to a cycloalkyl wherein the point of attachment is the aryl ring. Non-limiting examples of “aryl” include dihydro-indene and tetrahydronaphthalene wherein the point of attachment for each group is on the aromatic ring.

For example, is an “aryl” group. However, is a “cycloalkyl” group.

In an alternative embodiment “aryl” is “optionally substituted” with 1, 2, 3, or 4 substituents.

The term “heterocyclyl”, “heterocycle”, and “heterocyclo” includes saturated, and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. This term should not be confused with the capitalized term “Heterocyclic Moiety” that is in the present invention and separately defined. Heterocyclic rings comprise monocyclic 3, 4, 5, 6, 7, 8, 9, or 10 membered rings, as well as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 membered bicyclic ring systems (which can include bridged fused and spirofused bicyclic ring systems). It does not include rings containing -O-O-.-O-S- or -S-S- portions. Said “heterocycle” group may be optionally substituted, for example, with 1, 2, 3, 4 or more substituents that include but are not limited to, hydroxyl, Boc, halo, haloalkyl, cyano, alkyl, aralkyl, oxo, alkoxy, and amino. Examples of saturated heterocyclo groups include saturated 3, 4, 5, or 6-membered heteromonocyclic groups containing 1, 2, 3, or 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3, 4, 5, or 6-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms [e.g. morpholinyl]; saturated 3, 4, 5, or 6-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocycle radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclo groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3 -dihydrobenzofl, 4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2, 3, 4- tetrahydro-isoquinolyl, 1 ,2,3,4- tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7- trihydro-1, 2,4- triazolo[3,4-α]isoquinolyl, 3,4-dihydro-2H-benzo[l,4]oxazinyl, benzofl, 4]dioxanyl, 2,3- dihydro- lH-lλ.’-benzo[ d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl, , isoquinolin- l(2H)-onyl, benzo[d]oxazol-2(3H)-onyl, l,3-dihydro-2H-benzo[d]midazol-2-onyl, benzo[d]thiazole-2(3H)- onyl, l,2-dihydro-3H-pyrazol-3-onyl, 2(1H)-pyridinonyl, 2-piperazinonyl, indolinyl, and dihydrothiazolyl. The term “heterocyclyl”, “heterocycle”, and “heterocyclo” groups also include moieties where heterocycle radicals are fused/condensed with aryl or heteroaryl radicals: such as unsaturated condensed heterocycle group containing 1, 2, 3, 4, or 5 nitrogen atoms, for example, indoline, isoindoline, unsaturated condensed heterocycle group containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms, unsaturated condensed heterocycle group containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen atoms, and saturated, partially unsaturated and unsaturated condensed heterocycle group containing 1 or 2 oxygen or sulfur atoms.

In one embodiment “heterocycle” refers to a cyclic ring with one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocycle” refers to a cyclic ring with one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocycle” refers to a cyclic ring with two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocycle” refers to a cyclic ring with one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocycle” refers to a cyclic ring with one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms.

Non-limiting examples of “heterocycle” include aziridine, oxirane, thiirane, azetidine, 1,3- diazetidine, oxetane, and thietane.

Additional non-limiting examples of “heterocycle” include pyrrolidine, 3 -pyrroline, 2- pyrroline, pyrazolidine, and imidazolidine.

Additional non-limiting examples of “heterocycle” include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3 -oxathiolane.

Additional non-limiting examples of “heterocycle” include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

Additional non-limiting examples of “heterocycle” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the heterocycle ring.

For example, group. However, group.

Non-limiting examples of “heterocycle” also include:

Additional non-limiting examples of “heterocycle” include:

Additional non-limiting examples of “heterocycle” include:

Non-limiting examples of “heterocycle” also include: Non-limiting examples of “heterocycle” also include:

Additional non-limiting examples of “heterocycle” include:

Additional non-limiting examples of “heterocycle” include: In an alternative embodiment “heterocycle” is “optionally substituted” with 1, 2, 3, or 4 substituents.

The term “heteroaryl” denotes a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 it electrons shared in a cyclic array) and 1, 2, 3, 4, 5, or 6, heteroatoms independently selected from O, N, and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quartemized. Examples include, but are not limited to, unsaturated 5 to 6 membered heteromonocyclyl groups containing 1, 2, 3, or 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 477-1,2,4-triazolyl, 1H-1 ,2,3-triazolyl, 277-1,2,3- triazolyl]; unsaturated 5- or 6-membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5- or 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5- oxadiazolyl]; unsaturated 5 or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl], Additional examples include 8-, 9-, or 10-membered heteroaryl bicyclic groups such as indazolyl, indolyl, imidazo[l,5-a]pyridinyl, benzimidazolyl, 4(377)-quinazolinonyl, quinolinyl, isoquinolinyl, isoindolyl, thienothienyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzoxazolyl, benzothiazolyl, purinyl, coumarinyl, cinnolinyl, and tri azol opyridinyl.

In one embodiment “heteroaryl” is a 5 membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.

Non-limiting examples of 5 membered “heteroaryl” groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.

Additional non-limiting examples of 5 membered “heteroaryl” groups include:

In one embodiment “heteroaryl” is a 6 membered aromatic group containing 1, 2, or 3 nitrogen atoms (i.e. pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl). Non-limiting examples of 6 membered “heteroaryl” groups with 1 or 2 nitrogen atoms include:

In one embodiment “heteroaryl” is a 9 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

Non-limiting examples of “heteroaryl” groups that are bicyclic include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzooxazole, and benzothiazole.

Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: Additional non-limiting examples of “heteroaryl” groups that are bicyclic include:

In one embodiment “heteroaryl” is a 10 membered bicyclic aromatic group containing 1 or

2 atoms selected from nitrogen, oxygen, and sulfur.

Non-limiting examples of “heteroaryl” groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

Additional non-limiting examples of “heteroaryl” groups that are bicyclic include:

In an alternative embodiment “heteroaryl” is “optionally substituted” with 1, 2, 3, or 4 substituents.

The term “bicycle” refers to a ring system wherein two rings are fused together and each ring is independently selected from carbocycle, heterocycle, aryl, and heteroaryl. Non-limiting examples of bicycle groups include:

When the term “bicycle” is used in the context of a bivalent residue such as Linker the attachment points can be on separate rings or on the same ring. In certain embodiments both attachment points are on the same ring. In certain embodiments both attachment points are on different rings. Non-limiting examples of bivalent bicycle groups include:

In an alternative embodiment “bicycle” is “optionally substituted” with 1, 2, 3, or 4 substituents. The term “optionally substituted” denotes the substitution of a group herein by a moiety including, but not limited to, C ₁ -C ₁₀ alkyl, C ₂ -C10 alkenyl, C ₂ -C10 alkynyl, C ₃ -C12 cycloalkyl, C ₃ - C12 cycloalkenyl, C ₁ -C12 heterocycloalkyl, C ₃ -C12 heterocycloalkenyl, C ₁ -C10 alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C ₁ -C10 alkylamino, C ₁ -C10 dialkylamino, arylamino, diarylamino, C ₁ -C10 alkyl sulfonamino, arylsulfonamino, C ₁ -C10 alkylimino, arylimino, C ₁ -C10 alkyl sulfonimino, arylsulfonimino, hydroxyl, halo, thio, C ₁ -C10 alkylthio, arylthio, C ₁ -C10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, guanidine, ureido, cyano, nitro, azido, acyl, thioacyl, acyloxy, carboxyl, and carboxylic ester.

In one alternative embodiment any suitable group may be present on a “substituted” or “optionally substituted” position if indicated that forms a stable molecule and meets the desired purpose of the invention and includes, but is not limited to, e.g., halogen (which can independently be F, Cl, Br or I); cyano; hydroxyl; nitro; azido; alkanoyl (such as a C ₂ -C6 alkanoyl group); carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkyl including those having one or more thioether linkages; alkylsulfinyl; alkylsulfonyl groups including those having one or more sulfonyl linkages; aminoalkyl groups including groups having more than one N atoms; aryl (e.g., phenyl, biphenyl, naphthyl, or the like, each ring either substituted or unsubstituted); arylalkyl having for example, 1 to 3 separate or fused rings and from 6 to about 14 or 18 ring carbon atoms, with benzyl being an exemplary arylalkyl group; arylalkoxy, for example, having 1 to 3 separate or fused rings with benzyloxy being an exemplary arylalkoxy group; or a saturated or partially unsaturated heterocycle having 1 to 3 separate or fused rings with one or more N, O or S atoms, or a heteroaryl having 1 to 3 separate or fused rings with one or more N, O or S atoms, e.g. coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, and pyrrolidinyl. Such groups may be further substituted, e.g. with hydroxy, alkyl, alkoxy, halogen and amino.

In certain embodiments “optionally substituted” includes one or more substituents independently selected from halogen, hydroxyl, amino, cyano, -CHO, -COOH, -CONH2, alkyl including C ₁ -C ₆ alkyl, alkenyl including C ₂ -C ₆ alkenyl, alkynyl including C ₂ -C ₆ alkynyl, -C ₁ - C ₆ alkoxy, alkanoyl including C ₂ -C ₆ alkanoyl, C ₁ -C ₆ alkylester, (mono- and di-C ₁ - C6alkylamino)Co-C ₂ alkyl, haloalkyl including C ₁ -C ₆ haloalkyl, hydoxyC ₁ -C ₆ alkyl, ester, carbamate, urea, sulfonamide, -C ₁ -C6alkyl(heterocyclo), C ₁ -C6alkyl(heteroaryl), -C ₁ -C ₆ alkyl(C ₃ - C ₇ cycloalkyl), O-C ₁ -C6alkyl(C ₃ -C7cycloalkyl), B(OH)2, phosphate, phosphonate and haloalkoxy including C ₁ -C ₆ haloalkoxy.

In some embodiments, the suitable group present on a “substituted” or “optionally substituted” is divalent including, but not limited to, oxo (=0), =S, =CH2, etc. The suitable group on a “substituted” or “optional substituted” position may be monovalent, divalent, or trivalent such that it forms a stable molecule and meets the desired purpose of the invention.

In one embodiment a group described herein that can be substituted with 1, 2, 3, or 4 substituents is substituted with one substituent.

In one embodiment a group described herein that can be substituted with 1, 2, 3, or 4 substituents is substituted with two substituents.

In one embodiment a group described herein that can be substituted with 1, 2, 3, or 4 substituents is substituted with three substituents.

In one embodiment a group described herein that can be substituted with 1, 2, 3, or 4 substituents is substituted with four substituents.

“Aliphatic” refers to a saturated or unsaturated, straight, branched, or cyclic hydrocarbon. "Aliphatic" is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thus incorporates each of these definitions. In one embodiment, "aliphatic" is used to indicate those aliphatic groups having 1-20 carbon atoms. The aliphatic chain can be, for example, mono-unsaturated, di-unsaturated, tri-unsaturated, or polyunsaturated, or alkynyl. Unsaturated aliphatic groups can be in a cis or trans configuration. In one embodiment, the aliphatic group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one embodiment, the aliphatic group contains from 1 to about 8 carbon atoms. In certain embodiments, the aliphatic group is C ₁ - C ₂ , C ₁ -C ₃ , C ₁ -C ₄ , C ₁ -C ₅ or C ₁ -C ₆ . The specified ranges as used herein indicate an aliphatic group having each member of the range described as an independent species. For example, the term C ₁ - G> aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species. For example, the term C ₁ -C ₄ aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. In one embodiment, the aliphatic group is substituted with one or more functional groups that results in the formation of a stable moiety.

The term "heteroaliphatic" refers to an aliphatic moiety that contains at least one heteroatom in the chain, for example, an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atoms in place of a carbon atom. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. “Heteroaliphatic" is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. In one embodiment, "heteroaliphatic" is used to indicate a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms. In one embodiment, the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety. Nonlimiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, -O-alkyl-O-alkyl, alkyl-O- haloalkyl, etc.

A “dosage form” means a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, and the like. A “dosage form” can also include an implant, for example an optical implant.

An “effective amount” as used herein, means an amount which provides a therapeutic or prophylactic benefit.

By the term “modulating,” as used herein, is meant mediating a detectable increase or decrease in the level of a response in a patient compared with the level of a response in the patient in the absence of a treatment or compound, and/or compared with the level of a response in an otherwise identical but untreated patient. The term encompasses perturbing and/or affecting a native signal or response thereby mediating a beneficial therapeutic response in a patient, preferably, a human.

“Parenteral” administration of a pharmaceutical composition includes, e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), intrastemal injection, or infusion techniques. As used herein, the terms “peptide,” “polypeptide,” and “protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and the maximum number of amino acids present within the protein or peptide’s sequence is typically comparable to up to that found in nature. Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types. “Polypeptides” include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. The polypeptides include natural peptides, recombinant peptides, synthetic peptides, or a combination thereof.

To “treat” a disease as the term is used herein, means to reduce the frequency or severity of at least one sign or symptom of a disease or disorder experienced by a patient (i.e. palliative treatment) or to decrease a cause or effect of the disease or disorder (i.e. disease-modifying treatment).

Throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and should not be construed as a limitation on the scope of the invention. The description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

As used herein, “antiviral activity” refers to the activity demonstrated by a compound against a virus in various assays used in the field to evaluate antiviral activity, such as cytopathic effect (CPE) assays, plaque reduction assays, VSV-pseudotyped neutralization assays, and qPCR assays. In one aspect, the antiviral activity of compounds of the invention are measured using a CPE assay, and in particular, antiviral activity against SARS-CoV-2 is determined using a CPE assay measuring the protection of A549 ^+ACE2 cells, which are lung epithelial cells engineered to constitutively express human angiotensin-converting enzyme-2 (ACE2), after infection with a SARS-CoV-2 strain, such as SARS-CoV2, USA/WA-1/2020 strain. . A non-limiting example of a CPE assay includes the assay described in Yan et al. “Simple Ripid In Vitro Screening Method for SARS-CoV2 Anti-Virals That Identifies Potential Cytomorbidity-Associated False Positives”, Virology Journal, 2021, 18, 123, doi.org/10.1186/sl2985-021-01587-z.

As used herein, “pharmaceutical compositions” are compositions comprising at least one active agent, and at least one other substance, such as a carrier. “Pharmaceutical combinations” are combinations of at least two active agents which may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat any disorder described herein.

As used herein, “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts.

Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2) _n - COOH where n is 0-4, and the like, or using a different acid that produces the same counterion. Lists of additional suitable salts may be found, e.g., in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

The term “carrier” applied to pharmaceutical compositions/combinations of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided.

A “pharmaceutically acceptable carrier” means a carrier or excipient that is useful in preparing a pharmaceutical composition/combination that is generally safe, non-toxic and neither biologically nor otherwise inappropriate for administration to a patient, typically a human. In one embodiment, an excipient is used that is acceptable for veterinary use.

A “patient” or “subject” is a human or non -human animal in need of treatment or prevention of any of the disorders as specifically described herein, for example that is modulated by a natural (wild-type) or modified (non-wild type) protein that can be degraded according to the present invention, resulting in a therapeutic effect. As described further herein, the word patient or subject typically refers to a human patient or subject unless it is clear from the context or wording that, the disclosure is meant to include a non-human animal. Typically, the patient is a human. In an alternative embodiment, the patient or subject is a non-human animal in need of such therapy and responsive thereto.

A “therapeutically effective amount” of a pharmaceutical composition/combination of this invention means an amount effective, when administered to a patient, typically a human patient, to provide a therapeutic benefit such as an amelioration of symptoms or reduction or diminution of the disease itself.

A “prodrug” is a version of the parent molecule that is metabolized or chemically converted to the parent molecule in vivo, for example in a mammal or a human. Non-limiting examples of prodrugs include esters, amides, for example off a primary or secondary amine, carbonates, carbamates, phosphates, ketals, imines, oxazolidines, and thiazolidines. A prodrug can be designed to release the parent molecule upon a change in pH (for example in the stomach or the intestine) or upon action of an enzyme (for example an esterase or amidase). For example, when the parent molecule is:

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In the specification, singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed application. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

II. NSP3 Targeting Ligands Non-limiting examples of NSP3 Targeting Ligands for use in degraders of the present invention include: In certain embodiments the NSP3 Targeting Ligand is selected from:

In certain embodiments the NSP3 Targeting Ligand is selected from: In certain embodiments the NSP3 Targeting Ligand is selected from: In certain embodiments the NSP3 Targeting Ligand is selected from: In certain embodiments the NSP3 Targeting Ligand is selected from:

In certain embodiments the NSP3 Targeting Ligand is selected from: In certain embodiments the NSP3 Targeting Ligand is selected from:

In certain embodiments the NSP3 Targeting Ligand is selected from:

In certain embodiments the NSP3 Targeting Ligand is selected from:

In certain embodiments the NSP3 targeting ligand is selected from

III. EMBODIMENTS OF THE PRESENT INVENTION Embodiments of R ¹ , R ² , R ³ , R ⁴ and R ⁵

In certain embodiments, R ¹ is hydrogen.

In certain embodiments, R ¹ is alkyl.

In certain embodiments, R ¹ is alkenyl.

In certain embodiments, R ¹ is alkynyl. In certain embodiments, R ¹ is halogen. In certain embodiments, R ¹ is halogen, wherein the halogen is F. In certain embodiments, R ¹ is halogen, wherein the halogen is Cl. In certain embodiments, R ¹ is halogen, wherein the halogen is Br. In certain embodiments, R ¹ is halogen, wherein the halogen is I.

In certain embodiments, R ² is hydrogen. In certain embodiments, R ² is hydrogen, wherein the hydrogen is substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ .

In certain embodiments, R ² is alkyl. In certain embodiments, R ² is alkyl, wherein the alkyl is substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ .

In certain embodiments, R ² is haloalkyl. In certain embodiments, R ² is haloalkyl, wherein the haloalkyl is substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ .

In certain embodiments, R ² is alkenyl. In certain embodiments, R ² is alkenyl, wherein the alkenyl is substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ .

In certain embodiments, R ² is alkynyl. In certain embodiments, R ² is alkynyl, wherein the alkynyl is substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ .

In certain embodiments, R ² is aryl. In certain embodiments, R ² is aryl, wherein the aryl is substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ .

In certain embodiments, R ² is heteroaryl. In certain embodiments, R ² is heteroaryl, wherein the heteroaryl is substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ .

In certain embodiments, R ² is heterocycle. In certain embodiments, R ² is heterocycle, wherein the heterocycle is substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ .

In certain embodiments, R ² is C(O)R ⁹ . In certain embodiments, R ² is C(O)R ⁹ , wherein C(O)R ⁹ is substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ .

In certain embodiments, R ³ is hydrogen.

In certain embodiments, R ³ is alkyl.

In certain embodiments, R ³ is alkenyl.

In certain embodiments, R ³ is alkynyl.

In certain embodiments, R ³ is halogen. In certain embodiments, R ³ is halogen, wherein the halogen is F. In certain embodiments, R ³ is halogen, wherein the halogen is Cl. In certain embodiments, R ³ is halogen, wherein the halogen is Br. In certain embodiments, R ³ is halogen, wherein the halogen is I.

In certain embodiments, R ⁴ is hydrogen.

In certain embodiments, R ⁴ is alkyl. In certain embodiments, R ⁴ is alkenyl.

In certain embodiments, R ⁴ is alkynyl.

In certain embodiments, R ⁴ is halogen. In certain embodiments, R ⁴ is halogen, wherein the halogen is F. In certain embodiments, R ⁴ is halogen, wherein the halogen is Cl. In certain embodiments, R ⁴ is halogen, wherein the halogen is Br. In certain embodiments, R ⁴ is halogen, wherein the halogen is I.

In certain embodiments, R ³ and R ⁴ together with the carbon to which they are bound form a 3-, 4-, 5-, or 6-membered spirocarbocycle. In certain embodiments, R ³ and R ⁴ together with the carbon to which they are bound form a 3 -membered spirocarbocycle. In certain embodiments, R ³ and R ⁴ together with the carbon to which they are bound form a 4-membered spirocarbocycle. In certain embodiments, R ³ and R ⁴ together with the carbon to which they are bound form a 5- membered spirocarbocycle. In certain embodiments, R ³ and R ⁴ together with the carbon to which they are bound form a 6-membered spirocarbocycle.

In certain embodiments, R ³ and R ⁴ together with the carbon to which they are bound form a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N, O, and S, or an oxo group.

In certain embodiments, R ³ and R ⁴ together with the carbon to which they are bound form a 4-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N, O, and S, or an oxo group.

In certain embodiments, R ³ and R ⁴ together with the carbon to which they are bound form a 5-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N, O, and S, or an oxo group.

In certain embodiments, R ³ and R ⁴ together with the carbon to which they are bound form a 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N, O, and S, or an oxo group.

In certain embodiments, R ⁵ is alkyl.

In certain embodiments, R ⁵ is haloalkyl.

In certain embodiments, R ⁵ is alkenyl.

In certain embodiments, R ⁵ is alkynyl.

In certain embodiments, R ⁵ is halogen. In certain embodiments, R ⁵ is halogen, wherein the halogen is F. In certain embodiments, R ⁵ is halogen, wherein the halogen is Cl. In certain embodiments, R ⁵ is halogen, wherein the halogen is Br. In certain embodiments, R ⁵ is halogen, wherein the halogen is I.

In certain embodiments, R ⁵ is heteroaryl. In certain embodiments, R ⁵ is aryl. In certain embodiments, R ⁵ is heterocycle.

In certain embodiments, R ⁵ is cyano.

In certain embodiments, R ⁵ is -NR ⁷ R ⁸ . In certain embodiments, R ⁵ is -NR ⁷ C(O)R ⁹ . In certain embodiments, R ⁵ is -NR ⁷ C(S)R ⁹ . In certain embodiments, R ⁵ is -NR ⁷ C(O)R ⁹ . In certain embodiments, R ⁵ is -NR ⁷ S(O)2R ⁹ .

In certain embodiments, R ⁵ is -OR ⁷ '

In certain embodiments, R ⁵ is -SR ⁷ . In certain embodiments, R ⁵ is -S(O)2R ⁹ .

In certain embodiments, R ⁵ is -C(O)R ⁹ .

In certain embodiments at least one R ⁵ is oxo.

In certain embodiments one R ⁵ is oxo.

In certain embodiments two R ⁵ ’s are oxo.

Embodiments of R ¹⁵ and R ¹⁶

Non-limiting examples of R ¹⁵ and R ¹⁶ include: In certain embodiments, the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

5 In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula: In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

5 In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

5 In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

5

In certain embodiments, the compound of the present invention is of Formula:

5 In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments, the compound of the present invention is of Formula:

In certain embodiments the compound of the present invention is selected from:

In certain embodiments the compound of the present invention is selected from:

In certain embodiments the compound of the present invention is selected from:

In certain embodiments the compound of the present invention is selected from: In certain embodiments the compound of the present invention is selected from:

In the embodiments above and throughout the specification z is 0, 1, 2, 3, or 4. In certain embodiments the compound of the present invention is selected from:

Embodiments of R ¹⁶ , R ¹⁷ , R ¹⁸ , R ²⁷ , and R ²⁸

R ¹²

In certain embodiments R ¹⁶ is which is optionally substituted with

1, 2, 3, or 4 substituents independently selected from R ⁵ .

R ¹²

In certain embodiments R ¹⁶ is which is optionally substituted with

1, 2, 3, or 4 substituents independently selected from R ⁵ .

R ¹²

In certain embodiments R ¹⁶ is which is optionally substituted with

1, 2, 3, or 4 substituents independently selected from R ⁵ .

In certain embodiments which is optionally substituted with

1, 2, 3, or 4 substituents independently selected from R ⁵ .

In certain embodiments R ¹⁶ is R ¹² .

R ¹²

In certain embodiments R ¹⁶ is which is optionally substituted with

1, 2, 3, or 4 substituents independently selected from R ⁵ .

I l l R ¹²

In certain embodiments R ¹⁷ is which is optionally substituted with

1, 2, 3, or 4 substituents independently selected from R ⁵ .

17 R

In certain embodiments R is ¹² which is optionally substituted with

1, 2, 3, or 4 substituents independently selected from R ⁵ .

>7 R

In certain embodiments R is ¹² which is optionally substituted with

1, 2, 3, or 4 substituents independently selected from R ⁵ .

Heterocycle

17 R

In certain embodiments R is ¹² which is optionally substituted with

1, 2, 3, or 4 substituents independently selected from R ⁵ .

In certain embodiments which is optionally substituted with

1, 2, 3, or 4 substituents independently selected from R ⁵ .

R ¹²

In certain embodiments R ¹⁸ is which is optionally substituted with

1, 2, 3, or 4 substituents independently selected from R ⁵ .

In certain embodiments which is optionally substituted with

1, 2, 3, or 4 substituents independently selected from R ⁵ . In certain embodiments which is optionally substituted with, 2, 3, or 4 substituents independently selected from R ⁵ .

Heterocycle

R ¹²

In certain embodiments R ¹⁸ is which is optionally substituted with, 2, 3, or 4 substituents independently selected from R ⁵ .

R ¹²

In certain embodiments R ¹⁸ is which is optionally substituted with, 2, 3, or 4 substituents independently selected from R ⁵ .

In certain embodiments R ²⁷ is which is optionally substituted with 1, 2,, or 4 substituents independently selected from R ²⁹ .

In certain embodiments R ²⁷ is which is optionally substituted with 1, 2,, or 4 substituents independently selected from R ²⁹ .

In certain embodiments R ²⁷ is which is optionally substituted with 1, 2,, or 4 substituents independently selected from R ²⁹ .

Heterocycle

In certain embodiments R ²⁷ is which is optionally substituted with 1, 2,, or 4 substituents independently selected from R ²⁹ . In certain embodiments R ²⁸ is which is optionally substituted with 1, 2,

3, or 4 substituents independently selected from R ³⁰ .

In certain embodiments R ²⁸ is which is optionally substituted with 1, 2,

3, or 4 substituents independently selected from R ³⁰ .

In certain embodiments selected from , wherein each Y is independently selected from N, CH, or CR ⁵ , wherein 0, 1, 2, 3, or 4 (as context allows) instances of Y are selected to be N and are selected to produce a stable ring as well known to those skilled in the art and that forms a pharmaceutically acceptable compound.

In certain embodiments is selected from , wherein each Y is independently selected from N, CH, or CR ⁵ , wherein 0, 1, 2, 3, or 4 (as context allows) instances of Y are selected to be N and are selected to produce a stable ring as well known to those skilled in the art and that forms a pharmaceutically acceptable compound. Examples when present in a compound of the present invention include the following:

Additional examples include the following:

Additional examples include the following:

Additional examples include the following:

Examples when present in a compound of the present invention include:

when present in a compound of a present invention include:

Additional Embodiments:

1. In certain aspects a compound of Formula A is provided: or a pharmaceutically acceptable salt, A-oxide, isotopic derivative, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition; wherein:

Heterocyclic Moiety is selected from:

Q is CH ₂ , NR ² , O, or S; X ³ , X ⁴ , X ⁵ , and X ⁶ are independently selected from N, CH, and CR ⁵ , wherein one of X ³ , X ⁴ , X ⁵ , and X ⁶ is a carbon atom that is attached to Linker;

R ¹ , R ³ , R ⁴ , and R ⁶ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R ³ and R ⁴ together with the carbon to which they are bound form a 3-, 4-, 5-, or 6- membered spirocarbocycle, a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N, O, and S, or an oxo group; or R ¹ and R ⁶ are combine together to form a 1 or 2-carbon bridge; for example

each R ² is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and -C(O)R ⁹ , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ ; each R ⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR ⁷ R ⁸ , -OR ⁷ , -SR ⁷ , -C(O)R ⁹ , -C(S)R ⁹ , -S(O)R ⁹ , -S(O) ₂ R ⁹ , -OC(O)R ⁹ , -OC(S)R ⁹ , -OS(O)R ⁹ , -OS(O) ₂ R ⁹ , -SC(O)R ⁹ , -OS(O) ₂ R ⁹ , -NR ⁷ C(O)R ⁹ , -NR ⁷ C(S)R ⁹ , -NR ⁷ S(O)R ⁹ , -NR ⁷ S(O) ₂ R ⁹ , -P(O)(R ⁹ ) ₂ , -SP(O)(R ⁹ ) ₂ , -NR ⁷ P(O)(R ⁹ ) ₂ , and -OP(O)(R ⁹ ) ₂ ; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ ;

R ¹⁶ is selected from: independently selected from R ⁵ ; R ¹⁷ is selected from: independently selected from R ⁵ ; R ¹⁸ is selected from: and each of which R ¹⁸ is optionally substituted with 1, 2, 3, or 4 substituents independently selected

Cycle is a fused aryl or heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁵ and substituted with 1 R ¹² substituent; Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1,

2, 3, or 4 substituents independently selected from R ⁵ and substituted with 1 R ¹² substituent;

R ¹² is the attachment point to Linker;

R ⁷ and R ⁸ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R ¹⁴ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ ; each R ⁹ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR ⁷ R ⁸ , -OR ⁷ , and -SR ⁷ each of which is optionally substituted with 1, 2,

3, or 4 substituents independently selected from R ¹⁰ ; each R ¹⁰ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR ¹¹ R ¹³ , -OR ¹¹ , -SR ¹¹ , -C(O)R ¹⁴ , -C(S)R ¹⁴ , -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -OC(O)R ¹⁴ , -OC(S)R ¹⁴ , -OS(O)R ¹⁴ , -OS(O) ₂ R ¹⁴ , -NR ¹¹ C(O)R ¹⁴ , -NR ¹¹ C(S)R ¹⁴ , -NR ¹¹ S(O)R ¹⁴ , -NR ¹¹ S(O) ₂ R ¹⁴ , -P(O)(R ¹⁴ ) ₂ , -NR ¹¹ P(O)(R ¹⁴ ) ₂ , and -OP(O)(R ¹⁴ ) ₂ ; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁵ ;

R ¹¹ and R ¹³ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R ¹⁴ , -C(S)R ¹⁴ , -S(O)R ¹⁴ ,

-S(O) ₂ R ¹⁴ , and -P(O)(R ¹⁴ ) ₂ ; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁵ ; each R ¹⁴ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl) ₂ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁵ ; each R ¹⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl) ₂ ;

Linker is a bivalent chemical group; NSP3 Targeting Ligand is selected from:

y is 0 or 1;

Fused Cycle is a fused aryl, heteroaryl, cycloalkyl, or heterocycle group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁵ ;

X ¹⁷ is selected from CR ³³ R ³⁴ , C(O), C(S), S(O), and S(O) ₂ ; each x is independently 0, 1, 2, 3, or 4;

X ⁸ , X ⁹ , X ¹⁰ , X ¹¹ , X ¹² , X ¹³ , X ¹⁴ , and X ¹⁵ are independently selected from N, CH, and CR ²⁸ ;

, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²⁹ ; each R ²⁸ , R ²⁹ , and R ³⁰ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR ⁷ R ⁸ , -OR ⁷ , -SR ⁷ , -C(O)R ⁹ , - C(S)R ⁹ , -S(O)R ⁹ , -S(O) ₂ R ⁹ , -OC(O)R ⁹ , -OC(S)R ⁹ , -OS(O)R ⁹ , -OS(O) ₂ R ⁹ , -SC(O)R ⁹ , -OS(O) ₂ R ⁹ , -NR ⁷ C(O)R ⁹ , -NR ⁷ C(S)R ⁹ , -NR ⁷ S(O)R ⁹ , -NR ⁷ S(O) ₂ R ⁹ , -P(O)(R ⁹ ) ₂ , -SP(O)(R ⁹ ) ₂ , -NR ⁷ P(O)(R ⁹ ) ₂ , and -OP(O)(R ⁹ ) ₂ ; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ ; each R ³¹ , R ³² , R ³³ , and R ³⁴ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -C(O)R ⁹ , -C(S)R ⁹ , -S(O)R ⁹ , -S(O) ₂ R ⁹ , -OC(O)R ⁹ , -OC(S)R ⁹ , -OS(O)R ⁹ , -OS(O) ₂ R ⁹ , -SC(O)R ⁹ ,

-OS(O) ₂ R ⁹ , -NR ⁷ C(O)R ⁹ , -NR ⁷ C(S)R ⁹ , -NR ⁷ S(O)R ⁹ , -NR ⁷ S(O) ₂ R ⁹ , -P(O)(R ⁹ ) ₂ , -SP(O)(R ⁹ ) ₂ , -NR ⁷ P(O)(R ⁹ ) ₂ , and -OP(O)(R ⁹ ) ₂ ; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ .

2. The compound of embodiment 1 wherein Linker is selected from wherein:

X ¹ and X ² are independently at each occurrence selected from bond, heterocycle, NR ² , C(R ² ) ₂ , O, C(O), and S;

R ²⁰ , R ²¹ , R ²² , R ²³ , and R ²⁴ are independently at each occurrence selected from the group consisting of bivalent moieties selected from bond alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO ₂ -, -S(O)-, -C(S)-, -C(O)NR ² -, -NR ² C(O)-, -O-, -S-, -NR ² -, -C(R ⁴⁰ R ⁴⁰ )-, -P(O)(OR ²⁶ )O-, -P(O)(OR ²⁶ )-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁴⁰ ;

R ²⁶ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; and

R ⁴⁰ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl) ₂ , -NHSO ₂ (aliphatic, including alkyl), -N(aliphatic, including alkyljSChalkyl, -NHSChtaryl, heteroaryl or heterocycle), -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSChalkenyl, -N(alkyl)SO2alkenyl, -NHSChalkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, and cycloalkyl.

3. The compound of embodiment 2, wherein Linker is selected from: _and

4. The compound of embodiment 2, wherein Linker is selected from:

5. The compound of embodiment 2, wherein Linker is selected from:

6. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety is

7. The compound of embodiment 6, wherein Q is NH.

8. The compound of embodiment 6, wherein Q is NCH3. 9. The compound of embodiment 6, wherein Q is CH2.

10. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety is

11. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety is

12. The compound of any one of embodiments 1-11, wherein optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁵ .

13. The compound of any one of embodiments 1-11, wherein optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁵ . 14. The compound of any one of embodiments 1-11, wherein optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁵ .

Heterocycle

R ¹²

15. The compound of any one of embodiments 1-11, wherein R ¹⁶ is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁵ .

R ¹²

16. The compound of any one of embodiments 1-11, wherein R ¹⁶ is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁵ .

17. The compound of any one of embodiments 1-11, wherein R ¹⁶ is R ¹² .

18. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety is

19. The compound of embodiment 18, wherein optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁵ .

20. The compound of embodiment 18, wherein optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁵ .

17 R

21. The compound of embodiment 18, wherein R is ¹² optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁵ .

Heterocycle

17 R

22. The compound of embodiment 18, wherein R is ¹² optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁵ .

17 R

23. The compound of embodiment 18, wherein R is ¹² optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁵ .

24. The compound of embodiment 18, wherein R ¹⁷ is R ¹² .

25. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety is

R ¹²

26. The compound of embodiment 25, wherein R ¹⁸ is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁵ .

R ¹²

27. The compound of embodiment 25, wherein R ¹⁸ is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁵ .

28. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety is

29. The compound of embodiment 28, wherein cycle is phenyl.

30. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety is 31. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety is

32. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety is

33. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety is

34. The compound of any one of embodiments 1-5, wherein Heterocyclic Moiety is

35. The compound of any one of embodiments 31-34, wherein X ⁶ is CR ¹² .

36. The compound of any one of embodiments 31-34, wherein X ⁵ is CR ¹² .

37. The compound of any one of embodiments 31-34, wherein X ⁴ is CR ¹² .

38. The compound of any one of embodiments 31-34, wherein X ³ is CR ¹² .

39. The compound of any one of embodiments 31-34 or 36-38, wherein X ⁶ is CH.

40. The compound of any one of embodiments 31-34 or 36-38, wherein X ⁶ is CR ⁵ .

41. The compound of any one of embodiments 31-34 or 36-38, wherein X ⁶ is N.

42. The compound of any one of embodiments 31-35 or 37-41, wherein X ⁵ is CH.

43. The compound of any one of embodiments 31-35 or 37-41, wherein X ⁵ is CR ⁵ .

44. The compound of any one of embodiments 31-35 or 37-41, wherein X ⁵ is N.

45. The compound of any one of embodiments 31-36 or 38-44, wherein X ⁴ is CH.

46. The compound of any one of embodiments 31-36 or 38-44, wherein X ⁴ is CR ⁵ .

47. The compound of any one of embodiments 31-36 or 38-44, wherein X ⁴ is N.

48. The compound of any one of embodiments 31-37 or 39-47, wherein X ³ is CH.

49. The compound of any one of embodiments 31-37 or 39-47, wherein X ³ is CR ⁵ .

50. The compound of any one of embodiments 31-37 or 39-47, wherein X ³ is N.

51. The compound of any one of embodiments 1-5, wherein Heterocyclic is

52. The compound of any one of embodiments 1-51, wherein R ³ is hydrogen.

53. The compound of any one of embodiments 1-52, wherein R ⁴ is hydrogen.

54. The compound of any one of embodiments 1-53, wherein R ⁶ is hydrogen.

55. The compound of any one of embodiments 1-54, wherein Linker is of formula:

56. The compound of embodiment 55, wherein X ¹ is bond.

57. The compound of embodiment 55, wherein X ¹ is heterocycle.

58. The compound of embodiment 55, wherein X ¹ is NR ² .

59. The compound of embodiment 55, wherein X ¹ is C(O).

60. The compound of any one of embodiments 55-59, wherein X ² is bond.

61. The compound of any one of embodiments 55-59, wherein X ² is heterocycle.

62. The compound of any one of embodiments 55-59, wherein X ² is NR ² .

63. The compound of any one of embodiments 55-59, wherein X ² is C(O).

64. The compound of any one of embodiments 55-63, wherein R ²⁰ is bond.

65. The compound of any one of embodiments 55-63, wherein R ²⁰ is CH2.

66. The compound of any one of embodiments 55-63, wherein R ²⁰ is heterocycle.

67. The compound of any one of embodiments 55-63, wherein R ²⁰ is aryl.

68. The compound of any one of embodiments 55-63, wherein R ²⁰ is phenyl.

69. The compound of any one of embodiments 55-63, wherein R ²⁰ is bicycle.

70. The compound of any one of embodiments 55-69, wherein R ²¹ is bond.

71. The compound of any one of embodiments 55-69, wherein R ²¹ is CH2.

72. The compound of any one of embodiments 55-69, wherein R ²¹ is heterocycle.

73. The compound of any one of embodiments 55-69, wherein R ²¹ is aryl.

74. The compound of any one of embodiments 55-69, wherein R ²¹ is phenyl.

75. The compound of any one of embodiments 55-69, wherein R ²¹ is bicycle.

76. The compound of any one of embodiments 1-54, wherein Linker is of formula:

77. The compound of any one of embodiments 55-76, wherein R ²² is bond.

78. The compound of any one of embodiments 55-76, wherein R ²² is CH2.

79. The compound of any one of embodiments 55-76, wherein R ²² is heterocycle.

80. The compound of any one of embodiments 55-76, wherein R ²² is aryl. 81. The compound of any one of embodiments 55-76, wherein R ²² is phenyl.

82. The compound of any one of embodiments 55-76, wherein R ²² is bicycle.

83. The compound of any one of embodiments 1-54, wherein Linker is of formula:

84. The compound of any one of embodiments 55-83, wherein R ²³ is bond.

85. The compound of any one of embodiments 55-83, wherein R ²³ is CH2.

86. The compound of any one of embodiments 55-83, wherein R ²³ is heterocycle.

87. The compound of any one of embodiments 55-83, wherein R ²³ is aryl.

88. The compound of any one of embodiments 55-83, wherein R ²³ is phenyl.

89. The compound of any one of embodiments 55-83, wherein R ²³ is bicycle.

90. The compound of any one of embodiments 1-54, wherein Linker is of formula:

91. The compound of any one of embodiments 55-90, wherein R ²⁴ is bond.

92. The compound of any one of embodiments 55-90, wherein R ²⁴ is CH2.

93. The compound of any one of embodiments 55-90, wherein R ²⁴ is heterocycle.

94. The compound of any one of embodiments 55-90, wherein R ²⁴ is aryl.

95. The compound of any one of embodiments 55-90, wherein R ²⁴ is phenyl.

96. The compound of any one of embodiments 55-90, wherein R ²⁴ is bicycle.

97. The compound of any one of embodiments 55-90, wherein R ²⁴ is C(O).

98. The compound of any one of embodiments 1-97, wherein the NSP3 Targeting Ligand is selected from: 99. The compound of any one of embodiments 1-97, wherein the NSP3 Targeting Ligand is selected from: 100. The compound of any one of embodiments 1-97, wherein the NSP3 Targeting

Ligand is selected from:

101. The compound of any one of embodiments 1-97, wherein the NSP3 Targeting Ligand is selected from: . The compound of any one of embodiments 1-97, wherein the NSP3 Targeting Ligand is selected from: . The compound of any one of embodiments 1-97, wherein the NSP3 Targeting Ligand is selected from:

. The compound of any one of embodiments 1-97, wherein the NSP3 Targeting Ligand is selected from: . The compound of any one of embodiments 1-97, wherein the NSP3 Targeting Ligand is selected from: . The compound of any one of embodiments 103-105, wherein X ¹⁸ is CH. . The compound of any one of embodiments 103-105, wherein X ¹⁸ is N. . The compound of any one of embodiments 1-107, wherein X ¹⁶ is . The compound of any one of embodiments 1-105, wherein X ¹⁶ is 110. The compound of any one of embodiments 1-105, wherein X ¹⁶ is or

111. The compound of any one of embodiments 1-105, wherein X ¹⁶ is bond.

112. In certain embodiments a compound from Table 1 is provided.

113. In certain embodiments, a compound of any one of embodiments 1-113 that has antiviral activity EC50 less than 1 pM is provided.

114. In certain embodiments a pharmaceutical composition comprising an effective amount of a compound of any one of embodiments 1-114 and a pharmaceutically acceptable excipient is provided.

115. In certain embodiments a method of treating a coronavirus comprising administering an effective amount of a compound of any one of embodiments 1-114 or a pharmaceutical composition of embodiment 115 is provided.

116. The method of embodiment 116, wherein the coronavirus is SARS-CoV-2.

117. The method of embodiment 117, wherein the coronavirus is a SARS-CoV-2 variant.

118. The method of embodiment 118, wherein the SARS-CoV-2 variant is the alpha variant.

119. The method of embodiment 118, wherein the SARS-CoV-2 variant is the beta variant.

120. The method of embodiment 118, wherein the SARS-CoV-2 variant is the gamma variant.

121. The method of embodiment 118, wherein the SARS-CoV-2 variant is the delta variant.

122. The method of embodiment 118, wherein the SARS, CoV-2 variant is an omicron variant. 123. The method of embodiment 123, where the omicron variant is selected from BA.2,

BA.2.12.1, BA.2.75, BA.3, BA.4, orBA.5.

IV. EXEMPLARY COMPOUNDS OF THE PRESENT INVENTION In certain embodiments the Heterocyclic Moiety is selected from: In certain embodiments the Heterocyclic Moiety is selected from:

In certain embodiments the Heterocyclic Moiety is selected from: In certain embodiments the Heterocyclic Moiety is selected from:

In certain embodiments the Heterocyclic Moiety is selected from:

In certain embodiments the Heterocyclic Moiety is selected from: y y s selected from: . 5 158

In certain embodiments the Heterocyclic Moiety is selected from:

In certain embodiments the Heterocyclic Moiety is selected from:

In certain embodiments the Heterocyclic Moiety is selected from:

In certain embodiments the Heterocyclic Moiety is selected from:

In certain embodiments the Heterocyclic Moiety is selected from: In certain embodiments the Heterocyclic Moiety is selected from:

In certain embodiments the Heterocyclic Moiety is selected from:

In certain embodiments the Heterocyclic Moiety is selected from: In certain embodiments the Heterocyclic Moiety is selected from: In certain embodiments the Heterocyclic Moiety is selected from:

In certain embodiments the Heterocyclic Moiety is selected from:

In certain embodiments the Heterocyclic Moiety is selected from:

In certain embodiments the Heterocyclic Moiety is selected from: In certain embodiments the Heterocyclic Moiety is selected from:

5 In certain embodiments the Heterocyclic Moiety is selected from: In certain embodiments the Heterocyclic Moiety is selected from:

In certain embodiments the Heterocyclic Moiety is selected from: In certain embodiments the Heterocyclic Moiety is selected from:

In certain embodiments the Heterocyclic Moiety is selected from:

In alternative embodiments the Heterocyclic Moiety is selected from wherein Fused Cycle A, Fused Cycle B, and Fused Cycle C are independently selected from fused aryl, heteroaryl, cycloalkyl, and heterocycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁵ . In alternative embodiments the Heterocyclic Moiety is selected from In certain embodiments Fused Cycle A is pyrrole.

In certain embodiments Fused Cycle A is imidazole.

In certain embodiments Fused Cycle A is pyrazole.

In certain embodiments Fused Cycle A is pyrrolidine.

In certain embodiments Fused Cycle A is pyrrolidone. In certain embodiments Fused Cycle B is phenyl.

In certain embodiments Fused Cycle B is pyridine.

In certain embodiments Fused Cycle C is phenyl.

In certain embodiments Fused Cycle C is pyridine. In certain embodiments Heterocyclic Moiety or Heterocyclic Moiety ^B is selected from In certain embodiments Heterocyclic Moiety ^B is selected from In certain embodiments the compound of the present invention is selected from:

IV. LINKERS

A Linker is included in the compounds of the present invention, such as described in Formula A. Linker is a bond or a chemically stable bivalent group that covalently attaches the Heterocyclic Moiety to the selected NSP3 Targeting Ligand. In certain embodiments, Linker can be any chemically stable group that attaches the Heterocyclic Moiety to the NSP3 Targeting Ligand. In some embodiments, Linker has a chain of

2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 or more carbon atoms of which one or more carbon atoms can be replaced by a heteroatom such as O, N, S, or P, as long as the resulting molecule has a stable shelf life for at least two months, three months, six months, or one year as part of a pharmaceutically acceptable dosage form, and itself is pharmaceutically acceptable. In certain embodiments, the chain has 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 contiguous atoms in the chain. For example, the chain may include 1 or more ethylene glycol units, and in some embodiments, may have at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more contiguous, partially contiguous, or non-contiguous ethylene glycol the Linker. In certain embodiments, the chain has at least 1, 2,

3, 4, 5, 6, 7, or 8 branches which can be independently alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, or alkynyl substituents, which in one embodiment, each branch has 10, 8, 6, 4, 3, 2, or 1 carbon.

In other embodiments, the linker can include or be comprised of one or more of ethylene glycol, propylene glycol, lactic acid and/or glycolic acid. In general, propylene glycol adds hydrophobicity, while propylene glycol adds hydrophilicity. Lactic acid segments tend to have a longer half-life than glycolic acid segments. Block and random lactic acid-co-glycolic acid moieties, as well as ethylene glycol and propylene glycol, are known in the art to be pharmaceutically acceptable and can be modified or arranged to obtain the desired half-life and hydrophilicity. In certain aspects, these units can be flanked or interspersed with other moieties, such as aliphatic, including alkyl, heteroaliphatic, aryl, heteroaryl, heterocyclic, cycloalkyl, etc., as desired to achieve the appropriate drug properties.

In certain embodiments the compound of the present invention has one or more exit vectors that appropriately orients the NSP3 Targeting Ligand and/or E3 ligase ligand (heterocyclic moiety) to improve properties of the compound for example to increase binding potency or ternary complex formation. For example, in certain embodiments X ¹⁶ is an exit vector for the NSP3 Targeting Ligand. In certain embodiments, a compound of the present invention has more than one exit vector. In certain embodiments X ¹ or X ² is an exit vector for the E3 ligase ligand. The exit vector may make interactions with the protein it exits and/or may direct the linker portion and targeting ligand portion of the molecule at appropriate angles to allow formation of the ternary complex comprising the NSP3 Protein, compound of the present invention, and cereblon. In certain aspects, Linker is selected from wherein all variables are defined as above.

In certain embodiments the linker includes

In certain embodiments the linker includes In certain embodiments the linker includes

In certain embodiments the linker includes

In certain embodiments the linker includes

In certain embodiments the linker includes

R ⁴⁰ R ⁴⁰

In certain embodiments the linker includes

R ⁴⁰ R ⁴⁰

In certain embodiments the linker includes or

In certain embodiments the linker includes or

R ⁴⁰ R ⁴⁰

In certain embodiments the linker includes

In certain embodiments the linker includes In certain embodiments the linker includes

In certain embodiments the linker includes

The following are non-limiting examples of Linkers that can be used in this invention.

Based on this elaboration, those of skill in the art will understand how to use the full breadth of Linkers that will accomplish the goal of the invention.

As certain non -limiting examples, Linker includes:

In an additional embodiment Linker is selected from: In one embodiment X ¹ is attached to the NSP3 Targeting Ligand. In another embodiment X ² is attached to the NSP3 Targeting Ligand.

Non-limiting examples of moieties of R ²⁰ , R ²¹ , R ²² , R ²³ , and R ²⁴ include:

Additional non-limiting examples of moieties of R ²⁰ , R ²¹ , R ²² , R ²³ , and R ²⁴ include: Additional non-limiting examples of moieties of R ²⁰ , R ²¹ , R ²² , R ²³ , and R ²⁴ include: , Inadditionalembodiments,theLinkerisanoptionallysubstituted(p oly)ethyleneglycol havingatleast1,atleast2,atleast3,atleast4,atleast5,atleast6, atleast7,atleast8,atleast9, atleast10,ethyleneglycolunits,oroptionallysubstitutedalkylgr oupsinterspersedwithoptionally substituted,O,N,S,PorSiatoms.Incertainembodiments,Linkerisfl anked,substituted,or interspersed with an aryl,phenyl, benzyl, alkyl,alkylene, or heterocycle group. In certain embodiments,Linkermaybeasymmetricorsymmetrical.Insomeembodim ents,Linkerisa substitutedorunsubstitutedpolyethyleneglycolgroupranginginsi zefromabout1toabout12 ethyleneglycolunits,between1andabout10ethyleneglycolunits,ab out2about6ethylene glycolunits,betweenabout2and5ethyleneglycolunits,betweenabou t2and4ethyleneglycol units.Inanyoftheembodimentsofthecompoundsdescribedherein,Lin kergroupmaybeany suitablemoietyasdescribedherein. Inadditionalembodiments,Linkerisselectedfrom: -NR ⁶¹ (CH2)n1-(loweralkyl)-,-NR ⁶¹ (CH2)n1-(loweralkoxyl)-, -NR ⁶¹ (CH ₂ ) _n1 -(loweralkoxyl)-OCH ₂ -,-NR ⁶¹ (CH ₂ ) _n1 -(loweralkoxyl)-(loweralkyl)-OCH ₂ -, -NR ⁶¹ (CH ₂ ) _n1 -(cycloalkyl)-(loweralkyl)-OCH ₂ -,-NR ⁶¹ (CH ₂ ) _n1 -(heterocycloalkyl)-, -NR ⁶¹ (CH2CH2O)n1-(loweralkyl)-O-CH2-,-NR ⁶¹ (CH2CH2O)n1-(heterocycloalkyl)-O-CH2-, -NR ⁶¹ (CH2CH2O)n1-Aryl-O-CH2-,-NR ⁶¹ (CH2CH2O)n1-(heteroaryl)-O-CH2-, -NR ⁶¹ (CH ₂ CH ₂ O) _n1 -(cycloalkyl)-O-(heteroaryl)-O-CH ₂ -, -NR ⁶¹ (CH2CH2O)n1-(cycloalkyl)-O-Aryl-O-CH2-, -NR ⁶¹ (CH2CH2O)n1-(loweralkyl)-NH-Aryl-O-CH2-, -NR ⁶¹ (CH ₂ CH ₂ O) _n1 -(loweralkyl)-O-Aryl-CH ₂ , -NR ⁶¹ (CH2CH2O)n1-cycloalkyl-O-Aryl-,-NR ⁶¹ (CH2CH2O)n1-cycloalkyl-O-heteroaryl-, -NR ⁶¹ (CH2CH2)n1-(cycloalkyl)-O-(heterocycle)-CH2, -NR ⁶¹ (CH2CH2)ni-(heterocycle)-(heterocycle)-CH2, and -NR ⁶¹ -(heterocycle)-CH2; wherein nl is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

R ⁶¹ is H, methyl, or ethyl.

In additional embodiments, Linker is selected from: -N(R ⁶¹ )-(CH2) _m1 -O(CH2) _n2 -O(CH2) _o1 -O(CH2) _p1 -O(CH2) _q1 -O(CH ₂ ) _r1 -OCH2-,

-O-(CH2) _m1 -O(CH2) _n2 -O(CH2) _o1 -O(CH2) _p1 -O(CH2) _q1 -O(CH ₂ ) _r1 -OCH2-, -O-(CH2) _m1 -O(CH2) _n2 -O(CH2) _o1 -O(CH2) _p1 -O(CH2) _q1 -O(CH ₂ ) _r1 -O-;

-N(R ⁶¹ )-(CH2) _m1 -O(CH2) _n2 -O(CH2) _o1 -O(CH2) _p1 -O(CH2) _q1 -O(CH ₂ ) _r1 -O-;

-(CH2) _m1 -O(CH2) _n2 -O(CH2) _o1 -O(CH2) _p1 -O(CH2) _q1 -O(CH ₂ ) _r1 -O-; -(CH2) _m1 -O(CH2) _n2 -O(CH2) _o1 -O(CH2) _p1 -O(CH2) _q l-O(CH ₂ ) _r1 -OCH2-;

-O(CH ₂ ) _m1 O(CH2) _n2 O(CH2) _p1 O(CH ₂ ) _q1 OCH2-;

-O(CH ₂ ) _m1 O(CH2) _n2 O(CH2) _p1 O(CH ₂ ) _q1 OCH2-; wherein m1, n2, o1, p1, q1, and r1 are independently 1, 2, 3, 4, or 5; and R ⁶¹ is H, methyl, or ethyl. In additional embodiments, Linker is selected from:

, 5 In additional embodiments, Linker is selected from: , 10 , 15 , 198

, 5 , 10 In additional embodiments, Linker is selected from: , 199 d 5 , , 10 , 5 10

5 , 10 , 202

5 , 10 203

5 , 10 204 I dditi l bdi t Lik i l td f 5

. , ected from: 5 , 206

, 207

,

, In additional embodiments, Linker is selected from: 5 , 210

, 5 In additional embodiments, Linker is selected from: , 10 211

, 5 In additional embodiments, Linker is selected from: 10 , 212

, In additional embodiments, Linker is selected from: 5 , , , , and . In certain embodiments, Linker is selected from: , 10 In certain embodiments Linker is selected from: 15 , , , 213

, 5 In the above structure represent d . 10 In certain embodiments, Linker can be a 4-24 carbon atom linear chains, wherein one or more the carbon atoms in the linear chain can be replaced or substituted with oxygen, nitrogen, amide, fluorinated carbon, etc., such as the following: , 15 , , 214

5 10 , 215

, , 5 In certain embodiments, Linker can be a nonlinear chain, and can be, or include, aliphatic or aromatic or heteroaromatic cyclic moieties. In certain embodiments, Linker may include contiguous, partially contiguous or non- 10 contiguous ethylene glycol unit groups ranging in size from about 1 to about 12 ethylene glycol units, between 1 and about 10 ethylene glycol units, about 2 about 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, between about 2 and 4 ethylene glycol units, for example, 1, 2, 3, 4, 6, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units. In certain embodiments, Linker may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 15 fluorine substituents. In another embodiment Linker is perfluorinated. In yet another embodiment Linker is a partially or fully fluorinated poly ether. Nonlimiting examples of fluorinated Linker moieties include: , 20 216

, 5 , Additional non-limiting examples of moieties of R ²⁰ , R ²¹ , R ²² , R ²³ , and R ²⁴ include: 10 217

. Additional non-limiting examples of moieties of R ²⁰ , R ²¹ , R ²² , R ²³ , and R ²⁴ include: 5 , 10 In certain embodiments, the length can be adjusted as desired or as found necessary for the desired application. 15 V. METHODS OF TREATMENT A compound of the invention, such as a compound of Formula A, can be used in an effective amount to treat a host, including a human, in need thereof, optionally in a pharmaceutically acceptable carrier to treat a coronavirus described herein. In certain embodiments, the method comprises administering an effective amount of a 20 compound described herein, optionally including a pharmaceutically acceptable excipient, carrier, adjuvant, i.e., a pharmaceutically acceptable composition, optionally in combination with another bioactive agent or combination of agents. In certain embodiments a compound of the present invention is used to treat a SARS-CoV- 2 variant. In certain embodiments a compound of the present invention is used to treat SARS-CoV- 25 2 alpha variant. In certain embodiments a compound of the present invention is used to treat a 218

SARS-CoV-2 beta variant. In certain embodiments a compound of the present invention is used to treat a SARS-CoV-2 gamma variant. In certain embodiments a compound of the present invention is used to treat a SARS-CoV-2 delta variant. In certain embodiments a compound of the present invention is used to treat a SARS-C-V-2 omicron variant. 5 In certain embodiments a compound of the present invention is used to treat a coronavirus variant for example a SARS-CoV-2 variants selected from alpha, beta, gamma, delta, epsilon, eta, iota, kappa, mu, omicron, and zeta. Non limiting examples of SARS-CoV-2 alpha variants include B.1.1.7 and Q.1-Q.8. Non limiting examples of SARS-CoV-2 beta variants include B.1.351, B.1.351.2, and B.1.351.3. Non limiting examples of SARS-CoV-2 gamma variants include P.1, 10 P.1.1, and P.1.2. Non limiting examples of SARS-CoV-2 delta variants include B.1.617.2 and AY.1. Non limiting examples of SARS-CoV-2 epsilon variants include B.1.427 and B.1.429. Non limiting examples of SARS-CoV-2 eta variants include B.1.525. Non limiting examples of SARS- CoV-2 iota variants include B.1.526. Non limiting examples of SARS-CoV-2 kappa variants include B.1.617.1. Non limiting examples of SARS-CoV-2 mu variants include B.1.621 and 15 B.1.621.1. Non limiting examples of SARS-CoV-2 zeta variants include P.2. . Non limiting examples of SARs-CoV2 omicron variants include B.1.1.529 and sub-lineage variants BA.1, BA.2, BA.2.12.1, BA.2.75, BA.3, BA.4, and BA.5. In certain embodiments a compound of the present invention is used to treat a coronavirus other than SARS-CoV-2. Additional examples of coronaviruses include:, Severe Acute20 Respiratory Syndrome coronavirus (SARS-CoV), Bat SARS-like coronavirus WIV1 (Bat SL- CoV-WIVl), alpha coronaviruses 229E (HCoV-229E), New Haven coronavirus NL63 (HCoV- NL63), beta coronaviruses OC43 (HCoV-OC43), coronavirus HKIJ I (HCoV-HKU l ), and Middle East Respiratory Syndrome coronavirus (MERS-CoV). In certain embodiments a compound of the present invention is used to treat a new 25 coronavirus that has not yet been discovered or has not infected an appreciable number of people. VI. PHARMACEUTICAL COMPOSITIONS A selected compound of the present invention can be administered as the neat chemical, but is often administered as a pharmaceutical composition, that includes an effective amount for a 30 host, typically a human, in need of such treatment for any of the disorders described herein. Accordingly, the disclosure provides pharmaceutical compositions comprising an effective 219

amount of compound or pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier for any of the uses described herein. The pharmaceutical composition may contain a compound or salt as the only active agent, or, in an alternative embodiment, the compound and at least one additional active agent. 5 In certain embodiments the pharmaceutical composition is in a dosage form that contains from about 0.001 mg to about 1000 mg, from about 0.01 mg to about 800 mg, from about 1 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form. 10 Examples are dosage forms with at least about, or no more than, 0.001, 0.005, 0.010, 0.10, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt. Compounds disclosed herein may be administered orally, topically, systemically, parenterally, by inhalation or spray, sublingually, via implant, including ocular implant, transdermally, via buccal administration, rectally, as an ophthalmic solution, injection, including 15 intravenous, intra-aortal, intracranial, subdermal, intraperitioneal, subcutaneous, transnasal, sublingual, or rectal or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers. The pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as a solid dosage form, liquid, an aerosol, a cream, a gel, a pill, an injection or infusion 20 solution, a capsule, a tablet, a syrup, a transdermal patch, a subcutaneous patch, a dry powder, an inhalation formulation, in a medical device, suppository, buccal, or sublingual formulation, parenteral formulation, or an ophthalmic solution. Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose. 25 Carriers include excipients and diluents and should be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration in an effective amount to the patient being treated. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. 30 Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidents, lubricants, preservatives, stabilizers, 220

surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, and vegetable oils. Optional active agents may be 5 included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention. The pharmaceutical compositions/combinations can be formulated for oral administration. These compositions can contain any amount of active compound that achieves the desired result, for example between 0.1 and 99 weight % (wt.%) of the compound and usually at least about 5 10 wt.% of the compound. Some embodiments contain from about 25 wt.% to about 50 wt. % or from about 5 wt.% to about 75 wt.% of the compound. In certain embodiments the LNP contains a cationic or ionizable limit. Examples include but are not limited to: U.S. Patent Publication Nos. 20060083780 and 20060240554; U.S. Pat. Nos.5,208,036; 5,264,618; 5,279,833; 5,283,185; 5,753,613; and 5,785,992; and PCT Publication 15 No. WO 96/10390, the disclosures of which are each herein incorporated by reference in their entirety for all purposes. Formulations suitable for rectal administration are sometimes presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture. 20 Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof. Formulations suitable for transdermal administration may be presented as discrete patches 25 adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and sometimes take the form of an optionally buffered aqueous solution of the active compound. In one embodiment, microneedle patches or devices are provided for delivery of drugs across or into biological tissue, particularly 30 the skin. The microneedle patches or devices permit drug delivery at clinically relevant rates across or into skin or other tissue barriers, with minimal or no damage, pain, or irritation to the tissue. 221

Formulations suitable for administration to the lungs can be delivered by a wide range of passive breath driven and active power driven single/-multiple dose dry powder inhalers (DPI). The devices most commonly used for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet 5 nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. Selection of a suitable lung delivery device depends on parameters, such as nature of the drug and its formulation, the site of action, and pathophysiology of the lung. VII. GENERAL SYNTHESIS 10 The compounds described herein can be prepared by methods known by those skilled in the art. In one non-limiting example, the disclosed compounds can be made using the schemes below. Compounds of the present invention with stereocenters may be drawn without stereochemistry for convenience. One skilled in the art will recognize that pure enantiomers and 15 diastereomers can be prepared by methods known in the art. Examples of methods to obtain optically active materials include at least the following: i) physical separation of crystals – a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a conglomerate, and 20 the crystals are visually distinct; ii) simultaneous crystallization – a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the enantiomer is a conglomerate in the solid state; iii) enzymatic resolutions – a technique whereby partial or complete separation of a 25 racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis – a synthetic technique whereby at least one step in the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; 30 v) chemical asymmetric synthesis – a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce 222

asymmetry (i.e. chirality) in the product, which may be achieved by chiral catalysts or chiral auxiliaries; vi) diastereomer separations – a technique whereby a racemic compound is reaction with an enantiomerically pure reagent (the chiral auxiliary) that converts the 5 individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations – a technique whereby 10 diastereomers from the racemate quickly equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer of where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomers. The desired enantiomer is 15 then released from the diastereomer; viii) kinetic resolutions – this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; 20 ix) enantiospecific synthesis from non-racemic precursors – a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography – a technique whereby the enantiomers of a racemate 25 are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase (including vial chiral HPLC). The stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography – a technique whereby the racemate is volatilized and 30 enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; 223

xii) extraction with chiral solvents – a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; xiii) transport across chiral membranes – a technique whereby a racemate is place in 5 contact with a thin membrane barrier. The barrier may separate two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through; 10 xiv) simulated moving bed chromatography is used in one embodiment. A wide variety of chiral stationary phases are commercially available. SYNTHESIS OF REPRESENTATIVE COMPOUNDS OF THE PRESENT INVENTION 15 SYNTHESIS OF CRBN BINDERS Example 1 Synthesis of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidin e-2,6-dione hydrochloride and 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 5-yl]-1- piperidyl]acetic acid hydrochloride 20 224

To sodium hydride (in oil dispersion) 60% dispersion in mineral oil (53.51 g, 2.33 mol) was added THF (2300 mL) and the suspension was cooled to 5-10 °C. A solution of 2,6- 5 dibenzyloxypyridin-3-amine (1, 230 g, 750.76 mmol) in THF (1400 mL) was added at 5-10 °C over 20 minutes with exothermicity observed. The temperature was maintained for 30 minutes. To this solution was added 4-bromo-1-fluoro-2-nitrobenzene (2, 247.75 g, 1.13 mol, 138.41 mL) in THF (1600 mL) at 5-10 °C over 20 minutes. The solution was warmed to room temperature and stirred for 16 hours. The reaction mass was quenched with 10% water in THF (5 V) at below 10 10 °C, with observed exothermicity. Saturated NaCl solution (10 V) was added at below 15 °C and warmed to room temperature. The layers were separated, and the organic layer was concentrated under vacuum. The aqueous layer was taken and extracted with DCM (15 V). The organic layer was combined and washed with water (5 V) and concentrated completely under vacuum at 45 °C. The crude was charged into DCM (2.5 V) at 45 °C and maintained for 15 min 15 until dissolution, petroleum ether (10 V) was added at 45 °C and maintained for 1 hour at 45 °C. The mixture was cooled to ambient temperature and maintained for 30 min. The solid was filtered and washed with petroleum ether (2×3 V) to afford 2,6-dibenzyloxy-N-(4-bromo-2-nitro- phenyl)pyridin-3-amine (3, 400 g, 686 mmol, 91% yield). LC-MS (ES ⁺ ): m/z 506.32 [M + H] ⁺ . Step-2: 225

A solution of 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridin-3-amine (3, 50 g, 98.75 mmol) in acetonitrile (450 mL) and water (50 mL) was cooled to 0-5 °C and sodium borohydride (7.47 g, 197.49 mmol) was added portion-wise for 60 minutes, during which room temperature was maintained for 4 hours. Sodium borohydride (7.47 g, 197.49 mmol) was added at 0-5 °C and 5 temperature maintained for 2 hours. Then the reaction was quenched with 10% NH4Cl solution (5 V). Water was added (5 V), followed by DCM (10 V), and the mixture was stirred at RT for 15 min. The aqueous layer was extracted with DCM (10 V) and the combined organic layers were washed with water (10 V) and concentrated completely under vacuum at 40 °C. Petroleum ether was used to strip the residue (3 V), then charged into 10% EtOAc in petroleum ether (5 V) into a 10 crude residue and heated to 45 °C. The temperature was maintained at 45 °C for 30 min, cooled to RT, and maintained for 30 min. The product was filtered and washed with petroleum ether (3 V) to give 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2-diamine (4, 34 g, 69.73 mmol, 71% yield). LC-MS (ES ⁺ ): m/z 476.33 [M + H] ⁺ . Step-3: 15 To the stirred solution of 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2-diamine (4, 200 g, 419.85 mmol) in DMF (800 mL) was added 1,1'-carbonyldiimidazole (177.00 g, 1.09 mol) at 25- 35°C with observed exothermicity. Initial temperature 25°C was monitored with the final temperature of 35°C noted at 15 minutes. The reaction was stirred for 14 hours at room temperature. The reaction was charged into water (420 mL) at room temperature. Precipitation was 20 formed and the mixture was stirred for 3 hours. The solid was filtered and washed with water and petroleum ether (2×35 ml). The product was dried under vacuum for 7 hours at 50 °C to afford 6- bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1H-benzimidazol-2-one (5, 200 g, 391.43 mmol, 93% yield). LC-MS (ES ⁺ ): m/z 502.1 [M + H] ⁺ . Step-4: 25 To a stirred solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1H-benzimidazol-2-one (5, 108 g, 214.99 mmol) in DMF (1000 mL) was added sodium hydride (60% dispersion in mineral oil) (14.83 g, 644.96 mmol) portion-wise at 0-28°C. The reaction mixture was stirred for 1 hour, followed by dropwise addition of methyl iodide (stored over copper) (31.16 g, 214.99 mmol, 13.37 mL) over half an hour. The reaction mixture was diluted with ice cold water, and the resulting 30 solid was obtained, filtered, and dried over vacuum. The solid was extracted with ethyl acetate, then washed with brine, dried over sodium sulfate, and concentrated to dryness. The crude 226

compound was washed with pentane to afford 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl- benzimidazol-2-one (6, 95 g, 183.81 mmol, 86% yield) as a light brown solid. LC-MS (ES ⁺ ): m/z 516.14 [M + H] ⁺ . Step-5: 5 To a solution of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol- 2-one (6, 20 g, 38.73 mmol) in 1,4-dioxane (160 mL) and water (40 mL) was added sodium carbonate (12.32 g, 116.19 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H- pyridine-1-carboxylate (7, 15.57 g, 50.35 mmol). The reaction was purged with nitrogen for 20 minutes, then charged with palladium (0) tetrakis(triphenylphosphine) (2.24 g, 1.94 mmol) and 10 heated to 90-100 °C for 5 hours. The reaction was cooled to room temperature and filtered through a Celite bed and washed with EtOAc. The filtrate was distilled completely under vacuum at 45 °C. The crude product was dissolved in EtOAc (15 V) and separated with water (10 V). The organic layer was washed with water (5 V), brine (5 V), then dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo at 45 °C and purified by column chromatography (100-200 mesh15 silica gel, 0-30% ethyl acetate in petroleum ether) to afford tert-butyl 4-[1-(2,6-dibenzyloxy-3- pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]-3,6-dihydro-2H-py ridine-1-carboxylate (8, 21 g, 33.06 mmol, 85% yield). LC-MS (ES ⁺ ): m/z 619.41 [M + H] ⁺ . Step-6: To a solution of tert-butyl 4-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol -5-yl]- 20 3,6-dihydro-2H-pyridine-1-carboxylate (8, 40 g, 64.65 mmol) in methanol (1600 mL) was added 10% palladium on carbon, type 487, dry (12.00 g, 112.76 mmol) and nickel (12.00 g, 204.45 mmol). The reaction was heated at 60-65 °C under hydrogen atmosphere (10 kg) for 16 hours. The reaction mixture was then cooled to room temperature, filtered, and washed with DCM and MeOH. The filtrate was taken and distilled completely under vacuum at 45 °C. To the crude residue was 25 added IPA (3 V) and heated at 60 °C for 15 minutes. Petroleum ether (3 V) was added, and the mixture cooled to room temperature and further stirred for 1 hour. The solid was filtered and washed with petroleum ether to afford tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]piperidine-1-carboxylate (9, 21 g, 44 mmol, 69% yield). LC-MS (ES-): m/z 441.18 [M - H] -. 227

Step-7: To a stirred solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]piperidine-1-carboxylate (9, 1.6 g, 3.62 mmol) in DCM (30 mL) was added 4 M hydrogen chloride in 1,4-dioxane, 99% (16.00 mL) at 26 °C .The resulting reaction mixture was stirred at 26 5 °C for 3 hours. Upon completion of the reaction, the reaction mixture was concentrated in vacuo, washed with MTBE (50 mL) and concentrated to afford 3-[3-methyl-2-oxo-5-(4- piperidyl)benzimidazol-1-yl]piperidine-2,6-dione hydrochloride (10, 1.37 g, 3.24 mmol, 87% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 343.2 [M + H] ⁺ . Step-8: 10 To a stirred solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidin e-2,6-dione hydrochloride (10, 1 g, 2.64 mmol) in DMF (10 mL) was added tert-butyl 2-bromoacetate (11, 617.83 mg, 3.17 mmol, 464.53 μL) at 26 °C and stirred for 10 minutes before N,N- diisopropylethylamine (2.73 g, 21.12 mmol, 3.68 mL) was added. The resulting reaction mixture was stirred at 26 °C for 1.5 hour. Upon completion of the reaction, the reaction mixture was poured 15 into ice cold water (20 mL) and extracted with ethyl acetate (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 2-[4-[1-(2,6-dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]ace tate (12, 1.1 g, 2.40 mmol, 91% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 457.4 [M + H] ⁺ . Step-9: 20 To a stirred solution of tert-butyl 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 5-yl]-1-piperidyl]acetate (12, 1.0 g, 2.19 mmol) in DCM (34.00 mL) was added 4 M hydrogen chloride in 1,4-dioxane, 99% (40.00 mL) at 26 °C. The resulting reaction mixture was stirred at 26 °C for 20 hours. Upon completion of the reaction, the reaction mixture was concentrated in vacuo to afford 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 5-yl]-1-piperidyl]acetic 25 acid hydrochloride (13, 1 g, 1.65 mmol, 75% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 401.2 [M + H] ⁺ . 228

Example 2 Synthesis of 6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 5-yl]-1-piperidyl]- 6-oxo-hexanoic acid hydrochloride 5 To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 3-[3-methyl-2- oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (1, 1500 mg, 4.38 mmol) and 6-tert- butoxy-6-oxo-hexanoic acid (2, 1.07 g, 5.26 mmol) in anhydrous DMF (20 mL) were added N,N- diisopropylethylamine (2.83 g, 21.90 mmol, 3.82 mL) and HATU (2.50 g, 6.57 mmol) at ambient 10 temperature under nitrogen atmosphere. The contents were stirred at ambient temperature for 4 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (2×50 ml). The organic layers were combined and washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude product, which was purified by flash column chromatography (230-400 mesh silica gel, 8%15 of MeOH in DCM) to afford tert-butyl 6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]-6-oxo-hexanoate (3, 2.1 g, 3.75 mmol, 86% yield) as a syrupy liquid. LC-MS (ES ⁺ ): m/z 527.4 [M + H] ⁺ . Step-2: 229

To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 6-[4- [1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl] -1-piperidyl]-6-oxo-hexanoate (3, 1.5 g, 2.68 mmol) in anhydrous DCM (10 mL) was added 4.0 M hydrogen chloride solution in 1,4-dioxane (5.0 mL) at ambient temperature under nitrogen atmosphere. The contents were stirred 5 at ambient temperature for 12 hours. After completion, the reaction mixture was concentrated under reduced pressure to yield a crude product, which was triturated with 10% ethyl acetate in petroleum ether to afford 6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 5-yl]-1- piperidyl]-6-oxo-hexanoic acid hydrochloride (4, 1.2 g, 2.22 mmol, 83% yield) as a white solid.LC-MS (ES ⁺ ): m/z 471.2 [M + H] ⁺ . 10 The following CRBN binders (Examples 3-5) were prepared substantially following the method described above in Example 2, using the corresponding intermediate in Step-1. Ex. Intermediate in CRBN binder LC-MS 230

5 527.2 [M Example 6 Synthesis of 3-[6-fluoro-3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl] piperidine-2,6- dione hydrochloride 5 To a 20 mL glass-vial containing a well-stirred solution of 5-bromo-1-(2,6-dibenzyloxy-3- pyridyl)-6-fluoro-3-methyl-benzimidazol-2-one (1, 250 mg, 0.463 mmol) in 1,4-dioxane (2.5 mL) and water (0.3 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- 10 dihydro-2H-pyridine-1-carboxylate (2, 214.82 mg, 0.694 mmol) and sodium carbonate (98.18 mg, 0.926 mmol) at ambient temperature. Nitrogen gas was purged through the reaction mixture for 10 231

minutes. Subsequently, Pd(dppf)Cl ₂ ·DCM (37.82 mg, 0.0463 mmol) was added and stirring was continued at 90 °C for 16 h. The reaction mixture was passed through a pad of Celite and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (230-400 mesh silica gel, 35% EtOAc/petroleum ether) to 5 afford tert-butyl 4-[1-(2,6-dibenzyloxy-3-pyridyl)-6-fluoro-3-methyl-2-oxo-ben zimidazol-5-yl]- 3,6-dihydro-2H-pyridine-1-carboxylate (3, 350 mg, 0.423 mmol, 91% yield) as a colorless solid. LC-MS (ES ⁺ ): m/z 637.2 [M + H] ⁺ . Step 2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[1-10 (2,6-dibenzyloxy-3-pyridyl)-6-fluoro-3-methyl-2-oxo-benzimid azol-5-yl]-3,6-dihydro-2H- pyridine-1-carboxylate (3, 350 mg, 0.423 mmol) in anhydrous 1,4-dioxane (2 mL) was added palladium hydroxide on carbon, 20 wt.% 50% water (326.93 mg, 0.465 mmol) at ambient temperature. The reaction mixture was stirred at this temperature for 16 h under hydrogen atmosphere. After completion of the reaction, the reaction mixture was passed through a pad of 15 Celite and the Celite bed was washed with a mixture of 1:1 THF:DMF (200 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-6-fluoro-3- methyl-2-oxo-benzimidazol-5-yl]piperidine-1-carboxylate (4, 200 mg, 0.402 mmol, 95% yield) as a grey solid. LC-MS (ES ⁺ ): m/z 405.0 [M - isobutene + H] ⁺ . Step 3: 20 To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[1- (2,6-dioxo-3-piperidyl)-6-fluoro-3-methyl-2-oxo-benzimidazol -5-yl]piperidine-1-carboxylate (4, 200.32 mg, 0.402 mmol) in anhydrous DCM (1.5 mL) was added 4M HCl in 1,4-dioxane (1.21 mL) at 0 °C. The reaction was stirred at ambient temperature for 2 h. After completion of the reaction, the solvent was removed from the reaction mixture to give a crude material which was25 azeotroped with toluene (10 mL) and washed with MTBE (8 mL) to afford 3-[6-fluoro-3-methyl- 2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione hydrochloride (5, 150 mg, 0.349 mmol, 87 % yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 361.2 [M + H] ⁺ . 232

Example 7 Synthesis of 1-methyl-3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl] piperidine-2,6- dione and 2-[4-[3-methyl-1-(1-methyl-2,6-dioxo-3-piperidyl)-2-oxo-benz imidazol-5-yl]-1- piperidyl]acetic acid 5 To a 50 mL single neck round-bottom flask containing a well stirred solution of tert-butyl 4-[1- (2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]pip eridine-1-carboxylate hydrochloride (1, 300 mg, 620.08 μmol) in anhydrous DMF (5.02 mL) were added potassium 10 carbonate, anhydrous (342.81 mg, 2.48 mmol) and iodomethane (264.04 mg, 1.86 mmol, 115.81 μL) at room temperature. The reaction mixture stirred for 7 hours at 50 °C. After completion of the reaction, the solvent was evaporated under vacuum and water was added dropwise and sonicated. The solid precipitation was collected by filtration and dried under vacuum to obtain tert- butyl 4-[3-methyl-1-(1-methyl-2,6-dioxo-3-piperidyl)-2-oxo-benzimi dazol-5-yl]piperidine-1- 15 carboxylate (2, 250 mg, 546.62 μmol, 88% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 401.2 [M – tBu + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[3- methyl-1-(1-methyl-2,6-dioxo-3-piperidyl)-2-oxo-benzimidazol -5-yl]piperidine-1-carboxylate20 (2, 200 mg, 433.70 μmol) in anhydrous DCM (2.5 mL) was added 4.0 M hydrochloric acid in 1,4- 233

dioxane (2.71 mL) and the resulting solution was stirred at room temperature for 3 hours. The reaction mixture was then concentrated under reduced pressure and triturated with MTBE to afford 1-methyl-3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl] piperidine-2,6-dione hydrochloride (3, 160 mg, 407.25 μmol, 94% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 357.3 5 [M + H] ⁺ . Step-3: To a 25 mL round-bottom flask containing a well-stirred solution of 1-methyl-3-[3-methyl-2-oxo- 5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione hydrochloride (3, 160 mg, 403.18 μmol) in anhydrous DMF (2 mL) at 0 °C were added N,N-diisopropylethylamine (114.64 mg, 886.99 μmol, 10 154.50 μL) and tert-butyl bromoacetate (4, 94.37 mg, 483.81 μmol, 70.95 μL) under nitrogen atmosphere. The reaction was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into ice-water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to afford tert-butyl 2-[4-[3-methyl-1-(1-methyl-2,6-dioxo-3-piperidyl)-2-oxo-15 benzimidazol-5-yl]-1-piperidyl]acetate (5, 160 mg, 299.22 μmol, 74% yield) as a white solid. LC- MS (ES ⁺ ): m/z 471.3 [M + H] ⁺ . Step-4: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 2-[4- [3-methyl-1-(1-methyl-2,6-dioxo-3-piperidyl)-2-oxo-benzimida zol-5-yl]-1-piperidyl]acetate (5, 20 160 mg, 299.22 μmol) in DCM (5 mL) was added hydrogen chloride (4 M solution in 1,4-dioxane, 5 mL, 20 mmol) under nitrogen atmosphere and the resulting solution was stirred at room temperature for 4 hours. The reaction mixture was then concentrated under reduced pressure and triturated with MTBE to afford 2-[4-[3-methyl-1-(1-methyl-2,6-dioxo-3-piperidyl)-2-oxo- benzimidazol-5-yl]-1-piperidyl]acetic acid hydrochloride (6, 160 mg, 273.22 μmol, 91% yield) as 25 a pale-yellow solid. LC-MS (ES ⁺ ): m/z 415.4 [M + H] ⁺ . 234

Example 8 Synthesis of 4-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 5-yl]-4- piperidyl]butanal hydrochloride 5 To a 500 mL two-neck round-bottom flask containing a solution of 4-methylpyridine (1, 3.0 g, 32.21 mmol, 3.13 mL) in anhydrous THF (40 mL) was added n-BuLi (14.82 mL; 2.5 M in hexanes) at -78 °C and the resulting mixture was stirred for 30 minutes. Subsequently, 3-bromo- 1,1-dimethoxy-propane (2, 6.49 g, 35.44 mmol, 4.77 mL) in anhydrous THF (20 mL) was added 10 dropwise and the stirring was continued for 1 h at – 50 °C to – 30 °C. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution and 235

extracted with EtOAc (2 × 300 mL). The combined organic phase was washed with brine (50 mL), dried (Na2SO4), filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (230-400 mesh silica gel, 0-100% EtOAc in petroleum ether) to afford 4-(4,4-dimethoxybutyl)pyridine (3, 3.6 g, 17.74 mmol, 55% 5 yield) as a pale yellow liquid. LC-MS (ES ⁺ ): m/z 196.2 [M + H] ⁺ . Step-2: To a 250 mL single-neck round-bottom flask containing a well-stirred solution of 4-(4,4- dimethoxybutyl)pyridine (3, 3.6 g, 17.88 mmol) in anhydrous MeOH (60 mL) and AcOH (0.2 mL) was added palladium hydroxide on carbon, 20 wt.% 50% water (3.84 g, 5.46 mmol) at 10 ambient temperature. The resulting mire was stirred at this temperature for 16 h under hydrogen atmosphere (~1 atm). After complete consumption of starting material, the reaction mixture was passed through a Celite pad and the Celite pad was washed with MeOH (150 mL). The combined filtrate was concentrated under reduced pressure to afford 4-(4,4-dimethoxybutyl)piperidine (4, 3.5 g, 17.37 mmol, 97% yield) as a colorless liquid. LC-MS (ES ⁺ ): m/z 202.2 [M + H] ⁺ . 15 Step-3: To a 250 mL sealed tube containing a well-stirred solution of 4-(4,4-dimethoxybutyl)piperidine (4, 795.26 mg, 3.91 mmol) and 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol- 2-one (5, 1.7 g, 3.26 mmol) in dry 1-4-dioxane (30 mL) was added cesium carbonate (2.65 g, 8.15 mmol) and reaction mixture was purged with nitrogen gas for 5 minutes. Subsequently, RuPhos 20 (152.08 mg, 0.326 mmol) and RuPhos-Pd-G3 (272.59 mg, 0.326 mmol) were added and the reaction mixture was heated at 110 °C for 16 h. Upon completion, the reaction mixture was cooled to ambient temperature, filtered through a pad of Celite and Celite bed was washed with EtOAc (100 mL) and combined filtrate was concentrated under reduced pressure to obtain a crude residue, which was purified by column chromatography (60-120 mesh; 50 g silica gel, 0-80% EtOAc in25 petroleum ether) to afford 1-(2,6-dibenzyloxy-3-pyridyl)-5-[4-(4,4-dimethoxybutyl)-1-pi peridyl]- 3-methyl-benzimidazol-2-one (6, 1.1 g, 1.64 mmol, 50% yield) as a brown gum. LC-MS (ES ⁺ ): m/z 637.2 [M + H] ⁺ . Step-4: To a 250 mL single-neck round-bottom flask containing a well-stirred solution of 1-(2,6- 30 dibenzyloxy-3-pyridyl)-5-[4-(4,4-dimethoxybutyl)-1-piperidyl ]-3-methyl-benzimidazol-2-one (6, 1.1 g, 1.64 mmol) in anhydrous 1,4-dioxane (35 mL) was added palladium hydroxide on carbon, 236

20 wt.% 50% water (2.09 g, 2.98 mmol) at ambient temperature. The resulting mixture was stirred at this temperature for 16 h under hydrogen atmosphere (~1 atm). After consumption of the starting material, the reaction mixture was passed through a pad of Celite and the Celite bed was washed with 1,4-dioxane (200 mL). The filtrate was concentrated under reduced pressure and the obtained 5 crude product was washed with methyl tert-butyl ether (20 mL) to afford 3-[5-[4-(4,4- dimethoxybutyl)-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-y l]piperidine-2,6-dione (7, 550 mg, 1.03 mmol, 62% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 459.2 [M + H] ⁺ . Step-5: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 3-[5-[4-(4,4- 10 dimethoxybutyl)-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-y l]piperidine-2,6-dione (7, 140 mg, 0.262 mmol,) in anhydrous DCM (2.81 mL) was added 4M HCl in 1,4-dioxane (1.31 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 2 h. After completion of reaction, the mixture was concentrated to obtain a crude mass which was triturated with MTBE (10 mL) to afford 4-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 5-yl]-4-15 piperidyl]butanal hydrochloride (8, 120 mg, 0.189 mmol, 72% yield) as an off-white solid. LC- MS (ES ⁺ ): m/z 413.2 [M + H] ⁺ . Example 9 5-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 5-yl]-4-piperidyl]pentanal 20 hydrochloride stantially following the synthesis of 4-[1-[1-(2,6-dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]but anal hydrochloride. LC-MS (ES ⁺ ): m/z 427.4 [M + H] ⁺ . 237

Example 10 Synthesis of 5-[1-[1-(2,6-dioxo-3-piperidyl)-6-fluoro-3-methyl-2-oxo-benz imidazol-5-yl]-4- piperidyl]pentanal hydrochloride 5 238

To a 500 mL two-neck round-bottom flask containing a solution of 4-methylpyridine (1; 4 g, 42.95 mmol, 4.18 mL) in anhydrous THF (60 mL) was added n-BuLi (19.76 mL; 2.5 M/hexanes) at – 5 78°C and resulting mixture was stirred for 35 minutes. Subsequently, 4-bromobutoxy-tert-butyl- dimethyl-silane (2, 12.05 g, 45.1 mmol) in dry THF (20 mL) was added dropwise and stirring was continued for 2 h at -78 °C. The reaction was quenched with saturated ammonium chloride solution and the mixture was extracted with EtOAc (2 × 400 mL). The combined organic phase was dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to get a10 crude residue, which was purified by flash column chromatography (230-400 mesh silica gel, 10- 14% EtOAc in petroleum ether) to afford tert-butyl-dimethyl-[5-(4-pyridyl)pentoxy]silane (3, 11.5 g, 36.93 mmol, 86% yield) as a yellow liquid. LC-MS (ES ⁺ ): m/z 280.2 [M + H] ⁺ . Step-2: To a 500 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl- 15 dimethyl-[5-(4-pyridyl)pentoxy]silane (3, 5 g, 15.92 mmol) in anhydrous MeOH (120 mL) was added palladium hydroxide on carbon, 20 wt.% 50% water (4 g, 5.70 mmol) and acetic acid (956.13 mg, 15.92 mmol, 0.911 mL) at ambient temperature. The reaction mixture was stirred at this temperature for 16 h under hydrogen gas (bladder ~1 atm pressure). Upon completion of the reaction, the reaction mixture was filtered through Celite bed and Celite bed was washed with20 MeOH (500 mL). The combined filtrate was evaporated under reduced pressure to get tert-butyl- dimethyl-[5-(4-piperidyl)pentoxy]silane (4, 4.5 g, 15.60 mmol, 97% yield) as a yellow liquid. LC- MS (ES ⁺ ): m/z 286.2 [M + H] ⁺ . Step-3: To a 500 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl- 25 dimethyl-[5-(4-piperidyl)pentoxy]silane (4, 4.5 g, 15.60 mmol) in THF (80 mL) was added 239

saturated NaHCO ₃ solution (2.62 g, 31.20 mmol) at ambient temperature under nitrogen atmosphere and stirred for 10 min. Benzyl chloroformate 50% in toluene (3.19 g, 18.72 mmol) was added dropwise at 0°C and the resulting mixture was stirred at ambient temperature for 3 h. After completion, the reaction mixture was diluted with water (150 mL) and extracted with EtOAc (3 × 5 100 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude compound that was purified by flash column chromatography (230-400 mesh silica gel) with desired compound eluting at 10-15% EtOAc in petroleum ether to afford benzyl 4-[5-[tert- butyl(dimethyl)silyl]oxypentyl]piperidine-1-carboxylate (5; 6.8 g, 13.92 mmol, 89% yield) as 10 colorless liquid. LC-MS (ES ⁺ ): m/z 420.2 [M + H] ⁺ . Step-4: To a 250 mL single-neck round-bottom flask containing a well-stirred solution of benzyl 4-[5- [tert-butyl(dimethyl)silyl]oxypentyl]piperidine-1-carboxylat e (5, 6.8 g, 13.92 mmol) in anhydrous THF (60 mL) was added TBAF (27.85 mL; 1M/THF) at 0 °C and stirring was continued at ambient 15 temperature for 3 h. After completion, the reaction mixture was diluted with water (300 mL) and extracted with EtOAc (2 × 400 mL). The combined organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure to get a crude mass, which was purified by flash column chromatography (230-400 mesh silica gel, 40% EtOAc petroleum ether) to afford benzyl 4-(5-hydroxypentyl)piperidine-1-carboxylate (6, 4.1 g, 13.37 20 mmol, 96% yield) as a yellow liquid. LC-MS (ES ⁺ ): m/z 306.2 [M + H] ⁺ . Step-5: To a 10 mL single-neck round-bottom flask containing a well-stirred solution of benzyl 4-(5- hydroxypentyl)piperidine-1-carboxylate (6, 2 g, 6.48 mmol) in anhydrous DCM (20 mL) was added mixture of pyridinium chlorochromate (2.10 g, 9.72 mmol) and Celite (4 g) at 0 °C under 25 nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was filtered through a pad of Celite and Celite bed was washed with 1:1 EtOAc/petroleum ether (200 mL) and combined filtrate was concentrated to afford benzyl 4-(5-oxopentyl)piperidine-1-carboxylate (7, 1.9 g, 6.2 mmol, 96% yield) as a brown gum. LC-MS (ES ⁺ ): m/z 304.2 [M + H] ⁺ . 240

Step-6: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of benzyl 4-(5- oxopentyl)piperidine-1-carboxylate (7, 1.9 g, 6.2 mmol) in anhydrous MeOH (20 mL) were added 4-methylbenzenesulfonic acid; hydrate (235.85 mg, 1.24 mmol) and trimethyl orthoformate 5 (3.29 g, 31.00 mmol, 3.40 mL) at ambient temperature under nitrogen atmosphere. The reaction mixture was stirred at 70 °C for 2 h. After completion, the reaction mixture was poured into water (50 mL) and stirred for 5 minutes. The aqueous phase was extracted with EtOAc (2 × 300 mL). Combined organic phase was washed with brine (70 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and the filtrate was evaporated under reduced pressure to afford benzyl 4-(5,5- 10 dimethoxypentyl)piperidine-1-carboxylate (8, 2 g, 4.6 mmol, 74% yield) as a pale yellow liquid. 1H NMR (400 MHz, DMSO-d ₆ ). δ 7.40-7.32 (m, 5H), 5.06 (s, 1H), 4.33-4.30 (m, 1H), 4.03-3.97 (m, 2H), 3.20 (s, 6H), 2.76 (s, 2H), 1.78-1.67 (m, 2H), 1.52-1.47 (m, 2H), 1.39-1.38 (m, 2H), 1.27- 1.25 (m, 6H) and 1.20-1.18 (m, 2H). Step-7: 15 To a 250 mL single-neck round-bottom flask containing a well-stirred solution of benzyl 4-(5,5- dimethoxypentyl)piperidine-1-carboxylate (8, 2.0 g, 4.58 mmol) in anhydrous MeOH (40 mL) was added palladium hydroxide on carbon, 20 wt.% 50% water (2.0 g, 2.85 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 h under hydrogen atmosphere (~1 atm). After completion, the reaction mixture was passed through a Celite pad and 20 Celite bed was washed with MeOH (100 mL). The combined filtrate was concentrated under reduced pressure to afford 4-(5,5-dimethoxypentyl)piperidine (9, 950 mg, 4.39 mmol, 96% yield) as a colorless gum. LC-MS (ES ⁺ ): m/z 216.2 [M + H] ⁺ . Step-8: To a 100 mL sealed tube containing a well-stirred solution of 5-bromo-1-(2,6-dibenzyloxy-3-25 pyridyl)-6-fluoro-3-methyl-benzimidazol-2-one (10, 920 mg, 1.34 mmol) and 4-(5,5- dimethoxypentyl)piperidine (9, 438.13 mg, 2.01 mmol) in dry 1,4-dioxane (30 mL) was added cesium carbonate (1.09 g, 3.36 mmol) and the reaction mixture was purged with nitrogen for 5 minutes. Subsequently, Pd-PEPPSI-Ihept (26.13 mg, 0.026 mmol) was added and the reaction mixture was heated at 110 °C for 16 h. After completion, reaction mixture was cooled to 30 ambient temperature, filtered through Celite pad and Celite bed was washed with EtOAc (200 mL). Combined filtrate was concentrated under reduced pressure to get a crude mass which was 241

purified by flash silica-gel (230-400 mesh) column chromatography eluting with 30-40% EtOAc/petroleum ether to get 1-(2,6-dibenzyloxy-3-pyridyl)-5-[4-(5,5-dimethoxypentyl)-1- piperidyl]-6-fluoro-3-methyl-benzimidazol-2-one (11, 400 mg, 0.520 mmol, 39% yield) as a brown gum. UPLC-MS (ES ⁺ ): m/z 669.8 [M + H] ⁺ . 5 Step-9: To a 250 mL single-neck round-bottom flask containing a well-stirred solution of 1-(2,6- dibenzyloxy-3-pyridyl)-5-[4-(5,5-dimethoxypentyl)-1-piperidy l]-6-fluoro-3-methyl- benzimidazol-2-one (11, 400 mg, 0.520 mmol) in anhydrous 1,4-dioxane (20 mL) was added palladium hydroxide on carbon, 20 wt.% 50% water (900 mg, 1.28 mmol) at ambient temperature. 10 The resulting mixture was stirred at this temperature for 16 h under hydrogen gas (~1 atm). After completion, the reaction mixture was passed through a pad of Celite and Celite bed was washed with 1,4-dioxane (200 mL) and combined filtrate was concentrated under reduced pressure. The obtained crude was washed with MTBE (20 mL) and further purified by reverse phase C18 column chromatography (0.1% ammonium bicarbonate in water: ACN) to afford 3-[5-[4-(5,5- 15 dimethoxypentyl)-1-piperidyl]-6-fluoro-3-methyl-2-oxo-benzim idazol-1-yl]piperidine-2,6-dione (12, 60 mg, 0.111 mmol, 21% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 491.4 [M + H] ⁺ . Step-10: To a 10 mL single-neck round-bottom flask containing a well-stirred solution of 3-[5-[4-(5,5- dimethoxypentyl)-1-piperidyl]-6-fluoro-3-methyl-2-oxo-benzim idazol-1-yl]piperidine-2,6-dione 20 (12, 50 mg, 0.093 mmol) in dry DCM (1 mL) was added 4 N HCl in 1,4-dioxane (2 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 2 h. After completion, reaction mixture was concentrated under reduced pressure and crude thus obtained was washed with MTBE (20 mL) to get 5-[1-[1-(2,6-dioxo-3-piperidyl)-6-fluoro-3-methyl-2-oxo-benz imidazol-5-yl]-4- piperidyl]pentanal hydrochloride (13; 50 mg, 0.069 mmol, 74% yield) as a white solid. LC-MS 25 (ES ⁺ ): m/z 445.3 [M + H] ⁺ . 242

Example 11 Synthesis of 1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-y l]piperidine-4- carboxylic acid 5 To a 250 mL round-bottom flask containing a well stirred solution of 2,4-difluoro-1-nitro-benzene (1, 10 g, 62.86 mmol, 6.90 mL) was added 40% methyl amine in water (14.64 g, 188.57 mmol) at 0 °C dropwise over 10 min. The resulting mixture was stirred at rt for 1h at 0 °C. The observed yellow precipitate was filtered, washed with water (400 mL) and dried under reduced pressure to 10 give 5-fluoro-N-methyl-2-nitro-aniline (2, 8.5 g, 47.36 mmol, 75% yield) as a yellow solid. LCMS (ES ⁺ ): m/z 171.0 [M+H] ⁺ . Step-2: To a 500 mL single-neck round-bottom flask containing a well-stirred solution of 5-fluoro-N- methyl-2-nitro-aniline (2, 8.5 g, 46.96 mmol) in DMF (250 mL) was added N,N-15 diisopropylethylamine (30.35 g, 234.81 mmol, 40.90 mL) followed by tert-butyl piperidine-4- 243

carboxylate (3, 9.37 g, 42.26 mmol, HCl salt) at room temperature and the resulting mixture was stirred for 16 h at 90 °C. After completion of the reaction, the volatiles were removed under vacuum and the mixture was quenched with water (900 mL). The aqueous layer was extracted with EtOAc (3×900 mL), and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , 5 and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography (230-400 mesh silica gel, 20% EtOAc in Petroleum ether) to afford tert-butyl 1-[3-(methylamino)-4-nitro-phenyl]piperidine-4-carboxylate (4, 6.5 g, 18.01 mmol, 38% yield) as a yellow solid. LCMS (ES ⁺ ): m/z 336.2 [M+H] ⁺ . Step-3: 10 To a stirred solution of tert-butyl 1-[3-(methylamino)-4-nitro-phenyl]piperidine-4-carboxylate (4, 8 g, 22.16 mmol) in THF (200 mL) was added 10% palladium on carbon (9.43 g, 8.86 mmol).The reaction mixture was stirred at rt for 16 h under H2 atmosphere. After consumption of the starting material, the reaction mixture was filtered through a pad of Celite, which was washed with THF:dioxane (300 mL). The filtrate was evaporated to afford tert-butyl 1-[4-amino-3- 15 (methylamino)phenyl]piperidine-4-carboxylate (5, 6.5 g, 19.85 mmol, 90% yield) as a brown solid. LCMS (ES ⁺ ): m/z 306.2 [M+H] ⁺ . Step-4: To a 1 L single-neck round-bottom flask containing a stirred solution of tert-butyl 1-[4-amino-3- (methylamino)phenyl]piperidine-4-carboxylate (5, 6.5 g, 19.85 mmol) in THF (400 mL) was 20 added di(imidazol-1-yl)methanone (6, 6.44 g, 39.71 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×400 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was purified by column25 chromatography (60-120 mesh silica gel, 1-3% methanol in DCM) to afford tert-butyl 1-(3- methyl-2-oxo-1H-benzimidazol-5-yl)piperidine-4-carboxylate (7, 5.5 g, 16.35 mmol, 82% yield) as an off-white solid. LCMS (ES ⁺ ): m/z 332.2 [M+H] ⁺ . Step-5: To a 500 mL three-neck round-bottom flask containing well stirred solution of tert-butyl 1-(3- 30 methyl-2-oxo-1H-benzimidazol-5-yl)piperidine-4-carboxylate (7, 2.5 g, 7.39 mmol) in anhydrous THF (100 mL) was added sodium hydride (60% dispersion in mineral oil, 4.14 g, 244

103.50 mmol) at 0 °C. The resulting mixture was stirred at 0°C for 0.5 h. Then 3-bromopiperidine- 2,6-dione (8, 8.52 g, 44.36 mmol) in anhydrous THF (60 mL) was added slowly at 0 °C and the reaction was stirred for 16 h at 70 °C. Upon completion of the reaction, the reaction mixture was quenched with saturated NH ₄ Cl solution at 0°C and the aqueous layer was extracted with EtOAc 5 (3×75 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was washed with acetonitrile (100 mL) to afford tert-butyl 1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-y l]piperidine-4- carboxylate (9, 1.82 g, 4.00 mmol, 54% yield) as a white solid. LCMS (ES ⁺ ): m/z 443.2 [M+H] ⁺ . Step-6: 10 To a 100 mL single-neck round-bottom flask containing well stirred solution of tert-butyl 1-[1- (2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]pip eridine-4-carboxylate (9, 500 mg, 1.10 mmol) in anhydrous DCM (5 mL) was added 4 M HCl in dioxane (274.40 μL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The solvent was removed from the reaction mixture and the resulting crude was co-distilled with toluene (7 mL)15 and washed with MTBE (20 mL) to afford 1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]piperidine-4-carboxylic acid (10, 450 mg, 1.05 mmol, 95% yield, HCl salt) as a white solid. LCMS (ES ⁺ ): m/z 387.2 [M+H] ⁺ . Example 12 20 Synthesis of 1-[3-methyl-1-(1-methyl-2,6-dioxo-3-piperidyl)-2-oxo-benzimi dazol-5- yl]piperidine-4-carboxylic acid To a 50mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 1-[1- 25 (2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]pip eridine-4-carboxylate (1, 250 mg, 245

536.71 μmol) in anhydrous DMF (5 mL) was added K ₂ CO ₃ (222.46 mg, 1.61 mmol) and methyl iodide (228.54 mg, 1.61 mmol) at room temperature. The reaction mixture stirred for 5 h at room temperature. After completion of the reaction, the solvent was removed under vacuum, and the resulting crude product was purified by reverse phase column chromatography (C18 column, 5 solvent system A: 0.1% FA in water and B: CAN) to afford tert-butyl 1-[3-methyl-1-(1-methyl- 2,6-dioxo-3-piperidyl)-2-oxo-benzimidazol-5-yl]piperidine-4- carboxylate (2, 100 mg, 198.98 μmol, 37% yield, formic acid salt) as an off-white solid. LC-MS (ES ⁺ ): m/z 457.2 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing well-stirred solution of tert-butyl 1-[3- 10 methyl-1-(1-methyl-2,6-dioxo-3-piperidyl)-2-oxo-benzimidazol -5-yl]piperidine-4-carboxylate (2, 100 mg, 219.04 μmol) in anhydrous DCM (2 mL) was added 4 M HCl in dioxane (1.10 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was concentrated under vacuum and the crude product was washed with MTBE (2 mL) and dried to afford 1-[3-methyl-1-(1-methyl-2,6-dioxo-3-piperidyl)- 15 2-oxo-benzimidazol-5-yl]piperidine-4-carboxylic acid (90 mg, 185.40 μmol, 85% yield, HCl salt). LC-MS (ES ⁺ ): m/z 401.2 [M+ H] ⁺ . Example 13 Synthesis of 1-[1-(2,6-dioxo-3-piperidyl)-3-ethyl-2-oxo-benzimidazol-5-yl ]piperidine-4- carboxylic acid hydrochloride 20 246

To a 50 mL single-neck round-bottom flask containing to a well-stirred solution of 6-bromo-3- (2,6-dibenzyloxy-3-pyridyl)-1H-benzimidazol-2-one (1, 1 g, 1.79 mmol) in anhydrous DMF (15 5 mL) was added sodium hydride ( (137.29 mg, 3.58 mmol, 60% dispersion in mineral oil) at 0 °C. The reaction mixture was stirred at ambient temperature for 20 minutes before ethyl iodide (558.84 mg, 3.58 mmol, 0.288 mL) was added at 0 °C. Then the reaction was allowed to stir at ambient temperature for 2 h. Upon completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride (10 mL) and extracted with EtOAc (2 × 150 mL). The combined 10 organic phase was washed with water followed by brine and dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (230-400 mesh silica gel, 25-27% EtOAc/petroleum ether) to afford 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-ethyl-benzimidazol-2 -one (2, 1 g, 1.78 mmol, 93% yield) as a brown liquid. LC-MS (ES ⁺ ): m/z 532.0 [M+ H] ⁺ . 15 Step-2: To a 50 mL sealed tube containing a well-stirred solution of 5-bromo-1-(2,6-dibenzyloxy-3- pyridyl)-3-ethyl-benzimidazol-2-one (2, 720 mg, 1.28 mmol) and tert-butyl piperidine-4- carboxylate (3, 565.83 mg, 2.55 mmol) in anhydrous 1,4-dioxane (6 mL) was added cesium 247

carbonate (1.25 g, 3.83 mmol) and reaction mixture was degassed with N ₂ for 10 minutes. Subsequently, RuPhos-Pd-G3 (106.85 mg, 0.127 mmol) was added and the resulting mixture was degassed with N2 for another 5 minutes. The reaction mixture was stirred at 110 °C for 16 h. After completion of the reaction, the reaction mixture was passed through a pad of Celite and Celite bed 5 was washed with EtOAc (150 mL). The combined filtrate was concentrated under reduced pressure to give the crude product which was purified by flash column (230-400 mesh silica gel, 40% EtOAc/petroleum ether) to afford tert-butyl 1-[1-(2,6-dibenzyloxy-3-pyridyl)-3-ethyl-2-oxo- benzimidazol-5-yl]piperidine-4-carboxylate (4, 700 mg, 1.09 mmol, 85% yield) as a brown gum. LC-MS (ES ⁺ ): m/z 635.2 [M+ H] ⁺ . 10 Step-3: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 1-[1- (2,6-dibenzyloxy-3-pyridyl)-3-ethyl-2-oxo-benzimidazol-5-yl] piperidine-4-carboxylate (4, 600 mg, 0.935 mmol) in anhydrous 1,4-dioxane (6 mL) was added palladium hydroxide on carbon, 20 wt.% 50% water (1.18 g, 1.68 mmol) at ambient temperature. The reaction mixture was stirred at 15 this temperature for 16 h under hydrogen atmosphere. Upon completion of the reaction, the reaction mixture was passed through a pad of Celite and Celite bed was washed with EtOAc (150 mL). Combined filtrate was concentrated under reduced pressure to get tert-butyl 1-[1-(2,6-dioxo- 3-piperidyl)-3-ethyl-2-oxo-benzimidazol-5-yl]piperidine-4-ca rboxylate (5, 420 mg, 0.811 mmol, 86% yield) as a colorless gum. LC-MS (ES ⁺ ): m/z 457.4 [M+ H] ⁺ . 20 Step-4: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 1-[1- (2,6-dioxo-3-piperidyl)-3-ethyl-2-oxo-benzimidazol-5-yl]pipe ridine-4-carboxylate (5, 500 mg, 0.964 mmol) in anhydrous DCM (5 mL) was added 4 M HCl in 1,4-dioxane (2.41 mL) at 0 °C. The reaction mixture was stirred for 2 h at ambient temperature. Then the reaction mixture was 25 concentrated under reduced pressure to get a crude mass, which was washed with MTBE (10 mL) to afford 1-[1-(2,6-dioxo-3-piperidyl)-3-ethyl-2-oxo-benzimidazol-5-yl ]piperidine-4-carboxylic acid hydrochloride (6, 400 mg, 0.858 mmol, 89% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 401.2 [M+ H] ⁺ . 248

Example 14 Synthesis of 3-(6-fluoro-3-methyl-2-oxo-5-piperazin-1-yl-benzimidazol-1-y l) piperidine-2,6- dione hydrochloride 5 To a 250 mL single-neck round-bottom flask containing a well-stirred solution of 1,2,4-trifluoro- 5-nitro-benzene (1, 3.5 g, 19.76 mmol, 2.27 mL) in anhydrous DMF (35 mL) was added K ₂ CO ₃ (2.55 g, 19.76 mmol) and stirred for 5 minutes at room temperature. Then, tert-butyl piperazine- 1-carboxylate (2, 3.68 g, 19.76 mmol) in anhydrous DMF (15 mL) was added at 0 °C and stirring 10 was continued at room temperature for 3 hours. The mixture was filtered through a pad of Celite and concentrated under reduced pressure to get the crude compound. To this crude compound 1:1 mixture of MTBE and petroleum ether (50 mL) was added to get a solid that was filtered and dried 249

under reduced pressure to afford tert-butyl 4-(2,5-difluoro-4-nitro-phenyl) piperazine-1- carboxylate (3, 4 g, 11.53 mmol, 58% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 244.1 [M – Boc + H] ⁺ . Step-2: 5 To a 100 mL sealed-tube containing a well-stirred solution of tert-butyl 4-(2,5-difluoro-4-nitro- phenyl)piperazine-1-carboxylate (3, 4 g, 11.53 mmol) in 1,4-dioxane (30 mL) were added methylamine hydrochloride (1.17 g, 17.30 mmol) and N,N-diisopropylethylamine (4.47 g, 34.60 mmol, 6.03 mL) at room temperature. The reaction mixture was heated at 90 °C for 18 hours. The reaction mixture was filtered through a pad of Celite and washed with EtOAc (250 mL). The 10 filtrate was washed with water and dried over anhydrous Na ₂ SO _4. Concentration under reduced pressure afforded tert-butyl 4-[2-fluoro-5-(methylamino)-4-nitro-phenyl]piperazine-1- carboxylate (4, 3.5 g, 9.75 mmol, 85% yield) as a pale yellow solid. LC-MS (ES ⁺ ): m/z 299.2 [M – tBu + H] ⁺ Step-3: 15 To a 250 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[2- fluoro-5-(methylamino)-4-nitro-phenyl]piperazine-1-carboxyla te (4, 3.5 g, 9.68 mmol) in THF (100 mL), methanol (70 mL) and water (30 mL) were added zinc powder (325 mesh High Grade Material, 3.16 g, 48.39 mmol) and ammonium chloride (2.59 g, 48.39 mmol, 1.69 mL) at room temperature. The reaction mixture was heated at 80 °C for 4 hours. Thereafter, the mixture was 20 filtered through a pad of Celite and washed with EtOAc (250 mL). The filtrate was washed with water and dried over anhydrous Na ₂ SO _4. Concentration under reduced pressure afforded tert-butyl 4-[4-amino-2-fluoro-5-(methylamino)phenyl]piperazine-1-carbo xylate (5, 2.8 g, 7.46 mmol, 77% yield) as reddish brown gum. LC-MS (ES ⁺ ): m/z 325.2 [M + H] ⁺ . Step-4: 25 To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[4- amino-2-fluoro-5-(methylamino)phenyl]piperazine-1-carboxylat e (5, 2.8 g, 7.42 mmol) in THF (30 mL) was added 1,1'-carbonyldiimidazole (3.21 g, 22.27 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. Afterwards, solvent was evaporated, and the residue was partitioned between water and DCM. The organic layer was 30 separated, and the aqueous layer was extracted with DCM (2 × 200 mL). The combined organic layers were washed with water and dried over sodium sulfate to get the crude material that was 250

purified by a silica gel flash column chromatography (230-400 mesh silica gel; 50-60% EtOAc in petroleum ether) to afford tert-butyl 4-(6-fluoro-3-methyl-2-oxo-1H-benzimidazol-5- yl)piperazine-1-carboxylate (6, 1.5 g, 4.08 mmol, 55% yield) as a pale yellow solid. LC-MS (ES ⁺ ): m/z 351.2 [M + H] ⁺ . 5 Step-5: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-(6- fluoro-3-methyl-2-oxo-1H-benzimidazol-5-yl) piperazine-1-carboxylate (6, 500 mg, 1.36 mmol) in THF (30 mL) was added sodium hydride (60% dispersion in mineral oil, 727.21 mg, 18.98 mmol) at 0 °C in three portions over 5 min interval and stirred at room temperature for 1 hr. 10 A solution of 3-bromopiperidine-2,6-dione (7, 1.56 g, 8.13 mmol) in THF (10 mL) was added drop-wise at 0 °C. The mixture was heated at 65 °C for 16 hours and then quenched with saturated ammonium chloride solution at 0 °C. The aqueous solution was extracted with EtOAc (2 X 200 mL). The combined organic layers were dried over Na2SO4 and then concentrated to obtain the crude compound which was purified by a reversed-phase column chromatography [Column: 15 Silicycle C18-100 g; Mobile Phase A: 0.1% Formic acid in water and Mobile Phase B: Acetonitrile] to afford tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-6-fluoro-3-methyl-2-oxo- benzimidazol-5-yl] piperazine-1-carboxylate (8, 450 mg, 744.19 μmol, 55% yield) as a pale yellow gum. LC-MS (ES ⁺ ): m/z 462.2 [M + H] ⁺ . Step-6: 20 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[1- (2,6-dioxo-3-piperidyl)-6-fluoro-3-methyl-2-oxo-benzimidazol -5-yl] piperazine-1-carboxylate (8, 450 mg, 955.61 μmol) in DCM (7 mL) was added hydrogen chloride (4.0 M in 1,4-dioxane, 4.78 mL) at room temperature under nitrogen atmosphere. The resultant mixture was stirred at room temperature for 3 hours. Afterwards, the mixture was concentrated under reduced pressure to get 25 3-(6-fluoro-3-methyl-2-oxo-5-piperazin-1-yl-benzimidazol-1-y l) piperidine-2,6-dione hydrochloride (9, 400 mg, 818.04 μmol, 86% yield) as a pale-yellow gum. LC-MS (ES ⁺ ): m/z 362.2 [M + H] ⁺ . 251

Example 15 Synthesis of 3-[3-methyl-5-[3-(methylamino)propyl]-2-oxo-benzimidazol-1-y l]piperidine- 2,6-dione hydrochloride 5 To 50 mL sealed tube containing a well-stirred solution of 3-(5-bromo-3-methyl-2-oxo- benzimidazol-1-yl)piperidine-2,6-dione (1, 200 mg, 0.591 mmol) and tert-butyl N-methyl-N-prop- 2-ynyl-carbamate (2, 400.34 mg, 1.18 mmol) in anhydrous acetonitrile (5 mL) was added cesium carbonate (481.76 mg, 1.48 mmol) and the reaction mixture was degassed by purging nitrogen gas 10 for 5 minutes. Subsequently, XPhos (28.16 mg, 0.059 mmol) and XPhos-Pd-G3 (25.03 mg, 0.029 mmol) were added and the resulting mixture was heated at 90 °C for 16 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and Celite bed was washed with EtOAc (2 × 50 mL) and the combined filtrate was concentrated under reduced pressure. The obtained crude was purified by reverse phase column chromatography [Redisef-RF C1815 column, mobile phase: 0.1% formic acid in water: MeCN] to afford tert-butyl N-[3-[1-(2,6-dioxo- 3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynyl]-N -methyl-carbamate (3, 45 mg, 0.103 mmol, 18% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 371.2 [M -isobutene + H] ⁺ . Step-2: 252

To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl N-[3- [1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl] prop-2-ynyl]-N-methyl-carbamate (3, 45 mg, 0.102 mmol) in a mixture of anhydrous 1.4-dioxane (1 mL) and DMF (0.5 mL) was added palladium hydroxide on carbon, 20 wt.% 50% water (35.93 mg, 0.051 mmol) at ambient 5 temperature. The reaction mixture was stirred at this temperature for 16 h under hydrogen atmosphere (~1 atm). Upon completion of the reaction, the reaction mixture was passed through a pad of Celite and Celite bed was washed with mixture of 1:1 THF: DMF (50 mL). The filtrate was concentrated under reduced pressure to get tert-butyl N-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2- oxo-benzimidazol-5-yl]propyl]-N-methyl-carbamate (4, 35 mg, 0.081 mmol, 79% yield) as an off- 10 white solid. LC-MS (ES ⁺ ): m/z 375.0 [M -isobutene + H] ⁺ . Step-3: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl N-[3- [1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl] propyl]-N-methyl-carbamate (4, 35.35 mg, 0.081 mmol) in DCM (0.5 mL) was added 4 M HCl in 1,4-dioxane (0.203 mL) at 0 °C. 15 After completion of the addition, the resulting mixture was stirred at ambient temperature for 2 h. After completion of the reaction, excess solvent was removed from the reaction mixture to get crude mass which was azeotroped with toluene and washed with MTBE (5 mL) to get 3-[3-methyl- 5-[3-(methylamino)propyl]-2-oxo-benzimidazol-1-yl]piperidine -2,6-dione hydrochloride (5, 25 mg, 0.067 mmol, 83% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 331.2 [M + H] ⁺ . 20 253

Example 16 Synthesis of 6-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-y l]hexanal ared 5 following the method described on page 200-201 of WO2021127586 A1. Step-1: To a 50 mL sealed tube containing a well-stirred solution of 4-bromo-1-(2,6-dibenzyloxy-3- pyridyl)-3-methyl-benzimidazol-2-one (1, 0.5 g, 0.803 mmol) in anhydrous acetonitrile (5 mL) were added hex-5-yn-1-ol (2, 157.75 mg, 1.61 mmol, 0.179 mL) and triethylamine (243.97 mg, 10 2.41 mmol, 0.336 mL). The reaction mixture was purged with nitrogen gas for 5 minutes, then added copper iodide (15.31 mg, 0.08 mmol) and dichloropalladium;triphenylphosphane (56.41 mg, 0.08 mmol). The resulting reaction mixture was purged again with nitrogen gas for 2 minutes and then stirred at 90 °C for 10 h. After completion, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phase was dried 15 over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by column chromatography (60-120 mesh silica gel, 50-60% EtOAc/petroleum ether) to afford 1-(2,6-dibenzyloxy-3-pyridyl)-4-(6-hydroxyhex-1-ynyl)-3-meth yl-benzimidazol-2-one (3, 0.42 g, 0.66 mmol, 80% yield) as a light brown gummy liquid. LC-MS (ES ⁺ ): m/z 534.0 [M + H] ⁺ . 20 Step-2: To a 50 mL single-neck round-bottom flask containing a stirred solution of 1-(2,6-dibenzyloxy-3- pyridyl)-4-(6-hydroxyhex-1-ynyl)-3-methyl-benzimidazol-2-one (3, 0.42 g, 0.643 mmol) in 1,4- 254

dioxane (10 mL) was added 10% palladium on carbon (0.6 g, 5.64 mmol). The reaction mixture was bubbled with hydrogen gas for 10 minutes and then stirred under hydrogen atmosphere (1 atm) at ambient temperature for 16 h. After completion, the reaction mixture was purged with nitrogen gas, and the catalyst was removed by filtration through a pad of Celite and Celite bed was 5 washed with 1:1 THF/1,4-dioxane (100 mL). The filtrate was concentrated under reduced pressure to afford 3-[4-(6-hydroxyhexyl)-3-methyl-2-oxo-benzimidazol-1-yl]piper idine-2,6- dione (4, 0.24 g, 0.605 mmol, 94% yield) as a light brown gum. LC-MS (ES ⁺ ): m/z 360.2 [M + H] +. Step-3: 10 To a 100 mL single-neck round-bottom flask containing a well-stirred solution of 3-[4-(6- hydroxyhexyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2, 6-dione (4, 0.24 g, 0.66 mmol) in anhydrous DCM (10 mL) was added (1,1-diacetoxy-3-oxo-1,2-benziodoxol-1-yl) acetate (513.93 mg, 1.21 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 12 h. After completion, the reaction mixture was quenched with 15 sodium thiosulfate solution (2 g in 15 mL water) and sodium bicarbonate solution (2 g in 15 mL water) and the reaction mixture was stirred for 20 minutes at ambient temperature and then extracted with DCM (3 × 20 mL). The combined organic phase was washed with water (20 mL), brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure to afford 6-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4- 20 yl]hexanal (5, 0.22 g, 0.460 mmol, 75% yield) as a colorless liquid. LC-MS (ES ⁺ ): m/z 358.0 [M + H] ⁺ . 255

Example 17 Synthesis of (3R)-3-methyl-3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol- 1-yl]piperidine- 2,6-dione hydrochloride 5 To a 20 mL (2 × 1g) vial containing a well-stirred solution of 5-bromo-3-methyl-1H-benzimidazol- 2-one (1, 2 g, 8.81 mmol) and 2-bromopropanenitrile (2, 1.18 g, 8.81 mmol) in dimethylformamide (25 mL) was added cesium carbonate (5.74 g, 17.62 mmol) and the reaction mixture was heated to 85 °C for 2 hr. The reaction mixture was diluted with DCM (5 mL) 10 and poured into water. The combined organic layer was washed with brine solution (10 mL), dried 256

over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash column chromatography (100-200 mesh silica gel, 15-60% ethyl-acetate in petroleum ether) to afford 2-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)propanenitrile (3, 1.6 g, 5.70 mmol, 65% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.53 (d, J = 1.6 Hz, 5 1H), 7.35-7.30 (m, 2H), 5.82 (q, J = 7.2 Hz, 1H), 3.34 (s, 3H), 1.71 (d, J = 7.2 Hz, 3H) ppm. Step-2: In a 250 mL single-neck round-bottom flask, a well-stirred solution of 2-(5-bromo-3-methyl-2- oxo-benzimidazol-1-yl)propanenitrile (3, 1 g, 3.57 mmol) in tetrahydrofuran (40 mL) was cooled to -78 °C. Lithium disisopropyl amide solution (2 M, 8.92 mL) was added dropwise and the10 resulting mixture was stirred at -78 °C for 1 h, followed by the addition of methyl 3- bromopropanoate (4, 894.26 mg, 5.35 mmol) at -78 °C and stirred for 3 hr. The reaction mixture was quenched with saturated ammonium chloride solution (30 mL) at -78°C and then warmed up to room temperature and extracted with ethyl acetate (2 × 40 ml). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced 15 pressure to afford methyl 4-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)-4-cyano-pentano ate (5, 1.4 g, 2.77 mmol, 78% yield) as a yellow liquid. LC-MS (ES ⁺ ): m/z 366.2 [M + H] ⁺ . Step-3: To a 250 ml single-neck round bottom flask containing a stirred solution of methyl 4-(5-bromo-3- methyl-2-oxo-benzimidazol-1-yl)-4-cyano-pentanoate (5, 4 g, 10.92 mmol) in THF (40 mL) and 20 water (20 mL) was added lithium hydroxide monohydrate (2.29 g, 54.61 mmol) at room temperature and the resulting reaction mixture was stirred at room temperature for 3 hr. After completion of the reaction, 30 ml of water was added and the reaction mixture was extracted with ethyl acetate (2 × 40 ml). Then the aqueous layer was acidified with 1 N HCl solution and extracted with ethyl acetate (2 × 40 ml). The combined organic layer was dried over anhydrous25 sodium sulfate, filtered and concentrated under reduced pressure to afford 4-(5-bromo-3-methyl- 2-oxo-benzimidazol-1-yl)-4-cyano-pentanoic acid (6, 2.8 g, 4.18 mmol, 38% yield) as a colorless gummy liquid. LC-MS (ES ⁺ ): m/z 354.0 [M + H] ⁺ . Step-4: To a 40 mL screw-capped vial containing a well-stirred solution of 4-(5-bromo-3-methyl-2-oxo- 30 benzimidazol-1-yl)-4-cyano-pentanoic acid (6, 3.0 g, 8.52 mmol) were added acetic acid (15.74 g, 262.03 mmol, 15 mL), sulfuric acid (835.48 mg, 8.52 mmol, 456.54 μL) at room temperature. The 257

resulting reaction mixture was stirred at 90 °C for 3 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Then 100 ml of water was added to the obtained residue, and the precipitate was filtered and dried to give the crude product, which was purified by reverse phase column chromatography [Column: X select C18 (250*19) mm, 5 5 microns, Mobile phase: A: 0.1% HCOOH in water, B: Acetonitrile] to afford 3-(5-bromo-3- methyl-2-oxo-benzimidazol-1-yl)-3-methyl-piperidine-2,6-dion e (7, 2.1 g, 5.52 mmol, 65% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 352.0 [M + H] ⁺ . Step-5: To a 40 ml screw-capped vial containing a well-stirred solution of 3-(5-bromo-3-methyl-2-oxo- 10 benzimidazol-1-yl)-3-methyl-piperidine-2,6-dione (7, 1.5 g, 3.94 mmol) in THF (15 mL) and water (1 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyridine-1-carboxylate (8, 1.34 g, 4.34 mmol), K3PO4 (1.51 g, 7.10 mmol) and the reaction mixture was degassed with N2 for about 5 min before XPhos-Pd-G2 (232.71 mg, 295.77 μmol) was added at room temperature under nitrogen atmosphere. The resulting reaction mixture 15 was stirred at 80 °C for 2 hr. The reaction mixture was then cooled to room temperature, water (30 ml) was added, and the mixture was extracted with ethyl acetate (2 × 40 ml). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was purified by flash column chromatography (70% ethyl acetate in petroleum ether) to afford tert-butyl 4-[3-methyl-1-(3-methyl-2,6-dioxo-3-piperidyl)-2-oxo- 20 benzimidazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (9, 1.55 g, 3.21 mmol, 82% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 399.2 [M – isobutene + H] ⁺ . Step-6: An oven dried 250 mL single-neck round-bottom flask was charged with tert-butyl 4-[3-methyl- 1-(3-methyl-2,6-dioxo-3-piperidyl)-2-oxo-benzimidazol-5-yl]- 3,6-dihydro-2H-pyridine-1- 25 carboxylate (9, 1.8 g, 3.73 mmol) in dioxane (40 mL). The contents were degassed with N ₂ followed by the addition of palladium hydroxide on carbon, 20 wt.% 50% water (883.14 mg, 6.29 mmol). The resulting mixture was stirred at room temperature under hydrogen atmosphere (1kg pressure) for 16 h. Upon completion, the reaction mixture was filtered through a pad of Celite and the Celite bed was washed with 50% 1,4-dioxane in ethyl acetate (500 mL). The filtrate30 was concentrated under reduced pressure to afford tert-butyl 4-[3-methyl-1-(3-methyl-2,6-dioxo- 258

3-piperidyl)-2-oxo-benzimidazol-5-yl]piperidine-1-carboxy late (10, 1.75 g, 3.66 mmol, 98% yield) . LC-MS (ES ⁺ ): m/z 401.6 [M – isobutene + H] ⁺ . Step-7: The enantiomers of tert-butyl 4-[3-methyl-1-(3-methyl-2,6-dioxo-3-piperidyl)-2-oxo- 5 benzimidazol-5-yl]piperidine-1-carboxylate (10, 500 mg, 1.05 mmol) was separated by chiral SFC following the method: YMC Cellulose-SA, Flowrate : 5 mL/minutes, Co-Solvent : 40%, Co- Solvent Name : IPA, Injected Volume : 7μL, Temperature : 35 °C, Outlet Pressure: 100 bar. The early eluting peak at RT = 2.10 min was concentrated under reduced pressure to give tert-butyl 4- [3-methyl-2-oxo-1-[(3R)-3-methyl-2,6-dioxo-3-piperidyl]benzi midazol-5-yl]piperidine-1- 10 carboxylate (11, 220 mg, 0.481 mmol, 46% yield) as an off-white solid. Note: Configurations are arbitrarily assigned. LC-MS (ES ⁺ ): m/z 401.2 [M – isobutene + H] ⁺ . [a] ^22.9 = 17.0 (c 0.6, ACN). Step-8: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[3- methyl-2-oxo-1-[(3R)-3-methyl-2,6-dioxo-3-piperidyl]benzimid azol-5-yl]piperidine-1-15 carboxylate (11, 101.01 mg, 0.219 mmol) in anhydrous DCM (3 mL) was added 4 N HCl in 1,4- dioxane (0.547 mL) at 0 °C. The resulting solution was stirred at ambient temperature for 1 h. The volatiles were then evaporated under reduced pressure to afford (R)-3-methyl-3-(3-methyl-2- oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl) piperidine-2,6-dione hydrochloride (12, 80 mg, 0.201 mmol, 91% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 357.2 20 [M + H] ⁺ . 259

Example 18 Synthesis of 1-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxaz ol-6-yl) piperidine-4-carboxylic acid 5 To a 100 mL sealed tube containing a well-stirred solution of 5-fluoro-2-nitro-phenol (1, 2 g, 12.73 mmol) and tert-butyl piperidine-4-carboxylate hydrochloride (2, 3.39 g, 15.28 mmol) in anhydrous DMSO (15 mL) was added 4-methylmorpholine (5.15 g, 50.92 mmol, 5.6 mL) at ambient temperature under nitrogen atmosphere. The resulting reaction mixture was stirred at 100 10 °C for 16 h. Progress of reaction mass was monitored by UPLC-MS. Upon consumption of the starting material, the reaction mixture was diluted with cold water, and the precipitate was filtered and dried to afford the tert-butyl 1-(3-hydroxy-4-nitro-phenyl) piperidine-4-carboxylate (3, 4.1 g, 12.46 mmol, 98% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 323.0 [M + H] ⁺ . 260

Step-2: To a 250 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 1-(3- hydroxy-4-nitro-phenyl) piperidine-4-carboxylate (3, 4.2 g, 12.77 mmol) in anhydrous 1,4- dioxane (50 mL) was added Palladium hydroxide on carbon, 20 wt.% 50% water (4.48 g, 6.38 5 mmol) at ambient temperature. The resulting mixture was stirred at this temperature under hydrogen atmosphere (~1 atm) for 16 h. The reaction was monitored by UPLC. After consumption of the starting material, the reaction mixture was passed through a pad of Celite and the filtrate was concentrated under reduced pressure to afford tert-butyl 1-(4-amino-3-hydroxy-phenyl) piperidine-4-carboxylate (4, 3.8 g, 11.57 mmol, 91% yield) as a pink solid. LC-MS (ES ⁺ ): m/z 10 293.2 [M + H] ⁺ . Step-3: To a 100 mL single- neck round-bottom flask containing a well-stirred solution of tert-butyl 1-(4- amino-3-hydroxy-phenyl) piperidine-4-carboxylate (4, 3.8 g, 11.57 mmol) in anhydrous THF (40 mL) was added carbonyldiimidazole (2.81 g, 17.35 mmol) at 25 °C under inert atmosphere. After 15 completion of the addition, the reaction mixture was stirred at the same temperature for 16 h by which time TLC indicated complete consumption of starting material. The reaction mixture was concentrated under reduced pressure to give a crude residue which was purified by flash column chromatography (230-400 mesh silica gel, 0-100% EtOAc/petroleum ether) to afford tert-butyl 1- (2-oxo-3H-1,3-benzoxazol-6-yl)piperidine-4-carboxylate (5, 2.6 g, 8 mmol, 69% yield) as a 20 pink solid. LC-MS (ES ⁺ ): m/z 319.0 [M + H] ⁺ . Step-4: To a 500 mL three- neck round-bottom flask containing a well-stirred solution of tert-butyl 1-(2- oxo-3H-1,3-benzoxazol-6-yl) piperidine-4-carboxylate (5, 2.5 g, 7.70 mmol) in anhydrous THF (15 mL) was added sodium hydride (4.31 g, 107.74 mmol, 60% dispersion in mineral oil) in 25 portions at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 1 h. Subsequently, 3-bromopiperidine-2,6-dione (6, 8.87 g, 46.17 mmol) in anhydrous THF (15 mL) was added to the reaction mixture at 0 °C and reaction mixture was heated to 65 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to 0 °C and excess reagent was quenched with saturated ammonium chloride solution 30 (60 mL) dropwise and the aqueous phase was extracted with EtOAc (3 × 200 mL). The combined organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under 261 reduced pressure to give a crude solid, which was purified by flash column chromatography (230- 400 mesh silica gel) to afford tert-butyl 1-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl] piperidine-4-carboxylate (7, 1.5 g, 3.49 mmol, 45% yield) as a light blue solid. LC-MS (ES ⁺ ): m/z 430.4 [M + H] ⁺ . 5 Step-5: To a 250 mL single-neck round-bottom flask containing a solution of tert-butyl 1-[3-(2,6-dioxo- 3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl] piperidine-4-carboxylate (7, 1.5 g, 3.49 mmol) in anhydrous DCM (20 mL) was added 4M HCl in dioxane (8.73 mL) at 0 °C. The reaction mixture was stirred at ambient temperature for 16 h and the reaction progress was monitored by LCMS. 10 The reaction mixture was concentrated under reduced pressure to give the crude product, which was washed with MTBE to afford 1-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl] piperidine-4-carboxylic acid hydrochloride (8, 1.4 g, 3.38 mmol, 97% yield) as a blue solid. LC- MS (ES ⁺ ): m/z 374.2 [M + H] ⁺ . 15 Example 19 Synthesis of 6-(3-(2,6-Dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxaz ol-7-yl)hexanal

Step-1: To a 250 mL single-neck round-bottom flask containing a well-stirred solution of 2-amino-6- bromo-phenol (1, 3 g, 15.96 mmol) in anhydrous THF (60 mL) was added 1,1'- carbonyldiimidazole (7.76 g, 47.87 mmol) at ambient temperature. The resulting mixture was 5 stirred at 80 °C for 2 h and monitored by UPLC. Upon completion of the reaction, THF was removed from the reaction mixture under reduced pressure. The reaction crude was diluted with EtOAc (200 mL) and the organic layer was washed with aqueous 1.5N HCl solution (2 × 75 mL), dried over anhydrous Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure to afford 7-bromo-3H-1,3-benzoxazol-2-one (2, 3.1 g, 14.47 mmol, 91% yield) as a brown solid. 10 LC-MS (ES-): m/z 213.8 [M - H] -. Step-2: To a 500 mL three- neck round-bottom flask containing a well-stirred solution of 7-bromo-3H- 1,3-benzoxazol-2-one (2, 3.1 g, 14.48 mmol) in anhydrous THF (100 mL) was added sodium hydride (3.33 g, 86.91 mmol; 60% dispersion in mineral oil) at 0 °C. The resulting mixture was 15 stirred at 0 °C for 0.5 h. Then, 3-bromopiperidine-2,6-dione (3, 8.34 g, 43.45 mmol) in anhydrous THF (30 mL) was added slowly at 0 °C and stirring was continued for 16 h at 60 °C. Upon completion of the reaction, the reaction mixture was quenched with saturated NH ₄ Cl solution at 0 °C. The aqueous phase was extracted with EtOAc (3 × 75 mL) and the combined organic phase was dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced20 pressure to give a crude residue, which was recrystallized with acetic acid to afford 3-(7-bromo- 2-oxo-1,3-benzoxazol-3-yl) piperidine-2,6-dione (4, 1.7 g, 5.21 mmol, 36% yield) as a white solid. LC-MS (ES-): m/z 324.8 [M - H] -. Step-3: To a 50 mL sealed tube containing a well-stirred solution of 3-(7-bromo-2-oxo-1,3-benzoxazol-3- 25 yl) piperidine-2,6-dione (4, 0.5 g, 1.53 mmol) and hex-5-yn-1-ol (5, 450.86 mg, 4.59 mmol, 0.512 mL) in anhydrous acetonitrile (7 mL) was added TEA (619.81 mg, 6.13 mmol, 0.853 mL) at ambient temperature. The reaction mixture was purged with nitrogen gas for 10 minutes. Subsequently, copper (I) iodide (43.75 mg, 0.229 mmol) and dichlorobis(triphenylphosphine)palladium(II) (107.48 mg, 0.153 mmol) were added 30 and stirring was continued at 90 °C for 16 h, and the reaction progress was monitored by UPLC. Upon completion of the reaction, the reaction mixture was passed through a pad of Celite and the 263

filtrate was concentrated under reduced pressure to give a crude residue, which was purified by flash column chromatography (230-400 mesh silica gel, 90-95% EtOAc/petroleum ether) to afford 3-[7-(6-hydroxyhex-1-ynyl)-2-oxo-1,3-benzoxazol-3-yl] piperidine-2,6-dione (6, 0.35 g, 0.899 mmol, 59% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 343.3 [M + H] ⁺ . 5 Step-4: To a 50 mL single- neck round-bottom flask containing a well-stirred solution of 3-[7-(6- hydroxyhex-1-ynyl)-2-oxo-1,3-benzoxazol-3-yl] piperidine-2,6-dione (6, 0.35 g, 0.899 mmol) in anhydrous 1,4-dioxane (4 mL) was added Palladium hydroxide on carbon, 20 wt.% 50 % water (315.87 mg, 0.449 mmol) at ambient temperature. The resulting reaction mixture was stirred for 6 10 h at ambient temperature under hydrogen atmosphere (1 atm). Upon completion of the reaction as indicated by UPLC, the reaction mixture was passed through a pad of Celite and Celite bed was washed with THF (100 mL). The combined filtrate was concentrated under reduced pressure to afford 3-[7-(6-hydroxyhexyl)-2-oxo-1,3-benzoxazol-3-yl] piperidine-2,6-dione (7, 0.3 g, 0.743 mmol, 83% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 347.0 [M + H] ⁺ . 15 Step-5: To a 100 mL single- neck round-bottom flask containing a well-stirred solution of 3-[7-(6- hydroxyhexyl)-2-oxo-1,3-benzoxazol-3-yl] piperidine-2,6-dione (7, 0.3 g, 0.743 mmol) in anhydrous DMF (4 mL) was added Dess-Martin Periodinane (472.73 mg, 1.11 mmol) at 0 °C. The resulting mixture was stirred at ambient temperature for 2 h. Upon completion of the reaction as 20 indicated by UPLC, the reaction mixture was quenched with aqueous saturated sodium thiosulphate (5 mL) and aqueous saturated sodium bicarbonate (5 mL) solutions. Aqueous layer was extracted with DCM (3 × 40 mL). The combined organic phase was dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 6-[3-(2,6- dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl] hexanal (8, 0.24 g, 0.411 mmol, 55% yield) as an 25 off-white solid. LC-MS (ES ⁺ ): m/z 367.0 [M + Na] ⁺ . 264

Example 20 Synthesis of 6-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4- yl]amino]methyl]triazol-1-yl]hexanoic acid 5 as prepared following the method described on page 357 of WO2017197056 A1. To a stirred solution of 2-(2,6-dioxo-3-piperidyl)-4-(prop-2-ynylamino)isoindoline-1, 3-dione (1, 5 g, 16.06 mmol)and 6-azidohexanoic acid (2.52 g, 16.06 mmol) in water (25 mL) and THF (100 mL) were added (+)-sodium L-ascorbate (3.18 g, 16.06 mmol) and copper sulfate pentahydrate 10 (4.01 g, 16.06 mmol) at room temperature and stirred for 2 h. After completion of the reaction, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography (C18 column, 10mM ammonium acetate in water and acetonitrile as an eluent) to afford 6-[4-[[[2-(2,6-dioxo-3- 15 piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1- yl]hexanoic acid (3, 4.15 g, 8.55 mmol, 53.21% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 469.29 [M + H] ⁺ . Example 21 3-[1-methyl-6-(4-piperidyl)indazol-3-yl]piperidine-2,6-dione 20 265

Compound 3-[1-methyl-6-(4-piperidyl)indazol-3-yl]piperidine-2,6-dione was prepared following the method described on page 197-200 of WO2021127586 A1. Example 22 5 Synthesis of (R)-3-methyl-3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl) piperidine-2,6- dione 266

To a 1000 mL three-neck round bottom flask containing a well-stirred solution of methyl 6-bromo- 1H-indazole-3-carboxylate (1, 25 g, 98.01 mmol) in anhydrous MeCN (710.34 mL) were 5 added potassium carbonate, anhydrous, 99% (135.46 g, 980.13 mmol) and methyl iodide (69.56 g, 490.07 mmol, 30.51 mL) at ambient temperature. The resulting mixture was stirred at this temperature for 3 h and the reaction progress was monitored by UPLC. The reaction mixture was then passed through a pad of Celite, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (230-400 mesh silica10 gel, 35-40% EtOAc in petroleum ether) to afford methyl 6-bromo-1-methyl-indazole-3- carboxylate (2, 13.45 g, 49.47 mmol, 50 % yield) as an off-white solid and methyl 6-bromo-2- methyl-3,3a-dihydroindazole-3-carboxylate (3, 5.5 g, 19.66 mmol, 20% yield) as a pale yellow solid. 2: LCMS (ES+): m/z 271.0 [M+H] ⁺ . 15 3: LCMS (ES+): m/z 271.0 [M+H] ⁺ . Step-2: To a 2000 mL three-neck round bottom flask containing a well-stirred solution of methyl 6-bromo- 1-methyl-indazole-3-carboxylate (2, 13.14 g, 48.31 mmol) in THF (119.48 mL) was added DIBAL-H (1.2 M, 80.52 mL) at 0°C. The reaction was stirred at ambient temperature for 3 20 h and monitored by TLC and UPLC. Upon completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (3 × 200 mL). The organic phase was washed with water (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (silica gel, 230-400 mesh, 35-40% 25 Ethyl Acetate in Petroleum Ether) to afford (6-bromo-1-methyl-indazol-3-yl)methanol (4, 8.6 g, 35.57 mmol, 74% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 241.0 [M + H] ⁺ . Step-3: 267

To a 500 mL single-neck round bottom flask containing a well-stirred solution of (6-bromo-1- methyl-indazol-3-yl)methanol (4, 20 g, 82.96 mmol) in dichloromethane (150 mL) was added thionyl chloride (29.61 g, 248.88 mmol, 18.05 mL) at 0°C. The reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC and UPLC. Upon completion of 5 the reaction, the reaction mixture was concentrated under reduced pressure to afford 6-bromo-3- (chloromethyl)-1-methyl-indazole (5, 20.5 g, 74.77 mmol, 90% yield) as an off-white solid. UPLC-MS (ES ⁺ ): m/z 261.1 [M + H] ⁺ . Step-4: To a 250 mL round bottom flask with 6-bromo-3-(chloromethyl)-1-methyl-indazole (5, 8.5 g, 10 21.69 mmol) in DMF (50 mL) was added sodium cyanide (2.13 g, 43.39 mmol) at ambient temperature. The resulting reaction mixture was stirred at 60 °C for 16 h. Progress of the reaction was monitored by TLC and UPLC. Upon completion of the reaction, the reaction mixture was cooled to room temperature and poured into water (150 mL) and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous 15 sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (230-400 mesh silica gel, 30-40% ethyl acetate in petroleum ether) to afford 2-(6-bromo-1-methyl-indazol-3-yl)acetonitrile (6, 5.2 g, 20.71 mmol, 95% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 251.6 [M + H] ⁺ . Step-5: 20 To a 250 mL single-neck round bottom flask containing a well stirred solution of 2-(6-bromo-1- methyl-indazol-3-yl)acetonitrile (6, 1.8 g, 7.13 mmol) in tetrahydrofuran (100.00 mL) was added potassium bis(trimethylsilyl)amide (1 M, 7.13 mL) at -78°C over 10 min. The resulting reaction mixture was stirred at -78°C for 1 h. Methyl iodide (1.01 g, 7.13 mmol, 443.58 μL) was then added dropwise at -78°C. The resulting reaction mixture was stirred at -78°C for 20 25 min and the reaction progress was monitored by TLC and UPLC. The reaction mixture was then quenched with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (2 × 200 mL). The organic layer was washed with water (2 × 150mL), 10% sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (230-400 mesh30 silica gel, 35-40% ethyl acetate in petroleum ether) to afford 2-(6-bromo-1-methyl-indazol-3- 268

yl)propanenitrile (7, 480 mg, 1.49 mmol, 21% yield, off-white solid) and 2-(6-bromo-1-methyl- indazol-3-yl)-2-methyl-propanenitrile (8, 100 MG, 265.15 μmol, 4% yield). 7: UPLC-MS (ES ⁺ ): m/z 264.0 [M + H] ⁺ . 8: UPLC-MS (ES ⁺ ): m/z 278.1 [M + H] ⁺ . 5 Step-6: To a 250 mL single-neck round bottom flask containing a well stirred solution of 2-(6-bromo-1- methyl-indazol-3-yl)propanenitrile (7, 2.5 g, 8.73 mmol) in dioxane (36.51 mL) were added methyl acrylate (1.50 g, 17.45 mmol, 1.57 mL), benzyltrimethylammonium hydroxide, 40 wt. % (1.82 g, 4.36 mmol, 1.92 mL) at 0 °C. The resulting reaction mixture was stirred at room 10 temperature for 2 h. The reaction mixture was then quenched with saturated ammonium chloride solution (20 mL) at 0°C and extracted with ethyl acetate (2 × 30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 4-(6-bromo-1-methyl-indazol-3-yl)-4-cyano-pentanoate (9, 2.8 g, 7.08 mmol, 81% yield) as a yellow oil. LC-MS (ES ⁺ ): m/z 350.0 [M + H] ⁺ . 15 Step-7: To a 20 mL pressure vial containing a well-stirred solution of methyl 4-(6-bromo-1-methyl- indazol-3-yl)-4-cyano-pentanoate (9, 2.4 g, 3.77 mmol) were added acetic acid (11.32 g, 188.46 mmol, 10.79 mL) and sulfuric acid (369.68 mg, 3.77 mmol, 202.01 μL) at room temperature. The reaction mixture was stirred at 110 °C for 3 h while monitoring by UPLC and TLC. Upon 20 completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to give a residue, which was diluted with ethyl acetate (50 mL). The organics was then washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (230-400 mesh silica gel, 45-55% ethyl acetate in petroleum 25 ether) to afford 3-(6-bromo-1-methyl-indazol-3-yl)-3-methyl-piperidine-2,6-di one (10, 1.10 g, 3.12 mmol, 83% yield). LC-MS (ES ⁺ ): m/z 337.0 [M + H] ⁺ . Step-8: To a 20 mL glass-vial containing a well-stirred solution of 3-(6-bromo-1-methyl-indazol-3-yl)-3- methyl-piperidine-2,6-dione (10, 0.6 g, 1.78 mmol) in anhydrous DMF (10.02 mL) was30 added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyridine-1- carboxylate (11, 827.78 mg, 2.68 mmol) and cesium fluoride (542.20 mg, 3.57 mmol) at ambient 269

temperature. The reaction mixture was purged with nitrogen gas for 10 minutes. Subsequently, Pd(dppf)Cl2·DCM (291.50 mg, 0.356 mmol) was added and stirring was continued at 90 °C for 2 h. After completion of the reaction as shown by TLC, the reaction mixture was passed through a pad of Celite and the Celite bed was washed with EtOAc (350 mL). The filtrate 5 was concentrated under reduced pressure to give a crude mass which was purified by flash column chromatography (230-400 mesh silica gel, 40-50% EtOAc/petroleum ether) to afford tert-butyl 4- [1-methyl-3-(3-methyl-2,6-dioxo-3-piperidyl) indazol-6-yl]-3,6-dihydro-2H-pyridine-1- carboxylate (12, 850 mg, 1.71 mmol, 96% yield) as a brown solid. LC-MS (ES ⁺ ): m/z 439.3 [M + H] ⁺ . 10 Step-9: To a 25 mL single- neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[1- methyl-3-(3-methyl-2,6-dioxo-3-piperidyl) indazol-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (12, 850 mg, 1.71 mmol) in anhydrous 1,4-dioxane (10 mL) was added Palladium hydroxide on carbon, 20 wt.% 50% water (1.20 g, 1.71 mmol) at ambient temperature under nitrogen 15 atmosphere. The resulting mixture was stirred at ambient temperature under hydrogen atmosphere for 16 h. The progress of the reaction was monitored by TLC/UPLC. After complete consumption of the starting material, the reaction mixture was filtered through a pad of Celite and the Celite bed was washed with 1,4-dioxane (100 mL). The combined filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (230-40020 mesh silica gel, 40-50% EtOAc/petroleum ether) to afford tert-butyl 4-[1-methyl-3-(3-methyl-2,6- dioxo-3-piperidyl) indazol-6-yl]piperidine-1-carboxylate (13, 570 mg, 1.29 mmol, 76% yield) as a white solid. LC-MS (ES ⁺ ): m/z 385.2 [M -isobutene + H] ⁺ . Step-10: The enantiomers were separated by chiral SFC, Method details: Column Name: Lux A1, Co- 25 Solvent: 40% and Co-Solvent Name: IPA; Outlet Pressure: 100 bar; Temperature: 35 °C. After the separation, the first eluted fraction with RT = 2.30 minutes (arbitrarily assigned as R- isomer) was concentrated under reduced pressure to afford tert-butyl (R)-4-(1-methyl-3-(3- methyl-2,6-dioxopiperidin-3-yl)-1H-indazol-6-yl) piperidine-1-carboxylate (14, 200 mg, 0.444 mmol, 35% yield) (Chiral purity = 100%) as an off-white gum. ¹ H NMR (400 MHz, DMSO-d6). 30 δ10.85 (s, 1H), 7.72 (d, J = 11.2 Hz, 1H), 7.47 (s, 1H), 7.04 (d, J = 11.20 Hz, 1H), 4.12 (d, J = 270

11.6 Hz, 2H), 3.96-3.94 (m, 3H), 2.82-2.74 (m, 3H), 2.43-2.28 (m, 2H), 2.15-2.11 (m, 1H), 1.81 (d, J = 14.8 Hz, 2H), 1.64-1.54 (m, 5H) and 1.43 (s, 9H). LC-MS (ES ⁺ ): m/z 441.2 [M + H] ⁺ . Step-11: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (R)-4- 5 (1-methyl-3-(3-methyl-2,6-dioxopiperidin-3-yl)-1H-indazol-6- yl) piperidine-1-carboxylate (14, 85 mg, 0.192 mmol) in anhydrous DCM (2 mL) was added 4M HCl in 1,4-dioxane (0.48 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude product, which was washed with MTBE (2 mL) and dried to afford (R)-3-methyl-3-(1-methyl-6-(piperidin- 10 4-yl)-1H-indazol-3-yl) piperidine-2,6-dione hydrochloride (15, 73 mg, 0.190 mmol, 99% yield) as a white solid. LC-MS (ES ⁺ ): m/z 341.2 [M + H] ⁺ . Example 23 Synthesis of 1-(3-(2,6-Dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)pipe ridine-4- 15 carboxylic acid 271

To a 40 ml glass-vial containing a well-stirred solution of tert-butyl piperidine-4-carboxylate hydrochloride (2, 779.87 mg, 3.52 mmol) in 1,4 dioxane (8 mL) was added 6-bromo-3-(2,6- dibenzyloxy-3-pyridyl)-1-methyl-indazole (1, 800 mg, 1.60 mmol) at ambient temperature under nitrogen. The reaction mixture was degassed with N ₂ for 5 minutes followed by the addition 5 of cesium carbonate (1.30 g, 4.00 mmol) at the same temperature. After degassing for another 5 minutes, RuPhos (89.53 mg, 0.191 mmol) and RuPhos-Pd-G3 (66.86 mg, 0.079 mmol) were added and the reaction mixture was stirred at 100 °C for 16 h. The progress of the reaction was monitored by TLC/LCMS. After 16 h, reaction mixture was filtered through a pad of Celite and Celite bed was washed with EtOAc (2 × 50 mL). The combined organic phase was concentrated 10 under reduced pressure to give the crude product, which was purified by flash column chromatography (230-400 mesh silica gel, 15% EtOAc/petroleum ether) to afford tert-butyl 1-[3- (2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]piperidine -4-carboxylate (3, 360 mg, 0.577 mmol, 36% yield) as a brown liquid. LC-MS (ES ⁺ ): m/z 605.3 [M + H] ⁺ . Step-2: 15 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 1-[3- (2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]piperidine -4-carboxylate (3, 370 mg, 0.593 mmol) in anhydrous 1,4 dioxane (3 mL) was added Palladium hydroxide on carbon, 20 wt.% 50% water (666.79 mg, 0.949 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 16 h under hydrogen atmosphere. After the starting material was 20 consumed as indicated by UPLC, reaction mixture was passed through a pad of Celite and the Celite bed was washed with 1,4-dioxane (150 mL). The combined filtrate was concentrated under reduced pressure to give tert-butyl 1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]piperidin e- 4-carboxylate (4, 280 mg, 0.590 mmol, 97% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 427.6 [M + H] ⁺ . 25 Step-3: To a 50 ml single-neck round-bottom flask containing a well-stirred solution of tert-butyl 1-[3- (2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]piperidine-4-c arboxylate (4, 370 mg, 0.780 mmol) in anhydrous DCM (4 mL) was added 4M HCl in 1,4- dioxane (1.95 mL) at 0 °C. The reaction mixture was stirred for 2 h at ambient temperature. The reaction progress was monitored 30 by LCMS. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a crude residue, which was washed with MTBE to afford 1-[3-(2,6-dioxo-3- 272

piperidyl)-1-methyl-indazol-6-yl]piperidine-4-carboxylic acid hydrochloride (5, 330 mg, 0.705 mmol, 90% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 371.3 [M + H] ⁺ . Example 24 5 Synthesis of (R)-1-(1-Methyl-3-(3-methyl-2,6-dioxopiperidin-3-yl)-1H-inda zol-6-yl) piperidine-4-carboxylic acid hydrochloride To a 25 mL sealed tube containing a well-stirred solution of 3-(6-bromo-1-methyl-indazol-3-yl)- 10 3-methyl-piperidine-2,6-dione (1, 380 mg, 1.13 mmol) and tert-butyl piperidine-4-carboxylate hydrochloride (2, 418.82 mg, 1.89 mmol) in anhydrous 1,4-dioxane (8 mL) was added cesium carbonate (920.71 mg, 2.83 mmol) at ambient temperature. The reaction mixture was purged with nitrogen gas for 10 minutes. Subsequently, Pd‐PEPPSI‐IHeptCl (109.96 mg, 0.113 mmol) was added and stirring was continued at 100 °C for 16 h while the reaction progress was monitored by 15 UPLC. Reaction mixture was passed through a pad of Celite and the filtrate was concentrated under reduced pressure to give a crude residue, which was purified by flash column chromatography (230-400 mesh silica gel, 40% EtOAc/petroleum ether) to afford tert-butyl 1-[1- methyl-3-(3-methyl-2,6-dioxo-3-piperidyl) indazol-6-yl]piperidine-4-carboxylate (3, 400 mg, 0.792 mmol, 70% yield) as a pale yellow solid. LC-MS (ES ⁺ ): m/z 441.2 [M + H] ⁺ . 273

Step-2: The enantiomers (3) were separated by chiral SFC, Method details: Column Name: Chiral Pak AS- H, Co-Solvent: 40% and Co-Solvent Name: IPA; Outlet Pressure: 100 bar; Injected Volume: 0.007 ml, Temperature: 35 °C. After the separation, the early eluting peak with RT = 1.61 5 min (arbitrarily assigned as R-isomer) were concentrated under reduced pressure to afford tert- butyl (R)-1-(1-methyl-3-(3-methyl-2,6-dioxopiperidin-3-yl)-1H-inda zol-6-yl) piperidine-4- carboxylate (4, 150 mg, 0.311 mmol, 38% yield) (Chiral purity = 100%) as an off-white gum. LC- MS (ES ⁺ ): m/z 441.2 [M + H] ⁺ . Step-3: 10 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (R)-1- (1-methyl-3-(3-methyl-2,6-dioxopiperidin-3-yl)-1H-indazol-6- yl) piperidine-4-carboxylate (4, 150 mg, 0.323 mmol) in anhydrous DCM (4 mL) was added 4N HCl in 1,4-dioxane (0.808 mL) at 0 °C. The resulting solution was stirred at ambient temperature for 16 h. Upon completion of the reaction as indicated by UPLC-MS, the volatiles were evaporated under reduced pressure to afford 15 (R)-1-(1-methyl-3-(3-methyl-2,6-dioxopiperidin-3-yl)-1H-inda zol-6-yl) piperidine-4-carboxylic acid hydrochloride (5, 130 mg, 0.282 mmol, 87% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 385.2 [M + H] ⁺ . Example 25 20 3-[3-fluoro-4-(4-piperidyl)anilino]piperidine-2,6-dione hydrochloride 4-piperidyl)anilino]piperidine-2,6-dione hydrochloride was prepared following the method described on page 353-355 of WO2021127561 A1. 274

Example 26 Synthesis of 4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl] -4-oxo-butanoic acid 5 ng the method described on page 268 of WO2018237026 A1. Step-1: To a solution of 3-(4-piperazin-1-ylanilino)piperidine-2,6-dione (1, 800 mg, 2.46 mmol, HCl salt) in DMF (5 mL) was added DIPEA (3.18 g, 24.63 mmol, 4.29 mL), 4-tert-butoxy-4-oxo- 10 butanoic acid (2, 514.85 mg, 2.96 mmol) and HATU (1.40 g, 3.69 mmol) at 25°C. The reaction mixture was allowed to stir at 25°C for 4 h. Upon completion of the reaction, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with water (3 × 50 mL), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford tert-butyl 4-[4-[4-[(2,6-dioxo-3- 15 piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoate (3, 900 mg, 1.65 mmol, 66.95% yield) as a dark grey solid. LCMS (ES ⁺ ): m/z 445.2 [M+H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[4- [4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-4-ox o-butanoate (3, 700 mg, 1.57 20 mmol) in DCM (3 mL) was added TFA (5.92 g, 51.92 mmol, 4 mL) at 0°C and the reaction mixture was stirred at ambient temperature for 5 h. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure and the residue was 275

washed with MTBE (2 × 5 ml) to afford 4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin- 1-yl]-4-oxo-butanoic acid (4, 500 mg, 993.05 µmol, 63.06% yield, TFA salt) as green solid. LCMS (ES ⁺ ): m/z 388.8 [M+H] ⁺ . 5 Example 27 Synthesis of 1-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperidine-4-carbo xylic acid To a 100 mL sealed tube containing a well-stirred solution of 1-benzyloxy-4-bromo-benzene (1, 2 10 g, 7.60 mmol) and tert-butyl piperidine-4-carboxylate hydrochloride (2, 3.37 g, 15.20 mmol) in anhydrous 1,4-dioxane (30 mL) was added cesium carbonate (6.19 g, 19.00 mmol) at ambient temperature. Nitrogen gas was purged through the reaction mixture for 10 minutes. Subsequently, RuPhos (532.03 mg, 1.14 mmol) and RuPhos-Pd-G3 (635.71 mg, 0.760 mmol) were added and stirred at 110 °C for 16 h. Upon completion of the reaction as indicated by UPLC, the reaction 15 mixture was passed through a pad of Celite and the Celite bed was washed with EtOAc (100 mL). The combined filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (230-400 mesh silica gel, 10% EtOAc/petroleum ether) to afford tert-butyl 1-(4-benzyloxyphenyl)piperidine-4-carboxylate (3, 1.6 g, 4.14 mmol, 54% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 368.2 [M + H] ⁺ . 276

Step-2: To a 50 mL single-neck round bottom flask containing a well-stirred solution of tert-butyl 1-(4- benzyloxyphenyl)piperidine-4-carboxylate (3, 1.6 g, 4.14 mmol) in 1:1 anhydrous MeOH/EtOAc (20 mL) was added Palladium hydroxide on carbon, 20 wt.% 50% water (1.00 g, 1.43 mmol) at 5 ambient temperature. The resulting mixture was stirred at this temperature under hydrogen atmosphere (~1 atm) for 16 h and the reaction progress was monitored by UPLC. The reaction mixture was passed through a pad of Celite and Celite bed was washed with EtOAc (100 mL). The combined filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (230-400 mesh silica gel, 25% EtOAc/petroleum ether) 10 to afford tert-butyl 1-(4-hydroxyphenyl)piperidine-4-carboxylate (4, 1 g, 3.32 mmol, 80% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 278.2 [M + H] ⁺ . Step-3: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 1-(4- hydroxyphenyl)piperidine-4-carboxylate (4, 1 g, 3.32 mmol) in anhydrous DMF (10 mL) was 15 added sodium hydride (190.64 mg, 4.98 mmol, 60% dispersion in mineral oil) at 0 °C under nitrogen atmosphere and the resulting mixture was stirred for 15 minutes at 0 °C. Subsequently, 3- bromopiperidine-2,6-dione (5, 1.27 g, 6.63 mmol) in anhydrous DMF (10 mL) was added at 0 °C and resulting mixture was stirred at ambient temperature for 16 h. The reaction was monitored by UPLC. The reaction mixture was quenched with cold water and aqueous layer was extracted 20 with EtOAc (3 × 50 mL). The combined organic phase was dried over anhydrous Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (230-400 mesh silica gel, 60% EtOAc/petroleum ether) to afford tert-butyl 1-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]piperidine-4-carboxy late (6, 0.6 g, 1.37 mmol, 41% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 389.5 [M + H] ⁺ . 25 Step-4: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 1-[4- [(2,6-dioxo-3-piperidyl)oxy]phenyl]piperidine-4-carboxylate (6, 0.6 g, 1.37 mmol) in anhydrous DCM (5 mL) was added 4N HCl in 1,4-dioxane (6 mL) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at this temperature for 6 h and the reaction 30 was monitored by UPLC. Upon completion of the reaction, the solvent was removed from the reaction mixture to yield a crude compound which was co-evaporated with toluene (7 mL) to 277

afford 1-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]piperidine-4-carboxy lic acid (7, 0.55 g, 1.06 mmol, 77% yield) as a white solid. LC-MS (ES ⁺ ): m/z 333.2 [M + H] ⁺ . Example 28 5 Synthesis of 1-[1-methyl-6-(4-piperidyl)indazol-3-yl]hexahydropyrimidine- 2,4-dione hydrochloride 10 00 mL) was added methyl hydrazine (2, 85% aqueous solution) (51.83 g, 1.12 mol) at room temperature. The reaction mixture was heated at 125 °C in an autoclave for 7 hours. The reaction mixture was cooled to room temperature and poured into ice cold water (2000 ml) and stirred for15 30 minutes. The solidified mass was filtered-off, washed with water, and dried well to afford 6- 278

bromo-1-methyl-1H-indazol-3-amine (3, 25 g, 105.05 mmol, 84% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.63 (s, 2H), 7.02 (d, J = 8.0 Hz,1H), 5.54 (s, 2H), 3.71 (s, 3H). LC-MS (ES ⁺ ): m/z 226.0 [M + H] ⁺ . Step-2: 5 To the stirred solution of 6-bromo-1-methyl-indazol-3-amine (3, 50 g, 221.17 mmol) in hydrochloric acid (2 M, 500.00 mL, 1 mol) was added tetrabutylammonium bromide (7.13 g, 22.12 mmol) at room temperature. The reaction mixture was heated to 55 °C and acrylic acid (4, 23.91 g, 331.75 mmol, 22.77 mL) was added dropwise at this temperature. The reaction was heated to 100 °C for 12 hours. After the reaction was complete, the reaction mixture was 10 cooled to room temperature and diluted with ice cold water (1000 ml). It was neutralized to pH 6.5 -7 with 2 M sodium bicarbonate solution (1000 ml) under fast stirring. The solid precipitate was filtered off, washed with excess ice cold water, and dried to afford 3-[(6-bromo-1-methyl-indazol- 3-yl)amino]propanoic acid (5, 54 g, 163.30 mmol, 74% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 298.28 [M + H] ⁺ . 15 Step-3: To a stirred solution of 3-[(6-bromo-1-methyl-indazol-3-yl)amino]propanoic acid (5, 160 g, 536.67 mmol) in acetic acid (1.07 kg, 17.76 mol, 1.02 L) was added sodium cyanate (46.67 g, 717.88 mmol). The reaction mixture was heated at 100 °C for 12 hours. Upon completion, the reaction was cooled to room temperature, filtered through a Büchner funnel and the filter cake was20 washed with water (2 × 500 mL). The collected solid was dried to yield 1-(6-bromo-1-methyl- indazol-3-yl)hexahydropyrimidine-2,4-dione (6, 175 g, 527.69 mmol, 98% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 323.27 [M + H] ⁺ . Step-4: To a solution of 1-(6-bromo-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dio ne (6, 15 g,25 46.42 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H- pyridine-1-carboxylate (7, 18.66 g, 60.34 mmol) in 1,4-dioxane (150 mL) and water (30 mL) was added sodium acetate, anhydrous (11.42 g, 139.26 mmol) at room temperature. The reaction mixture was degassed with argon gas for 10 minutes and 1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (3.40 g, 4.64 mmol) was added. 30 The reaction mixture was degassed with argon for an additional 5 minutes before it was stirred at 90 °C for 16 hours. Subsequently, the reaction mixture was concentrated in vacuo to yield the 279

crude product, which was purified by column chromatography (silica gel 230-400 mesh, 70% ethyl acetate in petroleum ether) to afford tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (8, 18 g, 34.69 mmol, 75% yield) as a brown solid. LC-MS (ES ⁺ ): m/z 426.44 [M + H] ⁺ . 5 Step-5: A solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-y l]-3,6- dihydro-2H-pyridine-1-carboxylate (8, 3.6g, 8.46 mmol) in ethanol (30 ml) and DCM (10 ml) with a catalytic amount of glacial acetic acid (508.09 mg,8.46 mmol, 484.36 μL) was added to a Parr Shaker hydrogenator. Palladium on carbon, 10 wt. % (3.08 g,25.38 mmol) was added to this 10 mixture under inert atmosphere, and the resulting reaction was stirred for 16 hours at room temperature under hydrogen atmosphere. Upon completion, the reaction was filtered through Celite bed and washed with 10% MeOH/DCM. The filtrate was concentrated under reduced pressure to afford tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6- yl]piperidine-1-carboxylate (9, 3.6 g, 8.17 mmol, 97% yield). LC-MS (ES ⁺ ): m/z 428.45 [M + H] 15 ⁺ . Step-6: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[3- (2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]pip eridine-1-carboxylate (500 mg, 1.15 mmol) in anhydrous 1,4-dioxane (6 mL) was added 4.0 M hydrogen chloride solution in 1,4- 20 dioxane (2.87 mL, 11.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the volatiles were evaporated under vacuum to afford 1-[1-methyl-6-(4-piperidyl)indazol-3-yl]hexahydropyrimidine- 2,4-dione hydrochloride (400 mg, 1.08 mmol, 95% yield) as a pale yellow solid. LC-MS (ES ⁺ ): m/z 328.2 [M + H] ⁺ . 25 280

Example 29 Synthesis of 4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6- yl)piperidin-1-yl)-4-oxobutanoic acid 5 1-[1-methyl-6-(4-piperidyl)indazol-3-yl]hexahydropyrimidine- 2,4-dione hydrochloride (6 g, 16.5 mmol, 1 equiv.) was dissolved in DMF (120 mL).4-(tert-butoxy)-4-oxobutanoic acid (3.16 g, 18.1 mmol, 1.1 equiv.) was added to the reaction mixture. The reaction mixture was cooled to 0 ºC. N,N-diisopropylethylamine (7.17 mL, 5.32 g, 41.25 mmol, 2.5 equiv.) and HATU (9.4 g, 24.8 10 mmol, 1.5 equiv.) were added to the reaction mixture and stirred for 16 hours while warming to room temperature. The reaction mixture was diluted with sodium bicarbonate and extracted twice with ethyl acetate. The organic layer was dried with sodium sulfate, filtered and evaporated under reduced pressure to afford tert-butyl 4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl- 1H-indazol-6-yl)piperidin-1-yl)-4-oxobutanoate (10 g, quantitative yield). LC-MS (ES ⁺ ): m/z 15 484.1 [M + H] ⁺ . Step-2: Stirring at ambient temperature, crude tert-butyl 4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-4-oxobutanoate (10 g) from previous step was dissolved in dicholoromethane (100 mL). Hydrogen chloride (4M solution in 1,4-dioxane, 41.2 281 mL, 165 mmol, 10 equiv.) was added, and the reaction mixture was stirred for 16 hours at ambient temperature. The volatiles were evaporated and the crude product was purified by reverse phase chromatography to afford 4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6-yl)piperidin-1-yl)-4-oxobutanoic acid (5.1 g, 11.9 mmol, 72% yield over 2 steps). LC- 5 MS (ES ⁺ ): m/z 428.1 [M + H] ⁺ . Example 30 7-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6-yl)piperidin-1-yl)- 7-oxoheptanoic acid 10 trahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6- yl)piperidin-1-yl)-7-oxoheptanoic acid was synthesized following the method described in the synthesis of 4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6- yl)piperidin-1-yl)-4-oxobutanoic acid, using 4-(tert-butoxy)-4-oxoheptanoic acid as a building 15 block in Step-1. LC-MS (ES ⁺ ): m/z 470.1 [M + H] ⁺ . Example 31 Synthesis of 1-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihy dropyrimidine- 2,4(1H,3H)-dione 20

Compound 1- ne-2,4-dione was prepared following the method described on page 200-201 of WO2022032026 A1. Step-1: 5 To a 20 mL glass-vial containing a well-stirred solution of 1-(6-bromo-5-fluoro-1-methyl-indazol- 3-yl)hexahydropyrimidine-2,4-dione (1, 250 mg, 0.710 mmol) and tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine -1-carboxylate (2, 329.71 mg, 1.07 mmol) in anhydrous DMF (2.5 mL) was added cesium fluoride (215.96 mg, 1.42 mmol) at ambient temperature. The reaction mixture was purged with nitrogen gas for 5 minutes. 10 Subsequently, Pd(dppf)Cl2.DCM (116.10 mg, 0.142 mmol) was added and stirring was continued at 90 °C for 16 h and the reaction was monitored by UPLC. Upon completion of the reaction, the reaction mixture was passed through a pad of Celite and Celite bed was washed with EtOAc (200 mL). The combined filtrate was concentrated under reduced pressure to give a crude residue which was purified by flash column chromatography (230-400 mesh silica gel, 95%15 EtOAc/petroleum ether) to afford tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1- methyl-indazol-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (3, 300 mg, 0.629 mmol, 89% yield) as a grey solid. LC-MS (ES ⁺ ): m/z 444.2 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[3-20 (2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol -6-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate (3, 250 mg, 0.524 mmol) in anhydrous 1,4-dioxane (5 mL) was added Palladium hydroxide on carbon, 20 % wt. (294.85 mg, 0.419 mmol) at ambient temperature. The reaction mixture was stirred at this temperature under hydrogen atmosphere (~1 atm) for 16 h. Upon completion of the reaction as indicated by UPLC, the reaction mixture was passed through a pad 25 of Celite and the Celite bed was washed with a mixture of 1:1 THF:DMF (250 mL). The combined filtrate was concentrated under reduced pressure to afford tert-butyl 4-[3-(2,4- 283

dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol-6 -yl]piperidine-1-carboxylate (4, 200 mg, 0.412 mmol, 79% yield) as a grey solid. LC-MS (ES ⁺ ): m/z 390.2 [M + H] ⁺ . Step-3: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[3- 5 (2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol -6-yl]piperidine-1-carboxylate (4, 200 mg, 0.412 mmol) in anhydrous DCM (2 mL) was added 4 M HCl in 1,4-dioxane (1.24 mL) at 0 °C. After addition the contents were stirred at ambient temperature under nitrogen atmosphere for 2 h and monitored by UPLC. After completion of the reaction, the solvent was removed from the reaction mixture to give a residue which was azeotroped with toluene. The10 obtained crude product was washed with MTBE (10 mL) to afford 1-[5-fluoro-1-methyl-6-(4- piperidyl)indazol-3-yl]hexahydropyrimidine-2,4-dione hydrochloride (5, 150 mg, 0.381 mmol, 93% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 346.2 [M + H] ⁺ . Example 32 Synthesis of 1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-ind azol-6- 15 yl)piperidine-4-carboxylic acid epared following the method described on page 328-329 of WO2020132561 A1. Step-1: 20 To a 50 mL sealed tube containing a well-stirred solution of 1-(6-bromo-1-methyl-indazol-3- yl)hexahydropyrimidine-2,4-dione (1, 500 mg, 1.55 mmol) in anhydrous 1,4-dioxane (10 mL) were added tert-butyl piperidine-4-carboxylate hydrochloride (2, 514.61 mg, 2.32 mmol) and cesium carbonate (1.26 g, 3.87 mmol) at ambient temperature. The reaction mixture 284

was purged with nitrogen gas for 5 minutes before Pd‐PEPPSI‐IHeptCl (75.21 mg, 0.077 mmol) was added and resulting mixture was stirred at 110°C for 16 h while monitoring by UPLC- MS. Upon completion of the reaction, the reaction mixture was cooled to ambient temperature and filtered through a pad of Celite and the Celite bed was washed with EtOAc (200 mL). The filtrate 5 was evaporated to give a crude mass which was purified by reverse phase column chromatography (C18 column, Mobile phase A: 0.1% Formic acid in water; B: Acetonitrile) to obtain tert-butyl 1- [3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl] piperidine-4-carboxylate (3, 280 mg, 0.437 mmol, 28% yield) as a brown solid. LC-MS (ES ⁺ ): m/z 428.2 [M + H] ⁺ . Step-2: 10 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 1-[3- (2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]pip eridine-4-carboxylate (3, 280 mg, 0.484 mmol) in anhydrous DCM (5 mL) was added 4 M HCl in 1,4-dioxane (1.21 mL) at 0 °C under nitrogen atmosphere. The resulting solution was stirred at ambient temperature for 16 h and the reaction progress was monitored by UPLC-MS. The solvent was then evaporated under15 vacuum to yield a crude mass which was washed with MTBE (10 mL) to afford 1-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]piperidi ne-4-carboxylic acid hydrochloride (4, 150 mg, 0.328 mmol, 68% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 372.0 [M + H] ⁺ . 20 Example 33 Synthesis of 6-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-ind azol-7- yl)hexanal 285

A solution of 3-bromo-2-fluoro-benzonitrile (1, 25 g, 125.00 mmol) in ethanol (125.14 mL) was stirred at 25 °C for 10 min, then methylhydrazine (2, 74.86 g, 1.62 mol, 74.86 mL, 85% aq 5 solution) was added dropwise at room temperature. The reaction mixture was stirred at 90 °C for 16 h. After completion, the reaction mixture was evaporated in vacuo. To the resulting crude, water was added and the formed precipitate was filtered and dried to afford 7-bromo-1-methyl- indazol-3-amine (3, 24 g, 68.99 mmol, 55% yield) as an off white solid. LCMS (ES ⁺ ): m/z 226.96 [M + H] ⁺ . 10 Step-2: To a solution of 7-bromo-1-methyl-indazol-3-amine (3, 1 g, 4.42 mmol) in 2 M HCl (2 M, 10.00 mL) was added tetrabutylammonium bromide (142.59 mg, 442.34 μmol) at room temperature. The reaction mixture was warmed to 55 °C and acrylic acid (4, 382.51 mg, 5.31 mmol, 363.95 μL) was added dropwise at same temperature and stirred for 16 h at 90 °C. After completion, the 15 reaction mixture was neutralized by NaHCO ₃ (2 M, 100 mL). The precipitate was filtered and washed with water (100 mL) to afford 3-[(7-bromo-1-methyl-indazol-3-yl)amino]propanoic acid (5, 0.62 g, 1.81 mmol, 41% yield) as an off white solid. LCMS (ES ⁺ ): m/z 299.01 [M + H] ⁺ . Step-3: To a solution of compound 3-[(7-bromo-1-methyl-indazol-3-yl)amino]propanoic acid (5, 18 g, 20 60.38 mmol) in AcOH (150 mL) was added sodium cyanate (7.85 g, 120.75 mmol, 4.15 mL) at room temperature and the mixture was stirred at 65 °C for 16 h. Then 4 M HCl (180.00 mL) was added at 65 °C and stirred at 65 °C for 4 h. After completion of the reaction, the reaction mixture 286

was cooled to room temperature and neutralized with sat NaHCO ₃ (180-200 mL). Then the reaction mixture was filtered, the filter cake was washed with water (100 mL) and dried to give 1- (7-bromo-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (6, 15 g, 41.60 mmol, 69% yield) as a pale brown solid. LCMS (ES ⁺ ): m/z 323.44 [M + H] ⁺ . 5 Step-4: To a 50 mL sealed tube containing a well-stirred solution of 1-(7-bromo-1-methyl-indazol-3- yl)hexahydropyrimidine-2,4-dione (6, 600 mg, 1.84 mmol) and hex-5-yn-1-ol (7, 360.81 mg, 3.68 mmol, 0.41 mL) in anhydrous acetonitrile (12 mL) was added triethylamine (744.02 mg, 7.35 mmol, 1.02 mL) at ambient temperature. The reaction mixture was degassed with N2 for 5 minutes. 10 Subsequently, Pd(PPh ₃ ) ₂ Cl ₂ (129.02 mg, 0.183 mmol) and CuI (17.50 mg, 0.091 mmol) were added and the reaction mixture was stirred at 90 °C for 16 h. Progress of reaction was monitored by UPLC-MS. Thereafter, the reaction mixture was filtered through a pad of Celite and the Celite bed was washed with acetonitrile (100 mL) and the filtrate was evaporated under reduced pressure to give a residue which was purified by flash column chromatography (230-400 mesh silica gel,15 5-10% MeOH/DCM) to afford 1-[7-(6-hydroxyhex-1-ynyl)-1-methyl-indazol-3- yl]hexahydropyrimidine-2,4-dione (8, 400 mg, 1.07 mmol, 58% yield) as a yellow solid. LCMS (ES ⁺ ): m/z 341.2 [M + H] ⁺ . Step-5: To a 25 mL single-neck round-bottom flask was added a well-stirred solution of 1-[7-(6- 20 hydroxyhex-1-ynyl)-1-methyl-indazol-3-yl]hexahydropyrimidine -2,4-dione (8, 400 mg, 1.07 mmol) in anhydrous 1,4-dioxane (8 mL) at ambient temperature and the mixture was degassed with N2 for 5 minutes. Subsequently, Palladium hydroxide on carbon, 20% wt. (377.11 mg, 0.537 mmol) was added and the resulting reaction mixture was stirred at ambient temperature under hydrogen atmosphere (~1 atm) for 16 h. Thereafter, the reaction mixture was filtered through a 25 pad of Celite and the Celite bed was washed with 1,4-dioxane (100 mL). The combined filtrate was dried (anhydrous Na2SO4), filtered and concentrated under reduced pressure to afford 1-[7- (6-hydroxyhexyl)-1-methyl-indazol-3-yl]hexahydropyrimidine-2 ,4-dione (9, 200 mg, 0.573 mmol, 53% yield) as a brown solid. LCMS (ES ⁺ ): m/z 345.2 [M + H] ⁺ . Step-6: 30 To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 1-[7-(6- hydroxyhexyl)-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4- dione (9, 150 mg, 0.430 287

mmol) in anhydrous DMF (3 mL) was added Dess-Martin periodinane (273.85 mg, 0.645 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was filtered through a fritted syringe ,the frit was washed with DCM (50 mL). The filtrate was washed with saturated sodium thiosulfate solution (15 mL) followed by 5 with brine (15 mL) and dried over anhydrous Na2SO4, and filtered. The filtrate was evaporated under reduced pressure to afford 6-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-7- yl]hexanal (10, 140 mg, 0.318 mmol, 74% yield) as a yellow gum. LCMS (ES ⁺ ): m/z 345.2 [M + H] ⁺ . Example 34 10 Synthesis of 5-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]ind ol-5-yl) pentanal To a 100 mL pressure relief sealed tube containing a solution of 5-bromo-1-(2,6-dibenzyloxy-3- pyridyl) benzo[cd]indol-2-one (1, 2 g, 3.72 mmol) and pent-4-yn-1-ol (2, 626.09 mg, 7.44 mmol, 15 0.69 mL) in anhydrous acetonitrile (30 mL) was added TEA (1.13 g, 11.16 mmol, 1.56 mL) at ambient temperature. After the reaction mixture was purged with nitrogen gas for 5 288

minutes, copper (I) iodide (141.76 mg, 0.744 mmol) and bis(triphenylphosphine)palladium dichloride (313.46 mg, 0.446 mmol) were added at ambient temperature. The reaction mixture was stirred for 16 h at 90 °C. The reaction progress was monitored by UPLC and TLC. Then the reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under 5 reduced pressure to give the crude product, which was purified by flash column chromatography (240-400 mesh silica gel, 70% EtOAc/petroleum ether) to afford 1-(2,6-dibenzyloxy-3-pyridyl)- 5-(5-hydroxypent-1-ynyl)benzo[cd]indol-2-one (3, 2 g, 3.51 mmol, 94% yield) as a brown gum. LC-MS (ES ⁺ ): m/z 541.0 [M + H] ⁺ . Step-2: 10 To a 50 mL single-neck round-bottom flask containing a solution of 1-1-(2,6-dibenzyloxy-3- pyridyl)-5-(5-hydroxypent-1-ynyl) benzo[cd]indol-2-one (3, 1 g, 1.76 mmol) in anhydrous 1,4- dioxane (6 mL) and DMF (4 mL) was added Palladium hydroxide on carbon, 20 wt.% 50% water (1.23 g, 1.76 mmol) at ambient temperature. Then the reaction mixture was purged with hydrogen gas and stirred under hydrogen atmosphere for 16 h at ambient temperature. The reaction progress 15 was monitored by UPLC. The reaction mixture was filtered through a pad of Celite and the Celite bed was washed with 30% DMF in 1,4-dioxane solution. Then, the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in anhydrous DMF (4 mL) and 1,4- dioxane (6 mL) and Palladium hydroxide on carbon, 20 wt.% 50% water (616.96 mg, 0.878 mmol, 20% purity) was added at ambient temperature. Then the reaction mixture was stirred under 20 hydrogen atmosphere for 16 h at this temperature. After 16 h, the reaction mixture was filtered through Celite bed, and Celite bed was washed with 30% DMF in 1,4-dioxane solution. Subsequently, the filtrate was concentrated under reduced pressure to get a crude mass. The crude mass was purified by reverse phase column chromatography (C-18, 0.1% Formic acid in Water and Acetonitrile), and pure fractions were lyophilized to afford 3-[5-(5-hydroxypentyl)-2-oxo- 25 benzo[cd]indol-1-yl] piperidine-2,6-dione (4, 100 mg, 0.27 mmol, 15% yield) as a green solid. LC-MS (ES ⁺ ): m/z 367.0 [M + H] ⁺ . Step-3: To a 50 mL single-neck round-bottom flask containing a solution of 3-[5-(5-hydroxypentyl)-2- oxo-benzo[cd]indol-1-yl] piperidine-2,6-dione (4, 100 mg, 0.27 mmol) in anhydrous DMF (1 30 mL) was added Dess-Martin Periodinane (171.90 mg, 0.405 mmol) at ambient temperature. The reaction mixture was stirred for 3 h at ambient temperature. The reaction progress was monitored 289

by UPLC. After completion of reaction as indicated by UPLC, the reaction mixture was quenched with aqueous sodium thiosulphate solution (10 mL) and then extracted with EtOAc (2 × 50 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 5-[1-(2,6-dioxo-3- 5 piperidyl)-2-oxo-benzo[cd]indol-5-yl] pentanal (5, 80 mg, 0.175 mmol, 65% yield) as a brown gum. LC-MS (ES ⁺ ): m/z 365.2 [M + H] ⁺ . Example 35 Synthesis of (3R)-3-[5-(4-piperidyl)indolin-1-yl]piperidine-2,6-dione and (3S)-3-[5-(4- piperidyl)indolin-1-yl]piperidine-2,6-dione 10 To a stirred solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyridine-1-carboxylate (2, 15.61 g, 50.49 mmol) in 1,4-dioxane (60 mL) and water (40 mL), 290

were added 5-bromoindoline (1, 10.00 g, 50.49 mmol) and sodium carbonate (14.23 g, 151.47 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was degassed by bubbling with nitrogen for 5 min and then [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (2.06 g, 5 2.52 mmol) was added to the reaction mixture at room temperature. The reaction mixture was again degassed for 5 min and stirred at 85 °C for 8 h. After completion of the reaction as indicated by TLC, the reaction mass was poured into ice water (20 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude. The crude was purified by flash silica10 gel column chromatography, using 0-100% ethyl acetate in hexane as eluent to afford tert-butyl 4- indolin-5-yl-3,6-dihydro-2H-pyridine-1-carboxylate (3, 9.8 g, 32.62 mmol, 64.61% yield) as an off-white solid. LCMS (ES ⁺ ): m/z 301.4 [M + H] ⁺ . Step-2: To a stirred solution of tert-butyl 4-indolin-5-yl-3,6-dihydro-2H-pyridine-1-carboxylate (3, 8 g, 15 26.63 mmol) in 1,4-dioxane (100 mL) was added palladium, 10% on carbon (4 g, 26.63 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred under the pressure of hydrogen gas (bladder pressure) at room temperature for 16 h. After completion of the reaction, reaction mixture was diluted with MeOH (200 mL), filtered through Celite bed and the resulting filtrate was concentrated under reduced pressure to obtain crude. The crude was purified by 20 column chromatography (silica gel, 230-400 mesh), using 0-100% ethyl acetate in petroleum ether as eluent to afford tert-butyl 4-indolin-5-ylpiperidine-1-carboxylate (4, 4.8 g, 14.26 mmol, 53.55% yield) as a yellow solid. LCMS (ES ⁺ ): m/z 247.2 [M - tBu + H] ⁺ . Step-3: To a stirred solution of tert-butyl 4-indolin-5-yl-3,6-dihydro-2H-pyridine-1-carboxylate (4, 5 g,25 16.64 mmol) in DMF (50 mL) were added sodium bicarbonate (4.19 g, 49.93 mmol) and 3- bromopiperidine-2,6-dione (5, 4.79 g, 24.97 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 h. After completion of reaction, reaction mixture was concentrated under reduced pressure, dissolved in DCM (50 mL) and washed with water (2 × 50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and 30 concentrated under reduced pressure to obtain crude. The crude was purified by column chromatography (silica gel, 100-200 mesh), using 0-100% ethyl acetate in petroleum ether as 291

eluent to afford tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)indolin-5-yl]piperidine-1-carbox ylate (6, 2.3 g, 5.10 mmol, 30.64% yield) as a brown solid. LCMS (ES ⁺ ): m/z 414.4 [M + H] ⁺ . Step-4: Compound tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)indolin-5-yl]piperidine-1-carbox ylate (6, 1 g, 5 2.20 mmol) was purified by chiral SFC to separate ‘R' and 'S' isomers [Column: I Cellulose J, flow rate: 4 mL/min, elution: 80:20 (CO2:Co-solvent), Co-solvent: 0.2 % formic acid in acetonitrile/isopropanol]. The early eluting peak (arbitrarily assigned as R) tert-butyl 4-[1-[(3R)-2,6-dioxo-3- piperidyl]indolin-5-yl]piperidine-1-carboxylate (7, 420 mg, 998.43 μmol, 45.37% yield, 95.44% 10 enantiopurity) was isolated as a light blue solid. LCMS (ES ⁺ ): m/z 358.2 [M - tBu + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.76 (brs, 1H), 6.90 (s, 1H), 6.80 (dd, J = 1.20, 8.00 Hz, 1H), 6.40 (d, J = 8.00 Hz, 1H), 4.58 (dd, J = 4.80, 12.80 Hz, 1H), 4.12-4.01 (m, 2H), 3.83-3.73 (m, 1H), 3.44- 3.38 (m, 1H), 3.31-3.22 (m, 1H), 2.96-2.68 (m, 5H), 2.62-2.53 (m, 1H), 2.25-2.11 (m, 1H), 1.93- 1.85 (m, 1H), 1.72-1.66 (m, 2H), 1.47-1.35 (m, 11H). 15 The late eluting peak (arbitrarily assigned as S) tert-butyl 4-[1-[(3S)-2,6-dioxo-3- piperidyl]indolin-5-yl]piperidine-1-carboxylate (8, 210 mg, 462.65 μmol, 21.02% yield, 93.36% enantiopurity) was isolated as a brown solid. LCMS (ES ⁺ ): m/z 358.2 [M - tBu + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.75 (brs, 1H), 6.90 (s, 1H), 6.80 (d, J = 9.20 Hz, 1H), 6.40 (d, J = 8.00 Hz, 1H), 4.58 (dd, J = 4.80, 13.20 Hz, 1H), 4.11-4.02 (m, 2H), 3.43-3.22 (m, 3H), 2.94-2.70 (m, 20 5H), 2.61-2.53 (m, 1H), 2.24-2.12 (m, 1H), 1.95-1.86 (m, 1H), 1.74-1.65 (m, 2H), 1.46-1.34 (m, 11H). Step-5: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[1- [(3R)-2,6-dioxo-3-piperidyl]indolin-5-yl]piperidine-1-carbox ylate (7, 90 mg, 215.21 25 μmol) in anhydrous DCM (1.01 mL) was added 4 M HCl in 1,4-dioxane (1.08 mL) at 0 °C. The reaction was stirred at room temperature for 2 h. After completion of the reaction, the solvent was removed under vacuum and the resulting crude product was azeotroped with toluene and washed with MTBE to afford (3R)-3-[5-(4-piperidyl)indolin-1-yl]piperidine-2,6-dione (9, 80 mg, 212.66 μmol, 98.81% yield, HCl salt) as a pink solid. LCMS (ES ⁺ ): m/z 314.0 [M + H] ⁺ 292

Step-6: To a 25 ml round-bottom flask containing a solution of tert-butyl 4-[1-[(3S)-2,6-dioxo-3- piperidyl]indolin-5-yl]piperidine-1-carboxylate (8, 80 mg, 189.60 μmol) in DCM (0.8 mL) was added 4 M hydrogen chloride in 1,4-dioxane (529.06 μL) at 0°C. Then the reaction mixture was 5 stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford (3S)-3-[5-(4-piperidyl)indolin-1-yl]piperidine-2,6- dione (10, 65 mg, 185.79 μmol, 97.99% yield, HCl salt) as a brown solid. UPLC-MS (ES ⁺ ): m/z 314.5 [M + H] ⁺ 10 Example 36 Synthesis of Alkyne Intermediates To a 100 mL single-neck round-bottom flask containing a well-stirred solution of 4-15 ethynylpiperidine hydrochloride (1, 2 g, 13.05 mmol) and tert-butyl 4-formylpiperidine-1- carboxylate (2, 3.34 g, 15.66 mmol) in MeOH (20 mL) were added sodium acetate, anhydrous (2.14 g, 26.09 mmol) and acetic acid (7.83 g, 130.47 mmol, 7.47 mL) and the reaction mixture was stirred at ambient temperature for 1 h. Subsequently, MP-CNBH ₃ (2 mmol\g) (6.5 g, 13.05 mmol) was added in one portion and stirring was continued for another 16 h at ambient temperature. 20 Reaction was monitored by TLC. The solvent was evaporated under reduced pressure and obtained crude was diluted with water. The aqueous phase was basified with aq. NaHCO ₃ solution and extracted with DCM (2 × 150 mL) to afford tert-butyl 4-[(4-ethynyl-1-piperidyl) methyl]piperidine-1-carboxylate (3, 4.3 g, 13 mmol, 99% yield) as a brown solid. LC-MS (ES ⁺ ): m/z 307.2. [M + H] ⁺ . 293

Step-2: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[(4- ethynyl-1-piperidyl) methyl] piperidine-1-carboxylate (3, 5.0 g, 15.12 mmol) in anhydrous DCM (20 mL) was added 4M HCl in 1,4-dioxane (37.8 mL) at 0 °C. The resulting mixture was stirred at 5 ambient temperature for 1 h. After completion of the reaction, excess solvent was removed under reduced pressure to give a crude material that was washed with MTBE (20 mL) and dried to afford 4-ethynyl-1-(4-piperidyl methyl) piperidine hydrochloride (4, 3.73 g, 15.06 mmol, 99% yield) as a white solid. LC-MS (ES ⁺ ): m/z 207.2 [M + H] ⁺ . 10 To a 100 mL single-neck round-bottom flask containing a well-stirred solution of Oxalyl chloride (5.44 g, 42.87 mmol, 3.74 mL) in anhydrous DCM (50 mL) was added DMSO (6.70 g, 85.73 mmol, 6.08 mL) dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 1 h. Thereafter, tert-butyl 4-fluoro-4-(hydroxymethyl) piperidine-1-carboxylate (1, 5 g, 21.43 mmol) in 15 anhydrous DCM (50 mL) was added at -78 °C and stirring was continued at -78 °C for 2 h. Then the resulting acid was quenched with triethylamine (10.84 g, 107.17 mmol, 14.94 mL) at -78 °C and the mixture was slowly warmed to ambient temperature and stirred for 30 minutes. Progress of the reaction was monitored by TLC. To this reaction mixture cold water (100 mL) was added and the aqueous layer was extracted with DCM (2 × 50 mL). The combined organic phase was 20 washed with aqueous 1.5 N HCl (50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (230-400 mesh silica gel) with 40% EtOAc/pet ether as eluent to afford tert-butyl 4-fluoro-4-formyl-piperidine-1-carboxylate (2, 3.4 g, 13.88 mmol, 65% yield) as a colorless syrupy liquid. GC-MS (ES ⁺ ): m/z 231.1 [M + H] ⁺ . 294

Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 4- ethynylpiperidine hydrochloride (3, 2.03 g, 13.86 mmol) and tert-butyl 4-fluoro-4-formyl- piperidine-1-carboxylate (2, 3.40 g, 13.86 mmol) in MeOH (50 mL) were added Sodium acetate, 5 anhydrous (3.41 g, 41.59 mmol) and Acetic acid (8.33 g, 138.64 mmol, 7.94 mL) and the reaction mixture was stirred at ambient temperature for 1 h. Subsequently, MP-CNBH3 (6.80 g, 13.6 mmol; 2 mmol\g) was added in one portion and stirring was continued for another 16 h at ambient temperature. After completion of the reaction as indicated by TLC, excess solvent was evaporated in vacuo and water was added and the mixture was stirred for 15 minutes. The aqueous phase was 10 basified with aq. NaHCO ₃ solution and extracted with DCM (2 × 150 mL). The combined filtrate was dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 4-[(4-ethynyl-1-piperidyl) methyl]-4-fluoro-piperidine-1-carboxylate (4, 3.5 g, 7.20 mmol, 52% yield) as a colorless liquid. LC-MS (ES ⁺ ): m/z 325.2 [M + H] ⁺ . Step-3: 15 To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[(4- ethynyl-1-piperidyl) methyl]-4-fluoro-piperidine-1-carboxylate (4, 3.5 g, 7.20 mmol) in anhydrous dichloromethane (30 mL) was added 4N HCl/1,4-dioxane (3.60 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 2 h and monitored by UPLC. After completion of the reaction, the solvent was removed from the reaction mixture to 20 give the crude product, which was washed with MTBE followed by dichloromethane (50 mL) to afford 4-ethynyl-1-[(4-fluoro-4-piperidyl)methyl]piperidine hydrochloride (5, 1.8 g, 6.83 mmol, 95% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 225.0 [M + H] ⁺ . 25 To a 250 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4- ethynylpiperidine-1-carboxylate (1, 3.8 g, 18.16 mmol) in anhydrous DCM (30 mL) at ambient 295

temperature under nitrogen atmosphere was added 4M HCl in 1,4-dioxane (45.39 mL) and the resulting mixture was stirred at ambient temperature for 1 h. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated under reduced pressure to obtain a crude mass which was triturated with MTBE to afford 4-ethynylpiperidine hydrochloride (2, 2.6 g, 17.68 5 mmol, 97% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 9.07 (s, 2H), 3.14-2.97 (m, 3H), 2.95-2.90 (m, 2H), 2.75-2.69 (m, 1H), 1.98-1.92 (m, 2H) and 1.76-1.70 (m, 2H). Step-2: To a 20 mL glass-vial containing a well-stirred solution of 4-ethynylpiperidine hydrochloride (2, 3 g, 27.21 mmol) in EtOH (30 mL) was added tert-butyl 1-oxa-6-azaspiro [2.5] octane-6- 10 carboxylate (3, 5.8 g, 27.21 mmol) and the reaction mixture was stirred at 70 °C for 16 h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with ice-water, aqueous layer was extracted with EtOAc (3 × 150 mL). The combined organic phases were washed with water, brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl 4-[(4-ethynyl-1-piperidyl) methyl]-4-hydroxy-piperidine-1- 15 carboxylate (4, 9 g, 20.10 mmol, 74% yield) as a colorless liquid. LC-MS (ES ⁺ ): m/z 323.2 [M + H] ⁺ . Step-3: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[(4- ethynyl-1-piperidyl)methyl]-4-hydroxy-piperidine-1-carboxyla te (4, 8 g, 14.89 20 mmol) in anhydrous DCM (20 mL) was added 4M HCl in 1,4-dioxane (18.6 mL) at 0 °C. After completion of the addition, the resulting mixture was stirred at ambient temperature for 2 h. After completion of the reaction as indicated by UPLC, the solvent was removed from the reaction mixture to give the crude, which was co-evaporated with toluene and then washed with MTBE to afford 4-[(4-ethynyl-1-piperidyl)methyl]piperidin-4-ol hydrochloride (5, 3.9 g, 14.62 mmol, 98% 25 yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 223.2 [M + H] ⁺ . 296

To a 250 mL single-neck round-bottom flask containing a well-stirred solution of Oxalyl chloride (1.06 g, 8.32 mmol, 0.726 mL) in anhydrous DCM (20 mL) was added dropwise DMSO (1.30 g, 5 16.65 mmol, 1.18 mL) at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 1 h. Subsequently, tert-butyl 4-cyano-4-(hydroxymethyl) piperidine-1-carboxylate (1, 1.00 g, 4.16 mmol) in anhydrous DCM (20 mL) was added at -78 °C and stirring was continued at -78 °C for 4 h. Thereafter, the reaction was quenched with triethylamine (2.11 g, 20.81 mmol, 2.90 mL) at -78 °C and the mixture was slowly warmed to ambient temperature and stirred for 30 10 minutes and monitored by TLC. To the reaction mixture was added cold water (100 mL) and the aqueous phase was extracted with DCM (2 × 50 mL). The combined organic phases were washed with aqueous 1.5N HCl (50 mL), dried over anhydrous Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (230-400 mesh silica gel) with 40% EtOAc/pet ether as eluent to afford tert-butyl 15 4-cyano-4-formyl-piperidine-1-carboxylate (2, 600 mg, 2.06 mmol, 49% yield) as a colorless syrupy liquid. GC-MS (ES ⁺ ): m/z 238.1 [M] ⁺ . Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 4- ethynylpiperidine (3, 230.69 mg, 2.10 mmol) and tert-butyl 4-cyano-4-formyl-piperidine-1- 20 carboxylate (2, 733.50 mg, 2.52 mmol) in THF (15 mL) were added acetic acid (1.26 g, 20.98 mmol, 1.20 mL), sodium acetate, anhydrous (430.32 mg, 5.25 mmol) and Titanium(IV) isopropoxide (1.19 g, 4.20 mmol, 1.25 mL) at ambient temperature. The resulting mixture was stirred at 70 °C for 1 h. Subsequently, MP-CNBH3 (1.00 g, 1.89 mmol) was added at ambient temperature and stirring was continued at 70 °C for 16 h. The reaction progress was monitored by 25 UPLC. The reaction mixture was passed through a sintered funnel and the filtrate was concentrated 297

under reduced pressure to give a residue, which was neutralized with aqueous NaHCO ₃ and extracted with EtOAc (3 × 20 mL). The combined organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl 4-cyano-4- [(4-ethynyl-1-piperidyl)methyl]piperidine-1-carboxylate (4, 200 mg, 0.601 mmol, 29% yield) as 5 a yellow liquid. LC-MS (ES ⁺ ): m/z 332.4 [M + H] ⁺ . Step-3: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4- cyano-4-[(4-ethynyl-1-piperidyl)methyl]piperidine-1-carboxyl ate (4, 200 mg, 0.601 mmol) in anhydrous DCM (4 mL) was added 4 N HCl in 1,4-dioxane (1.50 mL) at ambient temperature 10 under nitrogen atmosphere. After completion of the addition, the resulting mixture was stirred at ambient temperature for 16 h. After completion of the reaction as indicated by UPLC, excess solvent was removed from the reaction mixture under reduced pressure to give the crude product, which was washed with MTBE (20 mL) to afford 4-[(4-ethynyl-1-piperidyl)methyl]piperidine-4- carbonitrile hydrochloride (5, 120 mg, 0.448 mmol, 74% yield) as an off-white solid. LC-MS 15 (ES ⁺ ): m/z 232.2 [M + H] ⁺ . To a 500 ml round-bottom flask containing a solution of tert-butyl 4-ethynylpiperidine-1- carboxylate (1, 7 g, 33.45 mmol) in anhydrous DCM (50 mL) was added 4.0 M hydrogen chloride 20 solution in dioxane (83.62 mL) at 0°C. The reaction mixture was stirred for three hours at room temperature. After completion of the reaction as indicated by LCMS, the reaction mixture was concentrated under reduced pressure to give the crude product, which was washed with MTBE to 298

afford the 4-ethynylpiperidine hydrochloride (2, 4.9 g, 33.31 mmol, 99% yield) as an off-yellow solid. LC-MS (ES ⁺ ): m/z 110.2 [M + H] ⁺ . Step-2: To a 20 mL screw-capped vial containing a well-stirred solution of 4-ethynylpiperidine (2, 700 5 mg, 6.35 mmol) in DMF (7.02 mL) was added triethylamine (1.61 g, 15.87 mmol, 2.21 mL) and ethyl 5-bromopentanoate (3, 1.99 g, 9.52 mmol) and the resulting suspension was heated at 70 °C for 3 hours. Afterwards, the reaction mixture was poured into water and extracted with DCM (2 × 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain ethyl 5-(4-ethynyl-1-piperidyl)pentanoate (4, 1 g, 3.79 mmol, 10 60% yield) as a dark gum. LC-MS (ES ⁺ ): m/z 238.2 [M + H] ⁺ . Step-3: The procedure was identical to that of Step-2 and ethyl 6-(4-ethynyl-1-piperidyl)hexanoate was obtained as a brown solid. LC-MS (ES ⁺ ): m/z 252.2 [M + H] ⁺ . 15 To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 7-oxa- 3-azabicyclo[4.1.0]heptane-3-carboxylate (1, 3.0 g, 15.06 mmol) in anhydrous DMSO (30 mL) at 10 °C was added lithium acetylide, ethylenediamine complex (2, 2.71 g, 30.11 mmol) under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 16 h. After 20 completion of the reaction as confirmed by LCMS, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 100 mL). The combined organic phase was washed with brine and evaporated under reduced pressure to give the crude, which was purified by flash column chromatography (230-400 mesh silica gel) with 0-50% EtOAc/pet ether as eluent to afford tert- butyl 4-ethynyl-3-hydroxypiperidine-1-carboxylate (3, 2.2 g, 8.52 mmol, 57% yield) as colorless 25 liquid. LC-MS (ES ⁺ ): m/z 170.0 [M – isobutene + H] ⁺ . 299

Step-2: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4- ethynyl-3-hydroxy-piperidine-1-carboxylate (3, 500 mg, 1.93 mmol) in anhydrous DCM (15 mL) was added DAST (622.48 mg, 0.51 mmol, 0.51 mL) at 0 °C under nitrogen atmosphere. The 5 resulting mixture was stirred at ambient temperature for 4 h. After completion of the reaction as confirmed by LCMS, the reaction mixture was diluted with NaHCO3 (30 mL) and extracted with DCM (2 × 200 mL). The combined organic phase was washed with brine and evaporated under reduced pressure to give the crude, which was purified by flash column chromatography (230-400 mesh silica gel) with 0-20% EtOAc/pet ether as eluent to afford tert-butyl 4-ethynyl-3-fluoro- 10 piperidine-1-carboxylate (4, 200 mg, 0.862 mmol, 45% yield) as a yellow liquid. LC-MS (ES ⁺ ): m/z 172.2 [M – isobutene + H] ⁺ . Step-3: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4- ethynyl-3-fluoro-piperidine-1-carboxylate (4, 200 mg, 0.862 mmol) in anhydrous DCM (2 mL) 15 was added 4 N HCl in 1,4-dioxane (2.16 mL) at 0 °C and the resulting mixture was stirred at ambient temperature for 2 h. After completion of the reaction as confirmed by UPLC, excess solvent was removed under reduced pressure to give a crude residue, which was washed with MTBE (2 × 10 mL) to afford 4-ethynyl-3-fluoro-piperidine hydrochloride (5, 140 mg, 0.788 mmol, 91% yield) as an off-white solid. LCMS (ES ⁺ ): m/z 128.2 [M + H] ⁺ . 20 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4- ethynyl-4-fluoro-piperidine-1-carboxylate (1, 500 mg, 2.20 mmol) in anhydrous DCM (4 mL) was added 4N HCl/1,4-dioxane (2.20 mL) at ambient temperature. The resulting mixture was stirred at 300

ambient temperature for 2 h. The reaction was monitored by UPLC. After completion of the reaction, excess solvent was removed from the reaction mixture to give the crude product, which was washed with MTBE (10 mL) to afford 4-ethynyl-4-fluoro-piperidine hydrochloride (2, 350 mg, 2.10 mmol, 95% yield) as an off-white solid. LCMS (ES ⁺ ): m/z 128.2 [M + H] ⁺ . 5 Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 4-ethynyl-4- fluoro-piperidine hydrochloride (2, 350 mg, 2.10 mmol) and tert-butyl 4-formylpiperidine-1- carboxylate (3, 536.51 mg, 2.52 mmol) in MeOH (10 mL) were added anhydrous Sodium acetate (343.92 mg, 4.19 mmol) and Acetic acid (1.26 g, 20.96 mmol, 1.20 mL) and the resulting reaction 10 mixture was stirred at ambient temperature for 1 h. Thereafter, MP-CNBH ₃ (1.2 g, 2.10 mmol; 2 mmol\g) was added in one portion and stirring was continued for another 16 h at ambient temperature. Reaction was monitored by TLC. Excess solvent was evaporated under reduced pressure and crude thus obtained was diluted with water. The aqueous layer was basified with aq. NaHCO ₃ solution and extracted with DCM (2 × 150 mL). The combined organic phase was dried15 over anhydrous Na2SO4, and concentrated under reduced pressure to afford tert-butyl 4-[(4- ethynyl-4-fluoro-1-piperidyl) methyl] piperidine-1-carboxylate (4, 650 mg, 1.54 mmol, 73% yield) as a colorless liquid. LCMS (ES ⁺ ): m/z 325.2 [M + H] ⁺ . Step-3: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[(4- 20 ethynyl-4-fluoro-1-piperidyl)methyl]piperidine-1-carboxylate (4, 650 mg, 1.54 mmol) in anhydrous DCM (5 mL) was added 4 M HCl in dioxane (112.50 mg, 3.09 mmol) at room temperature. The contents were stirred at room temperature for 2 h. The reaction was monitored by UPLC. After completion of the reaction, the solvent was removed from the reaction mixture to give the crude product, which was washed with MTBE (10 mL) to afford 4-ethynyl-4-fluoro-1-(4- 25 piperidylmethyl)piperidine hydrochloride (5, 400 mg, 1.45 mmol, 93.74% yield) as an off white solid. LCMS (ES ⁺ ): m/z 225.2 [M + H] ⁺ . 301

To a 100 mL single-neck round-bottom flask containing a well-stirred solution of 4- (hydroxymethyl)cyclohexanone (1, 2 g, 15.60 mmol) in dry DCM (30 mL) was added Imidazole 5 (2.12 g, 31.21 mmol) and resulting mixture was cooled to 0 °C, then tert-butyl-chloro-dimethyl- silane (4.70 g, 31.21 mmol, 5.81 mL) was added. The reaction mixture was stirred at ambient temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phase was dried over anhydrous Na2SO4, and concentrated under 10 reduced pressure to give a crude residue, which was purified by flash column chromatography (230-400 mesh silica gel) with 10-20% EtOAc/pet ether as eluent to afford 4-(((tert- butyldimethylsilyl)oxy)methyl)cyclohexan-1-one (2, 2.1 g, 8.66 mmol, 55% yield) as a colorless liquid. ¹ H NMR (400 MHz, CDCl3): δ 3.54 (d, J = 6.4 Hz, 2H), 2.50-2.35 (m, 4H), 2.13-2.10 (m, 2H), 1.98-1.91 (m, 1H), 1.50-1.43 (m, 2H), 0.94-0.92 (m, 9H) and 0.07-0.05 (m, 6H). 302

Step-2: To a 100 mL two-neck round-bottom flask containing a well-stirred solution of 5- (bromotriphenyl-l5-phosphaneyl)pentanoic acid (3, 5.21 g, 11.76 mmol) in dry THF (60 mL), was added 1 M lithium bis(trimethylsilyl)amide solution in THF (23.51 mL) dropwise at 0 °C under 5 nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 1 h and then 4- [[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexanone (950 mg, 3.92 mmol) in dry THF (10 mL) was added dropwise at 0 °C. The reaction mixture was stirred at ambient temperature for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (50 mL) at 0 °C 10 and extracted with EtOAc (3 × 100 mL). The combined organic phase was dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (60-120 mesh silica gel) with 10-15% EtOAc/pet ether as eluent to afford 5-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexylidene)p entanoic acid (4, 0.88 g, 2.69 mmol, 69% yield) as a colorless gummy liquid. LC-MS (ES ⁺ ): m/z 327.0 [M + H] ⁺ . 15 Step-3: To a 100 mL two-neck round-bottom flask containing a well-stirred solution 5-(4-(((tert- butyldimethylsilyl)oxy)methyl)cyclohexylidene)pentanoic acid (4, 0.8 g, 2.45 mmol) in MeOH (20 mL) was added 2M (diazo methyl)trimethylsilane in hexane (5, 12.25 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 3 h. 20 Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (20 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (60-120 mesh silica gel) with 15-20% EtOAc/pet ether as 25 eluent to afford methyl 5-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexylidene)p entanoate (6, 0.6 g, 1.76 mmol, 72% yield) as a colorless liquid. LC-MS (ES ⁺ ): m/z 341.2 [M + H] ⁺ . Step-4: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of methyl 5-(4- (((tert-butyldimethylsilyl)oxy)methyl)cyclohexylidene)pentan oate (6, 0.6 g, 1.76 mmol) in 1,4- 30 dioxane (10 mL) was added Palladium, 10% on carbon (625.93 mg, 0.528 mmol) and the resulting mixture was purged by bubbling hydrogen gas for 10 minutes. The mixture was then stirred under 303

hydrogen atmosphere (~ 1 atm) at ambient temperature for 4 h. Progress of the reaction was monitored by TLC and UPLC. After completion of the reaction, the reaction mixture was purged with nitrogen gas, and the catalyst was removed by filtration through a Celite pad and the Celite bed was washed with MeOH (100 mL). The filtrate was concentrated under reduced pressure to 5 afford methyl 5-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)pentan oate (7, 0.5 g, 1.46 mmol, 83% yield) as a colorless liquid. ¹ H NMR (400 MHz, CDCl3): δ 3.68 (s, 3H), 3.49-3.48 (m, 1H) 3.40 (d, J= 6.4 Hz, 1H), 2.35-2.30 (m, 2H), 1.83-1.72 (m, 3H), 1.65-1.53 (m, 3H), 1.48-1.28 (m, 6H), 1.22-1.15 (m, 3H), 0.94-0.90 (m, 10H) and 0.05 (s, 6H). Step-5: 10 To a 50 mL two-neck round-bottom flask containing a well-stirred solution of methyl 5-(4-(((tert- butyldimethylsilyl)oxy)methyl)cyclohexyl)pentanoate (7, 0.5 g, 1.46 mmol) in THF (10 mL) was added 1M TBAF in THF (4.38 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with saturated 15 ammonium chloride solution (20 mL) at 0 °C and extracted with EtOAc (3 × 30 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford a crude mass which was purified by column chromatography (60-120 mesh silica gel) with 20-30% EtOAc/pet ether as eluent to afford methyl 5-(4- (hydroxymethyl)cyclohexyl)pentanoate (8, 0.3 g, 1.31 mmol, 90% yield) as a colorless liquid. ¹ H 20 NMR (400 MHz, CDCl ₃ ): δ 3.69 (s, 3H), 3.47 (d, J = 6.4 Hz, 1H), 2.34 (t, J = 7.2 Hz, 2H), 1.80 (d, J = 0.8 Hz, 2H), 1.68-1.56 (m, 2H), 1.55-1.40 (m, 2H), 1.38-1.18 (m, 7H) and 0.98-0.80 (m, 5H). Step-6: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of methyl 5-(4- 25 (hydroxymethyl)cyclohexyl)pentanoate (8, 0.29 g, 1.27 mmol) in dry DCM (10 mL) was added (1,1-diacetoxy-3-oxo-1,2-benziodoxol-1-yl) acetate (1.08 g, 2.54 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with sodium thiosulfate solution (2 g in 15 mL) and sodium bicarbonate 30 solution (2 g in 15 mL) and the reaction mixture was stirred for 20 minutes at ambient temperature. The aqueous phase was extracted with DCM (3 × 20 mL) and the organic phase was washed with 304

water (20 mL), brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to afford methyl 5-(4-formylcyclohexyl)pentanoate (9, 0.28 g, 1.06 mmol, 83% yield) as a colorless liquid. ¹ H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 3.58 (s, 3H), 2.31 (t, J = 6 Hz, 2H), 2.15-2.12 (m, 1H), 1.95-1.92 (m, 1H), 1.85-1.82 (m, 1H), 1.80-1.69 (m, 2H), 1.50 (t, J = 7.2 5 Hz, 3H), 1.35-1.22 (m, 3H), 1.20-1.09 (m, 3H) and 0.90 (m, 2H). Step-7: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of methyl 5-(4- formylcyclohexyl)pentanoate (9, 0.28 g, 1.06 mmol) in MeOH (5 mL) was added potassium carbonate, anhydrous, 99% (291.65 mg, 2.11 mmol). The reaction mixture was cooled to 0 °C, 10 before dimethyl (1-diazo-2-oxopropyl)phosphonate (10, 405.40 mg, 2.11 mmol, 0.506 mL) was added under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 1 h. After completion of the reaction as indicated by LCMS, the reaction mixture was concentrated under reduced pressure, diluted with water (20 mL) and then extracted with EtOAc (3 × 30 mL). The combined organic phase was dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced 15 pressure to give a crude residue, which was purified by column chromatography (60-120 mesh silica gel) with 5-15% EtOAc/pet ether as eluent to afford methyl 5-(4- ethynylcyclohexyl)pentanoate (11, 0.13 g, 0.555 mmol, 53% yield) as a colorless liquid. ¹ H NMR (400 MHz, CDCl ₃ ). δ 3.69 (s, 3H), 2.32 (t, J = 4 Hz, 2H), 2.20-2.12 (m, 1H), 2.05 (s, 1H), 2.00 (d, J = 16 Hz, 1H), 1.73 (d, J = 12 Hz, 1H), 1.65-1.55 (m, 2H), 1.40-1.25 (m, 6H), 1.21-1.18 20 (m, 3H) and 0.89 (m, 2H). 305

Example 37 Synthesis of N-[(3-fluorophenyl)methyl]-1-[1-[4-[2-(4-piperidyl)ethynyl]- 1- naphthyl]ethyl]piperidine-4-carboxamide hydrochloride 5 306

To a 250 mL round-bottom flask containing a well-stirred solution of a mixture of 1-(4-bromo-1- naphthyl)ethanone (1, 1, 5.0 g, 19.07 mmol) in neat anhydrous titanium(IV) isopropoxide (50.31 mL) were added methyl piperidine-4-carboxylate (2, 4.10 g, 28.60 mmol, 3.86 mL) at ambient temperature. The reaction mixture was stirred at 80 °C for 6 h. The reaction mixture was cooled 5 to 0°C and sodium borohydride (3.60 g, 95.14 mmol) was added to the reaction mixture. The reaction mixture was stirred at 30°C for 3 h. After completion of the reaction, the reaction mixture was cooled to 0° C, diluted with water, and the solid precipitate was filtered. The filtrate was extracted with ethyl acetate (2 × 150 mL). The combined organic layers and washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced 10 pressure to give a crude residue, which was purified by flash column chromatography (60-120 mesh silica gel) with 0-100% ethyl acetate in petroleum ether as eluent to afford isopropyl 1-[1- (4-bromo-1-naphthyl)ethyl]piperidine-4-carboxylate (3, 3.5 g, 8.14 mmol, 43% yield) as a colorless thick liquid. LC-MS (ES ⁺ ): m/z 404.2 [M + H] ⁺ . Step-2: 15 To a 250 mL sealed tube containing a well stirred solution of isopropyl 1-[1-(4-bromo-1- naphthyl)ethyl]piperidine-4-carboxylate (3, 5 g, 12.37 mmol), tert-butyl 4-ethynylpiperidine-1- carboxylate (4, 3.36 g, 16.08 mmol) in anhydrous acetonitrile (60 mL) was added cesium carbonate (10.07 g, 30.91 mmol) at room temperature. The reaction mixture was purged with nitrogen gas for 10 minutes before XPhos (589.50 mg, 1.24 mmol) and XPhos-Pd-G3 (524.00 mg, 20 618.29 μmol) were added. The reaction was stirred at 90 °C for 5 hours. Upon completion of the reaction, the reaction mixture was filtered through a pad of Celite, the Celite bed was washed with ethyl acetate (500 mL). The filtrate was concentrated under reduced pressure to yield the crude compound, which was purified by flash column chromatography (230-400 mesh silica gel, 40% ethyl acetate in petroleum ether) to afford tert-butyl 4-[2-[4-[1-(4-isopropoxycarbonyl-1- 25 piperidyl)ethyl]-1-naphthyl]ethynyl]piperidine-1-carboxylate (5, 4 g, 7.36 mmol, 60% yield) as a light brown gummy solid. LC-MS(ES ⁺ ): m/z 533.2 [M + H] ⁺ . Step-3: To a 250 mL single neck round bottom flask containing a stirred solution tert-butyl 4-[2-[4-[1-(4- isopropoxycarbonyl-1-piperidyl)ethyl]-1-naphthyl]ethynyl]pip eridine-1-carboxylate (5, 4.08 g, 30 7.51 mmol) in methanol (40 mL) and THF (40 mL)and water (20 mL) was added lithium hydroxide monohydrate, 98% (3.15 g, 75.09 mmol) at ambient temperature and the resulting 307

mixture was stirred for 3 hours. Upon completion of the reaction, the volatiles were evaporated under vacuum to yield the crude product, which was acidified with 10% citric acid solution to pH=4 and extracted with 10% MeOH in DCM (2 × 400 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford 1-[1-[4-[2-(1-tert- 5 butoxycarbonyl-4-piperidyl)ethynyl]-1-naphthyl]ethyl]piperid ine-4-carboxylic acid (6, 3.67 g, 7.41 mmol, 99% yield) as a brown solid. LC-MS (ES ⁺ ): m/z 491.2 [M + H] ⁺ . Step-4: To a 100 mL round bottom flask containing a well-stirred solution of 1-[1-[4-[2-(1-tert- butoxycarbonyl-4-piperidyl)ethynyl]-1-naphthyl]ethyl]piperid ine-4-carboxylic acid (6, 4 g, 7.51 10 mmol) and (3-fluorophenyl)methanamine (7, 940.19 mg, 7.51 mmol, 857.05 μL) in anhydrous DMF (40 mL) was added N,N-diisopropylethylamine (4.85 g, 37.56 mmol, 6.54 mL) at room temperature under nitrogen atmosphere. After 5 minutes, HATU (4.28 g, 11.27 mmol) was added, and the resulting mixture was stirred at room temperature for 3 hours. Upon completion of the reaction, the reaction mixture was quenched with water (100mL), extracted with ethyl acetate 15 (3 × 150 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (100 g silica gel column, 0-100% ethyl acetate in petroleum ether) to afford tert-butyl 4-[2-[4-[1-[4-[(3-fluorophenyl)methylcarbamoyl]- 1-piperidyl]ethyl]-1-naphthyl]ethynyl]piperidine-1-carboxyla te (8, 3.5 g, 5.57 mmol, 74% yield) as a brown solid. LC-MS (ES ⁺ ): m/z 598.2 [M + H] ⁺ . 20 Step-5: To a 100 mL single-neck round-bottom flask containing a well stirred solution of tert-butyl 4-[2- [4-[1-[4-[(3-fluorophenyl)methylcarbamoyl]-1-piperidyl]ethyl ]-1-naphthyl]ethynyl]piperidine-1- carboxylate (8, 3.5 g, 5.56 mmol) in anhydrous DCM (5 mL) was added 4 M hydrogen chloride in 1,4-dioxane (5.56 mmol) at 0 °C. The contents were stirred at room temperature for 2 hours. After 25 completion of the reaction, the solvent was removed to give the crude compound, which was dissolved with toluene, evaporated to dryness, and washed with MTBE to afford N-[(3- fluorophenyl)methyl]-1-[1-[4-[2-(4-piperidyl)ethynyl]-1-naph thyl]ethyl]piperidine-4- carboxamide hydrochloride (9, 3 g, 5.21 mmol, 94% yield) as a brown solid. LC-MS (ES ⁺ ): m/z 498.2 [M + H] ⁺ . 30 308

Example 38 Synthesis of N-[(3-fluorophenyl)methyl]-1-[(1R)-1-[4-[2-(4-piperidyl)ethy nyl]-1- naphthyl]ethyl]piperidine-4-carboxamide hydrochloride 5 Compound tert-butyl 4-[2-[4-[1-[4-[(3-fluorophenyl)methylcarbamoyl]-1-piperidyl] ethyl]-1- naphthyl]ethynyl]piperidine-1-carboxylate (1, 300 mg) was subjected to chiral purification to separate the enantiomers, using the following method: Instrument: PIC 100; Column: Lux cellulose 2 (250 × 30) mm, 5 μm; Mobile Phase: CO ₂ : 0.5% Isopropyl amine in isopropyl alcohol 10 (70:30); Total Flow: 70 g/min; Back pressure: 100 bar; Wavelength: 220 nm; Cycle time: 10 min; Temperature: 35 °C. The early eluting fraction (RT=3.6 min, optical purity 100%), arbitrarily assigned as the R-isomer, was concentrated under reduced pressure to afford tert-butyl 4-[2-[4-[(1R)-1-[4-[(3- fluorophenyl)methylcarbamoyl]-1-piperidyl]ethyl]-1-naphthyl] ethynyl]piperidine-1-carboxylate 309

(2, 130 mg, 217.04 μmol, 43% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 598.2 [M + H] ⁺ . [α] ²² D +5.40º (c 1.0, CH3OH). The late eluting fraction (RT 4.28 min, optical purity 99.35%), arbitrarily assigned as the S-isomer, was concentrated under reduced pressure to afford tert-butyl 4-[2-[4-[(1S)-1-[4-[(3- 5 fluorophenyl)methylcarbamoyl]-1-piperidyl]ethyl]-1-naphthyl] ethynyl]piperidine-1-carboxylate (3, 130 mg, 217.26 μmol, 43% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 598.2 [M + H] ⁺ . [α] ²² D -5.40º (c 1.0, CH ₃ OH) Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[2-10 [4-[(1R)-1-[4-[(3-fluorophenyl)methylcarbamoyl]-1-piperidyl] ethyl]-1- naphthyl]ethynyl]piperidine-1-carboxylate hydrochloride (2, 130.41 mg, 203.56 μmol) in anhydrous DCM (0.6 mL) was added 4.0 M hydrogen chloride solution in dioxane (1.0 mL) at ambient temperature under nitrogen atmosphere. After 2 hours, the reaction mixture was concentrated under reduced pressure to give the crude product, which was triturated with 10%15 EtOAc in petroleum ether to afford N-[(3-fluorophenyl)methyl]-1-[1R)-1-[4-[2-(4- piperidyl)ethynyl]-1-naphthyl]ethyl]piperidine-4-carboxamide hydrochloride (4, 116 mg, 201.98 μmol, 99% yield) as a white solid. LC-MS (ES ⁺ ): m/z 498.2 [M + H] ⁺ . 310

Example 39 Synthesis of 1-[1-[4-[2-[1-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-ox o-benzimidazol-5- yl]-1-piperidyl]acetyl]-4-piperidyl]ethynyl]-1-naphthyl]ethy l]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (Compound 1) 5 To 1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidin-1- yl)acetic acid (2, 82.3 mg, 0.201 mmol) in anhydrous DMF (2 mL) were added DIPEA (121.98 mg, 0.943 mmol, 0.164 mL) and HATU (143.54 mg, 0.377mol) followed by N-(3-fluorobenzyl)- 10 1-(1-(4-(piperidin-4-ylethynyl)naphthalen-1-yl)ethyl)piperid ine-4-carboxamide (1, 100.82 mg, 0.188 mmol,) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 1 h. The progress of the reaction was monitored by UPLC. Excess solvent was removed under reduced pressure to give a crude residue, which was purified by reverse phase column chromatography (RediSep-RF Gold C18 column, mobile phase: 10 mm NH4HCO315 in water : MeCN) to afford 1-(1-(4-((1-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-ox o-2,3- dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)acetyl)piper idin-4-yl)ethynyl)naphthalen-1- 311

yl)ethyl)-N-(3-fluorobenzyl)piperidine-4-carboxamide (Compound 1, 55 mg, 0.062 mmol, 33% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 880.3 [M + H] ⁺ . 1H-NMR (400 MHz, DMSO-d ₆ ): δ 11.11 (s, 1H), 8.50-8.48 (m, 1H), 8.33-8.27 (m, 2H), 7.64-7.52 5 (m, 4H), 7.37-7.31 (m, 1H), 7.08-6.99 (m, 5H), 6.92 (d, J = 8.40 Hz, 1H), 5.37-5.29 (m, 1H), 4.25 (d, J = 6.00 Hz, 2H), 4.21-4.12 (m, 1H), 3.48-3.87 (m, 2H), 3.51-3.40 (m, 1H), 3.29 (s, 3H), 3.26- 3.21 (m, 3H), 3.16-2.85 (m, 5H), 2.81-2.61 (m, 3H), 2.18-1.96 (m, 9H), 1.82-1.50 (m, 10H), 1.39 (d, J = 6.40 Hz, 3H). 10 Example 40 Synthesis of 1-[1-[4-[2-[1-[4-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6- yl]-1-piperidyl]-4-oxo-butanoyl]-4-piperidyl]ethynyl]-1-naph thyl]ethyl]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (Compound 2) 15 Compound 2 was pre f Compound 1, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 907.7 [M + H] ⁺ . 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 9.37 (s, 1H), 8.67 – 8.22 (m, 3H), 7.87 – 7.80 (m, 2H), 7.78 – 7.61 (m, 2H), 7.56 (d, J = 8.5 Hz, 1H), 7.45 (s, 1H), 7.34 (td, J = 8.0, 6.1 Hz, 1H), 7.12 20 – 6.93 (m, 4H), 5.42 (t, J = 6.9 Hz, 1H), 4.57 (d, J = 12.7 Hz, 1H), 4.27 (d, J = 6.0 Hz, 2H), 4.08 (d, J = 13.3 Hz, 1H), 3.96 (s, 3H), 3.90 (t, J = 6.7 Hz, 2H), 3.42 (dd, J = 13.0, 8.6 Hz, 1H), 3.34 – 312

3.20 (m, 1H), 3.20 – 2.79 (m, 5H), 2.75 (t, J = 6.7 Hz, 2H), 2.70 – 2.52 (m, 5H), 2.46 – 2.36 (m, 1H), 2.16 – 1.35 (m, 9H). Example 41 5 1-[1-[4-[2-[1-[7-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6-yl]-1- piperidyl]-7-oxo-heptanoyl]-4-piperidyl]ethynyl]-1-naphthyl] ethyl]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (Compound 3) C ng the 10 corresponding intermediates. LC-MS (ES ⁺ ): m/z 949.7 [M + H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 10.54 (s, 1H), 9.38 – 9.30 (m, 1H), 8.53 – 8.33 (m, 3H), 7.90 – 7.78 (m, 2H), 7.78 – 7.68 (m, 2H), 7.55 (d, J = 8.5 Hz, 1H), 7.44 (s, 1H), 7.34 (td, J = 7.9, 6.1 Hz, 1H), 7.03 (ttd, J = 9.9, 5.0, 2.4 Hz, 4H), 5.42 (d, J = 7.0 Hz, 1H), 4.59 (d, J = 12.8 Hz, 1H), 4.27 15 (d, J = 6.0 Hz, 2H), 4.06 – 3.98 (m, 1H), 3.96 (s, 3H), 3.93 (s, 2H), 3.90 (t, J = 6.7 Hz, 2H), 3.76 (d, J = 13.7 Hz, 1H), 3.23 (s, 1H), 3.12 (td, J = 9.6, 5.0 Hz, 2H), 3.11 – 3.00 (m, 1H), 2.95 – 2.79 (m, 2H), 2.74 (t, J = 6.7 Hz, 2H), 2.66 – 2.55 (m, 1H), 2.35 (td, J = 7.4, 2.1 Hz, 4H), 2.08 – 1.99 (m, 1H), 2.03 – 1.81 (m, 4H), 1.79 (s, 1H), 1.72 (d, J = 6.6 Hz, 3H), 1.69 (s, 1H), 1.61 (s, 2H), 1.65 – 1.46 (m, 5H), 1.39 – 1.29 (m, 2H), 1.23 (s, 1H). 20 313

Example 42 N-[(3-fluorophenyl)methyl]-1-[1-[4-[2-[1-[2-[4-[3-methyl-1-( 1-methyl-2,6-dioxo-3- piperidyl)-2-oxo-benzimidazol-5-yl]-1-piperidyl]acetyl]-4-pi peridyl]ethynyl]-1- naphthyl]ethyl]piperidine-4-carboxamide (Compound 4) 5 Compound nd 1, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 895.2 [M + H] ⁺ . 1H-NMR (400 MHz, DMSO-d6): δ 8.53-8.49 (m, 1H), 8.49 (s, 1H), 8.33-8.27 (m, 2H), 7.63 (d, J = 10 7.20 Hz, 1H), 7.57-7.53 (m, 3H), 7.37-7.32 (m, 1H), 7.09-7.00 (m, 5H), 6.91 (d, J = 8.80 Hz, 1H), 5.41 (dd, J = 5.20, 12.60 Hz, 1H), 4.25 (d, J = 5.60 Hz, 2H), 4.21-4.15 (m, 1H), 4.01-3.91 (m, 2H), 3.55-3.45 (m, 3H), 3.31 (s, 3H), 3.30-3.10 (m, 4H), 3.04 (s, 3H), 2.99-2.96 (m, 2H), 2.79-2.76 (m, 2H), 2.20-1.90 (m, 8H), 1.89-1.51 (m, 11H), 1.39 (d, J = 6.40 Hz, 3H). 314

Example 43 1-[1-[4-[2-[1-[6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-ox o-benzimidazol-5-yl]-1- piperidyl]-6-oxo-hexanoyl]-4-piperidyl]ethynyl]-1-naphthyl]e thyl]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (Compound 5) 5 Co ing the corresponding intermediates. LC-MS (ES ⁺ ): m/z 950.2 [M + H] ⁺ . 1H-NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 8.50 (d, J = 7.60 Hz, 1H), 8.33-8.27 (m, 2H), 10 7.63-7.57 (m, 3H), 7.53 (d, J = 7.60 Hz, 1H), 7.37-7.31 (m, 1H), 7.11 (s, 1H), 7.06-6.99 (m, 4H), 6.91 (d, J = 7.60 Hz, 1H), 5.34 (dd, J = 5.20, 12.80, Hz, 1H), 4.58 (d, J = 12.6 Hz, 1H), 4.25 (d, J = 6.00 Hz, 2H), 4.20-4.15 (m, 1H), 4.08-3.91 (m, 2H), 3.82-3.70 (m, 1H), 3.16-3.00 (m, 2H), 2.80- 2.70 (m, 2H), 2.42-2.29 (m, 5H), 2.25-2.10 (m, 2H), 2.10-1.98 (m, 6H), 1.90-1.40 (m, 17H), 1.38 (d, J = 6.40 Hz, 3H). 15 315

Example 44 1-[1-[4-[2-[1-[7-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-ox o-benzimidazol-5-yl]-1- piperidyl]-7-oxo-heptanoyl]-4-piperidyl]ethynyl]-1-naphthyl] ethyl]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (Compound 6) 5 C g the corresponding intermediates. LC-MS (ES ⁺ ): m/z 964.2 [M + H] ⁺ . 1H-NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 8.50 (d, J = 8.40 Hz, 1H), 8.32-8.27 (m, 2H), 10 7.64-7.57 (m, 3H), 7.53 (d, J = 7.60 Hz, 1H), 7.37-7.31 (m, 1H), 7.10 (s, 1H), 7.06-7.00 (m, 4H), 6.99-6.90 (m, 1H), 5.35-5.32 (m, 1H), 4.61-4.52 (m, 1H), 4.25 (d, J = 6.00 Hz, 2H), 4.19-4.12 (m, 1H), 4.03-3.88 (m, 2H), 3.80-3.71 (m, 1H), 3.29-3.19 (m, 1H), 3.15-3.00 (m, 3H), 2.95-2.62 (m, 4H), 2.42-2.30 (m, 5H), 2.21-2.11 (m, 1H), 2.05-1.86 (m, 5H), 1.82-1.66 (m, 4H), 1.65-1.51 (m, 11H), 1.39-1.31 (m, 5H). 15 316

Example 45 1-[1-[4-[2-[1-[8-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-ox o-benzimidazol-5-yl]-1- piperidyl]-8-oxo-octanoyl]-4-piperidyl]ethynyl]-1-naphthyl]e thyl]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (Compound 7) 5 the corresponding intermediates. LC-MS (ES ⁺ ): m/z 978.2 [M + H] ⁺ . 1H-NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 8.34 (brs, 1H), 8.28 (d, J = 6.80 Hz, 1H), 7.63- 10 7.56 (m, 4H), 7.37-7.31 (m, 1H), 7.10 (s, 1H), 7.07-6.99 (m, 4H), 6.90 (d, J = 8.00 Hz, 1H), 5.34 (dd, J = 5.60, 12.60 Hz, 1H), 4.57 (d, J = 11.60 Hz, 1H), 4.25 (d, J = 6.00 Hz, 2H), 4.20-4.10 (m, 1H), 4.01-3.93 (m, 2H), 3.77-3.74 (m, 1H), 3.11-3.05 (m, 3H), 2.90-2.60 (m, 5H), 2.40-2.28 (m, 5H), 2.23-1.88 (m, 7H), 1.85-1.25 (m, 22H). 317

Example 46 N-[(3-fluorophenyl)methyl]-1-[(1R)-1-[4-[2-[1-[7-[4-[1-(2,6- dioxo-3-piperidyl)-3-methyl-2- oxo-benzimidazol-5-yl]-1-piperidyl]-7-oxo-heptanoyl]-4-piper idyl]ethynyl]-1- naphthyl]ethyl]piperidine-4-carboxamide (Compound 8) 5 C g the corresponding intermediates. LC-MS (ES ⁺ ): m/z 964.4 [M + H] ⁺ . 1H-NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 8.50 (d, J = 8.40 Hz, 1H), 8.33-8.27 (m, 2H), 10 7.63-7.57 (m, 3H), 7.53 (d, J = 7.60 Hz, 1H), 7.37-7.31 (m, 1H), 7.11 (s, 1H), 7.06-6.99 (m, 4H), 6.91 (d, J = 7.60 Hz, 1H), 5.39-5.31 (m, 1H), 4.13-4.52 (m, 1H), 4.25 (d, J = 6.00 Hz, 2H), 4.21- 4.13 (m, 1H), 4.04-3.91 (m, 2H), 3.83-3.73 (m, 1H), 3.25-3.01 (m, 4H), 2.95-2.83 (m, 1H), 2.81- 2.60 (m, 5H), 2.36-2.33 (m, 4H), 2.19-1.88 (m, 7H), 1.78-1.71 (m, 4H), 1.62-1.50 (m, 10H), 1.38 (d, J = 6.40 Hz, 3H), 1.35-1.33 (m, 2H). 15 Example 47 1-(1-(4-((1-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl) piperazin-1-yl)-4- oxobutanoyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)-N- (3-fluorobenzyl)piperidine-4- carboxamide (Compound 9) 20 318

Compound 9 was prepared substantially following the synthesis of Compound 1, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 868.5 [M + H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ): Δ 10.76 (s, 1H), 8.50 (d, J = 8 Hz, 1H), 8.32-8.27 (m, 2H), 7.64- 5 7.52 (m, 4H), 7.37-7.31 (m, 1H), 7.08-6.98 (m, 3H), 6.79 (d, J = 8.8 Hz, 2H), 6.63 (d, J = 8.8 Hz, 2H), 5.44 (d, J = 7.6 Hz, 1H), 4.26-4.16 (m, 4H), 3.97-3.90 (m, 1H), 3.84-3.77 (m, 1H), 3.65-3.55 (m, 4H), 3.39-3.35 (m, 1H), 3.31-3.22 (m, 1H), 3.12-3.02 (m, 2H), 2.98-2.85 (m, 4H), 2.82-2.65 (m, 2H), 2.63-2.55 (m, 5H), 2.21-1.98 (m, 5H), 1.96-1.81 (m, 2H), 1.78-1.67 (m, 2H), 1.65-1.51 (m, 4H) and 1.39 (d, J = 6.4 Hz, 3H). 10 Example 48 1-(1-(4-((1-(6-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxois oindolin-4-yl)amino)methyl)-1H- 1,2,3-triazol-1-yl)hexanoyl)piperidin-4-yl)ethynyl)naphthale n-1-yl)ethyl)-N-(3- fluorobenzyl)piperidine-4-carboxamide (Compound 10) 15 Compou 1, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 948.5 [M + H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ): δ 11.12 (s, 1H), 8.50 (d, J = 8.4 Hz, 1H), 8.32-8.26 (m, 2H), 8.03 20 (s, 1H), 7.63-7.52 (m, 5H), 7.37-7.31 (m, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.09-6.99 (m, 5H), 5.06 (dd, J = 13, 5.6 Hz, 1H), 4.59 (d, J = 6 Hz, 2H), 4.32 (t, J = 6.8 Hz, 2H), 4.25 (d, J = 6 Hz, 2H), 4.21-4.15 (m, 1H), 3.95-3.91 (m, 1H), 3.77-3.69 (m, 1H), 3.28-3.19 (m, 2H), 3.15-3.01 (m, 2H), 2.95-2.76 (m, 2H), 2.69-2.55 (m, 2H), 2.35-2.26 (m, 2H), 2.20-2.10 (m, 1H), 2.07-1.90 (m, 5H), 319

1.85-1.76 (m, 2H), 1.75-1.65 (m, 2H), 1.62-1.49 (m, 6H), 1.39 (d, J = 6.4 Hz, 3H) and 1.28-1.21 (m, 2H). Example 49 5 Synthesis of N-[(3-fluorophenyl)methyl]-1-[(1R)-1-[4-[2-[1-[6-[4-[3-methy l-2-oxo-1-[(3R)- 2,6-dioxo-3-piperidyl]benzimidazol-5-yl]-1-piperidyl]-6-oxo- hexanoyl]-4- piperidyl]ethynyl]-1-naphthyl]ethyl]piperidine-4-carboxamide (Compound 11) and N-[(3- fluorophenyl)methyl]-1-[(1R)-1-[4-[2-[1-[6-[4-[3-methyl-2-ox o-1-[(3S)-2,6-dioxo-3- piperidyl]benzimidazol-5-yl]-1-piperidyl]-6-oxo-hexanoyl]-4- piperidyl]ethynyl]-1- 10 naphthyl]ethyl]piperidine-4-carboxamide (Compound 12) N-[(3- fluorophenyl)methyl]-1-[(1R)-1-[4-[2-(4-piperidyl)ethynyl]-1 -naphthyl]ethyl]piperidine-4- carboxamide hydrochloride (1, 120.00 mg, 208.95 μmol) and 6-[4-[1-(2,6-dioxo-3-piperidyl)-3- 320

methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-6-oxo-hexano ic acid hydrochloride (2, 104.59 mg, 193.92 μmol) in anhydrous DMF (0.5 mL) were added N,N-diisopropylethylamine (135.02 mg, 1.04 mmol, 181.97 μL) and HATU (95.34 mg, 250.74 μmol) at ambient temperature under nitrogen atmosphere. After 4 hours, the reaction mixture was concentrated under reduced pressure 5 to give the crude product, which was purified by reversed-phase prep-HPLC [Column: Xbridge C8 (20 X 150) mm; Mobile phase: A: 0.1% Ammonium bicarbonate in water and Mobile Phase B: Acetonitrile] to afford N-[(3-fluorophenyl)methyl]-1-[(1R)-1-[4-[2-[1-[6-[4-[1-(2,6- dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-6- oxo-hexanoyl]-4- piperidyl]ethynyl]-1-naphthyl]ethyl]piperidine-4-carboxamide (65 mg, 66.05 μmol, 32% yield) as 10 a white solid. LC-MS (ES ⁺ ): m/z 950.2 [M + H] ⁺ . The diastereomers were then separated by Chiral SFC, following the method below: Instrument: PIC 175; Column: R,R Whelk (250 × 30) mm, 5μm; Mobile Phase: CO2: 0.1% Isopropylamine in {[ isopropyl alcohol: Acetonitrile] (1:1)} (50:50); Total Flow: 90 g/min; Back 15 pressure: 120 bar; Wavelength: 210 nm; Temperature: 35 °C. The early eluting fraction (RT 23.17 min) was collected at 0 °C, acidified with trifluoroacetic acid, concentrated under reduced pressure, and further purified by reverse-phase prep-HPLC [Column: X Bridge C18 (150 Xv19 mm) 5um; Mobile phase A: 0.1% formic acid in water and Mobile Phase B: Acetonitrile] to afford N-[(3-fluorophenyl)methyl]-1-[(1R)-1-[4-[2-[1-[6-[4-[3-methy l-2-oxo-20 1-[(3R)-2,6-dioxo-3-piperidyl]benzimidazol-5-yl]-1-piperidyl ]-6-oxo-hexanoyl]-4- piperidyl]ethynyl]-1-naphthyl]ethyl]piperidine-4-carboxamide formate (Compound 11, 10.5 mg, 10.47 μmol, 25% yield, 100% optical purity) as a white solid with stereochemistry arbitrarily assigned. LC-MS (ES ⁺ ): m/z 950.2 [M + H ] ⁺ . 25 ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.08 (s, 1H), 8.49-8.46 (m, 1H), 8.38-8.29 (m, 1H), 7.89-7.82 (m, 1H), 7.70-7.68 (m, 1H), 7.61-7.54 (m, 2H), 7.40-7.28 (m, 1H), 7.10 (s, 1H), 7.06-7.00 (m, 4H), 6.91 (d, J = 8.80 Hz, 1H), 5.34 (dd, J = 5.60, 12.60 Hz, 1H), 4.57 (d, J = 12.0 Hz, 1H), 4.30-4.20 (m, 2H), 4.10-3.90 (m, 3H), 3.85-3.71 (m, 1H), 3.30-3.17 (m, 2H), 3.15-2.99 (m, 4H), 2.90-2.65 (m, 5H), 2.38-2.33 (m, 5H), 2.10-1.89 (m, 5H), 1.86-1.38 (m, 17H). 30 The late eluting fraction (RT 27.55 min) was collected 0 °C, acidified with trifluoroacetic acid, concentrated under reduced pressure, and further purified by reverse-phase prep-HPLC 321

[Column: Sunfire C18 (150 X19 mm) 5um; Mobile phase A: 0.1% formic acid in water and Mobile Phase B: Acetonitrile] to afford N-[(3-fluorophenyl)methyl]-1-[(1R)-1-[4-[2-[1-[6-[4-[3- methyl-2-oxo-1-[(3S)-2,6-dioxo-3-piperidyl]benzimidazol-5-yl ]-1-piperidyl]-6-oxo-hexanoyl]-4- piperidyl]ethynyl]-1-naphthyl]ethyl]piperidine-4-carboxamide formate (Compound 12, 10.5 mg, 5 10.48 μmol, 25% yield, 100% optical purity) as a white solid with stereochemistry arbitrarily assigned. LC-MS (ES ⁺ ): m/z 950.2 [M + H ] ⁺ . 1H-NMR (400 MHz, DMSO- d ₆ ): δ 11.08 (s, 1H), 8.51-8.37 (m, 3H), 7.88-7.82 (m, 2H), 7.75- 7.73 (m, 1H), 7.38-7.32 (m, 1H), 7.10 (s, 1H), 7.07-7.00 (m, 4H), 6.91 (d, J = 8.80 Hz, 1H), 5.34 10 (dd, J = 5.20, 12.80 Hz, 1H), 4.58 (d, J = 12.0 Hz, 1H), 4.27 (d, J = 6.00 Hz, 2H), 4.15-3.90 (m, 3H), 3.85-3.75 (m, 1H), 3.30-3.20 (m, 2H), 3.20-3.00 (m, 4H), 2.95-2.60 (m, 5H), 2.38-2.33 (m, 5H), 2.02-1.92 (m, 5H), 1.88-1.33 (m, 17H). 322

Example 50 Synthesis of N-[(3-fluorophenyl)methyl]-1-[(1R)-1-[4-[2-[1-[2-[4-[3-methy l-2-oxo-1-[(3S)- 2,6-dioxo-3-piperidyl]benzimidazol-5-yl]-1-piperidyl]acetyl] -4-piperidyl]ethynyl]-1- naphthyl]ethyl]piperidine-4-carboxamide (Compound 13) 5 To a 25 mL single-neck round-bottom flask containing a well-stirred solution of N-[(3- fluorophenyl)methyl]-1-[(1R)-1-[4-[2-(4-piperidyl)ethynyl]-1 -naphthyl]ethyl]piperidine-4- carboxamide (1, 150 mg, 294.58 μmol) and 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- 10 benzimidazol-5-yl]-1-piperidyl]acetic acid (2, 118.43 mg, 294.58 μmol) in anhydrous DMF (1 mL) were added N,N-diisopropylethylamine (38.07 mg, 294.58 μmol, 51.31 μL) and HATU (112.01 mg, 294.58 μmol) at ambient temperature under nitrogen atmosphere and the contents were stirred at this temperature for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by reverse 15 phase prep-HPLC (Column: Xbridge C-18 20x150m mobile phase: A:0.1% Ammonium 323

bicarbonate in water, B:acetonitrile] and lyophilized to afford N-[(3-fluorophenyl)methyl]-1- [(1R)-1-[4-[2-[1-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2 -oxo-benzimidazol-5-yl]-1- piperidyl]acetyl]-4-piperidyl]ethynyl]-1-naphthyl]ethyl]pipe ridine-4-carboxamide (80 mg, 88.18 μmol, 30% yield), arbitrarily assigned as (1R), as a white solid. LC-MS (ES ⁺ ): m/z 950.0 [M + H] 5 ⁺ . The diastereomeric mixture of N-[(3-fluorophenyl)methyl]-1-[(1R)-1-[4-[2-[1-[2-[4-[1-(2,6- dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piper idyl]acetyl]-4-piperidyl]ethynyl]- 1-naphthyl]ethyl]piperidine-4-carboxamide (80 mg, 88.84 μmol) was purified by chiral SFC. Chiral SFC method: Instrument: PIC 175; Column: R, R Whelk (250*30) mm, 5μm 10 Mobile Phase: CO ₂ : {0.1% IPAm in IPA: acetonitrile (1:1)} (50:50); Total Flow: 90 g/min; Back pressure: 120 bar; Wavelength: 210 nm; Cycle time: 24.0min The early eluting isomer (RT=10.0 min) was collected at 0 °C, acidified by using trifluoroacetic acid (1.5 ml), concentrated under reduced pressure at 35 °C, and further purified by reverse-phase prep-HPLC (Column: Sunfire C18 (150 X 19 mm) 5um; mobile phase: A:0.1% formic acid in15 water, B:acetonitrile] and lyophilized to afford N-[(3-fluorophenyl)methyl]-1-[(1R)-1-[4-[2-[1-[2- [4-[3-methyl-2-oxo-1-[(3R)-2,6-dioxo-3-piperidyl]benzimidazo l-5-yl]-1-piperidyl]acetyl]-4- piperidyl]ethynyl]-1-naphthyl]ethyl]piperidine-4-carboxamide formate (3, 14 mg, 15.09 μmol, 17% yield,) with stereochemistry arbitrarily assigned as (1R,3R). LC-MS (ES ⁺ ): m/z 880.4 [M + H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 9.48-9.43 (m, 2H), 8.53-8.45 (m, 2H), 8.38 20 (dd, J = 3.20, 6.40 Hz, 1H), 7.88-7.82 (m, 2H), 7.76-7.74 (m, 2H), 7.38-7.33 (m, 1H), 7.16-7.09 (m, 6H), 5.45-5.35 (m, 2H), 4.50-4.38 (m, 2H), 4.28 (d, J = 6.00 Hz, 2H), 4.05-3.93 (m, 2H), 3.71- 3.59 (m, 3H), 3.22-3.11 (m, 4H), 3.06-2.83 (m, 5H), 2.76-2.62 (m, 2H), 2.13-1.92 (m, 10H), 1.83- 1.68 (m, 7H). The late eluting isomer (RT=11.53 min) was collected at 0 °C, acidified by using trifluoroacetic 25 acid (1.5 ml), concentrated under reduced pressure at 35 °C, and further purified by reverse-phase prep-HPLC (Column: Sunfire C18 (150 X19 mm) 5um; mobile phase: A:0.1% Formic Acid in water, B:acetonitrile] and lyophilized to afford N-[(3-fluorophenyl)methyl]-1-[(1R)-1-[4-[2-[1-[2- [4-[3-methyl-2-oxo-1-[(3S)-2,6-dioxo-3-piperidyl]benzimidazo l-5-yl]-1-piperidyl]acetyl]-4- piperidyl]ethynyl]-1-naphthyl]ethyl]piperidine-4-carboxamide formate (Compound 13, 13 mg, 30 14.00 μmol, 16% yield) with stereochemistry arbitrarily assigned as (1R,3S). LC-MS (ES ⁺ ): m/z 880.3 [M + H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.10 (s, 1H), 9.46-9.37 (m, 2H), 8.52-8.45 324

(m, 2H), 8.38 (dd, J = 3.20, 6.40 Hz, 1H), 7.88-7.82 (m, 2H), 7.76-7.74 (m, 2H), 7.38-7.33 (m, 1H), 7.10-6.96 (m, 5H), 5.39-5.35 (m, 2H), 4.39 (d, J = 4.00 Hz, 2H), 4.28 (d, J = 6.00 Hz, 2H), 4.11-3.93 (m, 2H), 3.71-3.55 (m, 3H), 3.22-3.01 (m, 5H), 3.00-2.83 (m, 3H), 2.76-2.62 (m, 3H), 2.22-1.92 (m, 10H), 1.83-1.68 (m, 7H). 5 Example 51 Synthesis of 1-[1-[4-[2-[1-[4-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-ox o-benzimidazol-5- yl]-4-piperidyl]butyl]-4-piperidyl]ethynyl]-1-naphthyl]ethyl ]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (Compound 14) 10 n of 4-[1-[1-(2,6- dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piper idyl]butanal hydrochloride (2, 200 mg, 0.343 mmol) and N-[(3-fluorophenyl)methyl]-1-[1-[4-[2-(4-piperidyl)ethynyl]- 1- naphthyl]ethyl]piperidine-4-carboxamide hydrochloride (1, 236.40 mg, 0.411 mmol) 15 in dry DMSO (2 mL) were added sodium acetate (112.55 mg, 1.37 mmol) and acetic acid (411.98 mg, 6.86 mmol, 392.73 μL) at ambient temperature. Subsequently, MP-Cyano borohydride, 2 mmol/g (257mg, 0.514 mmol) was added at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 h. The progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was filtered, and the filtrate was 325

evaporated under reduced pressure. The obtained crude was purified by reverse-phase HPLC (Redisep-RF Gold C18-100g column, Mobile Phase A: 10 mm NH4HCO3 in MQ-water in water and Mobile Phase B: Acetonitrile) to afford 1-[1-[4-[2-[1-[4-[1-[1-(2,6-dioxo-3-piperidyl)- 3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]butyl]-4-piper idyl]ethynyl]-1-naphthyl]ethyl]-N- 5 [(3-fluorophenyl)methyl]piperidine-4-carboxamide (Compound 14, 73 mg, 0.078 mmol, 22% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 894.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.06 (s, 1H), 8.50 (d, J = 8 Hz, 1H), 8.32-8.29 (m, 2H), 7.63-7.51 (m, 4H), 7.37-7.31 (m, 1H), 7.06-6.99 (m, 3H), 6.92 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 2 Hz, 1H), 6.64-6.61 (m, 1H), 5.32-5.25 (m, 1H), 4.25 (d, J = 6 Hz, 2H), 4.19-4.13 (m, 1H), 3.59-3.56 (m, 2H), 3.30 (s, 3H), 3.08 (m, 1H),10 2.92-2.65 (m, 6H), 2.60 (m, 3H), 2.35-2.12 (m, 3H), 2.06-1.90 (m, 5H), 1.77-1.71 (m, 6H), 1.59- 1.45 (m, 6H) and 1.44-1.24 (m, 10H). Example 52 Synthesis of 1-[1-[4-[2-[1-[5-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-ox o-benzimidazol-5-15 yl]-1-piperidyl]-5-oxo-pentyl]-4-piperidyl]ethynyl]-1-naphth yl]ethyl]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (Compound 15) 326

To a 10 mL single-neck round-bottom flask containing a well solution of N-[(3- fluorophenyl)methyl]-1-[1-[4-[2-(4-piperidyl)ethynyl]-1-naph thyl]ethyl]piperidine-4- 5 carboxamide hydrochloride (1, 50.00 mg, 92.85 μmol) in anhydrous DMF (148.24 μL) were added triethylamine (46.98 mg, 464.23 μmol, 64.71 μL) and tert-butyl 5-bromopentanoate (2, 66.05 mg, 278.54 μmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 hours. Thereafter, the solvent was evaporated under reduced pressure to give a residue that was triturated with MTBE (10 mL). The obtained solid was filtered10 and dried over vacuum to afford tert-butyl 5-[4-[2-[4-[1-[4-[(3-fluorophenyl)methylcarbamoyl]- 1-piperidyl]ethyl]-1-naphthyl]ethynyl]-1-piperidyl]pentanoat e (3, 55 mg, 65.01 μmol, 70% yield) as a brown solid. LC-MS(ES ⁺ ): m/z 598.6 [M - tBu + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 5-[4-15 [2-[4-[1-[4-[(3-fluorophenyl)methylcarbamoyl]-1-piperidyl]et hyl]-1-naphthyl]ethynyl]-1- piperidyl]pentanoate (3, 55 mg, 76.83 μmol) in anhydrous DCM (0.5 mL) was added hydrogen chloride (4.0M in dioxane, 576.25 μL) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 16 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and triturated with MTBE (10 mL) to get a solid that was filtered and dried 327

to afford 5-[4-[2-[4-[1-[4-[(3-fluorophenyl)methylcarbamoyl]-1-piperid yl]ethyl]-1- naphthyl]ethynyl]-1-piperidyl]pentanoic acid hydrochloride (4, 50 mg, 76.63 μmol, 99% yield) as a pale brown solid. LC-MS(ES ⁺ ): m/z 598.6 [M + H] ⁺ . Step-3: 5 To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 5-[4-[2-[4-[1-[4- [(3-fluorophenyl)methylcarbamoyl]-1-piperidyl]ethyl]-1-napht hyl]ethynyl]-1- piperidyl]pentanoic acid hydrochloride (4, 50 mg, 76.63 μmol) and 3-[3-methyl-2-oxo-5-(4- piperidyl)benzimidazol-1-yl]piperidine-2,6-dione hydrochloride (29.03 mg, 76.63 μmol) in anhydrous DMF (0.5 mL) were added N,N-diisopropylethylamine (59.42 mg, 459.78 μmol, 80.08 10 μL) and HATU (43.71 mg, 114.94 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 hours. Thereafter, the solvent was evaporated to get a residue, which was purified by reverse-phase column chromatography [Column: RediSep C18-30 g; Mobile Phase A: 0.1% Ammonium bicarbonate in water and Mobile Phase B: Acetonitrile] to afford 1-[1-[4-[2-[1-[5-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-ox o-15 benzimidazol-5-yl]-1-piperidyl]-5-oxo-pentyl]-4-piperidyl]et hynyl]-1-naphthyl]ethyl]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (Compound 15, 34 mg, 35.30 μmol, 46% yield) as an off-white solid. LC-MS(ES ⁺ ): m/z 922.2 [M + H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.09 (s, 1H), 8.50 (d, J = 8.40 Hz, 1H), 8.33-8.28 (m, 2H), 7.62-7.56 (m, 3H), 7.51 (d, J = 7.60 Hz, 1H), 7.11 (s, 1H), 7.09-7.01 (m, 4H), 6.92 (d, J = 8.00 Hz, 1H), 5.36 (dd, J = 5.60, 12.60 Hz, 20 1H), 4.58 (d, J = 12.0 Hz, 1H), 4.25 (d, J = 6.00 Hz, 2H), 4.10-4.12 (m, 1H), 3.16-3.00 (m, 2H), 2.95-2.60 (m, 5H), 2.40-2.25 (m, 4H), 2.23-2.00 (m, 3H), 2.10-1.00 (m, 6H), 1.89-1.43 (m, 17H), 1.39 (d, J = 6.80 Hz, 3H). 328 Example 53 N-[(3-fluorophenyl)methyl]-1-[(1R)-1-[4-[2-[1-[5-[4-[1-(2,6- dioxo-3-piperidyl)-3-methyl-2- oxo-benzimidazol-5-yl]-1-piperidyl]-5-oxo-pentyl]-4-piperidy l]ethynyl]-1- naphthyl]ethyl]piperidine-4-carboxamide (Compound 16) 5 Co sing the corresponding intermediates. LC-MS(ES-): m/z 920.2 [M - H]-. 1H-NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 8.49 (d, J = 9.20 Hz, 1H), 8.31-8.28 (m, 2H), 10 7.61-7.56 (m, 3H), 7.52 (d, J = 7.60 Hz, 1H), 7.37-7.31 (m, 1H), 7.10 (s, 1H), 7.06-6.99 (m, 4H), 6.92 (dd, J = 1.20, 8.00 Hz, 1H), 5.32 (dd, J = 5.30, 13.20 Hz, 1H), 4.61-4.52 (m, 1H), 4.25 (d, J = 6.00 Hz, 2H), 4.19-4.14 (m, 1H), 4.06-3.99 (m, 1H), 3.20-3.01 (m, 2H), 2.95-2.60 (m, 5H), 2.41- 2.30 (m, 5H), 2.29-2.11 (m, 3H), 2.11-1.90 (m, 6H), 1.88-1.68 (m, 6H), 1.67-1.46 (m, 10H), 1.39 (d, J = 6.40 Hz, 3H). 15 Example 54 1-[1-[4-[2-[1-[5-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6-yl]-1- piperidyl]-5-oxo-pentyl]-4-piperidyl]ethynyl]-1-naphthyl]eth yl]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (Compound 17) 20

Compound 17 was prepared substantially following the synthesis of Compound 15, using the corresponding intermediates. LC-MS(ES ⁺ ): m/z 907.4 [M + H] ⁺ . 1H-NMR (400 MHz, DMSO-d ₆ ): δ 10.54 (s, 1H), 8.50-8.48 (m, 1H), 8.32-8.27 (m, 2H), 7.61-7.55 5 (m, 4H), 7.51 (d, J = 7.60 Hz, 1H), 7.45 (s, 1H), 7.37-7.31 (m, 1H), 7.05-6.99 (m, 4H), 4.64-4.58 (m, 1H), 4.25 (d, J = 6.00 Hz, 2H), 4.20-4.13 (m, 1H), 4.10-4.02 (m, 1H), 3.96 (s, 3H), 3.90 (t, J = 6.40 Hz, 2H), 3.20-3.10 (m, 1H), 3.09-3.01 (m, 1H), 2.99-2.89 (m, 1H), 2.85-2.60 (m, 6H), 2.40- 2.31 (m, 4H), 2.29-2.10 (m, 3H), 2.07-1.80 (m, 6H), 1.78-1.45 (m, 13H), 1.38 (d, J = 6.40 Hz, 3H). 10 Example 55 1-[1-[4-[2-[1-[5-[4-[1-(2,6-dioxo-3-piperidyl)-6-fluoro-3-me thyl-2-oxo-benzimidazol-5- yl]piperazin-1-yl]-5-oxo-pentyl]-4-piperidyl]ethynyl]-1-naph thyl]ethyl]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (Compound 18) 15 Co sing the corresponding intermediates. LC-MS(ES-): m/z 940.2 [M - H] -. 1H-NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 8.49 (d, J = 8.80 Hz, 1H), 8.31-8.28 (m, 2H), 20 7.62-7.51 (m, 5H), 7.37-7.31 (m, 1H), 7.17 (d, J = 12.00 Hz, 1H), 7.05-6.95 (m, 5H), 5.38-5.28 (m, 1H), 4.25 (d, J = 6.00 Hz, 2H), 4.19-4.11 (m, 2H), 3.63-3.62 (m, 4H), 3.31 (s, 3H), 3.06-2.85 (m, 4H), 2.32-2.69 (m, 6H), 2.41-2.31 (m, 4H), 2.22-2.11 (m, 3H), 2.02-1.95 (m, 4H), 1.73-1.71 (m, 3H), 1.59-1.50 (m, 8H), 1.39 (d, J = 6.80 Hz, 3H). 330

Example 56 1-[1-[4-[2-[1-[5-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-5- fluoro-1-methyl-indazol-6-yl]- 1-piperidyl]-5-oxo-pentyl]-4-piperidyl]ethynyl]-1-naphthyl]e thyl]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (Compound 19) 5 Com using the corresponding intermediates. LC-MS(ES ⁺ ): m/z 926.3 [M + H] ⁺ . 1H NMR (400 MHz, DMSO-d6): δ 10.57 (s, 1H), 8.50 (d, J = 9.2 Hz, 1H), 8.33-8.27 (m, 2H), 7.62- 10 7.57 (m, 4H), 7.52 (d, J = 7.60 Hz, 1H), 7.40-7.31 (m, 2H), 7.07-6.99 (m, 3H), 4.66-4.58 (m, 1H), 4.25 (d, J = 6 Hz, 2H), 4.19-4.15 (m, 1H), 4.08-4.01 (m, 1H), 3.99 (s, 3H), 3.90 (t, J = 6.8 Hz, 2H), 3.23-3.12 (m, 3H), 3.09-3.02 (m, 1H), 2.95-2.82 (m, 3H), 2.79-2.66 (m, 4H), 2.42-2.33 (m, 3H), 2.22-2.11 (m, 2H), 2.05-1.95 (m, 4H), 1.92-1.65 (m, 7H), 1.63-1.56 (m, 8H) and 1.39 (d, J = 6.8 Hz, 3H). 15 Example 57 1-[1-[4-[2-[1-[5-[4-[1-(2,6-dioxo-3-piperidyl)-6-fluoro-3-me thyl-2-oxo-benzimidazol-5-yl]-1- piperidyl]-5-oxo-pentyl]-4-piperidyl]ethynyl]-1-naphthyl]eth yl]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (Compound 20) 20 33

Compound 20 was prepared substantially following the synthesis of Compound 15, using the corresponding intermediates. LC-MS(ES ⁺ ): m/z 941.2 [M + H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ): δ 11.10 (s, 1H), 8.50 (d, J = 8.4 Hz, 1H), 8.34-8.27 (m, 2H), 7.63- 5 7.53 (m, 4H), 7.37-7.31 (m, 1H), 7.16-7.11 (m, 2H), 7.07-6.99 (m, 3H), 5.36-5.32 (m, 1H), 4.61- 4.58 (m, 1H), 4.25 (d, J = 6 Hz, 2H), 4.23-4.15 (m, 1H), 4.05-3.98 (m, 1H), 3.18-3.00 (m, 5H), 2.95-2.50 (m, 11H), 2.42-2.39 (m, 2H), 2.38-2.35 (m, 2H), 2.22-1.95 (m, 6H), 1.85-1.50 (m, 14H) and 1.39 (d, J = 6.4 Hz, 3H). 10 Example 58 N-[(3-fluorophenyl)methyl]-1-[1-[4-[2-[1-[5-[4-[3-methyl-1-( 1-methyl-2,6-dioxo-3- piperidyl)-2-oxo-benzimidazol-5-yl]-1-piperidyl]-5-oxo-penty l]-4-piperidyl]ethynyl]-1- naphthyl]ethyl]piperidine-4-carboxamide (Compound 21) 15 Co ing the corresponding intermediates. LC-MS(ES ⁺ ): m/z 937.4 [M + H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ): δ 8.49 (d, J = 9.2 Hz, 1H), 8.32-8.27 (m, 2H), 7.59-7.56 (m, 3H), 7.51 (d, J = 7.6 Hz, 1H), 7.37-7.31 (m, 1H), 7.11 (s, 1H), 7.06-6.9 (m, 5H), 5.41 (dd, J = 12.8, 5.220 Hz, 1H), 4.61-4.53 (m, 1H), 4.25 (d, J = 6 Hz, 2H), 4.20-4.13 (m, 1H), 4.08-4.00 (m, 1H), 3.15- 2.90 (m, 6H), 2.81-2.63 (m, 7H), 2.60 (m, 1H), 2.40-2.30 (m, 5H), 2.25-2.10 (m, 3H), 2.10-1.90 (m, 6H), 2.00-1.66 (m, 6H), 1.65-1.46 (m, 9H) and 1.39 (d, J = 6.8 Hz, 3H). 332

Example 59 1-[1-[4-[2-[1-[6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-ox o-benzimidazol-5-yl]-1- piperidyl]-6-oxo-hexyl]-4-piperidyl]ethynyl]-1-naphthyl]ethy l]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (Compound 22) 5 except using tert-butyl 6-bromohexanoate in Step-1 and the corresponding CRBN binder in Step-3. LC-MS(ES ⁺ ): m/z 936.4 [M + H] ⁺ . 1H-NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 8.50 (d, J = 8.00 Hz, 1H), 8.33-8.28 (m, 2H), 10 7.63-7.56 (m, 3H), 7.52 (d, J = 7.60 Hz, 1H), 7.37-7.31 (m, 1H), 7.11 (s, 1H), 7.06-6.98 (m, 5H), 5.33 (dd, J = 5.20, 12.80 Hz, 1H), 4.564.56 (d, J = 12.6 Hz, 1H), 4.25 (d, J = 6.00 Hz, 2H), 4.20- 4.12 (m, 1H), 4.07-4.02 (m, 1H), 3.23-3.00 (m, 2H), 2.95-2.58 (m, 8H), 2.40-2.25 (m, 4H), 2.24- 2.10 (m, 3H), 2.10-1.90 (m, 5H), 1.84-1.67 (m, 5H), 1.65-1.42 (m, 10H), 1.32 (s, 3H), 1.30-1.22 (m, 2H). 15 Example 60 Synthesis of 1-(1-(4-((1-(2-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)piperidine-1-carbonyl)-1H-pyrazol-1 -yl)ethyl)piperidin-4- 333 yl)ethynyl)naphthalen-1-yl)ethyl)-N-(3-fluorobenzyl)piperidi ne-4-carboxamide (Compound 23) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of N-[(3- fluorophenyl)methyl]-1-[1-[4-[2-(4-piperidyl)ethynyl]-1-naph thyl]ethyl]piperidine-4- carboxamide hydrochloride (1, 250 mg, 0.430 mmol), ethyl 1-(2-oxoethyl)pyrazole-4-carboxylate trifluoroacetate (2, 350 mg, 0.957 mmol) in anhydrous MeOH (5 mL) were added Sodium acetate, anhydrous (105.98 mg, 1.29 mmol) and Acetic acid (1.31 g, 21.84 mmol, 1.25 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 2 h. Thereafter, MP- CNBH ₃ (430.62 mg, 0.861 mmol; 2 mmol\g) was added and stirring was continued for 16 h. The reaction was monitored by UPLC. Reaction mixture was passed through a sintered funnel and solid on the funnel was washed with MeOH (50 mL) and combined filtrate was concentrated under reduced pressure to get a crude mass. This reaction crude was purified by flash silica-gel (230-400 mesh) column with 9% MeOH/DCM to get ethyl 1-[2-[4-[2-[4-[1-[4-[(3- fluorophenyl)methylcarbamoyl]-1-piperidyl]ethyl]-1-naphthyl] ethynyl]-1- piperidyl]ethyl]pyrazole-4-carboxylate (3, 0.2 g, 0.280 mmol, 65% yield) as a brown syrupy liquid. LC-MS(ES ⁺ ): m/z 664.3 [M + H] ⁺ . Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of ethyl 1-[2-[4-[2- [4-[1-[4-[(3-fluorophenyl)methylcarbamoyl]-1-piperidyl]ethyl ]-1-naphthyl]ethynyl]-1- piperidyl]ethyl]pyrazole-4-carboxylate (3, 0.2 g, 0.280 mmol) in 1:1 THF/MeOH (4 mL) was added Lithium hydroxide, monohydrate (117.82 mg, 2.81 mmol) in water (2 mL) at ambient temperature. The resulting solution was stirred at ambient temperature for 5 h. The reaction was monitored by UPLC. The solvent was removed from the reaction mixture to get a crude mass. The crude mass was purified by reverse phase [Redisef-C18 column, Mobile phase: NH ₄ HCO ₃ in water and B : acetonitrile to get 1-[2-[4-[2-[4-[1-[4-[(3-fluorophenyl)methylcarbamoyl]-1- piperidyl]ethyl]-1-naphthyl]ethynyl]-1-piperidyl]ethyl]pyraz ole-4-carboxylic acid (4, 120 mg, 0.183 mmol, 65% yield) as an off-white solid. LC-MS(ES ⁺ ): m/z 637.4 [M + H] ⁺ . Step-3: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 1-[2-[4-[2-[4-[1- [4-[(3-fluorophenyl)methylcarbamoyl]-1-piperidyl]ethyl]-1-na phthyl]ethynyl]-1- piperidyl]ethyl]pyrazole-4-carboxylic acid (4; 65 mg, 0.099 mmol) in anhydrous DMF (1.5 mL) were added DIPEA (64.09 mg, 0.495 mmol, 0.086 mL) and HATU (75.42 mg, 0.198 mmol) followed by 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidin e-2,6-dione hydrochloride (5, 45.09 mg, 0.119 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 2 h. The progress of the reaction was monitored by UPLC. Excess solvent was removed under reduced pressure to get a crude residue. The crude mass was purified by reverse-phase column chromatography (Redisef-C18 column, Mobile phase A : 10 mm NH4HCO3 in water and B : MeCN) to furnish 1-[1-[4-[2-[1-[2- [4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol -5-yl]piperidine-1- carbonyl]pyrazol-1-yl]ethyl]-4-piperidyl]ethynyl]-1-naphthyl ]ethyl]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (Compound 23, 60 mg, 0.060 mmol, 61% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 962.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ11.08 (s, 1H), 8.50-8.48 (m, 1H), 8.32-8.26 (m, 2H), 8.11 (s, 1H), 7.69 (s, 1H), 7.60-7.49 (m, 4H), 7.37-7.31 (m, 1H), 7.12 (s, 1H), 7.06-6.98 (m, 4H), 6.90 (dd, J = 8.4, 1.2 Hz, 1H), 5.36-5.31 (m, 1H), 4.51-4.35 (bs, 2H), 4.27-4.24 (m, 4H), 4.18-4.12 (m, 1H), 3.06-2.99 (m, 2H), 2.91-2.50 (m, 11H), 2.35-2.25 (m, 2H), 2.18-2.11 (m, 2H), 2.06-1.92 (m, 6H), 1.85-1.82 (m, 2H), 1.70-1.53 (m, 9H) and 1.38 (d, J = 6.4 Hz, 3H). Example 61 Synthesis of 1-(1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-o xo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-yl)m ethyl)piperidin-4-

yl)ethynyl)naphthalen-1-yl)ethyl)-N-(3-fluorobenzyl)piper idine-4-carboxamide (Compound 24) Step-1: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of N-[(3- fluorophenyl)methyl]-1-[1-[4-[2-(4-piperidyl)ethynyl]-1-naph thyl]ethyl]piperidine-4- carboxamide hydrochloride (1, 0.2 g, 0.333 mmol) and tert-butyl 4-formylpiperidine-1- carboxylate (2, 142.15 mg, 0.666 mmol) in anhydrous MeOH (3 mL) were added sodium acetate, anhydrous (27.34 mg, 0.333 mmol) and acetic acid (2.10 g, 34.94 mmol, 2.00 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 2 h. Subsequently, MP- CNBH ₃ (0.33 g; 2mmol/g) was added and stirring was continued for 16 h. The reaction was monitored by UPLC. Reaction mixture was passed through a sintered funnel and solid on the funnel was washed with MeOH (25 mL) and combined filtrate was concentrated under reduced pressure to get a crude residue. This reaction crude was purified by flash column chromatography (230-400 mesh silica gel) with 10% MeOH/DCM as eluent to afford tert-butyl 4-[[4-[2-[4-[1-[4- [(3-fluorophenyl)methylcarbamoyl]-1-piperidyl]ethyl]-1-napht hyl]ethynyl]-1- piperidyl]methyl]piperidine-1-carboxylate (3, 0.21 g, 0.290 mmol, 87% yield) as a colorless gum. LC-MS (ES ⁺ ): m/z 695.2 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[[4- [2-[4-[1-[4-[(3-fluorophenyl)methylcarbamoyl]-1-piperidyl]et hyl]-1-naphthyl]ethynyl]-1- piperidyl]methyl]piperidine-1-carboxylate (3, 0.21 g, 0.290 mmol) in anhydrous dichloromethane (2 mL) was added 4N HCl in 1,4-dioxane (2 mL) at 0 °C and the resulting mixture was stirred at ambient temperature for 2 h. The progress of the reaction was monitored by UPLC. Excess solvent was removed under reduced pressure to give a crude residue, which was washed with MTBE (30 mL) and dried to afford N-[(3-fluorophenyl)methyl]-1-[1-[4-[2-[1-(4-piperidylmethyl) -4- piperidyl]ethynyl]-1-naphthyl]ethyl]piperidine-4-carboxamide hydrochloride (4, 180 mg, 0.283 mmol, 98% yield) as an off-white solid. LC-MS(ES ⁺ ): m/z 596.2 [M + H] ⁺ . Step-3: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 1-[1-(2,6-dioxo- 3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-c arboxylic acid formate (5, 70 mg, 0.161 mmol) in anhydrous DMF (2 mL) were added DIPEA (83.69 mg, 0.647 mmol, 0.112 mL) and HATU (92.33 mg, 0.242 mmol) followed by N-[(3-fluorophenyl)methyl]-1-[1-[4-[2-[1-(4- piperidylmethyl)-4-piperidyl]ethynyl]-1-naphthyl]ethyl]piper idine-4-carboxamide hydrochloride (4, 103.22 mg, 0.161 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 2 h. The progress of the reaction was monitored by UPLC. Excess solvent was removed under reduced pressure to give a crude residue, which was purified by reverse phase column chromatography (Redisef-C18 column, Mobile phase A : 10 mm NH4HCO3 in water and B : acetonitrile) to afford 1-[1-[4-[2-[1-[[1-[1-[1-(2,6-dioxo-3-piperidyl)- 3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-carbonyl]-4-pi peridyl]methyl]-4- piperidyl]ethynyl]-1-naphthyl]ethyl]-N-[(3-fluorophenyl)meth yl]piperidine-4-carboxamide (Compound 24, 35 mg, 0.035 mmol, 22% yield) as an off-white solid. ¹ NMR (400 MHz, DMSO-d ₆ ): δ 11.06 (s, 1H), 8.50 (d, J = 8.8 Hz, 1H), 8.32-8.29 (m, 2H), 7.64-7.57 (m, 3H), 7.53 (d, J = 7.6 Hz, 1H), 7.37-7.31 (m, 1H), 7.06-6.99 (m, 3H), 6.94 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 6.65-6.63 (m, 1H), 5.35-5.25 (m, 1H), 4.44-4.36 (m, 1H), 4.25 (d, J = 6 Hz, 2H), 4.21-4.13 (m, 1H), 4.03-3.95 (m, 1H), 3.64-3.57 (m, 2H), 3.11-2.98 (m, 2H), 2.90-2.50 (m, 14H), 2.22-2.16 (m, 5H), 2.03-1.95 (m, 5H), 1.81-1.71 (m, 10H), 1.59-1.53 (m, 3H), 1.39 (d, J = 6.4 Hz, 3H) and 1.09-0.85 (m, 2H). LC-MS (ES ⁺ ): m/z 963.4 [M + H] ⁺ . Example 62 Synthesis of 3-[4-[2-[4-[1-[4-[(3-fluorophenyl)methylcarbamoyl]-1-piperid yl]ethyl]-1- naphthyl]ethynyl]-1-piperidyl]propyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]piperidine-1-carboxylate (Compound 25)

Step-1: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of N-[(3- fluorophenyl)methyl]-1-[1-[4-[2-(4-piperidyl)ethynyl]-1-naph thyl]ethyl]piperidine-4- carboxamide hydrochloride (1, 350 mg, 0.609 mmol) in anhydrous DMF (7 mL) were added anhydrous Potassium carbonate (168.45 mg, 1.22 mmol) and Potassium iodide (101.17 mg, 0.609 mmol) followed by 3-bromopropoxy-tert-butyl-dimethyl-silane (2; 185.21 mg, 0.731 mmol) at ambient temperature. The reaction mixture was stirred at 90 °C for 3 h by which time reaction was complete as monitored by UPLC. The reaction mixture was concentrated under reduced pressure to remove excess solvent and crude mass thus obtained was diluted with water (100 mL) and extracted with EtOAc (2 × 200 mL). The combined organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (230-400 mesh silica gel; 50g SNAP) with 5-8% MeOH/DCM as eluent to afford 1-[1-[4-[2-[1-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-4-pip eridyl]ethynyl]-1- naphthyl]ethyl]-N-[(3-fluorophenyl)methyl]piperidine-4-carbo xamide (3, 250 mg, 0.354 mmol, 58% yield) as a pale yellow solid. LC-MS (ES ⁺ ): m/z 670.4 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 1-[1-[4-[2-[1-[3- [tert-butyl(dimethyl)silyl]oxypropyl]-4-piperidyl]ethynyl]-1 -naphthyl]ethyl]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (3, 250 mg, 0.354.49 mmol) in dry THF (5 mL) was added 1M TBAF in THF (0.7 mL, 0.789 mmol) at ambient temperature and the resulting mixture was stirred for 1 h. Upon completion of the reaction as indicated by UPLC, the reaction mixture was diluted with water (150 mL) and extracted with EtOAc (2 × 100 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford N-[(3-fluorophenyl)methyl]-1-[1-[4-[2-[1-(3-hydroxypropyl)-4 -piperidyl]ethynyl]-1- naphthyl]ethyl]piperidine-4-carboxamide (4, 150 mg, 0.263 mmol, 74% yield) as a pale yellow gummy liquid. LC-MS (ES ⁺ ): m/z 556.2 [M + H] ⁺ . Step-3: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of N-[(3- fluorophenyl)methyl]-1-[1-[4-[2-[1-(3-hydroxypropyl)-4-piper idyl]ethynyl]-1- naphthyl]ethyl]piperidine-4-carboxamide (4, 150 mg, 0.264 mmol) in dry THF (4 mL) were added 4-nitrophenyl chloroformate (79.97 mg, 0.396 mmol) and TEA (133.83 mg, 1.32 mmol, 0.2 mL) at 0 °C. The reaction mixture was allowed to stir for 2 h at ambient temperature. Thereafter, a solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1- yl]piperidine-2,6-dione hydrochloride (5, 110.24 mg, 0.290 mmol) in dry THF (2 mL) and TEA (133.83 mg, 1.32 mmol, 0.2 mL) were added to the reaction mixture at ambient temperature. The resulting mixture was stirring for 16 h at the same temperature. The reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (Redisep-RF Gold C18-100 g column, Mobile Phase A: 10 mM NH4HCO3 in MQ-water in water and Mobile Phase B: Acetonitrile) to afford 3-[4-[2-[4-[1-[4-[(3- fluorophenyl)methylcarbamoyl]-1-piperidyl]ethyl]-1-naphthyl] ethynyl]-1-piperidyl]propyl 4-[1- (2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]pip eridine-1-carboxylate (Compound 25, 93 mg, 0.092 mmol, 35% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 925.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.08 (s, 1H), 8.50 (d, J = 7.6 Hz, 1H), 8.32-8.29 (m, 2H), 7.63-7.51 (m, 4H), 7.37-7.31 (m, 1H), 7.11 (s, 1H), 7.06-7.00 (m, 4H), 6.95 (m, 1H), 5.40-5.28 (m, 1H), 4.28 (d, J = 6 Hz, 2H), 4.17 (m, 3H), 4.01 (m, 2H), 3.45 (m, 1H), 3.21-3.13 (m, 1H), 3.07-2.98 (m, 1H), 2.92-2.67 (m, 8H), 2.58 (m, 1H), 2.45-2.32 (m, 2H), 2.29-2.11 (m, 3H), 2.05-1.95 (m, 5H), 1.79-1.71 (m, 7H), 1.60-1.53 (m, 6H), 1.39-1.38 (m, 3H) and 0.95 (m, 1H). Example 63 Synthesis of 1-(1-(4-(5-(6-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo -2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-1-yl)-N-methyl-6-oxohexanami do)pentyl)naphthalen-1- yl)ethyl)-N-(3-fluorobenzyl)piperidine-4-carboxamide (Compound 26)

Step-1: To a 100 mL two-neck round-bottom flask containing a well-stirred suspension of sodium hydride (253.74 mg, 3.81 mmol; 60% dispersion in mineral oil) in anhydrous DMF (5 mL) at 0 °C was added a solution of tert-butyl N-pent-4-ynylcarbamate (1, 500 mg, 2.54 mmol) in anhydrous DMF (3 mL) and the resulting mixture was stirred for 1 h at ambient temperature. Methyl iodide (360.18 mg, 2.54 mmol, 0.157 mL) was added and the mixture was stirred at ambient temperature for 16 h. The reaction was monitored by TLC. Afterwards, the reaction mixture was quenched with saturated NH ₄ Cl (10 mL) and extracted with EtOAc (3 × 15 mL). The combined organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (230-400 mesh silica gel, 120 g) with 20% EtOAc/pet ether as eluent to afford tert-butyl N-methyl-N-pent-4-ynyl-carbamate (2, 260 mg, 1.25 mmol, 49% yield) as a brown liquid. ¹ H NMR (400 MHz, CDCl ₃ ). δ3.35 (S, 3H), 2.9-2.8 (m, 3H), 2.25-2.20 (m, 1H), 2.00-1.95 (m, 1H), 1.80-1.70 (m, 2H) and 1.43 (s, 9H). Step-2: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of 1-[1-(4-bromo- 1-naphthyl)ethyl]piperidine-4-carboxylic acid (3, 1.3 g, 3.59 mmol) in anhydrous DMF (15 mL) were added DIPEA (2.32 g, 17.95 mmol, 3.13 mL) and HATU (1.64 g, 4.31 mmol) followed by (3- fluorophenyl)methanamine (4, 673.63 mg, 5.38 mmol, 0.61 mL) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at this temperature for 2 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was poured into water (25 mL) and extracted with DCM (2 × 50 mL). The organic phase was combined and washed with brine (25 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to get a crude residue. Crude residue was purified by flash column chromatography (230- 400 mesh silica gel, 120 g) with 0-15% MeOH/DCM as eluent to afford 1-[1-(4-bromo-1- naphthyl)ethyl]-N-[(3-fluorophenyl)methyl]piperidine-4-carbo xamide (5, 1 g, 2.11 mmol, 59% yield) as a brown solid. LC-MS (ES ⁺ ): m/z 471.0 [M + H] ⁺ . Step-2: To a 25 mL sealed tube containing a well-stirred solution of 1-[1-(4-bromo-1-naphthyl)ethyl]-N- [(3-fluorophenyl)methyl]piperidine-4-carboxamide (5, 250 mg, 0.527 mmol) and tert-butyl N- methyl-N-pent-4-ynyl-carbamate (2, 109.49 mg, 0.527 mmol) in anhydrous acetonitrile (8 mL) was added cesium carbonate (429.50 mg, 1.32 mmol) at ambient temperature and the resulting mixture was degassed by bubbling nitrogen gas for 10 minutes. Subsequently, XPhos (25.14 mg, 0.052 mmol) and XPhos-Pd-G3 (22.32 mg, 0.026 mmol) were added, and the resulting mixture was degassed with N2 for an additional 5 minutes. The reaction mixture was stirred at 90 °C for 4 h. Progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was passed through a pad of Celite and Celite bed was washed with EtOAc (150 mL). The filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (230-400 mesh silica gel, 50 g) with 0-10% MeOH/DCM as eluent to afford tert-butyl N-[5-[4-[1-[4-[(3-fluorophenyl)methylcarbamoyl]-1- piperidyl]ethyl]-1-naphthyl]pent-4-ynyl]-N-methyl-carbamate (6, 115 mg, 0.184 mmol, 35% yield) as a pale yellow solid. LC-MS (ES ⁺ ): m/z 586.2 [M + H] ⁺ . Step-4: To a 25 mL single-neck round bottom flask containing a well-stirred solution of tert-butyl N-[5- [4-[1-[4-[(3-fluorophenyl)methylcarbamoyl]-1-piperidyl]ethyl ]-1-naphthyl]pent-4-ynyl]-N- methyl-carbamate (6, 90 mg, 0.144 mmol) in anhydrous EtOAc (2.5 mL) was added Palladium on carbon, 10 wt.% (40 mg, 0.033 mmol) at ambient temperature. The resulting mixture was stirred for 1 h at ambient temperature under hydrogen atmosphere. The reaction was monitored by UPLC. Upon completion of the reaction, the reaction mixture was passed through a pad of Celite and the Celite bed was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl N-[5-[4-[1-[4-[(3-fluorophenyl)methylcarbamoyl]-1-piperidyl] ethyl]-1- naphthyl]pentyl]-N-methyl-carbamate (7, 40 mg, 0.033 mmol, 97% yield) as a brown liquid. LC- MS (ES ⁺ ): m/z 590.2 [M + H] ⁺ . Step-5: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl N-[5- [4-[1-[4-[(3-fluorophenyl)methylcarbamoyl]-1-piperidyl]ethyl ]-1-naphthyl]pentyl]-N-methyl- carbamate (7, 115 mg, 0.183 mmol) in anhydrous DCM (2.5 mL) was added 4N HCl in 1,4- dioxane (8 mmol, 2 mL) at 0 °C and the resulting mixture was stirred at ambient temperature for 1 h. Upon completion of the reaction as indicated by UPLC, excess solvent was removed under reduced pressure to give a crude residue, which was washed with MTBE (10 mL) and dried to afford N-[(3-fluorophenyl)methyl]-1-[1-[4-[5-(methylamino)pentyl]-1 -naphthyl]ethyl]piperidine- 4-carboxamide hydrochloride (8, 120 mg, 0.159 mmol, 87% yield) as yellow solid. LC-MS (ES ⁺ ): m/z 490.2 [M + H] ⁺ . Step-6: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of N-[(3- fluorophenyl)methyl]-1-[1-[4-[5-(methylamino)pentyl]-1-napht hyl]ethyl]piperidine-4- carboxamide hydrochloride (8, 120 mg, 0.182 mmol) in anhydrous DMF (3 mL) were added DIPEA (70.75 mg, 0.547 mmol, 0.095 mL) and HATU (76.32 mg, 0.20 mmol) followed by 6-[4- [1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl] -1-piperidyl]-6-oxo-hexanoic acid (9, 93.32 mg, 0.182 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 2 h. The progress of the reaction was monitored by UPLC. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by reverse-phase HPLC (RediSep-RF Gold C18 column, mobile phase A: 10 mm NH4HCO3 in water B: Acetonitrile) to afford 1-[1-[4-[5-[[6-[4-[1-(2,6-dioxo-3-piperidyl)-3- methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-6-oxo-hexanoyl] -methyl-amino]pentyl]-1- naphthyl]ethyl]-N-[(3-fluorophenyl)methyl]piperidine-4-carbo xamide (Compound 26, 24 mg, 0.024 mmol, 14% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 8.51-8.47 (m, 1H), 8.30 (t, J = 6 Hz, 1H), 8.09-8.06 (m, 1H), 7.54-7.49 (m, 2H), 7.44 (d, J = 7.2 Hz, 1H), 7.36-7.29 (m, 2H), 7.10 (s, 1H), 7.05-7.01 (m, 4H), 6.95-6.92 (m, 1H), 5.36 (dd, J = 12.6, 5.2 Hz, 1H), 4.60-4.51 (m, 1H), 4.25 (d, J = 6 Hz, 2H), 4.16-4.08 (m, 1H), 4.05-3.95 (m, 1H), 3.35 (s, 3H), 3.27 (t, J = 7.6 Hz, 2H), 3.15-2.98 (m, 4H), 2.93 (s, 3H), 2.85 (m, 1H), 2.80-2.50 (m, 7H), 2.40-2.25 (m, 6H), 2.20-2.10 (m, 2H), 2.06-1.96 (m, 3H), 1.80-1.47 (m, 11H) and 1.45-1.30 (m, 5H). LC-MS (ES ⁺ ): m/z 942.4 [M + H] ⁺ . Example 64 Synthesis of N-[(3-fluorophenyl)methyl]-1-[1-[5-[2-(4-piperidyl)ethynyl]- 1- naphthyl]ethyl]piperidine-4-carboxamide

Step-1: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of 5- bromonaphthalene-1-carboxylic acid (1, 8 g, 31.86 mmol) in anhydrous DMF (200 mL) were added N,N-dimethylpyridin-4-amine (11.68 g, 95.59 mmol) and 3-(ethyliminomethyleneamino)- N,N-dimethyl-propan-1-amine hydrochloride (12.22 g, 63.73 mmol) followed by N- methoxymethanamine hydrochloride (2, 12.43 g, 127.45 mmol) at ambient temperature under nitrogen atmosphere. The contents were stirred at ambient temperature for 16 hours. After completion of the reaction, the reaction mixture was poured into water (500 mL) and extracted with EtOAc (2 × 500 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure to get the crude product, which was purified by column chromatography (100 g silica gel, 0-100% EtOAc/Petroleum ether) to afford 5-bromo-N-methoxy-N-methyl-naphthalene-1-carboxamide (3, 9 g, 26.35 mmol, 83% yield) as a thick colorless liquid. LC-MS (ES ⁺ ): m/z 295.9 [M + H] ⁺ . Step-2: To a 500 mL 3-neck round-bottom flask containing a well-stirred solution of 5-bromo-N- methoxy-N-methyl-naphthalene-1-carboxamide (3, 8.5 g, 24.88 mmol) in anhydrous THF (100 mL) was added anhydrous cerium (III) chloride (9.20 g, 37.32 mmol) at 0 °C. The resulting reaction mixture was stirred for 1 hour at room temperature before it was cooled to 0 °C and methyl magnesium bromide, 1 M solution in THF (149.28 mL, 149.28 mmol) was added dropwise. The resulting solution was stirred at room temperature 12 hours. Upon completion of the reaction, the reaction mixture was quenched slowly with saturated NH ₄ Cl solution (200 mL) at 0 ° C. The reaction mixture was filtered through a pad of celite, and the filter cake was washed with EtOAc and extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (100 g, silica gel, 0-100% EtOAc/Petroleum ether) to afford 1-(5-bromonaphthalen-1-yl)ethan-1-one (4, 6.5 g, 24.74 mmol, 99% yield) as a thick colorless liquid. LCMS (ES-): m/z 249.2 [M – H] -. Step-3: In a 100 mL sealed tube, 1-(5-bromonaphthalen-1-yl)ethan-1-one (4, 6 g, 22.84 mmol), methyl piperidine-4-carboxylate (5, 4.91 g, 34.26 mmol, 4.63 mL) and anhydrous titanium(IV) isopropoxide (60 mL) were mixed at ambient temperature. The reaction mixture was stirred at 80 °C for 6 hours. The reaction mixture was cooled to 0 °C and sodium borohydride (2.59 g, 68.52 mmol, 2.42 mL) was added. It was then stirred at 30 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to 0° C and diluted with EtOAc and washed successively with saturated sodium bicarbonate solution. The solid precipitation was filtered and the filtrate was extracted with EtOAc (2 × 150 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (230-400 mesh silica-gel neutralized with 10% triethylamine/petroleum ether, 0-100% EtOAc/petroleum ether) to afford isopropyl 1-[1-(5-bromo-1-naphthyl)ethyl]piperidine-4-carboxylate (6, 7 g, 14.97 mmol, 66% yield) as a colorless thick liquid. LC-MS (ES ⁺ ): m/z 405.9 [M+ H] ⁺ . Step-4: To a 50 mL sealed-tube containing a well-stirred solution of isopropyl 1-[1-(5-bromo-1- naphthyl)ethyl]piperidine-4-carboxylate (6, 1 g, 2.13 mmol) and tert-butyl 4-ethynylpiperidine-1- carboxylate (7, 578.67 mg, 2.77 mmol) in anhydrous acetonitrile (10 mL) was added cesium carbonate (2.08 g, 6.38 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was degassed with nitrogen gas for 10 minutes. Subsequently, XPhos-Pd-G3 (90.02 mg, 106.35 µmol) and dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (101.39 mg, 212.69 µmol) were added and the resulting mixture was degassed with nitrogen gas for another 5 minutes before being heated at 90 °C for 4 hours. Upon consumption of the starting material, the reaction mixture was then cooled to ambient temperature and poured into water (100 mL) and EtOAc (100 mL). It was then filtered through a pad of celite, and the filter cake was washed with EtOAc (50 mL) and extracted with EtOAc (2 × 150 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by Biotage® Isolera (230-400 mesh silica-gel with 0-100% ethyl acetate/Petroleum ether) to afford tert-butyl 4-[2-[5-[1-(4-isopropoxycarbonyl-1-piperidyl)ethyl]-1-naphth yl]ethynyl]piperidine-1- carboxylate (8, 1 g, 1.76 mmol, 83% yield) as a thick off-white solid. LC-MS (ES ⁺ ): m/z 533.4 [M + H] ⁺ . Step-5: To a well-stirred solution of a mixture of tert-butyl 4-[2-[5-[1-(4-isopropoxycarbonyl-1- piperidyl)ethyl]-1-naphthyl]ethynyl]piperidine-1-carboxylate (8, 1 g, 1.76 mmol) in 1:1:1 THF (10 mL):methanol (10 mL):water (10 mL) was added lithium hydroxide, monohydrate (740.47 mg, 17.65 mmol) at 0 °C. The reaction mixture was stirred for 12 hours at 30 °C. while the progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was concentrated under vacuum, diluted with water (50 mL), and extracted with MTBE (2 × 150 ml). The aqueous phase was acidified with citric acid solution (pH 4) and extracted with EtOAc (2 × 250 mL). The organic layer was concentrated under reduced pressure to give 1-[1-[5-[2-(1- tert-butoxycarbonyl-4-piperidyl)ethynyl]-1-naphthyl]ethyl]pi peridine-4-carboxylic acid (9, 900 mg, 1.74 mmol, 99% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 491.1 [M + H] ⁺ . Step-6: To a 10 mL single-neck round-bottom flask containing a well-stirred solution of 1-[1-[5-[2-(1-tert- butoxycarbonyl-4-piperidyl)ethynyl]-1-naphthyl]ethyl]piperid ine-4-carboxylic acid (9, 900 mg, 1.74 mmol) in anhydrous DMF (10 mL) were added N,N-diisopropylethylamine (1.13 g, 8.71 mmol, 1.52 mL) and HATU (993.91 mg, 2.61 mmol) followed by (3-fluorophenyl)methanamine (10, 327.12 mg, 2.61 mmol, 297.38 µL) at ambient temperature under nitrogen atmosphere. The contents were stirred at ambient temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (2 × 250 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by Biotage® Isolera (230-400 mesh silica-gel, 0-100% ethyl acetate/Petroleum ether). The product was further purified by reverse phase chromatography (Biotage C18120 g SNAP, with the mobile phase: Mobile Phase A : 0.1% Ammonium bicarbonate in water; Mobile phase B : Acetonitrile; Flow rate : 15 mL/min) to afford tert-butyl 4-[2-[5-[1-[4-[(3- fluorophenyl)methylcarbamoyl]-1-piperidyl]ethyl]-1-naphthyl] ethynyl]piperidine-1-carboxylate (11, 400 mg, 668.56 µmol, 38% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 598.3 [M + H] ⁺ . Step-7: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[2- [5-[1-[4-[(3-fluorophenyl)methylcarbamoyl]-1-piperidyl]ethyl ]-1-naphthyl]ethynyl]piperidine-1- carboxylate (11, 390 mg, 651.85 µmol) in DCM (4 mL) was added 4 M hydrogen chloride in 1,4- dioxane, 99% (21.9 mL, 87.69 mmol) at 0°C. The reaction mixture was stirred at ambient temperature for 2 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a residue, which was washed with MTBE (2×200 mL) and acetonitrile (50 ml) and dried to give N-[(3-fluorophenyl)methyl]-1-[1-[5-[2-(4- piperidyl)ethynyl]-1-naphthyl]ethyl]piperidine-4-carboxamide dihydrochloride (12, 370 mg, 639.66 µmol, 98% yield) as a white solid. LCMS (ES ⁺ ): m/z 498.3 [M + H] ⁺ . Example 65 Synthesis of 1-[1-[5-[2-[1-[4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl] piperazin-1-yl]-4- oxo-butanoyl]-4-piperidyl]ethynyl]-1-naphthyl]ethyl]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (Compound 27) To a solution of N-[(3-fluorophenyl)methyl]-1-[1-[5-[2-(4-piperidyl)ethynyl]- 1- naphthyl]ethyl]piperidine-4-carboxamide (1, 30 mg, 52.58 µmol, HCl salt) and 4-[4-[4-[(2,6- dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoi c acid (2, 20.42 mg, 52.58 µmol, TFA salt) in DMF (1.5 mL) was added DIPEA (33.98 mg, 45.79 µL) and HATU (39.98 mg, 105.1 µmol) and the reaction mixture was stirred for 2 h at RT. After completion of the reaction, the reaction mixture was diluted with ice water (5 ml) and the precipitate was filtered and dissolved in 20 % MeOH in dichloromethane. The solution was dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by preparative HPLC to afford 1-[1-[5-[2-[1-[4-[4- [4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-4-ox o-butanoyl]-4-piperidyl]ethynyl]- 1-naphthyl]ethyl]-N-[(3-fluorophenyl)methyl]piperidine-4-car boxamide (Compound 27, 5 mg, 5.65 µmol, 10.74% yield). LC-MS (ES ⁺ ): m/z 868.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 10.78 (bs, 1H), 8.50 (d, J = 8.8 Hz, 1H), 8.30 (t, J = 6 Hz, 1H), 8.19 (dd, J = 7, 2.4 Hz, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.60-7.58 (m, 2H), 7.49 (t, J = 7.2 Hz, 1H), 7.52-7.48 (m, 1H), 7.35-7.31 (m, 1H), 7.06-6.99 (m, 3H), 6.79 (d, J = 9.2 Hz, 1H), 6.63 (d, J = 8.8 Hz, 1H), 5.44 (d, J = 7.6 Hz, 1H), 4.25 (d, J = 6 Hz, 3H), 4.21-4.17 (m, 1H), 3.92 (m, 1H), 3.80 (m, 1H), 3.61-3.58 (m, 5H), 3.33 (m, 4H), 3.11 (m, 1H), 3.05 (m, 1H), 2.95-2.87 (m, 4H), 2.75 (m, 1H), 2.70 (m, 1H), 2.67 (s, 3H), 2.50 (m, 4H), 2.15 (m, 2H), 2.05 (m, 3H), 1.68-1.50 (m, 4H) and 1.40 (d, J = 6.8 Hz, 3H). Example 66 1-[1-[5-[2-[1-[6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-ox o-benzimidazol-5-yl]-1- piperidyl]-6-oxo-hexanoyl]-4-piperidyl]ethynyl]-1-naphthyl]e thyl]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (Compound 28) Compound 28 was prepared substantially following the synthesis of Compound 27. LC-MS (ES ⁺ ): m/z 950.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 8.49 (d, J = 8 Hz, 1H), 8.35-8.26 (m, 1H), 8.19 (d, J = 6.4 Hz, 1H), 7.68-7.55 (m, 3H), 7.52-7.46 (m, 1H), 7.37-7.31 (m, 1H), 7.10-6.99 (m, 5H), 6.91 (d, J = 8.4 Hz, 1H), 5.34 (dd, J = 12.8, 5.2 Hz, 1H), 4.57 (d, J = 12.8 Hz, 1H), 4.30-4.15 (m, 3H), 4.05-3.93 (m, 2H), 3.82-3.75 (m, 1H), 3.48-3.35 (m, 2H), 3.33 (s, 3H), 3.32-3.22 (m, 2H), 3.15-3.01 (m, 3H), 2.95-2.54 (m, 5H), 2.41-2.31 (m, 4H), 2.20-1.90 (m, 5H), 1.81-1.45 (m, 14H), 1.42-1.35 (m, 3H). Example 67 1-[1-[5-[2-[1-[5-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-ox o-benzimidazol-5-yl]-1- piperidyl]-5-oxo-pentyl]-4-piperidyl]ethynyl]-1-naphthyl]eth yl]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (Compound 29) Step-1: To a 50 mL round-bottom flask containing a well-stirred solution of N-[(3-fluorophenyl)methyl]- 1-[1-[5-[2-(4-piperidyl)ethynyl]-1-naphthyl]ethyl]piperidine -4-carboxamide (1, 160 mg, 289.36 μmol) and tert-butyl 5-bromopentanoate (2, 343.09 mg, 1.45 mmol) in DMF (2 mL) was added triethylamine (146.40 mg, 1.45 mmol, 201.66 μL) at room temperature. The reaction was stirred for 16 hours and concentrated under reduced pressure to obtain the crude material that was purified by flash column chromatography (230-400 mesh silica gel; EtOAc in petroleum ether) to afford tert-butyl 5-[4-[2-[5-[1-[4-[(3-fluorophenyl)methylcarbamoyl]-1-piperid yl]ethyl]-1- naphthyl]ethynyl]-1-piperidyl]pentanoate (3, 140 mg, 209.83 μmol, 73% yield) as an yellow gum. LC-MS (ES ⁺ ): m/z 654.4 [M + H] ⁺ . Step-2: To a 50 mL round-bottom flask containing a well-stirred solution of tert-butyl 5-[4-[2-[5-[1-[4- [(3-fluorophenyl)methylcarbamoyl]-1-piperidyl]ethyl]-1-napht hyl]ethynyl]-1- piperidyl]pentanoate (3, 140 mg, 209.83 μmol) in DCM (2 mL) was added hydrogen chloride solution (4.0 M in dioxane, 2 mL) dropwise at 0 °C under nitrogen atmosphere. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure to get a residue that was washed with MTBE and dried to afford 5-[4-[2-[5-[1-[4-[(3- fluorophenyl)methylcarbamoyl]-1-piperidyl]ethyl]-1-naphthyl] ethynyl]-1-piperidyl]pentanoic acid hydrochloride (4, 140 mg, 192.05 μmol, 92% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 598.3 [M + H] ⁺ . Step-3: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 5-[4-[2-[5-[1-[4- [(3-fluorophenyl)methylcarbamoyl]-1-piperidyl]ethyl]-1-napht hyl]ethynyl]-1- piperidyl]pentanoic acid hydrochloride (4, 165 mg, 249.76 μmol) and 3-[3-methyl-2-oxo-5-(4- piperidyl)benzimidazol-1-yl]piperidine-2,6-dione hydrochloride (5, 94.62 mg, 249.76 μmol) in anhydrous DMF (4 mL) were added N,N-diisopropylethylamine (161.39 mg, 1.25 mmol, 217.51 μL) and HATU (113.96 mg, 299.71 μmol) at ambient temperature under nitrogen atmosphere. After 1 hour, the reaction mixture was concentrated under reduced pressure to get the crude material which was purified by a reverse-phase prep-HPLC [Column: X-BRIDGE C8 (150 X 19) mm, 5 µm; Mobile phase A :10 mM Ammonium bicarbonate in water and Mobile Phase B: Acetonitrile] to obtain 1-[1-[5-[2-[1-[5-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-ox o- benzimidazol-5-yl]-1-piperidyl]-5-oxo-pentyl]-4-piperidyl]et hynyl]-1-naphthyl]ethyl]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (Compound 29, 72 mg, 76.95 μmol, 29% yield) as a white solid. LC-MS (ES ⁺ ): m/z 922.3 [M + H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 8.48 (d, J = 8.40 Hz, 1H), 8.30 (t, J = 6.00 Hz, 1H), 8.19 (d, J = 8.00 Hz, 1H), 7.61- 7.54 (m, 3H), 7.50-7.46 (m, 1H), 7.37-7.31 (m, 1H), 7.10 (s, 1H), 7.06-6.99 (m, 4H), 6.93-6.90 (m, 1H), 5.35-5.30 (m, 1H), 4.61-4.53 (m, 1H), 4.25 (d, J = 6.00 Hz, 2H), 4.21-4.13 (m, 1H), 4.06- 3.99 (m, 1H), 3.16-2.98 (m, 2H), 2.91-2.65 (m, 5H), 2.63-2.57 (m, 2H), 2.39-2.32 (m, 5H), 2.26- 2.11 (m, 3H), 2.08-1.95 (m, 5H), 1.80-1.70 (m, 6H), 1.61-1.49 (m, 10H), 1.40 (d, J = 6.40 Hz, 3H). Example 68 Synthesis of (R)-2-methyl-N-(1-(4-((1-(piperidin-4-ylmethyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)benzamide Step-1: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 2-methylbenzoic acid (1, 510 mg, 3.75 mmol) in anhydrous DMF (10 mL) were added DIPEA (2.42 g, 18.73 mmol, 3.26 mL) and HATU (2.14 g, 5.62 mmol) followed by (R)-1-(4-bromonaphthalen-1-yl)ethan-1- amine hydrochloride (2, 985.93 mg, 3.37 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 4 h. The progress of the reaction was monitored by UPLC. The reaction mixture was then concentrated under reduced pressure. The obtained crude residue was diluted with ice-cold water (20 mL) and the solid precipitate was filtered, washed with water (15 mL), and dried in vacuo to afford (R)-N-(1-(4- bromonaphthalen-1-yl)ethyl)-2-methylbenzamide (3, 1.3 g, 3.06 mmol, 82% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 368.0 [M + H] ⁺ . Step-2: To a 25 mL sealed tube containing a well-stirred solution of (R)-N-(1-(4-bromonaphthalen-1- yl)ethyl)-2-methylbenzamide (3, 0.15 g, 0.353 mmol) and 4-ethynyl-1-(4- piperidylmethyl)piperidine hydrochloride (4, 74.28 mg, 0.300 mmol) in anhydrous ACN (3 mL) and THF (2 mL) was added cesium carbonate (115.13 mg, 0.353 mmol) and the reaction mixture was degassed with N ₂ for 5 minutes. Subsequently, XPhos-Pd-G3 (59.82 mg, 0.070 mmol) and XPhos (33.69 mg, 0.070 mmol) were added and the resulting mixture was heated at 90 °C for 3 h. The reaction mixture was passed through a pad of Celite and Celite bed was washed. The combined filtrate was concentrated under reduced pressure and the crude product was purified by reverse phase (C18 column, mobile phase: 10 mm NH4HCO3 in water : MeCN) to afford (R)- 2-methyl-N-(1-(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)et hynyl)naphthalen-1- yl)ethyl)benzamide (5, 60 mg, 0.110 mmol, 31% yield) as a yellow gum. LC-MS (ES ⁺ ): m/z 494.2 [M + H] ⁺ .

Example 69 Synthesis of 2-methyl-N-((1R)-1-(4-((1-((1-(1-(3-methyl-1-(1-methyl-2,6-d ioxopiperidin-3- yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4- carbonyl)piperidin-4- yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)benza mide (Compound 30) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 1-[3-methyl-1- (1-methyl-2,6-dioxo-3-piperidyl)-2-oxo-benzimidazol-5-yl]pip eridine-4-carboxylic acid hydrochloride (2, 30 mg, 0.064 mmol) and (R)-2-methyl-N-(1-(4-((1-(piperidin-4- ylmethyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)benzam ide (1, 53.00 mg, 0.097 mmol) in anhydrous DMF (1 mL) were added HATU (37.02 mg, 0.097 mmol) and DIPEA (41.94 mg, 0.324 mmol, 0.056 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 3 h. After completion of the reaction as indicated by UPLC, excess solvent was removed from the reaction mixture under reduced pressure and the obtained crude was purified by reverse phase prep-HPLC (X-Select C18 (150 x 19) mm; 5 microns column; Mobile phase: A: 0.1% formic acid in MQ-water; B: acetonitrile; Flow rate: 15 mL/minutes) to afford 2-methyl-N- ((1R)-1-(4-((1-((1-(1-(3-methyl-1-(1-methyl-2,6-dioxopiperid in-3-yl)-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-yl)m ethyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)benzamide formate(Compound 30, 23 mg, 0.024 mmol, 38% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 876.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 8.93 (d, J = 7.6 Hz, 1H), 8.33-8.31 (m, 2H), 7.69-7.67 (m, 3H), 7.60 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 1.6 Hz, 2H), 7.26-7.23 (m, 2H), 6.95 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 2 Hz, 1H), 6.63 (dd, J = 8.8, 2 Hz, 1H), 5.93-5.89 (m, 1H), 5.39-5.34 (m, 1H), 4.42-4.38 (m, 1H), 4.03-3.98 (m, 1H), 3.64- 3.61 (m, 3H), 3.32 (s, 3H), 3.21 (m, 2H), 3.03-2.99 (m, 6H), 2.98-2.95 (m, 1H), 2.80-2.67 (m, 4H), 2.50 (m, 4H), 2.29 (m,1H), 2.28 (s, 3H), 2.12-2.08 (m, 3H), 2.02-1.99 (m, 3H), 1.79-1.71 (m, 7H) and 1.57 (d, J = 7.2 Hz, 3H). Example 70 Synthesis of N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methy l-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-y l)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-2-methylbenzamide (Compound 31) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 1-[1-(2,6-dioxo- 3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-c arboxylic acid hydrochloride (2, 100 mg, 0.222 mmol) in anhydrous DMF (3 mL) were added DIPEA (143.65 mg, 1.11 mmol, 0.19 mL), HATU (126.78 mg, 0.333 mmol) and (R)-2-methyl-N-(1-(4-((1-(piperidin-4- ylmethyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)benzam ide (1, 110 mg, 0.201 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at this temperature for 1 h. The progress of the reaction was monitored by UPLC. Upon completion of the reaction, excess solvent was removed under reduced pressure and the obtained crude was purified by reverse phase column chromatography (RediSep-RF Gold C18 column, mobile phase: 10 mm HCOOH in water : MeCN) to afford N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)- 3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidi ne-4-carbonyl)piperidin-4- yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)-2-me thylbenzamide formate (Compound 31, 77 mg, 0.084 mmol, 38% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 862.3 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.08 (s, 1H), 8.93 (d, J = 7.6 Hz, 1H), 8.32-8.31 (m, 2H), 7.69-7.66 (m, 3H), 7.59 (d, J = 7.6 Hz, 1H), 7.34-7.31 (m, 2H), 7.25-7.23 (m, 2H), 6.94 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 1.6 Hz, 1H), 6.64 (dd, J = 8.6, 2 Hz, 1H), 5.92-5.89 (m, 1H), 5.35- 5.29 (m, 1H), 4.43-4.40 (m, 1H), 4.03-3.97 (m, 1H), 3.63-3.60 (m, 3H), 3.31 (s, 3H), 3.05-2.91 (m, 3H), 2.90-2.85 (m, 1H), 2.72-2.66 (m, 4H), 2.66-2.50 (m, 7H), 2.28 (s, 3H), 2.14-2.06 (m, 2H), 2.00-1.97 (m, 2H), 1.89-1.75 (m, 3H), 1.72-1.65 (m, 4H), 1.56 (d, J = 6.8 Hz, 3H) and 1.12-0.83 (m, 2H). Example 71 Synthesis of 2-methyl-N-((1R)-1-(4-((1-(5-(4-(3-methyl-1-(1-methyl-2,6-di oxopiperidin-3-yl)- 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)-5 -oxopentyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)benzamide (Compound 32)

Step-1: To a 25 mL sealed tube containing a well-stirred solution of (R)-N-(1-(4-bromonaphthalen-1- yl)ethyl)-2-methylbenzamide (1, 250 mg, 0.583 mmol) in anhydrous ACN (6 mL) were added ethyl 5-(4-ethynyl-1-piperidyl)pentanoate (2, 307.91 mg, 1.17 mmol) and Cesium carbonate (570.66 mg, 1.75 mmol) at ambient temperature. The resulting reaction mixture was degassed with N2 for 5 minutes. Subsequently, XPhos-Pd-G3 (24.70 mg, 0.029 mmol) and XPhos (27.80 mg, 0.058 mmol) were added at ambient temperature. The mixture was degassed with N2 for an additional 5 minutes and stirred at 90 °C for 4 h. After completion of the reaction as indicated by UPLC, the reaction mixture was filtered through a pad of Celite and Celite bed was washed with EtOAc (200 mL). The filtrate was concentrated under reduced pressure and the obtained residue was purified by flash column (230-400 mesh silica gel, 50 g) with 0-15% MeOH/DCM as eluent to afford ethyl (R)-5-(4-((4-(1-(2-methylbenzamido)ethyl)naphthalen-1- yl)ethynyl)piperidin-1-yl)pentanoate (3, 200 mg, 0.353 mmol, 60% yield) as a pale yellow gum. LC-MS (ES ⁺ ): m/z 525.2 [M + H] ⁺ . Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of ethyl (R)-5-(4- ((4-(1-(2-methylbenzamido)ethyl)naphthalen-1-yl)ethynyl)pipe ridin-1-yl)pentanoate (3, 200 mg, 0.350 mmol) in MeOH (2 mL),THF (2 mL) and water (1 mL) was added lithium hydroxide, monohydrate (147.15 mg, 3.51 mmol) at ambient temperature and the resulting mixture was stirred for 4 h. After completion of the reaction as indicated by TLC, volatiles from the reaction mixture were removed under reduced pressure and the obtained residue was diluted with water (50 mL) and extracted with MTBE (100 mL). The aqueous phase was acidified with 10% citric acid solution to pH=4 and extracted with 10% MeOH/ DCM (2 × 150 mL). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to afford (R)-5-(4-((4-(1-(2- methylbenzamido)ethyl)naphthalen-1-yl)ethynyl)piperidin-1-yl )pentanoic acid (4, 150 mg, 0.300 mmol, 86% yield) as a pale yellow solid. UPLC-MS (ES ⁺ ): m/z 497.2 [M + H] ⁺ . Step-3: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of (R)-5-(4-((4-(1- (2-methylbenzamido)ethyl)naphthalen-1-yl)ethynyl)piperidin-1 -yl)pentanoic acid (4, 150 mg, 0.295 mmol) and 1-methyl-3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl] piperidine-2,6- dione hydrochloride (5, 117.46 mg, 0.295 mmol) in anhydrous DMF (5 mL) were added DIPEA (191.27 mg, 1.48 mmol, 0.258 mL) and HATU (168.82 mg, 0.443 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at this temperature for 4 h. Upon completion of the reaction as indicated by UPLC, the solvent was removed from the reaction mixture and the obtained crude was purified by reverse phase prep-HPLC (X-Select C18 (150 x 19) mm; 5 microns column, Mobile phase: A:0.1% formic acid in MQ-water; B: Acetonitrile; Flow rate: 15 mL/minutes) to afford 2-methyl-N-((1R)-1-(4-((1-(5-(4-(3-methyl-1- (1-methyl-2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benz o[d]imidazol-5-yl)piperidin-1- yl)-5-oxopentyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl )benzamide formate (Compound 32, 66 mg, 0.072 mmol, 24% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 8.93 (d, J = 7.6 Hz, 1H), 8.33-8.30 (m, 2H), 7.69-7.61 (m, 3H), 7.60 (d, J = 7.6 Hz, 1H), 7.35-7.31 (m, 2H), 7.31-7.23 (m, 2H), 7.10 (s, 1H), 7.03 (d, J = 8 Hz, 1H), 6.89 (d, J = 0.8 Hz, 1H), 5.91 (m, 1H), 5.43-5.42 (m, 1H), 4.63-4.50 (m, 1H), 4.13- 3.98 (m, 1H), 3.30-3.20 (m, 4H), 3.11-3.03 (m, 3H), 3.02 (s, 3H), 2.99-2.95 (m, 2H), 2.80-2.75 (m, 3H), 2.68-2.67 (m, 1H), 2.56-2.51 (m, 4H), 2.40 (m, 3H), 2.34 (s, 3H), 2.33 (m, 1H), 2.08-2.01 (m, 3H), 1.63-1.59 (m, 3H), 1.57-1.55 (m, 4H) and 1.54 (d, J = 7.2 Hz, 3H). LC-MS (ES ⁺ ): m/z 835.4 [M + H] ⁺ . Example 72 Synthesis of N-((1R)-1-(4-((1-(5-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)piperidin-1-yl)-5-oxopentyl)piperid in-4-yl)ethynyl)naphthalen-1- yl)ethyl)-2-methylbenzamide (Compound 33) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of (R)-5-(4-((4-(1- (2-methylbenzamido)ethyl)naphthalen-1-yl)ethynyl)piperidin-1 -yl)pentanoic acid (1, 70 mg, 0.124 mmol) in anhydrous DMF (2 mL) were added DIPEA (80.15 mg, 0.620 mmol), HATU (70.74 mg, 0.186 mmol), 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidin e-2,6- dione (2, (93.98 mg, 0.248 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at this temperature for 1 h. Upon completion of the reaction as indicated by UPLC, excess solvent was removed under reduced pressure and the obtained crude was purified by reverse phase column chromatography (C18 column, mobile phase: 10 mm NH4HCO3 in water : MeCN) to afford N-((1R)-1-(4-((1-(5-(4-(1-(2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin- 1-yl)-5-oxopentyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-2-methylbenzamide (Compound 33, 55 mg, 0.065 mmol, 53% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 8.90 (d, J = 7.6 Hz, 1H), 8.33-8.29 (m, 2H), 7.67-7.64 (m, 3H), 7.58 (d, J = 7.6 Hz, 1H), 7.34-7.30 (m, 2H), 7.25-7.23 (m, 2H), 7.10 (d, J = 1.2 Hz, 1H), 7.02 (d, J = 8 Hz, 1H), 6.93-6.89 (m, 1H), 5.95-5.85 (m, 1H), 5.35-5.31 (m, 1H), 4.65-4.53 (m, 1H), 4.09-3.98 (m, 1H), 3.17-3.09 (m, 1H), 2.90-2.74 (m, 6H), 2.72-2.59 (m, 3H), 2.5 (m, 5H), 2.39-2.33 (m, 3H), 2.28 (s, 3H), 2.00-1.98 (m, 3H), 1.80-1.76 (m, 4H) and 1.58-1.50 (m, 9H). LC-MS (ES ⁺ ): m/z 821.4 [M + H] ⁺ . Example 73 Synthesis of 5-[4-[2-[4-[1-[4-(imidazo[1,5-a]pyridin-6-ylmethylcarbamoyl) -1- piperidyl]ethyl]-1-naphthyl]ethynyl]-1-piperidyl]pentanoic acid

Step-1: To a 250 mL sealed-tube containing a well-stirred solution of potassium N-Boc-aminomethyl trifluoroborate (2, 1.5 g, 7.61 mmol) and 6-bromoimidazo[1,5-a]pyridine (1, 1.5 g, 7.61 mmol) in 1,4-dioxane (70 mL) and water (7 mL) was added cesium carbonate (7.44 g, 22.84 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was degassed by bubbling nitrogen gas into the reaction mixture for 5 minutes. Subsequently, Pd(OAc) ₂ (341.84 mg, 1.52 mmol) and CataCXium (272.96 mg, 0.761 mmol) were added and the resulting mixture was degassed with N2 for another 5 minutes and the reaction mixture was heated to 120 °C for 16 h. The progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was cooled to ambient temperature, diluted with EtOAc (150 mL) and filtered through a pad of Celite, and the Celite bed was washed with EtOAc (350 mL). The filtrate was concentrated under reduced pressure to get a crude residue, which was purified by flash column chromatography (230-400 mesh silica gel) with 10% MeOH/DCM as eluent to afford tert- butyl N-(imidazo[1,5-a]pyridin-6-ylmethyl)carbamate (3, 700 mg, 2.73 mmol, 36% yield) as a brown solid. LC-MS (ES ⁺ ): m/z 248.2 [M + H] ⁺ . Step-2: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl N- (imidazo[1,5-a]pyridin-6-ylmethyl)carbamate (3, 700 mg, 2.72 mmol) in anhydrous DCM (7 mL) was added 4 N HCl in 1,4-dioxane (54.35 mmol, 2.48 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 2 h. Upon completion of the reaction as indicated by UPLC, the solvent was removed from the reaction mixture. The obtained crude was co-distilled with toluene (15 mL) to afford imidazo[1,5-a]pyridin-6-ylmethanamine hydrochloride (4, 500 mg, 2.55 mmol, 94% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 148.1 [M + H] ⁺ . Step-3: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 1-[1-[4-[2-(1-tert- butoxycarbonyl-4-piperidyl)ethynyl]-1-naphthyl]ethyl]piperid ine-4-carboxylic acid (5, 300 mg, 0.599 mmol), in anhydrous DMF (7 mL) were added DIPEA (387.22 mg, 3.00 mmol, 0.52 mL) and HATU ((341.77 mg, 0.898 mmol) at ambient temperature under nitrogen atmosphere. To the flask was added (R)-1-(4-bromonaphthalen-1-yl)ethan-1-amine hydrochloride (4, 248.97 mg, 1.20 mmol). The resulting mixture was stirred at ambient temperature for 3 h. Upon completion of the reaction as confirmed by UPLC, the reaction mixture was evaporated under vacuum to get a crude residue. The crude residue was purified by flash column chromatography (230-400 mesh silica gel) with 5% MeOH/DCM as eluent to afford tert-butyl 4-[2-[4-[1-[4-(imidazo[1,5-a]pyridin-6- ylmethylcarbamoyl)-1-piperidyl]ethyl]-1-naphthyl]ethynyl]pip eridine-1-carboxylate (6, 300 mg, 0.423 mmol, 71% yield) as a brown sticky solid. LC-MS (ES ⁺ ): m/z 620.4 [M + H] ⁺ . Step-4: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[2- [4-[1-[4-(imidazo[1,5-a]pyridin-6-ylmethylcarbamoyl)-1-piper idyl]ethyl]-1- naphthyl]ethynyl]piperidine-1-carboxylate (6, 300 mg, 0.421 mmol) in DCM (7 mL) was added 4 N HCl in 1,4 dioxane (8.42 mmol, 2.11 mL) at 0 °C. The resulting mixture was stirred for 2 h at ambient temperature. After completion of the reaction as confirmed by UPLC, the reaction mixture was concentrated to give the crude product, which was triturated with MTBE (15 mL) to afford N- (imidazo[1,5-a]pyridin-6-ylmethyl)-1-[1-[4-[2-(4-piperidyl)e thynyl]-1- naphthyl]ethyl]piperidine-4-carboxamide hydrochloride (7, 220 mg, 0.350 mmol, 83% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 520.2 [M + H] ⁺ . Step-5: To a 50 mL round-bottomed flask containing a well-stirred solution of N-(imidazo[1,5-a]pyridin- 6-ylmethyl)-1-[1-[4-[2-(4-piperidyl)ethynyl]-1-naphthyl]ethy l]piperidine-4-carboxamide hydrochloride (7, 188.49 mg, 1.86 mmol) in anhydrous DMF (5 mL) were added triethylamine (188.49 mg, 1.86 mmol, 0.259 mL) and methyl 5-bromopentanoate (8, 176.68 mg, 0.745 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at 70 °C for 4 h. Thereafter, the reaction mixture was poured into ice-cold water (20 mL) and extracted with EtOAc (3 × 100 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 5-[4-[2-[4-[1-[4- (imidazo[1,5-a]pyridin-6-ylmethylcarbamoyl)-1-piperidyl]ethy l]-1-naphthyl]ethynyl]-1- piperidyl]pentanoate (9, 180 mg, 0.247 mmol, 66% yield) as a yellow gum. LC-MS (ES ⁺ ): m/z 677.2 [M + H] ⁺ . Step-6: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 5-[4- [2-[4-[1-[4-(imidazo[1,5-a]pyridin-6-ylmethylcarbamoyl)-1-pi peridyl]ethyl]-1- naphthyl]ethynyl]-1-piperidyl]pentanoate (9, 180 mg, 0.239 mmol) in DCM (5 mL) was added 4 N HCl/1,4 dioxane ( 4.79 mmol, 0.218 mL) at 0 °C. The resulting mixture was stirred for 2 h at ambient temperature. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated in vacuo, and the obtained crude product was triturated with MTBE (15 mL) to afford 5-[4-[2-[4-[1-[4-(imidazo[1,5-a]pyridin-6-ylmethylcarbamoyl) -1-piperidyl]ethyl]-1- naphthyl]ethynyl]-1-piperidyl]pentanoic acid hydrochloride (10, 150 mg, 0.205 mmol, 86% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 621.2 [M + H] ⁺ .

Example 74 Synthesis of 1-(1-(4-((1-(5-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-ox o-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-1-yl)-5-oxopentyl)piperidin- 4-yl)ethynyl)naphthalen-1- yl)ethyl)-N-(imidazo[1,5-a]pyridin-6-ylmethyl)piperidine-4-c arboxamide (Compound 34) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 5-[4-[2-[4-[1-[4- (imidazo[1,5-a]pyridin-6-ylmethylcarbamoyl)-1-piperidyl]ethy l]-1-naphthyl]ethynyl]-1- piperidyl]pentanoic acid hydrochloride (1, 150 mg, 0.203 mmol) in anhydrous DMF (4 mL) were added DIPEA (131.45 mg, 1.02 mmol, 0.177 mL) and HATU (116.02 mg, 0.305 mmol) followed by 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidin e-2,6-dione hydrochloride (2, 77.85 mg, 0.203 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 2 h. The progress of the reaction was monitored by UPLC. Excess solvent was removed under reduced pressure to get a crude residue. The crude mass was purified by reverse phase (Redisef-C18 column, Mobile phase A : 10 mm NH4HCO3 in water and B : acetonitrile) to afford 1-[1-[4-[2-[1-[5-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-ox o- benzimidazol-5-yl]-1-piperidyl]-5-oxo-pentyl]-4-piperidyl]et hynyl]-1-naphthyl]ethyl]-N- (imidazo[1,5-a]pyridin-6-ylmethyl)piperidine-4-carboxamide (Compound 34, 55 mg, 0.056 mmol, 28% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 8.49 (d, J = 8.8 Hz, 1H), 8.34 (s, 1H), 8.30-8.23 (m, 2H), 8.12 (d, J = 0.8 Hz, 1H), 7.61-7.55 (m, 3H), 7.52- 7.48 (m, 2H), 7.30 (s, 1H), 7.10 (s, 1H), 7.02 (d, J = 8 Hz, 1H), 6.92 (dd, J = 8.4, 1.2 Hz, 1H), 6.64 (dd, J = 9.4, 1.6 Hz, 1H), 5.40-5.22 (m, 1H), 4.62-4.53 (m, 1H), 4.17-4.14 (m, 3H), 4.08-3.99 (m, 1H), 3.15-3.02 (m, 2H), 2.92-2.50 (m, 9H), 2.39-2.33 (m, 5H), 2.32-2.11 (m, 2H), 2.02-1.95 (m, 6H), 1.82-1.66 (m, 6H), 1.63-1.49 (m, 10H) and 1.38 (d, J = 6.8 Hz, 3H). LC-MS (ES ⁺ ): m/z 944.4 [M + H] ⁺ . Example 75 Synthesis of 1-(1-(4-((1-(7-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-ox o-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-1-yl)-7-oxoheptanoyl)piperid in-4-yl)ethynyl)naphthalen-1- yl)ethyl)-N-(imidazo[1,5-a]pyridin-6-ylmethyl)piperidine-4-c arboxamide (Compound 35) To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 7-[4-[1-(2,6- dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piper idyl]-7-oxo-heptanoic acid hydrochloride (2, 160 mg, 0.276 mmol) in anhydrous DMF (3 mL) were added DIPEA (178.60 mg, 1.38 mmol, 0.24 mL), HATU (157.64 mg, 0.414 mmol) and N-(imidazo[1,5-a]pyridin-6- ylmethyl)-1-[1-[4-[2-(4-piperidyl)ethynyl]-1-naphthyl]ethyl] piperidine-4-carboxamide hydrochloride (1, 192.14 mg, 0.276 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at this temperature for 2 h. Upon completion of the reaction as indicated by UPLC, excess solvent was removed under reduced pressure and the obtained residue was purified by reverse phase column chromatography (Redisef-C18 column, Mobile phase A : 10 mm HCOOH in water and B : acetonitrile) to afford 1-[1-[4-[2-[1-[7-[4-[1-(2,6-dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-7- oxo-heptanoyl]-4- piperidyl]ethynyl]-1-naphthyl]ethyl]-N-(imidazo[1,5-a]pyridi n-6-ylmethyl)piperidine-4- carboxamide formate (Compound 35, 57 mg, 0.054 mmol, 20% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 8.46-8.42 (m, 2H), 8.34-8.27 (m, 2H), 8.14 (s, 1H), 7.90-7.45 (m, 5H), 7.31 (s, 1H), 7.11 (s, 1H), 7.01 (d, J = 8 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.64 (d, J = 9.2 Hz, 1H), 5.38-5.31 (m, 1H), 4.61-4.55 (m, 1H), 4.19-4.13 (m, 3H), 4.02-3.91 (m, 3H), 3.81-3.73 (m, 2H), 3.31-3.20 (m, 2H), 3.15-3.01 (m, 4H), 2.95-2.71 (m, 5H), 2.65-2.50 (m, 2H), 2.37-2.33 (m, 3H), 2.03-1.88 (m, 6H), 1.85-1.50 (m, 15H) and 1.37-1.29 (m, 4H). LC-MS (ES ⁺ ): m/z 986.2 [M + H] ⁺ . Example 76 Synthesis of tert-butyl (R)-(4-methyl-3-((1-(4-(piperidin-4-ylethynyl)naphthalen-1- yl)ethyl)carbamoyl)phenyl)carbamate, tert-butyl (R)-(3-((1-(4-((1-((4-hydroxypiperidin-4- yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carba moyl)-4-

methylphenyl)carbamate and tert-butyl (R)-(4-methyl-3-((1-(4-((1-(piperidin-4- ylmethyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carbam oyl)phenyl)carbamate

Step-1: To a 2000 mL three-neck round-bottom flask containing a well-stirred solution of 1-(4-bromo-1- naphthyl) ethanone (1, 40 g, 160.58 mmol) in anhydrous THF (800 mL) were added (S)-2- methylpropane-2-sulfinamide (2, 29.19 g, 240.86 mmol) and Titanium ethoxide (109.89 g, 481.7 mmol, 101 mL) at ambient temperature. The reaction mixture was stirred at 70 °C for 16 h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with water (1200 mL). The solid was filtered off by passing through a pad of Celite and the Celite bed was washed with EtOAc (900 mL). The filtrate was extracted with EtOAc (3 × 1000 mL) and the combined organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude residue, which was purified by column chromatography (60-120 mesh silica-gel) with 20% EtOAc/pet ether as eluent to afford (S,E)-N-(1-(4-bromonaphthalen-1- yl)ethylidene)-2-methylpropane-2-sulfinamide (3, 33 g, 88.3 mmol, 55% yield) as a pale yellow liquid. LC-MS (ES ⁺ ): m/z 354.1 [M + H] ⁺ . Step-2: To a 3000 mL three-neck round-bottom flask containing a well-stirred solution of (S,E)-N-(1-(4- bromonaphthalen-1-yl)ethylidene)-2-methylpropane-2-sulfinami de (3, 17 g, 45.5 mmol) in anhydrous THF (500 mL) was added 1 M L-Selectride in THF (136.49 mL) dropwise at -78 °C under nitrogen atmosphere. The resulting reaction mixture was stirred at -78 °C for 5 h. After completion of the reaction as indicated by UPLC, the reaction mixture was quenched with saturated ammonium chloride solution (1000 mL) dropwise at 0 °C followed by ice-cold water (500 mL) and the mixture was stirred for 0.5 h at 0 °C. Then the aqueous phase was extracted with EtOAc (3 × 1000 mL) and the combined organic phase was dried over Na ₂ SO ₄ , and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (230- 400 mesh silica gel) with 80-100% EtOAc/pet ether as eluent to afford (S)-N-((R)-1-(4- bromonaphthalen-1-yl)ethyl)-2-methylpropane-2-sulfinamide (4, 12 g, 29.1 mmol, 64% yield) as a pale yellow liquid. LC-MS (ES ⁺ ): m/z 354.1 [M + H] ⁺ . Step-3: To a 500 mL single-neck round-bottom flask containing a well-stirred solution of (S)-N-((R)-1-(4- bromonaphthalen-1-yl)ethyl)-2-methylpropane-2-sulfinamide (4, 25.97 g, 62.97 mmol) in anhydrous DCM (20 mL) was added 4 M HCl in 1,4-dioxane (236 mL) at 5 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 10 h. After completion of the reaction as indicated by TLC, excess solvent was removed under reduced pressure. The obtained crude was washed with MTBE (100 mL), filtered through filter paper and the filtrate was concentrated in vacuo at 45 °C for 0.5 h to afford (R)-1-(4-bromonaphthalen-1- yl)ethan-1-amine hydrochloride (5, 15.5 g, 53.1 mmol, 84% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 8.76 (s, 3H), 8.23-8.29 (m, 2H), 8.02 (d, J = 7.6 Hz, 1H), 7.70-7.71 (m, 3H), 5.32-5.34 (m, 1H) and 1.61 (d, J = 6.8 Hz, 3H). Step-4: To a 100 mL three-neck round-bottom flask containing a well-stirred solution of 5-amino-2- methyl-benzoic acid (6, 10 g, 66.15 mmol), 1M NaOH Solution (1M, 66.15 mL) in 1,4-dioxane (70 mL) and water (70 mL) was added tert-butoxycarbonyl tert-butyl carbonate (15.16 g, 69.46 mmol, 15.94 mL) at 0 °C. The resulting reaction mixture was stirred at ambient temperature for 1 h. Thereafter, the reaction mixture was acidified to pH~4 using 10% citric acid solution at 0 °C. The solid precipitate was filtered, washed with water (50 mL) and dried under vacuum to afford 5-(tert-butoxycarbonylamino)-2-methyl-benzoic acid (7, 10 g, 38.76 mmol, 59% yield) as a white solid. LC-MS (ES-): m/z 250.2 [M - H] -. Step-5: To a stirred solution of 5-(tert-butoxycarbonylamino)-2-methyl-benzoic acid (7, 4 g, 15.50 mmol) in anhydrous DMF (50 mL) were added HATU (7.07 g, 18.61 mmol) and DIPEA (5.01 g, 38.76 mmol, 6.75 mL) at ambient temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 5 minutes, then (R)-1-(4-bromonaphthalen-1-yl)ethan-1-amine hydrochloride (5, 3.62 g, 12.4 mmol) was added. The reaction mixture was stirred at ambient temperature for 3 h. After completion of the reaction as indicated by TLC, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 200 mL). The combined organic phase was washed with cold water (3 × 30 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by column chromatography (230-400 mesh silica gel) to afford tert-butyl (R)-(3-((1-(4-bromonaphthalen-1-yl)ethyl)carbamoyl)-4- methylphenyl)carbamate (8, 5.5 g, 9.6 mmol, 62% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 427.0 [M – isobutene + H] ⁺ . Step-6: To a 50 mL sealed tube containing a well stirred solution of tert-butyl (R)-(3-((1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)carbama te (8, 1.0 g, 1.74 mmol) and 4- ethynylpiperidine hydrochloride (9, 687.67 mg, 4.34 mmol) in 1:1 anhydrous acetonitrile/THF (20 mL) was added cesium carbonate (3.40 g, 10.4 mmol) and reaction mixture was degassed with N ₂ for 5 minutes. Subsequently, XPhos (165.68 mg, 0.347 mmol) and XPhos-Pd-G3 (294.17 mg, 0.347 mmol) were added and the resulting mixture was degassed with N2 for 5 minutes. The reaction mixture was stirred at 90 °C for 4 h while progress of reaction was monitored by UPLC- MS. Thereafter, the reaction mixture was filtered through a pad of Celite and Celite bed was washed with DCM. The combined filtrate was concentrated under reduced pressure yield a crude residue, which was purified by flash column chromatography (230-400 mesh silica gel, 100 g) with 0-20% MeOH/DCM as eluent to afford tert-butyl (R)-(4-methyl-3-((1-(4-(piperidin-4- ylethynyl)naphthalen-1-yl)ethyl)carbamoyl)phenyl)carbamate (10, 400 mg, 0.742 mmol, 43% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 512.4 [M + H] ⁺ . Step-7: To a 50 mL sealed tube containing a well-stirred solution of tert-butyl (R)-(3-((1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)carbama te (8, 1250 mg, 0.382 mmol) and 4-[(4-ethynyl-1-piperidyl)methyl]piperidin-4-ol hydrochloride (11, 198.20 mg, 0.765 mmol) in anhydrous acetonitrile (5 mL) was added cesium carbonate (748.16 mg, 2.30 mmol) and the reaction mixture was degassed with N2 for 10 minutes. Subsequently, XPhos (36.49 mg, 0.076 mmol) and XPhos-Pd-G3 (32.39 mg, 0.038 mmol) were added, and the resulting mixture was degassed with N ₂ for another 5 minutes. Then the reaction mixture was stirred at 90 °C for 5 h. Progress of reaction was monitored by UPLC-MS. Thereafter, the reaction mixture was filtered through a pad of Celite and the Celite bed was washed with DCM 10% MeOH/DCM (200 mL). The filtrate was concentrated under reduced pressure to give the crude, which was purified by reverse-phase column chromatography (Column: RediSep C18 (100 g SNAP), Mobile phase: A: 0.1% Formic acid in water, B: MeCN). The fractions having desired product were concentrated under reduced pressure to remove acetonitrile and then diluted with 10% sodium bicarbonate solution (100 mL), brine (50 mL) and extracted with EtOAc (3 × 200 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford tert-butyl (R)-(3- ((1-(4-((1-((4-hydroxypiperidin-4-yl)methyl)piperidin-4-yl)e thynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)carbamate (12, 170 mg, 0.226 mmol, 70% yield) as a pale yellow solid. UPLC-MS (ES ⁺ ): m/z 625.5 [M + H] ⁺ . Step-8: To a 50 mL sealed tube containing a well-stirred solution of tert-butyl (R)-(3-((1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)carbama te (8, 350 mg, 0.535 mmol) and 4-ethynyl-1-(4-piperidylmethyl)piperidine hydrochloride (13, 332.14 mg, 1.37 mmol) in a mixture of anhydrous acetonitrile (5 mL) and THF (2 mL) was added cesium carbonate (436.43 mg, 1.34 mmol) and the resulting mixture was degassed by bubbling N ₂ for 10 minutes. Subsequently, XPhos (25.54 mg, 0.053 mmol) and XPhos-Pd-G3 (22.68 mg, 0.026 mmol) were added, and the resulting mixture was degassed with N2 for an additional 5 minutes. The reaction mixture was stirred at 90 °C for 3 h and progress of the reaction mass was monitored by UPLC- MS. After completion of the reaction, the reaction mixture was allowed to cool to ambient temperature, filtered through a pad of Celite and the Celite bed was washed with 10% MeOH/DCM (200 mL). The filtrate was concentrated under reduced pressure and the crude product was purified by reverse phase column chromatography (Column: RediSep C18 (100 g SNAP), Mobile phase: A: 0.1% formic acid in water and B: acetonitrile). The fractions having the desired product were concentrated under reduced pressure to remove acetonitrile and was then diluted with 10% sodium bicarbonate solution (100 mL), brine (50 mL) and extracted with EtOAc (2 × 200 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to afford tert- butyl (R)-(4-methyl-3-((1-(4-((1-(piperidin-4-ylmethyl)piperidin-4 -yl)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)phenyl)carbamate (14, 300 mg, 0.379 mmol, 70% yield) as a pale yellow solid. LC-MS (ES ⁺ ): m/z 609.4 [M + H] ⁺ . The following targeting ligands (Example 77-79) were prepared using the method described above in the synthesis of tert-butyl (R)-(4-methyl-3-((1-(4-(piperidin-4-ylethynyl)naphthalen-1- yl)ethyl)carbamoyl)phenyl)carbamate in Example 76, with the corresponding alkyne intermediate in Step-6.

Example 79 Synthesis of tert-butyl N-[4-methyl-3-[1-[4-[2-(4-piperidyl)ethynyl]-1- naphthyl]ethylcarbamoyl]phenyl]carbamate Step-1: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 1-(4-bromo-1- naphthyl)ethanamine (1, 320mg, 1.19 mmol) in anhydrous DMF (3 mL) were added DIPEA (461.29 mg, 3.57 mmol, 0.621 mL) and HATU (542.86 mg, 1.43 mmol) followed by 5-(tert- butoxycarbonylamino)-2-methyl-benzoic acid (2, 456.15 mg, 1.78 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at this temperature for 3 h. Upon completion of the reaction as confirmed by UPLC, the reaction mixture was concentrated under reduced pressure and the obtained crude was purified by flash column chromatography (230-400 mesh silica gel; 50 g) with 40-50% EtOAc/pet ether as eluent to afford tert-butyl N-[3-[1-(4- bromo-1-naphthyl)ethylcarbamoyl]-4-methyl-phenyl]carbamate (3, 310 mg, 0.493 mmol, 42% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 485.0 [M + H] ⁺ . Step-2: To a 25 mL sealed tube containing a well-stirred solution of tert-butyl N-[3-[1-(4-bromo-1- naphthyl)ethylcarbamoyl]-4-methyl-phenyl]carbamate (3, 290 mg, 0.461 mmol) and 4- ethynylpiperidine hydrochloride (4, 89.70 mg, 0.554 mmol) in anhydrous acetonitrile (4 mL) was added cesium carbonate (376.27 mg, 1.15 mmol) at ambient temperature and the resulting mixture was degassed by bubbling nitrogen gas for 5 minutes. Subsequently, XPhos (22.02 mg, 0.046 mmol) and XPhos-Pd-G3 (19.55 mg, 0.023 mmol) were added, and the resulting mixture was degassed with nitrogen gas for an additional 5 minutes. The reaction mixture was stirred at 90 °C for 4 h. Progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was passed through a pad of Celite and the Celite pad was washed with EtOAc (50 mL). The combined filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography (230-400 mesh silica gel; 50 g) with 0-15% MeOH/DCM as eluent to obtain tert-butyl N-[4-methyl-3-[1-[4-[2-(4-piperidyl)ethynyl]-1- naphthyl]ethylcarbamoyl]phenyl]carbamate (5, 80 mg, 0.128 mmol, 28% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 512.2 [M + H] ⁺ .

Example 80 Synthesis of (R)-5-amino-N-(1-(4-((1-(6-(3-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)-1- methyl-1H-indazol-7-yl)hexyl)piperidin-4-yl)ethynyl)naphthal en-1-yl)ethyl)-2- Step-1: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 6-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-7-yl]hexanal (2, 150 mg, 0.341 mmol) in anhydrous DMSO (2.5 mL) were added tert-butyl (R)-(4-methyl-3-((1-(4-(piperidin-4- ylethynyl)naphthalen-1-yl)ethyl)carbamoyl)phenyl)carbamate (1, 147.23 mg, 0.273 mmol), anhydrous sodium acetate (140.16 mg, 1.71 mmol), acetic acid (205.21 mg, 3.42 mmol, 0.195 mL) and MP-CNBH ₃ (2 mmol/1 g) (300 mg, 0.601 mmol) were added at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at this temperature for 16 h. After completion of the reaction as indicated by LCMS, the reaction mixture was filtered and washed with THF (20 mL) and concentrated under reduced pressure. The obtained residue was purified by reversed-phase column chromatography (Mobile Phase A: 10 mm ABC in water and Mobile Phase B: Acetonitrile) to afford tert-butyl (R)-(3-((1-(4-((1-(6-(3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)-1-methyl-1H-indazol-7-yl)hexyl)piperidin-4-yl)ethynyl)na phthalen-1-yl)ethyl)carbamoyl)-4- methylphenyl)carbamate (3, 80 mg, 0.086 mmol, 25% yield) as a pale brown solid. LC-MS (ES ⁺ ): m/z 838.4 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (R)-(3- ((1-(4-((1-(6-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-m ethyl-1H-indazol-7- yl)hexyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carbam oyl)-4-methylphenyl)carbamate (3, 80 mg, 0.086 mmol) in anhydrous DCM (1 mL) under nitrogen atmosphere was added 4M HCl in 1,4-dioxane (126.32 mg, 3.46 mmol, 0.157 mL) at 0 °C and the resulting solution was stirred at ambient temperature for 2 h. After completion of the reaction as indicated by LCMS, excess solvent was removed under reduced pressure to get the residue which was triturated with MTBE to get a crude residue. The crude mass was subjected to purification by a reversed-phase preparative HPLC [Column: X SELECT C18150 x 19 mm) 5μm; Mobile Phase A: 10 mM Formic acid in water and Mobile Phase B: Acetonitrile] and fractions having compounds were lyophilized to afford (R)-5-amino-N-(1-(4-((1-(6-(3-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)-1-methyl-1H- indazol-7-yl)hexyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)et hyl)-2-methylbenzamide formate (Compound 36, 66 mg, 0.081 mmol, 94% yield) as a beige solid. LC-MS (ES ⁺ ): m/z 738.3 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.54 (s, 1H), 8.76 (d, J = 8 Hz, 1H), 8.33-8.28 (m, 2H), 7.67-7.62 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 7.47-7.44 (m, 1H), 7.16 (d, J = 6.4 Hz, 1H), 7.10-7.01 (m, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.55-6.49 (m, 2H), 5.95-5.85 (m, 1H), 4.98 (brs, 2H), 4.19 (s, 3H), 3.88 (t, J = 6.8 Hz, 2H), 3.05 (t, J = 8 Hz, 2H), 2.84-2.70 (m, 4H), 2.35-2.26 (m, 3H), 2.24- 2.15 (m, 2H), 2.08 (s, 3H), 2.00-1.90 (m, 1H), 1.75-1.65 (m, 4H), 1.54 (d, J = 6.8 Hz, 3H), 1.54 (d, J = 6.8 Hz, 3H) and 1.49-1.35 (m, 4H). Example 81 Synthesis of 5-amino-N- 1-(4-((1-(6-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)hexyl)piperidin-4-yl)ethyny l)naphthalen-1-yl)ethyl)-2- methylbenzamide (Compound 37) Step-1: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (R)-(4- methyl-3-((1-(4-(piperidin-4-ylethynyl)naphthalen-1-yl)ethyl )carbamoyl)phenyl)carbamate (1, 0.14 g, 0.212 mmol) and 6-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-y l]hexanal (2, 190.18 mg, 0.425 mmol) in anhydrous DMSO (5 mL) was added acetic acid (153.38 mg, 2.55 mmol, 0.146 mL) and the reaction mixture was stirred at ambient temperature for 1 h. Subsequently, MP-CNBH ₃ (0.3 g; 2.0 mmol/g) was added and suspension was stirred for 16 h at ambient temperature. The reaction progress was monitored by TLC and UPLC. After completion of the reaction, the reaction mixture was filtered by normal filter paper and the filtrate was concentrated under reduced pressure. The obtained crude was purified by reverse phase column chromatography (C18 column, solvent system A: 0.1% Formic acid in water and B: MeCN) and the fractions having desired product were lyophilized to afford tert-butyl (3-(((1R)-1-(4-((1-(6-(1- (2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benz o[d]imidazol-4- yl)hexyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carbam oyl)-4-methylphenyl)carbamate (3; 0.035 g, 0.031 mmol, 15% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 853.4 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (3- (((1R)-1-(4-((1-(6-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-o xo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)hexyl)piperidin-4-yl)ethynyl)naphthale n-1-yl)ethyl)carbamoyl)-4- methylphenyl)carbamate (3, 30 mg, 0.027 mmol) in anhydrous DCM (3 mL) was added 4N HCl in 1,4-dioxane (0.3 mL) at 5 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 3 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The obtained crude product was purified by reverse phase column chromatography (0.1 % formic acid in water: MeCN) to afford 5-amino-N-((1R)-1-(4-((1-(6-(1-(2,6-dioxopiperidin-3-yl)-3-m ethyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)hexyl)piperidin-4-yl)ethyny l)naphthalen-1-yl)ethyl)-2- methylbenzamide formate (Compound 37, 6 mg, 0.007 mmol, 27% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 753.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 8.76 (d, J = 8 Hz, 1H), 8.75-8.28 (m, 2H), 7.67-7.62 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 6.97-6.93 (m, 2H), 6.89-6.84 (m, 2H), 6.55-6.50 (m, 2H), 5.88 (quin, J = 7.2 Hz, 1H), 5.39 (dd, J = 5.2,12.4 Hz, 1H), 4.98 (brs, 2H), 3.56 (s, 3H), 2.92-2.85 (m, 3H), 2.85-2.80 (m, 1H), 2.78-2.71 (m, 3H), 2.65-2.55 (m, 2H), 2.25-2.21 (m, 2H), 2.09 (s, 3H), 2.05-1.91 (m, 3H), 1.80-1.68 (m, 2H), 1.65-1.57 (m, 2H), 1.53 (d, J = 6.8 Hz, 3H), 1.50-1.39 (m, 4H), 1.37-1.35 (m, 3H).

Example 82 5-amino-N-((1R)-1-(4-((1-(5-(1-(2,6-dioxopiperidin-3-yl)-2-o xo-1,2-dihydrobenzo[cd]indol- 5-yl)pentyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)-2- methylbenzamide (Compound 38) Compound 38 was prepared substantially following the synthesis of Compound 36, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 760.3 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.13 (s, 1H), 8.77 (d, J = 8 Hz, 1H), 8.33-8.28 (m, 2H), 8.02 (d, J = 7.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.66-7.57 (m, 4H), 7.57-7.52 (m, 2H), 7.15 (d, J = 7.2 Hz, 1H), 6.84 (d, J = 8 Hz, 1H), 6.60-6.40 (m, 2H), 5.95-5.75 (m, 1H), 5.44 (dd, J = 12.8, Hz, 1H), 4.99 (brs, 2H), 3.18-3.16 (m, 3H), 3.19-2.90 (m, 1H), 2.90-2.70 (m, 4H), 2.20-2.01 (m, 5H), 2.00-1.89 (m, 3H), 1.89-1.62 (m, 5H), 1.65-1.49 (m, 6H) and 1.50-1.30 (m, 2H). Example 83 5-amino-N-((1R)-1-(4-((1-(6-(3-(2,6-dioxopiperidin-3-yl)-2-o xo-2,3-dihydrobenzo[d]oxazol- 7-yl)hexyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)-2-m ethylbenzamide (Compound 39) Compound 39 was prepared substantially following the synthesis of Compound 36, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 740.2 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.26 (s, 1H), 8.76 (d, J = 8 Hz, 1H), 8.32-8.28 (m, 2H), 7.68- 7.63 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 7.16-7.12 (m, 2H), 7.03 (dd, J = 7.4, 0.8 Hz, 1H), 6.84 (d, J = 8 Hz, 1H), 6.54-6.50 (m, 2H), 5.90-5.86 (m, 1H), 5.38-5.33 (m, 1H), 5.19-4.62 (bs, 2H), 2.94- 2.82 (m, 2H), 2.85-2.64 (m, 6H), 2.50-2.32 (m, 2H), 2.31-2.18 (m, 3H), 2.15 (s, 3H), 1.97-1.95 (m, 2H), 1.90-1.83 (m, 2H), 1.74-1.72 (m, 2H), 1.54 (d, J = 7.2 Hz, 3H), 1.47-1.44 (m, 2H) and 1.35-1.24 (m, 4H). Example 84 Synthesis of 5-amino-N-(1-(4-((1-(6-(4-(1-(2,6-dioxopiperidin-3-yl)-3-met hyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)-6-oxohexano yl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-2-methylbenzamide (Compound 40) Step-1: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl N-[4- methyl-3-[1-[4-[2-(4-piperidyl)ethynyl]-1-naphthyl]ethylcarb amoyl]phenyl]carbamate (1, 80 mg, 0.128 mmol) in anhydrous DMF (1.5 mL) were added DIPEA (49.71 mg, 0.384 mmol, 0.067 mL)) and HATU (58.50 mg, 0.153 mmol) followed by 6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]-6-oxo-hexanoic acid (2, 77.01 mg, 0.153 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 1 h. The progress of the reaction was monitored by UPLC. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by reverse-phase HPLC (RediSep-RF Gold C18 column, Mobile phase A : 10 mm Formic acid in water and B: Acetonitrile) to afford tert-butyl N-[3-[1-[4-[2-[1-[6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2 - oxo-benzimidazol-5-yl]-1-piperidyl]-6-oxo-hexanoyl]-4-piperi dyl]ethynyl]-1- naphthyl]ethylcarbamoyl]-4-methyl-phenyl]carbamate formate (3, 45 mg, 0.041 mmol, 32% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 964.2 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl N-[3- [1-[4-[2-[1-[6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]-6- oxo-hexanoyl]-4-piperidyl]ethynyl]-1-naphthyl]ethylcarbamoyl ]-4-methyl-phenyl]carbamate formate (3, 45 mg, 0.041 mmol) in anhydrous DCM (1 mL) was added 4N HCl in 1,4-dioxane (22.99 mmol, 5.75 mL) at 0 °C and the resulting mixture was stirred at ambient temperature for 1 h. The progress of the reaction was monitored by UPLC. Upon completion of the reaction, excess solvent was removed under reduced pressure to give the crude product, which was purified by reverse-phase HPLC (RediSep-RF Gold C18 column, mobile phase A: 10 mm NH4HCO3 in water B: Acetonitrile) to afford 5-amino-N-[1-[4-[2-[1-[6-[4-[1-(2,6-dioxo-3-piperidyl)-3-met hyl-2- oxo-benzimidazol-5-yl]-1-piperidyl]-6-oxo-hexanoyl]-4-piperi dyl]ethynyl]-1-naphthyl]ethyl]-2- methyl-benzamide (Compound 40, 16.2 mg, 0.018 mmol, 45% yield) as an off-white solid. LC- MS (ES ⁺ ): m/z 864.3 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.10 (s, 1H), 8.76 (d, J = 8 Hz, 1H), 8.32-8.29 (m, 2H), 7.68-7.63 (m, 3H), 7.57 (d, J = 7.2 Hz, 1H), 7.11 (s, 1H), 7.01 (d, J = 8 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8 Hz, 1H), 6.55-6.50 (m, 2H), 5.90-5.86 (m, 1H), 5.36-5.32 (m, 1H), 4.98 (s, 2H), 4.61-4.55 (m, 1H), 4.06-3.92 (m, 2H), 3.82-3.74 (m, 1H), 3.33 (s, 3H), 3.30-3.29 (m, 1H), 3.10-3.07 (m, 2H), 2.92-2.60 (m, 5H), 2.42-2.32 (m, 3H), 2.10 (s, 3H), 2.03-1.89 (m, 3H), 1.85-1.53 (m, 15H). Example 85 Synthesis of 5-amino-N-((1R)-1-(4-((1-((1-(1-(3-(2,6-dioxopiperidin-3-yl) -1-methyl-1H- indazol-6-yl)piperidine-4-carbonyl)-4-hydroxypiperidin-4-yl) methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-2-methylbenzamide (Compound 41) Step-1: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 1-[3-(2,6-dioxo- 3-piperidyl)-1-methyl-indazol-6-yl] piperidine-4-carboxylic acid hydrochloride (2, 72.60 mg, 0.155 mmol) in anhydrous DMF (1.5 mL) was added HATU (88.54 mg, 0.232 mmol), DIPEA (100.32 mg, 0.776 mmol, 0.135 mL) and tert-butyl (R)-(3-((1-(4-((1-((4-hydroxypiperidin-4- yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carba moyl)-4-methylphenyl)carbamate (1, 100 mg, 0.155 mmol) at ambient temperature. The reaction mixture was stirred at this temperature for 2 h. Upon completion of the reaction as indicated by UPLC, the reaction mixture was diluted with water (50 mL), extracted with EtOAc (3 × 100 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude residue was purified by reverse phase column chromatography (10 mM ammonium bicarbonate solution/acetonitrile) to afford tert-butyl (3-(((1R)-1-(4-((1-((1-(1-(3- (2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin e-4-carbonyl)-4- hydroxypiperidin-4-yl)methyl)piperidin-4-yl)ethynyl)naphthal en-1-yl)ethyl)carbamoyl)-4- methylphenyl)carbamate (3, 60 mg, 0.057 mmol, 37% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 977.3 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing well-stirred solution of tert-butyl (3- (((1R)-1-(4-((1-((1-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl -1H-indazol-6-yl)piperidine-4- carbonyl)-4-hydroxypiperidin-4-yl)methyl)piperidin-4-yl)ethy nyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)carbamate (3, 60 mg, 0.057 mmol) in anhydrous DCM (1 mL) was added 4N HCl in 1,4 dioxane (0.142 mL) at 0 °C. The resulting reaction mixture was stirred at ambient temperature for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude product which was washed with MTBE (2 mL) and dried under vacuum. The crude solid was purified by reverse phase column chromatography (X Select C18 (150 × 19 mm) 5 microns with mobile phase 0.1% formic acid in water : acetonitrile) to afford 5-amino-N-((1R)-1-(4-((1-((1-(1-(3-(2,6-dioxopiperidin-3-yl) -1- methyl-1H-indazol-6-yl)piperidine-4-carbonyl)-4-hydroxypiper idin-4-yl)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-2-methylbenzamide formate (Compound 41, 27 mg, 0.028 mmol, 50% yield) as a white solid. LC-MS (ES ⁺ ): m/z 877.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.86 (s, 1H), 8.77 (d, J = 8 Hz, 1H), 8.34-8.29 (m, 2H), 7.68-7.63 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 6.91 (dd, J = 9, 1.2 Hz, 1H), 6.85-6.84 (m, 2H), 6.55- 6.50 (m, 2H), 5.93-5.81 (m, 1H), 4.99 (br s, 2H), 4.27-4.24 (m, 2H), 4.11-4.01 (m, 1H), 3.89 (s, 3H), 3.86-3.70 (m, 3H), 3.10-2.70 (m, 7H), 2.65-2.55 (m, 2H), 2.41-2.23 (m, 4H), 2.21-2.11 (m, 2H), 2.10-2.02 (m, 1H), 2.08 (s, 3H), 2.00-1.90 (m, 2H), 1.85-1.68 (m, 6H), 1.54 (d, J = 6.8 Hz, 3H), 1.52 (m, 2H) and 1.43-1.33 (m, 2H). Example 86 Synthesis of 5-amino-N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl) -3-ethyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl) piperidine-4-carbonyl)-4-hydroxypiperidin-4- yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)-2-me thylbenzamide (Compound Step-1: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (R)-(3- ((1-(4-((1-((4-hydroxypiperidin-4-yl)methyl)piperidin-4-yl)e thynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)carbamate (1, 85 mg, 0.11 mmol) and 1-[1-(2,6-dioxo-3- piperidyl)-3-ethyl-2-oxo-benzimidazol-5-yl]piperidine-4-carb oxylic acid hydrochloride (2, 51.94 mg, 0.110 mmol) in anhydrous DMF (2 mL) were added HATU (63.06 mg, 0.165 mmol) and DIPEA (71.45 mg, 0.552 mmol, 0.096 mL) and the reaction mixture was stirred at ambient temperature for 2 h. After completion of the reaction, the reaction mixture was quenched with ice-water. The solid precipitate was filtered, washed with water and dried under vacuum to afford tert-butyl (3-(((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-eth yl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl) piperidine-4-carbonyl)-4-hydroxypiperidin-4- yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carba moyl)-4-methylphenyl)carbamate (3, 100 mg, 0.058 mmol, 53% yield) as a brown solid. LC-MS (ES ⁺ ): m/z 1008.4 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (3- (((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-ethyl- 2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl) piperidine-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)piperi din-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)c arbamate (3, 100 mg, 0.058 mmol) in anhydrous DCM (2 mL) was added 4N HCl in 1,4-dioxane (0.147 mL) at - 78 °C. The resulting mixture was stirred at ambient temperature for 2 h and monitored by UPLC. After completion of the reaction, excess solvent was removed from the reaction mixture and the crude product was purified by reverse phase prep-HPLC (XBridge C18 (150 x 19 mm) 5 micron 0.1% ABC in water : MeCN) to afford 5-amino-N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl) -3- ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine- 4-carbonyl)-4-hydroxypiperidin- 4-yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)-2- methylbenzamide (Compound 42, 19 mg, 0.020 mmol, 35% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 908.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.06 (s, 1H), 8.76 (d, J = 8 Hz, 1H), 8.34-8.28 (m, 2H), 7.68- 7.63 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.88-6.83 (m, 2H), 6.63 (dd, J = 8.8, 2 Hz, 1H), 6.55-6.50 (m, 2H), 5.95-5.85 (m, 1H), 5.40-5.25 (m, 1H), 4.98 (bs, 2H), 4.56 (m, 1H), 4.25 (s, 1H), 4.10-4.01 (m, 1H), 3.86-3.85 (m, 2H), 3.79-3.69 (m, 1H), 3.63-3.60 (m, 2H), 3.51-3.49 (m, 2H), 3.43-3.41 (m, 2H), 3.00-2.80 (m, 4H), 2.79-2.60 (m, 4H), 2.46 (m, 2H), 2.34- 2.33 (m, 1H), 2.30 (s, 2H), 2.09 (m, 3H), 2.01-1.90 (m, 3H), 1.76-1.71 (m, 6H), 1.54 (d, J = 6.8 Hz, 3H), 1.52 (m, 2H) and 1.24-1.18 (m, 3H). Example 87 Synthesis of 5-amino-N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl) -3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)- 4-hydroxypiperidin-4- yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)-2-me thylbenzamide (Compound 43) Step-1: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (R)-(3- ((1-(4-((1-((4-hydroxypiperidin-4-yl)methyl)piperidin-4-yl)e thynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)carbamate (1, 170 mg,0. 269 mmol) and 1-[1-(2,6-dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-car boxylic acid hydrochloride (2,121.17 mg, 0.269 mmol) in dry DMF (4 mL) were added HATU (153.63 mg, 0.404 mmol) and DIPEA (174.07 mg, 1.35 mmol, 0.235 mL) and the resulting mixture was stirred at ambient temperature for 2 h. Upon completion of the reaction, excess solvent was evaporated under reduced pressure and ice-cold water (50 mL) was added. The solid precipitate was filtered, washed with water (5 mL) and dried in vacuo to afford tert-butyl (3-(((1R)-1-(4-((1-((1-(1-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidine-4- carbonyl)-4-hydroxypiperidin-4-yl)methyl)piperidin-4-yl)ethy nyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)carbamate (3, 130 mg, 0.118 mmol, 44% yield) as an off- white solid. LC-MS (ES ⁺ ): m/z 994.5 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (3- (((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)-4-hydroxypiperi din-4-yl)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)c arbamate (3, 130 mg, 0.117 mmol) in anhydrous DCM (3 mL) was added 4N HCl in 1,4-dioxane ( 0.294 mL) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at this temperature for 2 h. Upon completion of the reaction, the solvent was removed and the crude product was purified by reverse phase prep-HPLC (X-Select C18 (150 x 19) mm) 5 microns column; Mobile phase: A:0.1% formic acid in MQ-water; B: acetonitrile; Flow rate: 15 mL/minutes) to afford 5- amino-N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3 -methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)-4-hydroxypiperi din-4-yl)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-2-methylbenzamide formate (Compound 43, 45 mg, 0.0 47 mmol, 40% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 894.2 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.07 (s, 1H), 8.76 (d, J = 8 Hz, 1H), 8.29-8.32 (m, 2H), 7.68-7.63 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8 Hz, 2H), 6.65-6.62 (m, 1H), 6.55-6.52 (m, 2H), 5.89-5.86 (m, 1H), 5.29-5.26 (m, 1H), 5.01-4.98 (bs, 2H), 4.08-4.05 (m, 1H), 3.75-3.72 (m, 2H), 3.63-3.60 (m, 3H), 3.30 (s, 3H), 2.98-2.86 (m, 5H), 2.80-2.60 (m, 7H), 2.45 (m, 2H), 2.38 (m, 2H), 2.08 (s, 3H), 2.00-1.95 (m, 3H), 1.79-1.71 (m, 6H), 1.54 (d, J = 7.2 Hz, 3H) and 1.50- 1.40 (m, 2H). Example 88 Synthesis of 5-amino-N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl) -3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)p iperidin-4- yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)-2-me thylbenzamide (Compound 44) Step-1: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 1-[1-(2,6-dioxo- 3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-c arboxylic acid (2, 150 mg, 0.349 mmol) in anhydrous DMF (5 mL) were added HATU (159.41 mg, 0.441 mmol), DIPEA (112.89 mg, 0.873 mmol, 0.152 mL) and tert-butyl (R)-(4-methyl-3-((1-(4-((1-(piperidin-4- ylmethyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carbam oyl)phenyl)carbamate (1, 276.24 mg, 0.349 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at this temperature for 3 h. After completion of the reaction as indicated by UPLC, excess solvent was evaporated under reduced pressure and ice-cold water was added to the flask. The solid precipitate was filtered, washed with water (10 mL) and dried in vacuo to afford tert-butyl (3-(((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-met hyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-yl)m ethyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)c arbamate (3, 250 mg, 0.130 mmol, 37% yield) as a brown solid. LC-MS (ES ⁺ ): m/z 978.6 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (3- (((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-yl)m ethyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)c arbamate (3, 250 mg, 0.130 mmol) in anhydrous DCM (4 mL) was added trifluoroacetic acid (29.75 mg, 0.260 mmol, 0.020 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 1 h. After completion of the reaction as indicated by TLC, excess solvent was removed from the reaction mixture under reduced pressure to get a crude mass. This reaction crude was purified by reverse phase prep- HPLC (X-Select C18 (150 x 19) mm) 5 microns column, Mobile phase: A:0.1% formic acid in MQ-water; B: acetonitrile; Flow rate: 15 mL/minutes) to afford 5-amino-N-((1R)-1-(4-((1-((1- (1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 H-benzo[d]imidazol-5- yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-y l)ethynyl)naphthalen-1-yl)ethyl)-2- methylbenzamide formate (Compound 44, 45 mg, 0.047 mmol, 36% yield) as a white solid. LC- MS (ES ⁺ ): m/z 877.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.10 (s, 1H), 9.34-9.26 (bs, 2H), 8.89 (d, J = 7.6 Hz, 1H), 8.34-8.29 (m, 2H), 7.77-7.67 (m, 3H), 7.61-7.58 (m, 1H), 7.25-6.99 (m, 3H), 6.89-6.80 (m, 3H), 5.92-5.89 (m, 1H), 5.42-5.28 (m, 1H), 4.48-4.36 (m, 1H), 4.08-3.96 (m, 2H), 3.84-3.62 (m, 2H), 3.39-3.35 (m, 4H), 3.18-3.12 (m, 7H), 2.96-2.86 (m, 3H), 2.68-2.57 (m, 2H), 2.34-2.28 (m, 1H), 2.15-2.05 (m, 9H), 2.02-1.83 (m, 6H), 1.55 (d, J = 6.8 Hz, 3H) and 1.38-1.00 (m, 2H).

Example 89 5-amino-N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl) -3-ethyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)-4-fluoropiperid in-4-yl)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-2-methylbenzamide (Compound 45) Compound 45 was prepared substantially following the synthesis of Compound 41, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 909.0 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 8.77 (d, J = 8 Hz, 1H), 8.34-8.29 (m, 2H), 7.58- 7.63 (m, 4H), 6.95-6.83 (m, 3H), 6.65-6.62 (m, 1H), 6.55-6.50 (m, 2H), 5.90-5.86 (m, 1H), 5.30- 5.26 (m, 1H), 4.99 (s, 2H), 4.25-4.10 (m, 1H), 3.87-3.83 (m, 3H), 3.63-3.60 (m, 2H), 2.93-2.51 (m, 10H), 2.39 (m, 3H), 2.08 (s, 3H), 2.01-1.95 (m, 4H), 1.75-1.73 (m, 10H), 1.54 (d, J = 6.8 Hz, 3H) and 1.24-1.19 (m, 4H). Example 90 5-amino-N-((1R)-1-(4-((1-((4-cyano-1-(1-(1-(2,6-dioxopiperid in-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piper idin-4-yl)methyl)piperidin- 4-yl)ethynyl)naphthalen-1-yl)ethyl)-2-methylbenzamide (Compound 46) Compound 46 was prepared substantially following the synthesis of Compound 41, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 903.2 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.01 (bs,1H), 8.76 (d, J = 8 Hz, 1H), 8.34-8.28 (m, 2H), 7.69- 7.64 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.86-6.84 (m, 2H), 6.64 (d, J = 2 Hz, 1H), 6.53-6.50 (m, 2H), 5.88 (m, 1H), 5.30-5.27 (m, 1H), 4.98 (brs, 2H), 4.52-4.48 (m, 1H), 4.10-3.98 (m, 1H), 3.62 (d, J = 12 Hz, 2H), 3.33 (s, 3H), 3.31-3.10 (m, 1H), 2.93-2.50 (m, 13H), 2.08 (s, 3H), 2.01-1.95 (m, 6H), 1.77-1.73 (m, 6H), 1.55 (d, J = 6.8 Hz, 3H) and 1.50-1.25 (m, 2H). Example 91 5-amino-N-((1R)-1-(4-((1-((1-(1-(3-(2,6-dioxopiperidin-3-yl) -2-oxo-2,3- dihydrobenzo[d]oxazol-6-yl)piperidine-4-carbonyl)-4-fluoropi peridin-4- yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)-2-me thylbenzamide (Compound Compound 47 was prepared substantially following the synthesis of Compound 41, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 882.3 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.19 (s, 1H), 9.41 (bs, 2H), 8.82 (d, J = 7.6 Hz, 1H), 8.34-8.31 (m, 2H), 7.69-7.66 (m, 3H), 7.59 (d, J = 7.2 Hz, 1H), 7.10-7.08 (m, 2H), 6.91 (d, J = 8.4 Hz, 1H), 6.80 (dd, J = 8.8, 2 Hz, 1H), 6.64-6.61 (m, 2H), 5.89 (m, 1H), 5.30 (dd, J = 5.2, 13.2 Hz, 1H), 4.30-4.25 (m, 1H), 3.97-3.94 (m, 1H), 3.66-3.63 (m, 2H), 3.33-3.16 (m, 4H), 3.25 -3.00 (m, 2H), 2.94-2.90 (m, 3H), 2.83-2.72 (m, 3H), 2.69-2.63 (m, 2H), 2.34-2.23 (m, 2H), 2.16-2.03 (m, 8H), 1.85-1.62 (m, 7H) and 1.55 (d, J = 6.8 Hz, 3H). Example 92 5-amino-N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl) -3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)-4-fluoropipe ridin-4-yl)methyl)piperidin- 4-yl)ethynyl)naphthalen-1-yl)ethyl)-2-methylbenzamide (Compound 48) Compound 48 was prepared substantially following the synthesis of Compound 41, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 895.3 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.06 (s, 1H), 8.77 (d, J = 7.2 Hz, 1H), 8.32-8.31 (m, 2H), 7.68- 7.66 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 7.6 Hz, 2H), 6.65 (d, J = 8 Hz, 1H), 6.57-6.52 (m, 2H), 5.88 (m, 1H), 5.32-5.28 (m, 1H), 5.07 (bs, 2H), 4.26-4.20 (m, 2H), 4.18-3.87 (m, 2H), 3.65-3.61 (m, 4H), 3.31 (s, 3H), 2.98-2.52 (m, 9H), 2.49-2.39 (m, 4H), 2.08 (s, 3H), 2.00-1.97 (m, 4H), 1.78-1.62 (m, 7H) and 1.54 (d, J = 6.8 Hz, 3H). Example 93 5-amino-N-((1R)-1-(4-((1-((1-(1-(3-(2,6-dioxopiperidin-3-yl) -2-oxo-2,3- dihydrobenzo[d]oxazol-6-yl)piperidine-4-carbonyl)-4-hydroxyp iperidin-4- yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)-2-me thylbenzamide (Compound 4 Compound 49 was prepared substantially following the synthesis of Compound 41, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 880.3 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.19 (s, 1H), 8.77 (d, J = 8 Hz, 1H), 8.34-8.28 (m, 2H), 7.68- 7.63 (m, 3H), 7.57 (d, J = 7.2 Hz, 1H), 7.09-7.06 (m, 2H), 6.84 (d, J = 8 Hz, 1H), 6.78 (dd, J = 8.8, 2 Hz, 1H), 6.55-6.50 (m, 2H), 5.88 (m, 1H), 5.30 (dd, J = 13, 5.6 Hz, 1H), 4.98 (brs, 2H), 4.32-4.15 (m, 1H), 4.09-4.01 (m, 1H), 3.71-3.62 (m, 3H), 2.97-2.85 (m, 3H), 2.77-2.66 (m, 6H), 2.50-2.42 (m, 4H), 2.34-2.29 (m, 2H), 2.14-2.08 (m, 4H), 1.95-1.92 (m, 2H), 1.78-1.69 (m, 6H) and 1.55-1.40 (m, 7H). Example 94 5-amino-N-((1R)-1-(4-((1-((1-(1-(4-((2,6-dioxopiperidin-3-yl )oxy)phenyl)piperidine-4- carbonyl)-4-fluoropiperidin-4-yl)methyl)piperidin-4-yl)ethyn yl)naphthalen-1-yl)ethyl)-2- methylbenzamide (Compound 50) Compound 50 was prepared substantially following the synthesis of Compound 41, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 841.3 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1H), 8.76 (d, J = 8 Hz, 1H), 8.34-8.29 (m, 2H), 7.69- 7.63 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 6.92-6.84 (m, 5H), 6.55-6.50 (m, 2H), 5.89-5.81 (m, 1H), 5.02-4.98 (m, 3H), 4.18-4.11 (m, 1H), 3.84-3.79 (m, 1H), 3.57-3.54 (m, 2H), 3.30 (m, 2H), 2.82- 2.68 (m, 5H), 2.67-2.50 (m, 6H), 2.39-2.33 (m, 2H), 2.18-2.05 (m, 2H), 2.10-2.06 (s, 3H), 1.99- 1.91 (m, 3H), 1.78-1.70 (m, 7H), 1.54 (d, J = 6.8 Hz, 3H) and 1.50 (m, 1H). Example 95 (R)-5-amino-N-(1-(4-((1-((1-(1-(3-(2,4-dioxotetrahydropyrimi din-1(2H)-yl)-1-methyl-1H- indazol-6-yl)piperidine-4-carbonyl)-4-fluoropiperidin-4-yl)m ethyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-2-methylbenzamide (Compound 51) Compound 51 was prepared substantially following the synthesis of Compound 41, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 880.3 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ10.51 (s, 1H), 8.76 (d, J = 8 Hz, 1H), 8.38-8.28 (m, 2H), 7.70- 7.61 (m, 3H), 7.57 (d, J = 7.2 Hz, 1H), 7.45 (d, J = 9.2 Hz, 1H), 6.88-6.80 (m, 2H), 6.92 (dd, J = 9.2, 1.6 Hz, 1H), 6.89-6.80 (m, 2H), 5.88 (m, 1H), 4.98 (bs, 2H), 4.20-4.10 (m, 1H), 3.92-3.80 (m, 8H), 3.48-3.25 (m, 2H), 3.01-2.78 (m, 8H), 2.74 (t, J = 6.8 Hz, 2H), 2.60-2.57 (m, 1H), 2.50 (m, 2H), 2.46-2.35 (m, 2H), 2.09 (s, 3H), 2.01-1.88 (m, 3H), 1.80-1.67 (m, 6H) and 1.54 (d, J = 7.2 Hz, 3H). Example 96 (R)-5-amino-N-(1-(4-((1-((1-(1-(3-(2,4-dioxotetrahydropyrimi din-1(2H)-yl)-1-methyl-1H- indazol-6-yl)piperidine-4-carbonyl)-4-hydroxypiperidin-4-yl) methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-2-methylbenzamide (Compound 52) Compound 52 was prepared substantially following the synthesis of Compound 41, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 879.2 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 10.59 (s, 1H), 8.76 (d, J = 10.8 Hz, 1H), 8.28 (m, 2H), 7.67- 7.64 (m, 3H), 7.58-7.56 (m, 1H), 7.44 (d, J = 12 Hz, 1H), 6.93-6.83 (m, 3H), 6.55-6.49 (m, 2H), 5.91-5.86 (m, 1H), 4.97 (bs, 2H), 4.08-4.05 (m, 1H), 3.97-3.65 (m, 3H), 3.2.87-2.84 (m, 7H), 2.74- 2.72 (m, 3H), 2.50 (m, 2H), 2.35-2.27 (m, 4H), 2.09 (m, 1H), 2.08 (s, 3H), 1.94 (m, 3H), 1.78-1.72 (m, 7H) and 1.65-1.25 (m, 8H). Example 97 5-amino-2-methyl-N-((R)-1-(4-((1-((1-(1-(1-methyl-3-((R)-3-m ethyl-2,6-dioxopiperidin-3- yl)-1H-indazol-6-yl)piperidine-4-carbonyl)piperidin-4-yl)met hyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)benzamide (Compound 53) Compound 53 was prepared substantially following the synthesis of Compound 41, using the corresponding intermediates. 10.83 (s, 1H), 8.78 (d, J = 8 Hz, 1H), 8.79-8.77 (m, 2H), 7.68- 7.56 (m, 5H), 6.92 (d, J = 1.6 Hz, 1H), 6.86-6.83 (m, 2H), 6.49-6.48 (m, 2H), 5.89-5.85 (m, 1H), 5.10-4.91 (m, 2H), 4.41-4.38 (m, 1H), 4.03 (m, 1H), 3.92 (s, 3H), 3.87-3.80 (m, 2H), 3.40 (m, 3H), 3.07-3.04 (m, 1H), 2.84-2.67 (m, 6H), 2.50 (m, 2H), 2.45-2.40 (m, 2H), 2.39-2.33 (m, 2H), 2.14 (m, 1H), 2.12 (s, 3H), 2.10-2.01 (m, 2H), 1.99-1.98 (m, 4H), 1.81-1.76 (m, 4H), 1.61 (s, 3H), 1.54 (d, J = 5.2 Hz, 3H) and 1.03-1.01 (m, 2H). Example 98 5-amino-N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl) -3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-y l)methyl)-4-fluoropiperidin- 4-yl)ethynyl)naphthalen-1-yl)ethyl)-2-methylbenzamide (Compound 54) Compound 54 was prepared substantially following the synthesis of Compound 44, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 895.2 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.25 (bs, 2H), 8.89 - 8.84 (m, 1H), 8.42 - 8.21 (m, 2H), 7.76 - 7.57 (m, 4H), 7.02 - 6.84 (m, 3H), 6.74 - 6.53 (m, 3H), 5.96 - 5.84 (m, 1H), 5.36 - 5.26 (m, 1H), 4.49 - 4.39 (m, 1H), 4.10 - 4.00 (m, 1H), 3.67 - 3.56 (m, 4H), 3.45 (m, 2H), 3.31 (s, 3H), 3.23 – 3.00 (m, 5H), 2.99-2.70 (m, 3H), 2.66 - 2.57 (m, 4H), 2.50 (m, 2H), 2.10 - 2.09 (s, 3H), 2.06 (m, 1H), 2.03 - 1.92 (m, 1H), 1.87 - 1.67 (m, 6H), 1.53 (d, J = 6.8 Hz, 3H) and 1.14 - 1.05 (m, 2H). Example 99 Synthesis of tert-butyl (R)-3-((4-methyl-3-((1-(4-((1-(piperidin-4-ylmethyl)piperidi n-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)phenyl)amino)azet idine-1-carboxylate, tert- butyl (R)-3-((3-((1-(4-((1-((4-fluoropiperidin-4-yl)methyl)piperid in-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)azetidine-1- carboxylate, tert-butyl (R)-3-((4-methyl-3-((1-(4-(piperidin-4-ylethynyl)naphthalen- 1- yl)ethyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate and tert-butyl 3-((3-(((1R)-1-(4- ((3-fluoropiperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carba moyl)-4- methylphenyl)amino)azetidine-1-carboxylate

Step-1: To a 500 mL single-neck round-bottom flask containing a well-stirred solution of 5-amino-2- methyl-benzoic acid (1, 10 g, 66.15 mmol) in MeOH (150 mL) were added tert-butyl 3- oxoazetidine-1-carboxylate (2, 16.99 g, 99.23 mmol), anhydrous sodium acetate (16.28 g, 198.46 mmol) and acetic acid (1.99 g, 33.08 mmol, 1.89 mL) at ambient temperature under nitrogen atmosphere. The reaction mixture was stirred at this temperature for 8 h under nitrogen atmosphere, then MP-Cyanoborohydride (26.46 g, 52.92 mmol) was added, and the resulting suspension was stirred for 12 h. After completion of the reaction as confirmed by TLC and LCMS, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained crude was diluted with water (100 mL) and extracted with EtOAc (3 × 150 mL). The combined organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC [Redi Sep-RF C18 column, 30 g; CV26.4 mL – 35 mL/minutes] mobile phase: 0.1% formic acid in water: MeCN] to afford 5- [(1-tert-butoxycarbonylazetidin-3-yl)amino]-2-methyl-benzoic acid (3, 8 g, 24.94 mmol, 38% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 251.0 [M – isobutene + H] ⁺ . Step-2: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of 5-[(1-tert- butoxycarbonylazetidin-3-yl)amino]-2-methyl-benzoic acid (3, 1.2 g, 3.72 mmol) in anhydrous DMF (10 mL) were added HATU (2.12 g, 5.58 mmol), DIPEA (2.40 g, 18.61 mmol, 3.24 mL) and (R)-1-(4-bromonaphthalen-1-yl)ethan-1-amine (4, 863.62 mg, 3.35 mmol) at ambient temperature. The reaction mixture was stirred at this temperature for 4 h. After completion of the reaction as indicated by TLC, the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3 × 100 mL). The combined organic phase was dried (Na ₂ SO ₄ ), filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (230-400 mesh silica gel) with 38% EtOAc/pet ether as eluent to afford tert-butyl (R)-3-((3-((1-(4-bromonaphthalen-1-yl)ethyl)carbamoyl)-4- methylphenyl)amino)azetidine-1-carboxylate (5, 1.8 g, 2.98 mmol, 80% yield) as a yellow gum. LC-MS (ES ⁺ ): m/z 482.3 [M – isobutene + H] ⁺ . Step-3: To a 100 mL sealed tube containing a well-stirred solution of tert-butyl (R)-3-((3-((1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)a zetidine-1-carboxylate (5, 1 g, 1.67 mmol) and 4-ethynyl-1-(4-piperidylmethyl)piperidine hydrochloride (6, 819.78 mg, 3.34 mmol) in anhydrous ACN (20 mL) was added cesium carbonate (1.63 g, 5.01 mmol) and reaction mixture was degassed with N ₂ for 5 minutes. Subsequently, XPhos-Pd-G3 (70.74 mg, 0.0835 mmol) and XPhos (79.68 mg, 0.167 mmol) were added, and the resulting mixture was heated at 90 °C for 3 h. The reaction mixture was passed through a pad of Celite and Celite bed was washed with EtOAc (50 mL). The combined filtrate was concentrated under reduced pressure to yield a crude residue, which was purified by flash column chromatography (230-400 mesh silica gel) with 10% MeOH/DCM as eluent to afford tert-butyl (R)-3-((4-methyl-3-((1-(4-((1-(piperidin-4- ylmethyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carbam oyl)phenyl)amino)azetidine-1- carboxylate (7, 650 mg, 0.812 mmol, 49% yield) as a yellow gum. LC-MS (ES ⁺ ): m/z 664.4 [M + H] ⁺ . Step-4: To a 25 mL sealed-tube containing a well-stirred solution of tert-butyl (R)-(3-((1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)carbama te (5, 300 mg, 0.467 mmol) and 4-ethynyl-1-[(4-fluoro-4-piperidyl)methyl]piperidine hydrochloride (8, 246.55 mg, 0.935 mmol) in anhydrous acetonitrile (5 mL) and THF (1 mL) was added cesium carbonate (381.20 mg, 1.17 mmol) at ambient temperature. Nitrogen gas was purged through the reaction mixture for 10 minutes. Subsequently, XPhos (44.62 mg, 0.093 mmol) and XPhos-Pd-G3 (79.23 mg, 0.093 mmol) were added and stirring was continued at 90 °C for 3 h. The reaction was monitored by UPLC. Upon completion of the reaction, the reaction mixture was passed through a pad of Celite, and the filtrate was concentrated under reduced pressure. The obtained crude was purified by reverse phase HPLC (RediSep-Rf Gold C18 column, Mobile phase A : Formic acid in water and B : Acetonitrile) to afford tert-butyl (R)-3-((3-((1-(4-((1-((4-fluoropiperidin-4- yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carba moyl)-4- methylphenyl)amino)azetidine-1-carboxylate (9, 150 mg, 0.153 mmol, 33% yield) as a brown sticky solid. LC-MS (ES ⁺ ): m/z 682.4 [M + H] ⁺ . Step-5: To a 50 mL sealed tube containing a well-stirred solution of tert-butyl (R)-3-((3-((1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)a zetidine-1-carboxylate (5, 300.00 mg, 0.467 mmol) and 4-ethynylpiperidine hydrochloride (10, 89.49 mg, 0.608 mmol) in anhydrous acetonitrile (20 mL) was added cesium carbonate (381.20 mg, 1.17 mmol) and the reaction mixture was degassed by purging nitrogen for 5 minutes. Subsequently, XPhos-Pd-G3 (19.81 mg, 0.023 mmol) and XPhos (22.31 mg, 0.046 mmol) were added, and the resulting mixture was heated at 90 °C for 4 h. Upon completion of the reaction, the reaction mixture was passed through a pad of Celite and the Celite bed was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography (230-400 mesh silica gel) with 10% MeOH/DCM as eluent to afford tert-butyl (R)-3-((4-methyl-3-((1-(4-(piperidin-4-ylethynyl)naphthalen- 1- yl)ethyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (11, 180 mg, 0.303 mmol, 65% yield) as a brown gummy solid. LC-MS (ES ⁺ ): m/z 567.2 [M + H] ⁺ . Step-6: To a 100 mL sealed-tube containing a well-stirred solution of tert-butyl (R)-3-((3-((1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)a zetidine-1-carboxylate (5, 300 mg, 0.506 mmol) and 4-ethynyl-3-fluoro-piperidine hydrochloride (12, 117.22 mg, 0.659 mmol) in anhydrous acetonitrile (8 mL) was added cesium carbonate (412.97 mg, 0.001 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was degassed by bubbling nitrogen gas into the reaction mixture for 5 minutes. Subsequently, XPhos-Pd-G3 (21.46 mg, 0.025 mmol) and dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (24.17 mg, 0.05 mmol) were added and the resulting mixture was degassed further by bubbling nitrogen gas into the reaction mixture for 5 minutes. Then the reaction mixture was heated to 90 °C for 4 h and progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was cooled to ambient temperature, diluted with EtOAc (20 mL) and filtered through a pad of Celite, and the Celite bed was washed with EtOAc (100 mL). Water (20 mL) was added to the filtrate and the aqueous phase was extracted with EtOAc (2 × 150 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The obtained crude was purified by flash column chromatography (230-400 mesh silica gel) with 0-10% MeOH/DCM as eluent to afford tert-butyl 3-((3-(((1R)-1-(4-((3- fluoropiperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl )-4-methylphenyl)amino)azetidine- 1-carboxylate (13, 250 mg, 0.379 mmol, 75% yield) as a brown solid. LC-MS (ES ⁺ ): m/z 585.2 [M + H] ⁺ . The following targeting ligands (Example 100-101) were prepared using the method described above in the synthesis of tert-butyl (R)-3-((4-methyl-3-((1-(4-((1-(piperidin-4-ylmethyl)piperidi n- 4-yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)phenyl)amino)az etidine-1-carboxylate in Example 99, with the corresponding alkyne intermediate in Step-3.

Example 102 Synthesis of tert-butyl 3-[4-methyl-3-[1-[4-[2-[1-(4-piperidylmethyl)-4-piperidyl]et hynyl]-1- naphthyl]ethylcarbamoyl]anilino]azetidine-1-carboxylate Step-1: To a 500 mL single-neck round-bottom flask containing a well-stirred solution of 1-(4-bromo-1- naphthyl)ethanone (1, 5 g, 20.07 mmol) in MeOH (150 mL) was added ammonium acetate (15.47 g, 200.72 mmol) and sodium cyanoborohydride (1.89 g, 30.11 mmol) at ambient temperature under nitrogen atmosphere. The reaction mixture was stirred at 75 °C for 7 h. The reaction progress was monitored by UPLC and TLC, and upon completion of the reaction, the reaction mixture was acidified to pH~2 using trifluoroacetic acid at 0°C and concentrated under reduced pressure. Water (200 mL) was added to the obtained residue and the aqueous phase was extracted with EtOAc (3 × 150 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude, which was purified by column chromatography (230-400 mesh silica gel) with 15% MeOH/DCM as eluent to afford 1-(4-bromo-1-naphthyl)ethanamine (2, 4.2 g, 16.44 mmol, 83% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 8.57 (s, 2H), 8.28-8.30 (m, 2H), 8.04 (d, J = 7.6 Hz, 1H), 7.76-7.78 (m, 2H), 7.64 (d, J = 7.6 Hz, 1H), 5.32-5.33 (m, 1H) and 1.61 (d, J = 6.8 Hz, 3H). Step-2: To a well-stirred solution of 1-(4-bromo-1-naphthyl)ethanamine (2, 2 g, 7.48 mmol) in anhydrous DMF (20 mL) were added 5-[(1-tert-butoxycarbonylazetidin-3-yl)amino]-2-methyl-benzo ic acid (3, 3.09 g, 8.98 mmol), HATU (4.27 g, 11.22 mmol) and DIPEA (2.90 g, 22.44 mmol, 3.91 mL) at ambient temperature under nitrogen atmosphere. The resulting reaction mixture was stirred at ambient temperature for 3 h. After completion of the reaction as indicated by UPLC, the solvent was evaporated under reduced pressure and the crude product was purified by flash column chromatography (230-400 mesh silica gel) with 40% EtOAc/pet ether as eluent to afford tert-butyl 3-[3-[1-(4-bromo-1-naphthyl)ethylcarbamoyl]-4-methyl-anilino ]azetidine-1-carboxylate (4, 1.5 g, 1.83 mmol, 24% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 484.2 [M + H] ⁺ . Step-3: To a 25 mL sealed tube containing a well-stirred solution tert-butyl 3-[3-[1-(4-bromo-1- naphthyl)ethylcarbamoyl]-4-methyl-anilino]azetidine-1-carbox ylate (4, 200 mg, 0.241 mmol) in anhydrous acetonitrile (5 mL) were added 4-ethynyl-1-(4-piperidylmethyl)piperidine hydrochloride (5, 148.02 mg, 0.603 mmol) and Cs ₂ CO ₃ (235.98 mg, 0.724 mmol) at ambient temperature. The resulting reaction mixture was degassed by bubbling nitrogen gas for 5 minutes. Subsequently, XPhos-Pd-G3 (10.22 mg, 0.012 mmol) and XPhos (11.51 mg, 0.024 mmol) were added at ambient temperature. The reaction mixture was degassed with N ₂ for an additional 5 minutes and was then stirred at 90 °C for 3 h. Thereafter, the reaction mixture was cooled to ambient temperature and filtered through a pad of Celite and the Celite bed was washed with EtOAc (200 mL). The filtrate was evaporated under reduced pressure to give the crude product that was purified by flash column chromatography (230-400 mesh silica gel) with 10% MeOH in DCM as eluent to afford tert-butyl 3-[4-methyl-3-[1-[4-[2-[1-(4-piperidylmethyl)-4- piperidyl]ethynyl]-1-naphthyl]ethylcarbamoyl]anilino]azetidi ne-1-carboxylate (6, 130 mg, 0.189 mmol, 79% yield) as a pale yellow gum. LC-MS (ES ⁺ ): m/z 664.4 [M + H] ⁺ . The following targeting ligand (Example 103) was prepared using the method described above in Example 102, with the corresponding alkyne intermediate in Step-3.

Example 104 Synthesis of (S)-5-(4-((4-(1-(5-((1-(tert-butoxycarbonyl)azetidin-3-yl)am ino)-2- methylbenzamido)ethyl)naphthalen-1-yl)ethynyl)piperidin-1-yl )pentanoic acid

Step-1: Compound 1-(4-bromo-1-naphthyl)ethanone (1, 2 g, 7.63 mmol) was subjected to chiral SFC separation to separate the diastereomers following the method: YMC Cellulose-C, Flowrate : 4 mL/min, Co-Solvent : 40%, Co-Solvent Name : IPA, Injected Volume : 2μL, Temperature : 35 °C, Outlet Pressure: 100 bar. The early eluting peak at RT = 2.59 minutes was concentrated under reduced pressure to afford (S)-1-(4-bromonaphthalen-1-yl)ethan-1-amine (2, 550 mg, 2.09 mmol, 27% yield) as an off-white solid. [α] _D ^22.4 = -36.4 (c, 0.5 g/100 mL). ¹ H NMR (400 MHz, DMSO- d6): δ 8.57 (s, 2H), 8.28-8.30 (m, 2H), 8.04 (d, J = 7.6 Hz, 1H), 7.76-7.78 (m, 2H), 7.64 (d, J = 7.6 Hz, 1H), 5.32-5.33 (m, 1H) and 1.61 (d, J = 6.80 Hz, 3H). Note: Configurations are arbitrarily assigned. Step-2: To a well-stirred solution of (S)-1-(4-bromonaphthalen-1-yl)ethan-1-amine (2, 650.00 mg, 2.47 mmol) in anhydrous DMF (10 mL) were added 5-[(1-tert-butoxycarbonylazetidin-3-yl)amino]-2- methyl-benzoic acid (3, 1.03 g, 2.96 mmol), HATU (1.41 g, 3.70 mmol) and DIPEA (1.60 g, 12.34 mmol, 2.15 mL) at ambient temperature under nitrogen atmosphere. The resulting reaction mixture was stirred at ambient temperature for 3 h. After completion of the reaction as indicated by UPLC, excess solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (230-400 mesh silica gel) with 40% EtOAc/pet ether as eluent to afford tert-butyl (S)-3-((3-((1-(4-bromonaphthalen-1-yl)ethyl)carbamoyl)-4- methylphenyl)amino)azetidine-1-carboxylate (4, 500 mg, 0.846 mmol, 34% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 484.0 [M – isobutene + H] ⁺ . Step-3: To a 50 mL sealed tube containing a well-stirred solution of tert-butyl (S)-3-((3-((1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)a zetidine-1-carboxylate (4, 500.00 mg, 0.844 mmol) in anhydrous acetonitrile (10 mL) were added ethyl 5-(4- ethynylpiperidin-1-yl)pentanoate (5, 385.09 mg, 1.69 mmol) and Cs2CO3 (825.93 mg, 2.53 mmol) at ambient temperature. The resulting reaction mixture was degassed with N ₂ for 5 minutes, before XPhos-Pd-G3 (35.76 mg, 0.042 mmol) and XPhos (40.24 mg, 0.084 mmol) were added at ambient temperature. The mixture was degassed for an additional 5 minutes and the tube was sealed. The reaction mixture was stirred at 90 °C for 3 h. The reaction progress was monitored by UPLC/TLC. Thereafter, the reaction mixture was cooled to ambient temperature and filtered through a pad of Celite and the Celite bed was washed with EtOAc (200 mL). The filtrate was concentrated in vacuo and then purified by flash column chromatography (230-400 mesh silica gel) with 10% MeOH/DCM as eluent to afford tert-butyl (S)-3-((3-((1-(4-((1-(5-ethoxy-5- oxopentyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carba moyl)-4- methylphenyl)amino)azetidine-1-carboxylate (6, 430 mg, 0.564 mmol, 67% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 681.4 [M + H] ⁺ . Step-4: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (S)-3- ((3-((1-(4-((1-(5-ethoxy-5-oxopentyl)piperidin-4-yl)ethynyl) naphthalen-1-yl)ethyl)carbamoyl)-4- methylphenyl)amino)azetidine-1-carboxylate (6, 430.00 mg, 0.568 mmol) in 1:1 THF/MeOH (8 mL) was added lithium hydroxide, monohydrate (190.80 mg, 4.55 mmol) in water (2 mL) at ambient temperature. The resulting mixture was stirred at this temperature for 4 h. The progress of reaction was monitored by UPLC. Thereafter, the reaction mixture was diluted with water (25 mL) and extracted with MTBE (20 mL). The aqueous phase was acidified with 10% citric acid solution to pH=4 and then extracted with 10% MeOH/DCM (3 × 150 mL). The combined organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford (S)-5-(4-((4-(1-(5-((1-(tert-butoxycarbonyl)azetidin-3-yl)am ino)-2- methylbenzamido)ethyl)naphthalen-1-yl)ethynyl)piperidin-1-yl )pentanoic acid (7, 310 mg, 0.444 mmol, 78% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 667.4 [M + H] ⁺ . The following targeting ligands (Examples 105-106) were prepared using the method described above in Example 104, with the corresponding bromide intermediate in Step-3.

Example 107 Synthesis of tert-butyl (R)-3-((3-((1-(4-bromonaphthalen-1-yl)ethyl)carbamoyl)-4- methylphenyl)carbamoyl)azetidine-1-carboxylate Step-1: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of methyl 5-amino- 2-methyl-benzoate (1, 500 mg, 3.03 mmol) and 1-tert-butoxycarbonylazetidine-3-carboxylic acid (2, 609.06 mg, 3.03 mmol) in anhydrous DMF (8 mL) were added DIPEA (1.96 g, 15.13 mmol, 2.64 mL) and 1-propylphosphonic anhydride solution, 50 wt. % in EtOAc (3.85 g, 6.05 mmol) at ambient temperature under nitrogen atmosphere and the resulting mixture was stirred at ambient temperature for 4 h. After completion of the reaction as indicated by UPLC, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 150 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to yield a crude mass which was purified by flash column chromatography (230-400 mesh silica gel) with 35-40% EtOAc/pet ether as eluent to get tert-butyl 3-[(3-methoxycarbonyl-4- methyl-phenyl)carbamoyl]azetidine-1-carboxylate (3, 600 mg, 1.71 mmol, 56% yield) as a pale yellow solid. LC-MS (ES-): m/z 347.0 [M - H] -. Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution tert-butyl 3-[(3- methoxycarbonyl-4-methyl-phenyl)carbamoyl]azetidine-1-carbox ylate (3, 600 mg, 1.70 mmol) in 1:1 THF/MeOH (4 mL) was added LiOH.H2O (408.31 mg, 17.05 mmol) in water (2 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 h. After completion of the reaction as indicated by UPLC, excess solvent was removed from the reaction mixture under reduced pressure and the residue was dissolved into aqueous citric acid solution (50 mL). The aqueous phase was extracted with EtOAc (2 × 100 mL) and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to afford 5- [(1-tert-butoxycarbonylazetidine-3-carbonyl)amino]-2-methyl- benzoic acid (4, 500 mg, 1.49 mmol, 87% yield) as a pale yellow solid. LC-MS (ES-): m/z 333.2 [M - H] -. Step-3: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 5-[(1-tert- butoxycarbonylazetidine-3-carbonyl)amino]-2-methyl-benzoic acid (4, 350 mg, 1.04 mmol) in anhydrous DMF (5 mL) were added DIPEA (401.79 mg, 3.11 mmol) and HATU (591.04 mg, 1.55 mmol) followed by (1R)-1-(4-bromo-1-naphthyl)ethanamine hydrochloride (5, 303.06 mg, 1.04 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 3 h. Upon completion of the reaction as indicated by UPLC, the volatiles were evaporated under vacuum to give a crude residue which was diluted with water (100 mL) and extracted with EtOAc (2 × 200 mL). The combined organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (230-400 mesh silica gel) with 50-60% EtOAc/pet ether as eluent to afford tert- butyl (R)-3-((3-((1-(4-bromonaphthalen-1-yl)ethyl)carbamoyl)-4- methylphenyl)carbamoyl)azetidine-1-carboxylate (6, 300 mg, 0.459 mmol, 44% yield) as a pale yellow solid. LC-MS (ES ⁺ ): m/z 468.0 [M - CO ₂ ^t Bu + H] ⁺ . Example 108 Synthesis of 5-(azetidin-3-ylamino)-2-methyl-N-((1R)-1-(4-((1-((1-(1-(3-m ethyl-1-(1-methyl- 2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidaz ol-5-yl)piperidine-4- carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)ethynyl)naphth alen-1-yl)ethyl)benzamide (Compound 55) Step-1: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (R)-3- ((4-methyl-3-((1-(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl )ethynyl)naphthalen-1- yl)ethyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (1, 120 mg, 0.157 mmol) and 1-[3- methyl-1-(1-methyl-2,6-dioxo-3-piperidyl)-2-oxo-benzimidazol -5-yl]piperidine-4-carboxylic acid hydrochloride (2, 70.83 mg, 0.157.26 mmol) in anhydrous DMF (5 mL) were added DIPEA (203.24 mg, 1.57 mmol, 0.273 mL) and HATU (89.69 mg, 0.235 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 h. After completion of the reaction as monitored by UPLC, ice-water was added, solid formed was filtered and washed with water and dried under reduced pressure to get tert-butyl 3-((4-methyl-3-(((1R)-1-(4-((1-((1- (1-(3-methyl-1-(1-methyl-2,6-dioxopiperidin-3-yl)-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5- yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-y l)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (3, 150 mg, 0.106 mmol, 68% yield) as a pale yellow solid. LC-MS (ES ⁺ ): m/z 1047.4 [M + H] ⁺ . Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 3-((4- methyl-3-(((1R)-1-(4-((1-((1-(1-(3-methyl-1-(1-methyl-2,6-di oxopiperidin-3-yl)-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piper idin-4-yl)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)phenyl)amino)azet idine-1-carboxylate (3, 150 mg, 0.114 mmol) in anhydrous DCM (5 mL) were added 4N HCl in 1,4-dioxane (0.573 mL) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 2 h. Reaction progress was monitored by UPLC-MS. The volatiles were evaporated under reduced pressure to give the crude product, which was purified by reverse phase column chromatography (Column : X Select C18 (250 x 19) mm, 5 microns; Mobile phase A: 0.1% formic acid; B:MeCN) to obtain 5-(azetidin-3-ylamino)-2-methyl-N-((1R)-1-(4-((1-((1-(1-(3-m ethyl-1- (1-methyl-2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benz o[d]imidazol-5-yl)piperidine-4- carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)ethynyl)naphth alen-1-yl)ethyl)benzamide formate (Compound 55, 61 mg, 0.058 mmol, 51% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.83 (d, J = 8 Hz, 1H), 8.34-8.23 (m, 2H), 7.69-7.64 (m, 3H), 7.57 (d, J = 7.2 Hz, 1H), 7.08-6.93 (m, 2H), 6.84 (s, 1H), 6.62 (dd, J = 8.8, 2 Hz, 1H), 6.49-6.47 (m, 2H), 6.30 (d, J = 6.4 Hz, 1H), 5.90-5.87 (m, 1H), 5.36 (dd, J = 13, 5.2 Hz, 1H), 4.39-4.28 (m, 2H), 4.20-4.10 (m, 2H), 4.05-3.90 (m, 1H), 3.71-3.60 (m, 5H), 3.31 (s, 3H), 3.03 (s, 3H), 3.01 (m, 2H), 2.89-2.60 (m, 9H), 2.30-2.06 (m, 4H), 2.11 (s, 3H), 2.04-1.90 (m, 3H), 1.88-1.62 (m, 9H), 1.54 (d, J = 6.4 Hz, 3H) and 1.10-0.85 (m, 2H). LC-MS (ES ⁺ ): m/z 947.0 [M + H] ⁺ . Example 109 Synthesis of 5-(azetidin-3-ylamino)-N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxo piperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine -4-carbonyl)-4- fluoropiperidin-4-yl)methyl)piperidin-4-yl)ethynyl)naphthale n-1-yl)ethyl)-2- methylbenzamide (Compound 56) Step-1: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (R)-3- ((3-((1-(4-((1-((4-fluoropiperidin-4-yl)methyl)piperidin-4-y l)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxy late (1, 150 mg, 0.153 mmol) in anhydrous DMF (3 mL) were added DIPEA (139.73 mg, 1.08 mmol, 0.18 mL) and HATU (164.43 mg, 0.432 mmol) followed by 1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]piperidine-4-carboxylic acid (2, 110 mg, 0.216 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 2 h. The progress of the reaction was monitored by UPLC. Excess solvent was removed under reduced pressure to get a crude residue and the latter was diluted with ice-cold water (20 mL) and solid precipitated out was filtered. Solid on the filter was washed with water (10 mL) and dried in vacuo to afford tert-butyl 3-((3-(((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)-4-fluoropiperid in-4-yl)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)azetidine-1-carboxylate (3, 230 mg, 0.124 mmol, 58% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 1050.6 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 3-((3- (((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)-4-fluoropiperid in-4-yl)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)azetidine-1-carboxylate (3; 230 mg, 0.124 mmol) in anhydrous DCM (4 mL) was added trifluoroacetic acid (71.16 mg, 0.624 mmol, 0.048 mL) at 0 °C and the resulting mixture was stirred at ambient temperature for 0.5 h. The progress of the reaction was monitored by UPLC. Excess solvent was removed under reduced pressure to give the crude product, which was purified by reverse phase column chromatography (C18 column, mobile phase: 10 mm HCOOH in water : MeCN) to afford 5-(azetidin-3-ylamino)- N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methy l-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)-4-fluoropiperid in-4-yl)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-2-methylbenzamide formate (Compound 56, 60 mg, 0.058 mmol, 47% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 8.84 (d, J = 7.6 Hz, 1H), 8.38-8.29 (m, 2H), 7.73-7.67 (m, 3H), 7.58 (d, J = 7.6 Hz, 1H), 7.00-6.95 (m, 2H), 6.86 (bs, 1H), 6.66 (bs, 1H), 6.50 (d, J = 6 Hz, 2H), 6.34 (bs, 1H), 5.92-5.87 (m, 1H), 5.33- 5.29 (m, 1H), 4.35-4.25 (m, 4H), 3.81-3.74 (m, 2H), 3.65-3.62 (m, 5H), 3.53-3.41 (m, 2H), 3.32 (s, 3H), 3.20 (m, 2H), 2.93-2.73 (m, 7H), 2.50 (m, 3H), 2.33-2.12 (m, 2H), 2.11 (s, 3H), 2.10-1.98 (m, 5H), 1.71-1.63 (m, 6H) and 1.56 (d, J = 7.2 Hz, 3H). LC-MS (ES ⁺ ): m/z 950.4 [M + H] ⁺ . Example 110 5-(azetidin-3-ylamino)-N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxo piperidin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)- 4-hydroxypiperidin- 4yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)-2-m ethylbenzamide di-trifluoro acetate (Compound 57) Compound 57 was prepared substantially following the synthesis of Compound 55, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 948.2 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.15 (s, 1H), 8.85-8.75 (m, 2H), 8.33-8.29 (m, 2H), 7.59- 7.69 (m, 4H), 7.00-6.97 (m, 3H), 6.50 (d, J = 6 Hz, 2H), 5.90-5.87 (m, 1H), 5.44-5.31 (m, 2H), 4.42-4.38 (m, 1H), 4.37-4.25 (m, 2H), 4.23-4.10 (m, 1H), 3.80-3.74 (m, 8H), 3.45-3.40 (m, 6H), 3.30-3.15 (m, 3H), 3.06-3.04 (m, 2H), 2.90-2.80 (m, 3H), 2.58-2.50 (3H), 2.34-2.23 (m, 3H), 2.11 (s, 3H), 2.09-2.06 (m, 2H), 2.03-1.90 (m, 1H), 1.87-1.65 (m, 5H) and 1.56-1.55 (m, 5H). Example 111 5-(azetidin-3-ylamino)-N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxo piperidin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)p iperidin-4- yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)-2-me thylbenzamide (Compound 58) Compound 58 was prepared substantially following the synthesis of Compound 56, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 932.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.10 (s, 1H), 8.85-8.84 (m, 2H), 8.31 (m, 2H), 7.72-7.53 (m, 4H), 7.17-7.10 (m, 2H), 7.00-6.97 (m, 2H), 6.55-6.47 (m, 2H), 5.90-5.87 (m, 1H), 5.36-5.33 (m, 1H), 4.40-4.38 (m, 2H), 4.36-4.35 (m, 2H), 4.01-3.90 (m, 1H), 3.83-3.80 (m, 3H), 3.73-3.60 (m, 4H), 3.46 (s, 3H), 3.35-3.11 (m, 8H), 2.94-2.92 (m, 2H), 2.68-2.65 (m, 3H), 2.36-2.32 (m, 1H), 2.20-2.10 (m, 8H), 1.90-1.80 (m, 6H), 1.56-1.55 (d, J = 7.2 Hz, 3H) and 1.24 (m, 2H). Example 112 5-(azetidin-3-ylamino)-N-(1-(4-((1-((1-(1-(1-(2,6-dioxopiper idin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piper idin-4-yl)methyl)piperidin- 4-yl)ethynyl)naphthalen-1-yl)ethyl)-2-methylbenzamide (Compound 59) Compound 59 was prepared substantially following the synthesis of Compound 56, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 932.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.12 (bs, 1H), 8.82 (d, J = 8 Hz, 1H), 8.34-8.29 (m, 3H), 7.68-7.64 (m, 2H), 7.57 (d, J = 7.6 Hz, 1H), 6.97-6.84 (m, 2H), 6.84 (m, 1H), 6.64 (m, 1H), 6.46 (m, 2H), 6.27 (d, J = 6.8 Hz, 1H), 5.90-5.87 (m, 1H), 5.29 (dd, J = 12.8, 5.6 Hz, 1H), 4.45-4.35 (m, 1H), 4.33-4.25 (m, 1H), 4.20-4.11 (m, 1H), 4.05-3.95 (m, 2H), 3.62-3.58 (m, 4H), 3.50 (m, 2H), 3.31 (s, 3H), 3.05-2.90 (m, 2H), 2.85-2.65 (m, 4H), 2.65-2.50 (m, 4H), 2.30-2.13 (m, 5H), 2.11 (s, 3H), 2.05-1.90 (m, 3H), 1.88-1.62 (m, 8H), 1.55 (d, J = 6.8 Hz, 3H) and 1.10-0.82 (m, 2H). Example 113 5-(azetidin-3-ylamino)-N-((1R)-1-(4-((1-((4-cyano-1-(1-(1-(2 ,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine -4-carbonyl)piperidin-4- yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)-2-me thylbenzamide (Compound Compound 60 was prepared substantially following the synthesis of Compound 55, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 957.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.17 (s, 1H), 8.82 (d, J = 8 Hz, 1H), 8.33-8.27 (m, 1H), 7.69- 7.64 (m, 4H), 7.56 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 1.6 Hz, 2H), 6.83 (s, 1H), 6.63 (d, J = 2 Hz, 1H), 6.46-6.44 (m, 2H), 6.15 (d, J = 6.8 Hz, 1H), 5.89-5.85 (m, 1H), 5.30-5.25 (m, 1H), 4.43 (m, 1H), 4.23-4.22 (m, 1H), 4.20-4.07 (m, 1H), 3.90-3.86 (m, 2H), 3.30 (s, 3H), 3.18-3.12 (m, 2H), 2.69-2.60 (m, 12H), 2.10 (s, 3H), 1.97-1.88 (m, 7H), 1.76-1.72 (m, 7H), 1.76-1.72 (m, 6H) and 1.39-1.35 (m, 2H).

Example 114 5-(azetidin-3-ylamino)-2-methyl-N-((R)-1-(4-((1-((1-(1-(1-me thyl-3-((R)-3-methyl-2,6- dioxopiperidin-3-yl)-1H-indazol-6-yl)piperidine-4-carbonyl)p iperidin-4- yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)benza mide (Compound 61) Compound 61 was prepared substantially following the synthesis of Compound 56, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 930.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 8.35-8.26 (m, 3H), 7.68-7.56 (m, 5H), 6.96 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 9.2 Hz, 1H), 6.83 (s, 1H), 6.48-6.46 (m, 2H), 6.25 (d, J = 6.4 Hz, 1H), 5.90-5.87 (m, 1H), 4.41 (m, 1H), 4.30 (m, 1H), 4.12-3.96 (m, 3H), 3.85 (s, 3H), 3.80-3.72 (m, 2H), 3.69-3.58 (m, 3H), 3.10-2.97 (m, 3H), 2.90-2.78 (m, 4H), 2.35 (m, 2H), 2.30-2.21 (m, 6H), 2.15 (m, 5H), 2.01 (s, 3H), 1.85-1.72 (m, 9H), 1.61 (s, 3H) and 1.55 (d, J = 6.80 Hz, 3H).

Example 115 Synthesis of 5-(azetidin-3-ylamino)-N-((1R)-1-(4-((1-(4-(1-(1-(2,6-dioxop iperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin- 4-yl)butyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-2-methylbenzamide (Compound 62) Step-1: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 4-[1-[1-(2,6- dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piper idyl]butanal hydrochloride (2, 120 mg, 0.188 mmol) and tert-butyl (R)-3-((4-methyl-3-((1-(4-(piperidin-4-ylethynyl)naphthalen- 1- yl)ethyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (1, 123.83 mg, 0.207 mmol) in anhydrous DMSO (3 mL) were added sodium acetate, anhydrous (77.40 mg, 0.943 mmol) and acetic acid (113.32 mg, 1.89 mmol, 0.1 mL) and the resulting mixture was stirred at ambient temperature for 1 h. Subsequently, MP-CNBH3 (2mmol\g) (147 mg, 0.283 mmol) was added in one portion and stirring was continued for another 16 h at ambient temperature. reaction After completion of the reaction as indicated by LC-MS, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The obtained crude product was purified by reverse phase column chromatography (RediSep-RF Gold C18 column, mobile phase: 10 mm HCOOH in water : MeCN) to afford tert-butyl 3-((3-(((1R)-1-(4-((1-(4-(1-(1-(2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin- 4-yl)butyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)azetidine-1-carboxylate formate (3, 90 mg, 0.085 mmol, 45% yield) as a colorless liquid. LC-MS (ES ⁺ ): m/z 936.6 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 3-((3- (((1R)-1-(4-((1-(4-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-4-yl)butyl)piperidin-4-yl)et hynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxy late formate (3, 90.00 mg, 0.085 mmol) in anhydrous DCM (2 mL) was added 4N HCl in 1,4-dioxane (1.3 mL, 0.786 mmol) at 0 °C and the resulting mixture was stirred at ambient temperature for 2 h. The progress of the reaction was monitored by UPLC. Excess solvent was removed under reduced pressure and the obtained crude was purified by reverse phase column chromatography (RediSep-RF Gold C18 column, mobile phase: 10 mm HCOOH in water : MeCN) to afford 5-(azetidin-3-ylamino)-N- ((1R)-1-(4-((1-(4-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-4-yl)butyl)piperidin-4-yl)et hynyl)naphthalen-1-yl)ethyl)-2- methylbenzamide formate (Compound 62, 63 mg, 0.067 mmol, 79% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 8.82 (d, J = 8 Hz, 1H), 8.34-8.28 (m, 3H), 7.69- 7.64 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 6.97-6.91 (m, 2H), 6.82 (d, J = 2 Hz, 1H), 6.63 (d, J = 2 Hz, 1H), 6.47-6.46 (m, 2H), 6.26 (d, J = 6.8 Hz, 1H), 5.90-5.87 (m, 1H), 4.28-4.26 (m, 1H), 4.02 (t, J = 2 Hz, 2H), 3.62-3.58 (m, 4H), 3.30 (s, 3H), 2.90-2.50 (m, 7H), 2.34-2.33 (m, 3H), 2.31-2.21 (m, 2H), 2.11 (s, 3H), 2.00-1.97 (m, 3H), 1.77-1.72 (m, 4H), 1.56-1.54 (d, J = 6.8 Hz, 3H), 1.45- 1.44 (m, 2H) and 1.25-1.29 (m, 8H). LC-MS (ES ⁺ ): m/z 864.4 [M + H] ⁺ . Example 116 5-(azetidin-3-ylamino)-N-[1-[4-[2-[1-[5-[1-[1-(2,6-dioxo-3-p iperidyl)-6-fluoro-3-methyl-2- oxo-benzimidazol-5-yl]-4-piperidyl]pentyl]-4-piperidyl]ethyn yl]-1-naphthyl]ethyl]-2- methyl-benzamide (Compound 63) Compound 63 was prepared substantially following the synthesis of Compound 62, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 895.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.07 (s, 1H), 8.80 (d, J = 8 Hz, 1H), 8.34-8.29 (m, 2H), 7.68- 7.56 (m, 4H), 7.12 (d, J = 12 Hz, 1H), 6.96-6.92 (m, 2H), 6.47-6.45 (m, 2H), 6.23 (d, J = 6.8 Hz, 1H), 5.90-5.87 (m, 1H), 5.35-5.25 (m, 1H), 4.35 (m, 1H), 4.02 (m, 1H), 3.61-3.57 (m, 3H), 3.32 (s, 3H), 2.95-2.70 (m, 5H), 2.65 (m, 2H), 2.50 (m, 4H), 2.30 (m, 2H), 2.20 (m, 2H), (2.11 (s, 3H), 2.01-1.91 (m, 3H), 1.80-1.65 (m, 4H), 1.55 (d, J = 7.20 Hz, 3H), 1.49-1.41 (m, 2H) and 1.40-1.22 (m, 9H). Example 117 5-(azetidin-3-ylamino)-N-[1-[4-[2-[1-[4-[1-[1-(2,6-dioxo-3-p iperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-4-piperidyl]butyl]-4-piperidyl]ethynyl]-1 -naphthyl]ethyl]-2-methyl- benzamide (Compound 64) Compound 64 was prepared substantially following the synthesis of Compound 62, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 863.3 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H), 8.81 (d, J = 8 Hz, 1H), 8.35-8.27 (m, 2H), 7.68- 7.64 (m, 3H), 7.58-7.56 (m, 1H), 6.98-6.91 (m, 2H), 6.82 (d, J = 2 Hz, 1H), 6.63 (dd, J = 8.4, 2 Hz, 1H), 6.49-6.47 (m, 2H), 6.32 (d, J = 4 Hz, 1H), 5.95-5.85 (m, 1H), 5.40-5.20 (m, 1H), 4.35 (m, 1H), 4.10 (m, 2H), 3.69-3.64 (m, 3H), 3.59-3.56 (m, 3H), 2.98-2.80 (m, 3H), 2.73-2.68 (m, 2H), 2.58 (m, 3H), 2.34-2.32 (m, 2H), 2.30-2.12 (m, 2H), 2.04 (s, 3H), 1.99-1.96 (m, 3H), 1.77- 1.72 (m, 4H), 1.55 (d, J = 7.20 Hz, 3H), 1.49 (m, 2H) and 1.40-1.15 (m, 9H). Example 118 3-(carboxymethoxy)-4-chloro-5-[3-[[(4S)-1-[[3-[[4-[1-(2,6-di oxo-3-piperidyl)-2-oxo- benzo[cd]indol-6-yl]-3,3-difluoro-piperidine-1-carbonyl]amin o]phenyl]methylsulfonyl]-2,2- dimethyl-4-piperidyl]amino]phenyl]thiophene-2-carboxylic acid (Compound 65)

Step-1: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 5-[4-[2-[4-[1-[[5- [(1-tert-butoxycarbonylazetidin-3-yl)amino]-2-methyl-benzoyl ]amino]ethyl]-1- naphthyl]ethynyl]-1-piperidyl]pentanoic acid (1, 150 mg, 157.46 μmol) and 3-[3-methyl-2-oxo-5- (4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione hydrochloride (2, 60.87 mg, 157.46 μmol) in anhydrous DMF (5 mL) were added and N,N-diisopropylethylamine (101.75 mg, 787.29 μmol, 137.13 μL) and HATU (89.81 mg, 236.19 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 hours. Afterwards, the mixture was concentrated under vacuum to get the crude material which was purified by reverse-phase column chromatography [Column: SiliaSep C1860 g; Mobile phase A: 0.1% Formic acid in water and Mobile Phase B: Acetonitrile] to afford tert-butyl 3-[3-[1-[4-[2-[1-[5-[4-[1-(2,6-dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-5- oxo-pentyl]-4-piperidyl]ethynyl]- 1-naphthyl]ethylcarbamoyl]-4-methyl-anilino]azetidine-1-carb oxylate formate (3, 80 mg, 71.96 μmol, 46% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 991.4 [M + H] ⁺ . Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 3-[3- [1-[4-[2-[1-[5-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]-5- oxo-pentyl]-4-piperidyl]ethynyl]-1-naphthyl]ethylcarbamoyl]- 4-methyl-anilino]azetidine-1- carboxylate formate (3, 90 mg, 80.69 μmol) in anhydrous DCM (2.96 mL) were added hydrogen chloride solution (4.0 M in 1,4-dioxane, 403.47 μL, 1.61 mmol) at room temperature under nitrogen atmosphere. After 2 hours, the solution was concentrated under reduced pressure to get the crude material which was purified by reverse-phase prep-HPLC [Column: X Select C18 (250 X 19) mm, 5 µm; Mobile Phase A: 10 mM Ammonium bicarbonate in water and Mobile Phase B: Acetonitrile] to obtain 5-(azetidin-3-ylamino)-N-[1-[4-[2-[1-[5-[4-[1-(2,6-dioxo-3-p iperidyl)-3- methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-5-oxo-pentyl]-4 -piperidyl]ethynyl]-1- naphthyl]ethyl]-2-methyl-benzamide (Compound 65, 23 mg, 24.08 μmol, 30% yield) as an off- white solid. LC-MS (ES-): m/z 889.2 [M - H] -. ¹ H-NMR (400 MHz, DMSO-d6): δ 11.11 (brs, 1H), 8.80 (d, J = 8.00 Hz, 1H), 8.33-8.27 (m, 1H), 7.66-7.63 (m, 3H), 7.56 (d, J = 7.60 Hz, 1H), 7.22 (s, 1H), 7.01 (d, J = 8.00 Hz, 1H), 6.93-6.91 (m, 2H), 6.45-6.40 (m, 2H), 6.06 (d, J = 6.80 Hz, 1H), 5.91-5.84 (m, 1H), 5.36-5.32 (m, 1H), 4.61-4.52 (m, 1H), 4.21-4.11 (m, 1H), 4.07-3.98 (m, 1H), 3.71-3.68 (m, 1H), 3.14-3.08 (m, 2H), 2.89-2.62 (m, 6H), 2.35-2.30 (m, 6H), 2.26-2.14 (m, 3H), 2.10 (s, 3H), 2.00-1.90 (m, 4H), 1.83-1.63 (m, 5H), 1.60-1.49 (m, 11H). Example 119 5-(azetidin-3-ylamino)-N-[1-[4-[2-[1-[5-[4-[3-(2,6-dioxo-3-p iperidyl)-1-methyl-indazol-6-yl]- 1-piperidyl]-5-oxo-pentyl]-4-piperidyl]ethynyl]-1-naphthyl]e thyl]-2-methyl-benzamide (Compound 66) Compound 66 was prepared substantially following the synthesis of Compound 65, except using TFA and DCM for Boc-deprotection in Step-2. LC-MS (ES ⁺ ): m/z 876.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.88 (s, 1H), 8.84-8.28 (m, 2H), 8.32-8.29 (m, 2H), 7.69- 7.57 (m, 5H), 7.43 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.50-6.49 (m, 2H), 6.33-6.32 (m, 1H), 5.88 (quin, J = 7.2 Hz, 1H), 4.61-4.58 (m, 1H), 4.35-4.31 (m, 2H), 4.25 (m, 2H), 4.03-3.98 (m, 1H), 3.97 (s, 3H), 3.85-3.71 (m, 2H), 3.50 (m, 4H), 3.30 (s, 3H), 3.17-3.03 (m, 4H), 2.97-2.91 (m, 1H), 2.68-2.64 (m, 2H), 2.50-2.40 (m, 2H), 2.37-2.30 (m, 2H), 2.19-2.17 (m, 2H), 2.16 (s, 3H), 1.90-1.83 (m, 2H), 1.71-1.68 (m, 3H) and 1.56-1.54 (m, 6H). Example 120 5-(azetidin-3-ylamino)-N-[1-[4-[2-[1-[5-[4-[3-(2,4-dioxohexa hydropyrimidin-1-yl)-5-fluoro- 1-methyl-indazol-6-yl]-1-piperidyl]-5-oxo-pentyl]-4-piperidy l]ethynyl]-1-naphthyl]ethyl]-2- methyl-benzamide (Compound 67) Compound 67 was prepared substantially following the synthesis of Compound 65, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 894.2 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 10.80 (s, 1H), 8.81 (d, J = 8 Hz, 1H), 8.33-8.27 (m, 2H), 7.66-7.56 (m, 5H), 7.39 (d, J = 11.2 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.47 (s, 2H), 6.35-6.25 (m, 1H), 5.90-5.86 (m, 1H), 4.64 (m, 1H), 4.32-4.22 (m, 1H), 4.10-4.00 (m, 3H), -3.98 (s, 3H), 3.89 (t, J = 6.4 Hz, 3H), 3.60 (m, 3H), 3.21-3.13 (m, 3H), 2.80-2.71 (m, 4H), 2.40-2.33 (m, 3H), 2.27-2.19 (m, 2H), 2.11 (s, 3H), 2.00-1.90 (m, 2H), 1.90-1.82 (m, 2H), 1.76-1.69 (m, 4H) and 1.63-1.50 (m, 8H). Example 121 5-(azetidin-3-ylamino)-N-[1-[4-[2-[1-[5-[4-[1-[(3S)-2,6-diox o-3-piperidyl]indolin-5-yl]-1- piperidyl]-5-oxo-pentyl]-4-piperidyl]ethynyl]-1-naphthyl]eth yl]-2-methyl-benzamide (Compound 68) Compound 68 was prepared substantially following the synthesis of Compound 65, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 862.3 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.90 (s, 1H), 8.81 (d, J = 8 Hz, 1H), 8.34-8.28 (m, 3H), 7.67-7.63 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 9.2 Hz, 1H), 6.89 (s, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.47-6.45 (m, 2H), 6.39 (d, J = 8 Hz, 1H), 6.23 (d, J = 6.8 Hz, 1H), 5.93-5.85 (m, 1H), 4.61-4.49 (m, 2H), 4.35 (m, 1H), 4.0 (m, 3H), 3.58 (m, 2H), 3.29 (m, 2H), 3.13-3.02 (m, 2H), 2.93-2.87 (m, 2H), 2.85-2.65 (m, 5H), 2.59 (m, 4H), 2.41-2.29 (m, 5H), 2.25-2.12 (m, 3H), 2.1 (s, 3H), 2.05-1.85 (m, 3H), 1.80-1.67 (m, 4H), 1.55 (d, J = 7.6 Hz, 3H) and 1.52-1.45 (m, 2H). Example 122 5-(azetidin-3-ylamino)-N-[1-[4-[2-[1-[5-[4-[1-[(3R)-2,6-diox o-3-piperidyl]indolin-5-yl]-1- piperidyl]-5-oxo-pentyl]-4-piperidyl]ethynyl]-1-naphthyl]eth yl]-2-methyl-benzamide (Compound 69) Compound 69 was prepared substantially following the synthesis of Compound 65, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 862.3 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 10.8 (bs,1H), 8.83 (d, J = 8 Hz, 1H), 8.29-8.32 (m, 3H), 7.67- 7.64 (m, 3H), 7.57 (d, J = 7.2 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.89 (s, 1H), 6.80 (d, J = 8 Hz, 1H), 6.47 (bs, 2H), 6.38 (d, J = 8 Hz, 2H), 5.90-5.85 (m, 1H), 4.55 (m, 2H), 4.36-4.25 (m, 1H), 4.18-4.03 (m, 2H), 4.01-3.92 (m, 2H), 3.30-3.20 (m, 2H), 3.10- 3.02 (m, 2H), 2.92-2.70 (m, 5H), 2.60-2.57 (m, 2H), 2.41-2.30 (m, 5H), 2.21-2.18 (m, 3H), 2.11 (s, 3H), 2.01-1.85 (m, 3H), 1.79-1.65 (m, 4H), 1.60-1.42 (m, 9H) and 0.85 (m, 1H). Example 123 5-(azetidin-3-ylamino)-N-[1-[4-[2-[1-[5-[4-[4-[(2,6-dioxo-3- piperidyl)amino]-2-fluoro- phenyl]-1-piperidyl]-5-oxo-pentyl]-4-piperidyl]ethynyl]-1-na phthyl]ethyl]-2-methyl- benzamide (Compound 70) Compound 70 was prepared substantially following the synthesis of Compound 65, except using TFA and DCM for Boc-deprotection in Step-2. LC-MS (ES ⁺ ): m/z 855.2 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 10.81 (s, 1H), 8.85 (d, J = 2.8 Hz, 1H), 8.73 (brs, 1H), 8.34- 8.268 (m, 2H), 7.77-7.62 (m, 3H), 7.60 (m, 1H), 7.00-6.94 (m, 2H), 6.51-6.44 (m, 4H), 5.92-5.85 (m, 1H), 6.10-5.95 (m, 1H), 5.90 (m, 1H), 4.59-4.50 (m, 1H), 4.37-4.24 (m, 4H), 3.99-3.90 (m, 2H), 3.82-3.73 (m, 3H), 3.48-3.41 (m, 3H), 3.25-3.00 (m, 5H), 3.00-2.84 (m, 1H), 2.69-2.60 (m, 2H), 2.35-2.25 (m, 2H), 2.15-2.02 (m, 6H), 1.98-1.82 (m, 3H), 1.81-1.65 (m, 4H), 1.62-1.50 (m, 4H), 1.30-1.11 (m, 2H). Example 124 5-(azetidin-3-ylamino)-N-[1-[4-[2-[1-[5-[4-[3-(2,4-dioxohexa hydropyrimidin-1-yl)-1-methyl- indazol-6-yl]-1-piperidyl]-5-oxo-pentyl]-4-piperidyl]ethynyl ]-1-naphthyl]ethyl]-2-methyl- benzamide (Compound 71) Compound 71 was prepared substantially following the synthesis of Compound 65, using the corresponding intermediates. LC-MS (ES-): m/z 874.2 [M - H] -. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ10.54 (s, 1H), 8.80 (d, J = 8 Hz, 1H), 8.32-8.27 (m, 2H), 7.65 (m, 3H), 7.55-7.54 (m, 2H), 7.49 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8 Hz, 1H), 6.43 (m, 2H), 6.08 (d, J = 6.4 Hz, 1H), 5.89-5.85 (m, 1H), 4.61-4.58 (m, 1H), 4.20 (m, 1H), 4.06-4.03 (m, 1H), 3.91 (s, 3H), 3.88 (m, 2H), 3.78-3.76 (m, 3H), 3.17-3.11 (m, 2H), 2.95 (m, 2H), 2.92 (m, 1H), 2.89 (m, 4H), 2.68-2.65 (m, 2H), 2.39-2.36 (m, 2H), 2.33-2.30 (m, 2H), 2.21 (m, 2H), 2.10 (s, 3H), 1.95 (m, 2H), 1.85 (m, 2H), 1.80-1.65 (m, 3H) and 1.60-1.49 (m, 7H). Example 125 5-(azetidin-3-ylamino)-N-((1R)-1-(4-((1-(5-((3-(1-(2,6-dioxo piperidin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5-yl)propyl)(methyl)amino)-5 -oxopentyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-2-methylbenzamide (Compound 72) Compound 72 was prepared substantially following the synthesis of Compound 65, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 880.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.09 (s, 1H), 8.82 (d, J = 8 Hz, 1H), 8.33-8.27 (m, 3H), 7.67-7.63 (m, 3H), 7.56 (d, J = 7.6 Hz, 1H), 6.92-7.02 (m, 4H), 6.47 (d, J = 6.8 Hz, 2H), 6.29 (d, J = 6.8 Hz, 1H), 5.90-5.86 (m, 1H), 4.35-4.25 (m, 1H), 4.12-4.07 (m, 2H), 3.68-3.64 (m, 2H), 3.33 (s, 3H), 2.95 (s, 2H), 2.92-2.83 (m, 2H), 2.80 (s, 2H), 2.75-2.69 (m, 4H), 2.69-2.60 (m, 2H), 2.59-2.55 (m, 2H), 2.38-2.20 (m, 6H), 2.11 (s, 3H), 1.98-1.93 (m, 3H), 1.90-1.80 (m, 1H), 1.76- 1.72 (m, 3H), 1.55 (d, J = 6.80 Hz, 3H), 1.50-1.42 (m, 4H). Example 126 5-(azetidin-3-ylamino)-2-methyl-N-((R)-1-(4-((1-(5-(4-(1-met hyl-3-((R)-3-methyl-2,6- dioxopiperidin-3-yl)-1H-indazol-6-yl)piperidin-1-yl)-5-oxope ntyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)benzamide (Compound 73) Compound 73 was prepared substantially following the synthesis of Compound 65, except using TFA and DCM for Boc-deprotection in Step-2. LC-MS (ES ⁺ ): m/z 889.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 8.85 (d, J = 2.4 Hz, 1H), 8.33-8.28 (m, 2H), 7.77-7.67 (m, 4H), 7.58 (dd, J = 7.4, 3.2 Hz, 1H), 7.45 (d, J = 5.6 Hz, 1H), 7.06-6.97 (m, 2H), 6.50 (s, 2H), 6.32 (s, 1H), 5.90-5.87 (m, 1H), 4.68-4.55 (m, 1H), 4.35 (m, 1H), 4.25 (m, 2H), 4.4.05 (m, 1H), 3.95 (d, J = 4.4 Hz, 3H), 3.80-3.62 (m, 2H), 3.50 (s, 3H), 3.24-2.90 (m, 7H), 2.65 – 2.30 (m, 4H), 2.20-2.05 (m, 6H), 2.01-1.79 (m, 4H), 1.78-1.45 (m, 12H) and 1.28-1.23 (m, 2H).

Example 127 5-(azetidin-3-ylamino)-N-((1S)-1-(4-((1-(5-(4-(1-(2,6-dioxop iperidin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)-5-oxope ntyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-2-methylbenzamide (Compound 74) Compound 74 was prepared substantially following the synthesis of Compound 65, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 892.2 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.11 (bs, 1H), 8.80 (d, J = 8 Hz, 1H), 8.33-8.27 (m, 2H), 7.66-7.63 (m, 3H), 7.56 (d, J = 7.6 Hz, 1H), 7.22 (s, 1H), 7.01 (d, J = 8 Hz, 1H), 6.93-6.91 (m, 2H), 6.45-6.40 (m, 2H), 6.25 (m, 1H), 5.91-5.84 (m, 1H), 5.36-5.32 (m, 1H), 4.61-4.52 (m, 1H), 4.21-4.11 (m, 1H), 4.07-3.98 (m, 2H), 3.71-3.68 (m, 4H), 3.32 (s, 3H), 3.14-3.08 (m, 2H), 2.89- 2.50 (m, 6H), 2.35-2.30 (m, 4H), 2.26-2.14 (m, 2H), 2.10 (s, 3H), 2.00-1.90 (m, 3H), 1.83-1.63 (m, 5H) and 1.60-1.49 (m, 9H).

Example 128 5-(azetidin-3-ylamino)-2-methyl-N-((R)-1-(4-((1-(5-(4-(3-met hyl-1-((R)-3-methyl-2,6- dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5 -yl)piperidin-1-yl)-5- oxopentyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)benza mide (Compound 75) Compound 75 was prepared substantially following the synthesis of Compound 65, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 905.2 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.97 (s, 1H), 8.40-8.28 (m, 2H), 7.78-7.70 (m, 3H), 7.64- 7.50 (m, 1H).7.34-7.30 (m,1H), 7.27-7.24 (m, 1H), 7.11-7.09 (m, 1H), 7.00-6.90 (m, 2H), 6.51- 6.42 (m, 2H), 6.34 (bs, 1H), 5.91-5.87 (m, 1H), 4.60 (m, 1H), 4.40 (m, 1H), 4.31(m, 2H), 4.15 (m, 1H), 4.10-3.92 (m, 2H), 3.70-3.60 (m, 3H), 3.28 (s, 3H), 3.25-2.91 (m, 6H), 2.90-2.68 (m, 3H), 2.65 (m, 1H), 2.50 (m, 2H), 2.34-2.30 (m, 2H), 2.11-1.91 (m, 10H), 1.82-1.70 (m, 5H) and 1.68-1.51 (m, 6H).

Example 129 Synthesis of 5-(azetidin-3-ylamino)-N-((1R)-1-(4-((1-(5-(4-(1-(2,6-dioxop iperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin- 1-yl)-5-oxopentyl)-3- fluoropiperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)-2-methyl benzamide (Compound 76) Step-1: To a 20 mL screw-capped glass vial containing a well-stirred solution of tert-butyl 3-((3-(((1R)-1- (4-((3-fluoropiperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)ca rbamoyl)-4- methylphenyl)amino)azetidine-1-carboxylate (1, 250.00 mg, 0.376 mmol) in anhydrous DMF (2 mL) were added ethyl 5-bromopentanoate (2, 94.40 mg, 0.451 mmol) and DIPEA (243.14 mg, 1.88 mmol, 0.328 mL) at ambient temperature. The mixture was stirred at 80 °C for 2 h. After completion of the reaction as monitored by UPLC, volatiles from the reaction mixture were removed under reduced pressure. The reaction mixture was diluted with water (30 mL), extracted with DCM (3 x 520 mL). Combined organic phase was dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 3-((3-(((1R)- 1-(4-((1-(5-ethoxy-5-oxopentyl)-3-fluoropiperidin-4-yl)ethyn yl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxy late (3, 300 mg, 0.349 mmol, 93% yield) as a brown liquid. LC-MS (ES ⁺ ): m/z 713.2 [M + H] ⁺ . Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 3-((3- (((1R)-1-(4-((1-(5-ethoxy-5-oxopentyl)-3-fluoropiperidin-4-y l)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxy late (3, 300.00 mg, 0.353 mmol) in a mixture of MeOH (2 mL), THF (2 mL)and water (1 mL) was added lithium hydroxide monohydrate (74.17 mg, 1.77 mmol) at ambient temperature and the resulting mixture was stirred for 2 h. After completion of the reaction as indicated by TLC, volatiles from the reaction mixture were evaporated in vacuo and the obtained residue was diluted with water (50 mL) and extracted with MTBE (100 mL). The aqueous phase was acidified with 10% citric acid solution to pH=4 and extracted with 10% MeOH/ DCM (2 × 150 mL). The combined organic phase was dried over anhydrous Na2SO4, concentrated under reduced pressure to afford 5-(4-((4-((R)-1-(5-((1-(tert- butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenzamido)ethyl) naphthalen-1-yl)ethynyl)-3- fluoropiperidin-1-yl)pentanoic acid (4, 180 mg, 0.229 mmol, 64% yield) as an off-white solid. LC- MS (ES ⁺ ): m/z 685.2 [M + H] ⁺ . Step-3: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 5-(4-((4-((R)-1- (5-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-2-methylben zamido)ethyl)naphthalen-1- yl)ethynyl)-3-fluoropiperidin-1-yl)pentanoic acid (4, 180.00 mg, 0.228 mmol) in anhydrous DMF (2 mL) were added DIPEA (147.77 mg, 1.14 mmol, 0.199 mL) and HATU (130.42 mg, 0.343 mmol). Compound 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidin e-2,6-dione hydrochloride (5, 105.42 mg, 0.275 mmol) was added later to the flask at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 4 h. After completion of the reaction as indicated by UPLC, excess solvent was evaporated under reduced pressure and ice-cold water was added. The resulting solid precipitate was filtered, washed with water (5 mL) and dried in vacuo to afford tert-butyl 3-((3-(((1R)-1-(4-((1-(5-(4-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidin-1-yl)-5- oxopentyl)-3-fluoropiperidin-4-yl)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)phenyl)amino)azetidine-1-carboxylate (6, 150 mg, 0.092 mmol, 40% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 1010.4 [M + H] ⁺ . Step-4: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 3-((3- (((1R)-1-(4-((1-(5-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-1-yl)-5-oxopentyl)-3-fluorop iperidin-4-yl)ethynyl)naphthalen- 1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carbo xylate (6, 150 mg, 0.092 mmol) in dry DCM (2 mL) was added 4N HCl in 1,4-dioxane (0.461 mL) at 0 °C. The resulting reaction mixture was stirred at ambient temperature for 2 h. After completion of the reaction as monitored by UPLC, excess solvent was evaporated under reduced pressure. The obtained crude product was purified by reverse phase prep-HPLC [X-Select C18 (150 x 19) mm 5 microns column] Mobile phase: A:0.1% formic acid in MQ-water; B: Acetonitrile; Flow rate: 15 mL/minutes and fractions having desired product were lyophilized to afford 5-(azetidin-3-ylamino)-N-((1R)-1-(4-((1-(5-(4- (1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-b enzo[d]imidazol-5-yl)piperidin-1- yl)-5-oxopentyl)-3-fluoropiperidin-4-yl)ethynyl)naphthalen-1 -yl)ethyl)-2-methylbenzamide formate (Compound 76, 30 mg, 0.031 mmol, 34% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 8.83 (d, J = 7.6 Hz, 1H), 8.33-8.32 (m, 2H), 7.60-7.59 (m, 4H), 7.10 (s, 1H), 7.02-7.00 (m, 2H), 6.99-6.90 (m, 1H), 6.51-6.47 (m, 2H), 6.33 (d, J = 6.4 Hz, 1H), 5.89 (m, 1H), 5.34 (dd, J = 12.6, 5.6 Hz, 1H), 4.62-4.59 (m, 2H), 4.34 (m, 1H), 4.24 (m, 2H), 4.05-3.95 (m, 1H), 3.77 (m, 2H), 3.20-3.4 (m, 2H), 2.80-2.67 (m, 3H), 2.62-2.56 (m, 2H), 2.50 (m, 9H), 2.50-2.46 (m, 3H), 2.32 (m, 2H), 2.12 (s, 3H), 2.02-1.90 (m, 1H), 1.80-1.76 (m, 3H) and 1.55 (d, J = 6.8 Hz, 3H), 1.52 (m, 6H). LC-MS (ES ⁺ ): m/z 909.4 [M + H] ⁺ . Example 130 Synthesis of 5-(azetidin-3-ylamino)-N-((1R)-1-(4-((4-(5-(4-(1-(2,6-dioxop iperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin- 1-yl)-5- oxopentyl)cyclohexyl)ethynyl)naphthalen-1-yl)ethyl)-2-methyl benzamide (Compound 77) Step-1: To a 50 mL sealed-tube containing a well-stirred solution of tert-butyl (R)-3-((3-((1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)a zetidine-1-carboxylate (1, 0.2 g, 0.337 mmol) in acetonitrile (5 mL) were added methyl 5-(4-ethynylcyclohexyl)pentanoate (2, 112.53 mg, 0.506 mmol) and cesium carbonate (329.83 mg, 1.01 mmol). The reaction mixture was purged with nitrogen gas for 5 minutes before XPhos (16.09 mg, 0.033 mmol) and XPhos-Pd-G3 (28.56 mg, 0.033 mmol) were added, and the mixture was purged with nitrogen gas for an additional 2 minutes and stirred at 90 °C for 2 h. After completion of the reaction as indicated by UPLC and TLC, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 30 mL). The combined organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (230-400 mesh silica gel) with 40-45% EtOAc/pet ether as eluent to afford tert- butyl (R)-3-((3-((1-(4-((4-(5-methoxy-5-oxopentyl)cyclohexyl)ethyn yl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxy late (3, 0.18 g, 0.235 mmol, 70% yield) as a light yellow solid. LC-MS (ES-): m/z 678.5 [M - H] -. Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (R)-3- ((3-((1-(4-((4-(5-methoxy-5-oxopentyl)cyclohexyl)ethynyl)nap hthalen-1-yl)ethyl)carbamoyl)-4- methylphenyl)amino)azetidine-1-carboxylate (3, 0.18 g, 0.235 mmol) in 3:2:1 THF /MeOH/Water (6 mL) was added lithium hydroxide; hydrate (49.35 mg, 1.18 mmol) at ambient temperature. The reaction mixture was stirred at this temperature for 2 h. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure. The residue was dissolved into water (10 mL) and cooled to 0 °C, then acidified to pH~3 with 5% citric acid solution (4 mL). The solid precipitate was filtered, washed with water (30 mL), pet ether (30 mL, and then dried under reduced pressure at 50 °C for 1 h to afford (R)-5-(4-((4-(1-(5-((1-(tert- butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenzamido)ethyl) naphthalen-1- yl)ethynyl)cyclohexyl)pentanoic acid (4, 0.13 g, 0.168 mmol, 72% yield) as an off-white solid. LC-MS (ES-): m/z 664.2 [M - H] -. Step-3: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 3-(3-methyl-2- oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl) piperidine-2,6-dione hydrochloride (5, 87.09 mg, 0.211 mmol) in dry DMF (3 mL) was added DIPEA (20.16 mg, 0.156 mmol, 0.027 mL) and HATU (59.30 mg, 0.156 mmol) followed by (R)-5-(4-((4-(1-(5-((1-(tert- butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenzamido)ethyl) naphthalen-1- yl)ethynyl)cyclohexyl)pentanoic acid (4, 0.12 g, 0.156 mmol). The reaction mixture was stirred at ambient temperature for 2 h. After completion of the reaction as indicated by LCMS, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 30 mL). The combined organic phase was washed with cold water (3 × 20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to afford tert-butyl 3-((3-(((1R)-1-(4-((4-(5-(4-(1-(2,6-dioxopiperidin-3-yl)- 3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidi n-1-yl)-5- oxopentyl)cyclohexyl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl )-4- methylphenyl)amino)azetidine-1-carboxylate (6, 0.15 g, 0.121 mmol, 77% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 990.6 [M + H] ⁺ . Step-4: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 3-((3- (((1R)-1-(4-((4-(5-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-1-yl)-5-oxopentyl)cyclohexyl )ethynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)azetidine-1-carboxy late (6, 0.14 g, 0.112 mmol) in dry DCM (5 mL) was added 4N HCl/1,4-dioxane (1.20 mL) at 5 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the obtained crude was purified by reverse-phase HPLC (Redisep-RF C18-120 g column, mobile phase A: 0.1% formic acid in water and B: Acetonitrile) to afford 5-(azetidin-3-ylamino)-N-((1R)-1-(4-((4-(5-(4-(1-(2,6-dioxop iperidin-3- yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pipe ridin-1-yl)-5- oxopentyl)cyclohexyl)ethynyl)naphthalen-1-yl)ethyl)-2-methyl benzamide formate (Compound 77, 0.055 g, 0.058 mmol, 51% yield) as an off white solid. LC-MS (ES ⁺ ): m/z 890.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.08 (s, 1H), 8.79 (d, J = 8 Hz, 1H), 8.27-8.34 (m, 2H), 7.61-7.66 (m, 3H), 7.55-7.58 (m, 1H), 7.11 (s, 1H), 7.02 (d, J = 8 Hz, 1H), 6.91-6.94 (m, 2H), 6.44-6.46 (m, 2H), 6.16 (d, J = 6.4 Hz, 1H), 5.88 (m, 1H), 5.34 (dd, J =12.6, 5.6 Hz, 1H), 4.60 (d, J = 8 Hz, 1H), 4.27-4.18 (m, 1H), 4.10 (m, 1H), 3.87 (t, J = 7.2 Hz, 2H), 3.50 (t, J = 7.6 Hz, 2H), 3.35 (s, 3H), 3.12 (m, 1H), 2.85-2.75 (m, 3H), 2.63-2.59 (m, 2H), 2.34 (m, 2H), 2.11 (m, 5H), 2.05-1.99 (m, 1H), 1.80 (m, 4H), 1.62-1.42 (m, 10H), 1.40-1.16 (m, 6H) and 1.05-0.95 (m, 2H). Example 131 N-(3-(((1R)-1-(4-((1-(5-(4-(1-(2,6-dioxopiperidin-3-yl)-3-me thyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-1-yl)-5-oxopentyl)piperidin- 4-yl)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)azetidine-3-carboxamide (Compound 78) Compound 78 was prepared substantially following the synthesis of Compound 77, using tert- butyl (R)-3-((3-((1-(4-bromonaphthalen-1-yl)ethyl)carbamoyl)-4- methylphenyl)carbamoyl)azetidine-1-carboxylate and ethyl 5-(4-ethynyl-1-piperidyl)pentanoate in Step-1. LC-MS (ES ⁺ ): m/z 919.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.01 (bs, 1H), 10.16 (s, 1H), 8.92 (d, J = 8 Hz, 1H), 8.33- 8.30 (m, 2H), 7.68-7.66 (m, 3H), 7.58-7.56 (m, 2H), 7.52 (s, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.10 (s, 1H), 7.02 (d, J = 8 Hz, 1H), 6.92 (d, J = 8 Hz, 1H), 5.94-5.90 (m, 1H), 5.36-5.32 (m, 1H), 4.60 (m, 1H), 4.09-4.00 (m, 5H), 3.73 (m, 1H), 3.14-3.11 (m, 1H), 2.93-2.90 (m, 4H), 2.86-2.84 (m, 1H), 2.68-2.63 (m, 5H), 2.50 (m, 3H), 2.48-2.40 (m, 4H), 2.38 (s, 3H), 2.24-2.21 (m, 4H), 1.81-1.63 (m, 4H) and 1.56-1.49 (m, 9H).

Example 132 Synthesis of 5-(azetidin-3-ylamino)-N-[1-[4-[2-[1-[6-[4-[1-(2,6-dioxo-3-p iperidyl)-3-methyl- 2-oxo-benzimidazol-5-yl]-1-piperidyl]-6-oxo-hexyl]-4-piperid yl]ethynyl]-1-naphthyl]ethyl]- 2-methyl-benzamide (Compound 79) Step-1: To a 50 mL sealed tube containing a well-stirred solution of tert-butyl 3-[3-[1-(4-bromo-1- naphthyl)ethylcarbamoyl]-4-methyl-anilino]azetidine-1-carbox ylate (1, 300 mg, 0.408 mmol) in anhydrous acetonitrile (7 mL) were added ethyl 6-(4-ethynyl-1-piperidyl)hexanoate (2, 484.20 mg, 1.02 mmol) and cesium carbonate (399.17 mg, 1.23 mmol) at ambient temperature. Nitrogen gas was purged through the reaction mixture for 10 minutes. Subsequently, XPhos (19.45 mg, 0.040 mmol) and XPhos-Pd-G3 (34.57 mg, 0.040 mmol) were added, and the mixture was stirred at 90 °C for 4 h. The reaction was monitored by UPLC/TLC. After completion of the reaction, the reaction mixture was passed through a pad of Celite and the Celite bed and washed with EtOAc (2 × 50 mL). The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography (230-400 mesh silica gel; 50 g) with 0-100% EtOAc/pet ether as eluent to afford tert-butyl 3-[3-[1-[4-[2-[1-(6-ethoxy-6-oxo-hexyl)-4-piperidyl]ethynyl] -1- naphthyl]ethylcarbamoyl]-4-methyl-anilino]azetidine-1-carbox ylate (3, 155 mg, 0.139 mmol), 34% yield) as a pale brown solid. UPLC-MS (ES ⁺ ): m/z 710.7 [M + H] ⁺ . Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of in tert-butyl 3-[3- [1-[4-[2-[1-(6-ethoxy-6-oxo-hexyl)-4-piperidyl]ethynyl]-1-na phthyl]ethylcarbamoyl]-4-methyl- anilino]azetidine-1-carboxylate (3, 180 mg, 187.64 mmol) 1:1 THF/MeOH (2.5 mL) was added lithium hydroxide, monohydrate (62.99 mg, 1.50 mmol) in water (1.5 mL) at ambient temperature. The resulting mixture was stirred at this temperature for 3 h. Upon completion of the reaction as indicated by UPLC, the reaction mixture was diluted with water (15 mL) and extracted with MTBE (15 mL). The aqueous phase was acidified with 10% citric acid solution to pH = 4 and then extracted with 10% MeOH/DCM (3 × 70 mL). The combined organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to afford 6-[4-[2-[4-[1-[[5-[(1-tert- butoxycarbonylazetidin-3-yl)amino]-2-methyl-benzoyl]amino]et hyl]-1-naphthyl]ethynyl]-1- piperidyl]hexanoic acid (4, 150 mg, 0.155 mmol, 83% yield) as a pale yellow solid. LC-MS (ES ⁺ ): m/z 681.6 [M + H] ⁺ . Step-3: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 6-[4-[2-[4-[1-[[5- [(1-tert-butoxycarbonylazetidin-3-yl)amino]-2-methyl-benzoyl ]amino]ethyl]-1- naphthyl]ethynyl]-1-piperidyl]hexanoic acid (4, 150 mg, 0.155 mmol) and 3-[3-methyl-2-oxo-5- (4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione hydrochloride (5, 59.05 mg, 0.155 mmol) in anhydrous DMF (2 mL) were added DIPEA (100.73 mg, 779.38 μmol, 135.75 μL) and HATU (88.90 mg, 0.233 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at this temperature for 2 h. Upon completion of the reaction as indicated by UPLC, excess solvent was removed under reduced pressure. Ice-cold water (10 mL) was added to the obtained residue and the formed solid precipitated was filtered, washed with water (10 mL) and dried in vacuo to furnish tert-butyl 3-[3-[1-[4-[2-[1-[6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2 - oxo-benzimidazol-5-yl]-1-piperidyl]-6-oxo-hexyl]-4-piperidyl ]ethynyl]-1- naphthyl]ethylcarbamoyl]-4-methyl-anilino]azetidine-1-carbox ylate (6, 120 mg, 0.085 mmol, 55% yield) as a pale yellow solid. UPLC-MS (ES ⁺ ): m/z 1005.8 [M + H] ⁺ . Step-4: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 3-[3- [1-[4-[2-[1-[6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]-6- oxo-hexyl]-4-piperidyl]ethynyl]-1-naphthyl]ethylcarbamoyl]-4 -methyl-anilino]azetidine-1- carboxylate (6, 120 mg, 0.085 mmol) in anhydrous DCM (2 mL) was added trifluoroacetic acid (392.01 mg, 3.44 mmol, 264.87 μL) at 0 °C temperature under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 1 h. Upon completion of the reaction, excess solvent was evaporated under reduced pressure and the obtained crude was purified by reversed-phase preparative HPLC (Column: X SELECT C18 (150 x 19)mm, 5 μm; Mobile Phase A: 10 mm NH ₄ HCO ₃ in MQ-water in water and Mobile Phase B: Acetonitrile) to afford 5- (azetidin-3-ylamino)-N-[1-[4-[2-[1-[6-[4-[1-(2,6-dioxo-3-pip eridyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]-6-oxo-hexyl]-4-piperidyl]eth ynyl]-1-naphthyl]ethyl]-2-methyl- benzamide (Compound 79, 31 mg, 0.032 mmol, 38% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.08 (bs, 1H), 8.77 (d, J = 7.2 Hz, 1H), 8.34-8.28 (m, 2H), 7.67-7.63 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 7.10 (s, 1H), 7.02 (d, J = 8 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.46- 6.42 (m, 2H), 6.02 (d, J = 6.4 Hz, 1H), 5.88 (t, J = 6.8 Hz, 1H), 5.34 (dd, J = 12.2, 5.6 Hz, 1H), 4.66 (d, J = 7.6 Hz, 1H), 4.16-4.14 (m, 1H), 4.05-3.97 (m, 1H), 3.66 (m, 1H), 3.13-3.07 (m, 2H), 2.95-2.60 (m, 10H), 2.37-2.27 (m, 6H), 2.20-2.18 (m, 5H), 2.01-1.95 (m, 5H), 1.83-1.71 (m, 6H), 1.58-1.46 (m, 6H) and 1.35-1.32 (m, 3H). LC-MS (ES ⁺ ): m/z 905.2 [M + H] ⁺ . Example 133 Synthesis of tert-butyl (3S,4S)-3-fluoro-4-((3-(((R)-1-(4-((1-((4-hydroxypiperidin-4 - yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carba moyl)-4- methylphenyl)amino)pyrrolidine-1-carboxylate Step-1: To a 20 mL sealed tube containing a well-stirred solution of methyl 5-bromo-2-methyl-benzoate (1, 560.78 mg, 2.45 mmol) and tert-butyl (3S,4S)-3-amino-4-fluoropyrrolidine-1-carboxylate (2, 500 mg, 2.45 mmol) in anhydrous 1,4-dioxane (10 mL) was added cesium carbonate (1.99 g, 6.12 mmol) at ambient temperature. Nitrogen gas was purged through the reaction mixture for 10 minutes. Subsequently, XPhos (233.41 mg, 0.489 mmol) and tris (dibenzylideneacetone)dipalladium (0) (448.35 mg, 0.489 mmol) were added and stirring was continued at 100 °C for 16 h. Upon completion of the reaction as confirmed by UPLC, the reaction mixture was passed through a pad of Celite and Celite bed was washed with DCM. The combined filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (230-400 mesh silica gel) with 25% EtOAc/pet ether as eluent to afford tert-butyl (3S,4S)-3-fluoro-4-((3-(methoxycarbonyl)-4-methylphenyl)amin o)pyrrolidine-1- carboxylate (3, 850 mg, 2.3 mmol, 93% yield) as a yellow gum. LC-MS (ES ⁺ ): m/z 297.2 [M – isobutene + H] ⁺ . Step-2: To a stirred solution of tert-butyl (3S,4S)-3-fluoro-4-((3-(methoxycarbonyl)-4- methylphenyl)amino)pyrrolidine-1-carboxylate (3, 850 mg, 2.27 mmol) in a mixture of THF (6.98 mL), water (2 mL) and MeOH (2 mL) was added lithium hydroxide monohydrate, 98% (951.45 mg, 22.7 mmol) at 0 °C. The reaction mixture was stirred for 16 h under nitrogen atmosphere at ambient temperature. The progress of reaction was monitored by TLC. Thereafter, the reaction mixture was diluted with water (25 mL) and extracted with MTBE (20 mL). The aqueous phase was acidified with 10% citric acid solution till pH=4 and extracted with EtOAc (3 × 80 mL). The combined organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure to afford 5-(((3S,4S)-1-(tert-butoxycarbonyl)-4- fluoropyrrolidin-3-yl)amino)-2-methylbenzoic acid (4, 650 mg, 1.90 mmol, 84% yield) as a white solid. LC-MS (ES-): m/z 337.1 [M - H] -. Step-3: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 5-(((3S,4S)-1- (tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)amino)-2-methy lbenzoic acid (4, 650 mg, 1.88 mmol) and (1R)-1-(4-bromo-1-naphthyl)ethanamine hydrochloride (5, 490.5 mg, 1.69 mmol) in anhydrous DMF (7 mL) were added DIPEA (2.43 g, 18.8 mmol, 3.3 mL) and HATU (1.07 g, 2.8 mmol) at ambient temperature under nitrogen atmosphere, and the resulting mixture was stirred at ambient temperature for 4 h. Upon completion of the reaction as confirmed by UPLC, the reaction mixture was diluted with water (100 mL) and the aqueous phase was extracted with EtOAc (2 × 200 mL). The combined organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography (230-400 mesh silica gel) with 40-50% EtOAc/pet ether as eluent to get tert-butyl (3S,4S)-3-((3-(((R)-1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)- 4-fluoropyrrolidine-1- carboxylate (6, 650 mg, 1.04 mmol, 55% yield) as a pale yellow solid. LC-MS (ES ⁺ ): m/z 514.1 [M – isobutene + H] ⁺ . Step-4: To a 8 mL glass-vial containing a well-stirred solution of tert-butyl (3S,4S)-3-((3-(((R)-1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)- 4-fluoropyrrolidine-1- carboxylate (6, 0.06 g, 0.096 mmol) in 1:1 acetonitrile/THF (4.8 mL) were added cesium carbonate (187.9 mg, 0.576 mmol) and 4-[(4-ethynyl-1-piperidyl)methyl]piperidin-4-ol hydrochloride (7, 75.38 mg, 0.288 mmol). The reaction mixture was purged with nitrogen gas for 5 minutes before XPhos (9.17 mg, 0.0192 mmol) and XPhos-Pd-G3 (16.27 mg, 0.0192 mmol) were added. The reaction mixture was purged with nitrogen gas for 2 minutes and stirred at 90 °C for 1.5 h in microwave. Progress of the reaction was monitored by TLC and UPLC. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 30 mL). The combined organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product, which was purified by reverse phase column chromatography (Column: RediSep C18 (100 g SNAP), Mobile phase: A: 0.1% formic acid in water, B: acetonitrile). The fractions were concentrated under reduced pressure to remove acetonitrile and then diluted with 10% sodium bicarbonate solution (100 mL) and brine (50 mL) and then extracted with EtOAc (3 × 200 mL). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford tert-butyl (3S,4S)-3-fluoro-4-((3- (((R)-1-(4-((1-((4-hydroxypiperidin-4-yl)methyl)piperidin-4- yl)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)pyrrolidine-1-carbo xylate (8, 0.033 g, 0.0436 mmol, 45% yield) as a light yellow solid. LC-MS (ES ⁺ ): m/z 712.4 [M + H] ⁺ . The following targeting ligands (Examples 134-135) were prepared using the method described above in Example 133, with the corresponding alkyne intermediates in Step-4.

Example 136 Synthesis of tert-butyl (3R,4S)-3-fluoro-4-((3-(((R)-1-(4-((1-((4-hydroxypiperidin-4 - yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carba moyl)-4- methylphenyl)amino)pyrrolidine-1-carboxylate

Step-1: To a 20 mL glass-vial containing a well-stirred solution of methyl 5-bromo-2-methyl-benzoate (1, 400 mg, 1.75 mmol) and tert-butyl (3S,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate (2, 427.97 mg, 2.1 mmol) in anhydrous 1,4-dioxane (5 mL) was added cesium carbonate (1.42 g, 4.37 mmol) and the resulting mixture was degassed with N2 for 10 minutes. Subsequently, XPhos (166.49 mg, 0.349 mmol) and tris(dibenzylideneacetone)dipalladium (0) (319.80 mg, 0.349 mmol) were added and the resulting mixture was degassed with N ₂ for another 5 minutes. The reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction as indicated by TLC, the reaction mixture was passed through a pad of Celite and Celite bed was washed with EtOAc (150 mL). The filtrate was concentrated under reduced pressure to give the crude, which was purified by flash column chromatography (230-400 mesh silica gel) with 25% EtAOc/pet ether as eluent to afford tert-butyl (3R,4S)-3-fluoro-4-((3-(methoxycarbonyl)-4- methylphenyl)amino)pyrrolidine-1-carboxylate (3, 450 mg, 1.2 mmol, 69% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 297.1 [M – isobutene + H] ⁺ . Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (3R,4S)-3-fluoro-4-((3-(methoxycarbonyl)-4-methylphenyl)amin o)pyrrolidine-1-carboxylate (3, 450 mg, 1.2 mmol) in 1:1 anhydrous THF/MeOH (4 mL) was added lithium hydroxide, monohydrate (503.71 mg, 12 mmol) in water (2 mL) at ambient temperature. The resulting mixture was stirred at this temperature for 16 h. After completion of the reaction as indicated by UPLC, excess solvent was removed from the reaction mixture under reduced pressure and the residue was dissolved in aqueous citric acid solution (50 mL). The aqueous layer was extracted with 15% MeOH/DCM (2 × 100 mL) and the combined organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 5-(((3S,4R)-1-(tert-butoxycarbonyl)- 4-fluoropyrrolidin-3-yl)amino)-2-methylbenzoic acid (4, 400 mg, 1.13 mmol, 95% yield) as a brown liquid. LC-MS (ES ⁺ ): m/z 283.0 [M – isobutene + H] ⁺ . Step-3: To a 50 mL round-bottomed flask containing a well-stirred solution of 5-(((3S,4R)-1-(tert- butoxycarbonyl)-4-fluoropyrrolidin-3-yl)amino)-2-methylbenzo ic acid (4, 450 mg, 1.28 mmol), (R)-1-(4-bromonaphthalen-1-yl)ethan-1-amine hydrochloride (5, 369.59 mg, 1.28 mmol) in anhydrous DMF (5 mL) were added HATU (728.16 mg, 1.92 mmol) and DIPEA (825.02 mg, 6.38 mmol, 1.11 mL) and the resulting mixture was stirred at ambient temperature for 4 h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with ice-water, and the aqueous phase was extracted with EtOAc (2 × 200 mL). The combined organic phase was washed with water followed by brine and dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (230-400 mesh silica gel) with 50% EtOAc/pet ether as eluent to yield tert-butyl (3S,4R)-3-((3-(((R)-1-(4-bromonaphthalen-1-yl)ethyl)carbamoy l)-4-methylphenyl)amino)-4- fluoropyrrolidine-1-carboxylate (6, 680 mg, 1.11 mmol, 87% yield) as a colorless liquid. LC-MS (ES ⁺ ): m/z 514.2 [M – isobutene + H] ⁺ . Step-4: To a 15 mL sealed tube containing a well-stirred solution of tert-butyl (3S,4R)-3-((3-(((R)-1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)- 4-fluoropyrrolidine-1- carboxylate (6, 200 mg, 0.326 mmol) and 4-[(4-ethynyl-1-piperidyl)methyl]piperidin-4-ol hydrochloride (7, 260.95 mg, 0.978 mmol) in anhydrous ACN (2 mL) and DMF (3 mL) was added cesium carbonate (265.57 mg, 0.815 mmol) at ambient temperature. Nitrogen gas was purged through the reaction mixture for 10 minutes. Subsequently, XPhos (31.09 mg, 0.065 mmol) and XPhos-Pd-G3 (41.40 mg, 0.049 mmol) were added and stirring was continued at 90 °C for 4 h. After completion of the reaction as confirmed by LCMS, the reaction mixture was passed through a pad of Celite and Celite bed was washed with 15% MeOH/DCM (100 mL). Excess solvent was removed under vacuum and the crude product was purified by flash column chromatography (230-400 mesh silica gel) with 25% MeOH/DCM as eluent to afford tert-butyl (3R,4S)-3-fluoro-4-((3-(((R)-1-(4-((1-((4-hydroxypiperidin-4 -yl)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)pyrrolidine-1-carboxylate (8, 95 mg, 0.13 mmol, 40% yield) as a brown solid. LC-MS (ES ⁺ ): m/z 712.2 [M + H] ⁺ . Step-5: To a 50 mL sealed tube containing a well-stirred solution of tert-butyl (3S,4R)-3-((3-(((R)-1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)- 4-fluoropyrrolidine-1- carboxylate (6, 200 mg, 0.302 mmol) and 4-ethynyl-1-[(4-fluoro-4-piperidyl)methyl]piperidine hydrochloride (9, 238.89 mg, 0.906 mmol) in 1:1 anhydrous MeCN/THF (5 mL) was added cesium carbonate (246.24 mg, 0.775 mmol) and the resulting reaction mixture was degassed with N2 for 10 minutes. Subsequently, XPhos (14.41 mg, 0.030 mmol) and XPhos- Pd-G3 (12.79 mg, 0.015 mmol) were added, and the resulting mixture was degassed with nitrogen gas for an additional 5 minutes. The reaction mixture was stirred at 90 °C for 4 h. Progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was passed through a pad of Celite and Celite bed was washed with EtOAc (200 mL). The filtrate was concentrated under reduced pressure and the obtained crude was purified by flash column chromatography (230-400 mesh silica gel) with 0-15% MeOH/DCM as eluent to afford tert-butyl (3R,4S)-3-fluoro-4-((3-(((R)-1-(4-((1-((4-fluoropiperidin-4- yl)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)pyrrolidine-1-carboxylate (10, 150 mg, 0.178 mmol, 59% yield) as a pale yellow solid. LC-MS (ES ⁺ ): m/z 714.4 [M + H] ⁺ . Step-6: To a 50 mL sealed tube containing a well-stirred solution of tert-butyl (3S,4R)-3-((3-(((R)-1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)- 4-fluoropyrrolidine-1- carboxylate (6, 250 mg, 0.377 mmol) and 4-ethynyl-1-(4-piperidylmethyl)piperidine hydrochloride (11, 119.34 mg, 0.481 mmol) in anhydrous acetonitrile (5 mL) was added cesium carbonate (307.80 mg, 0.944 mmol) and reaction mixture was degassed by purging nitrogen for 5 minutes. Subsequently, XPhos-Pd-G3 (15.99 mg, 0.018 mmol) and XPhos (18.01 mg, 0.037 mmol) were added, and the resulting mixture was heated at 90 °C for 5 h. Upon completion of the reaction, the reaction mixture was passed through a pad of Celite and the Celite bed was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure and the obtained crude was purified by flash column chromatography (230-400 mesh silica gel) with 15% MeOH/DCM as eluent to afford tert-butyl (3R,4S)-3-fluoro-4-((4-methyl-3-(((R)-1-(4-((1-(piperidin-4- ylmethyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carbam oyl)phenyl)amino)pyrrolidine-1- carboxylate (12, 200 mg, 0.283 mmol, 75% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 696.4 [M + H] ⁺ . Example 137 Synthesis of N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methy l-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)-4-hydroxypip eridin-4-

yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)-5 -(((3S,4S)-4-fluoropyrrolidin-3- yl)amino)-2-methylbenzamide (Compound 80) Step-1: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 1-[1-(2,6-dioxo- 3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-c arboxylic acid hydrochloride (2, 70.72 mg, 0.157 mmol) in anhydrous DMF (2 mL) were added DIPEA (84.68 mg, 0.655 mmol, 0.114 mL) and HATU (59.79 mg, 0.157 mmol) at ambient temperature under nitrogen atmosphere. Subsequently, tert-butyl (3S,4S)-3-fluoro-4-((3-(((R)-1-(4-((1-((4-hydroxypiperidin-4 - yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carba moyl)-4- methylphenyl)amino)pyrrolidine-1-carboxylate (1, 0.1 g, 0.131 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove DMF, diluted with cold-water (10 mL). The solid precipitate was filtered, washed with cold-water (10 mL), dried in vacuo for 10 minutes, and washed with pet ether (10 mL) and dried under vacuum at 50 °C for 0.5 h to afford tert-butyl (3S,4S)-3-((3-(((1R)-1-(4- ((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-d ihydro-1H-benzo[d]imidazol-5- yl)piperidine-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pip eridin-4-yl)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)-4-fluoropyrrolidin e-1-carboxylate (3, 0.09 g, 0.052 mmol, 39% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 1080.7 [M + H] ⁺ . Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (3S,4S)-3-((3-(((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)-4-hydroxypip eridin-4-yl)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)-4-fluoropyrrolidine-1- carboxylate (3, 0.1 g, 0.057 mmol) in anhydrous DCM (3 mL) was added 4N HCl in 1,4-dioxane (1 mL) at 5 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (0.1% Formic acid in water: MeCN) to afford N-((1R)-1-(4- ((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-d ihydro-1H-benzo[d]imidazol-5-yl) piperidine-4-carbonyl)-4-hydroxypiperidin-4-yl) methyl) piperidin-4-yl)ethynyl)naphthalen-1- yl)ethyl)-5-(((3S,4S)-4-fluoropyrrolidin-3-yl)amino)-2-methy lbenzamide formate (Compound 80, 22 mg, 0.02 mmol, 35% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.06 (s, 1H), 8.83 (d, J = 8 Hz, 1H), 8.33-8.28 (m, 2H), 7.68-7.56 (m, 4H), 6.99-6.92 (m, 2H), 6.84 (s, 1H), 6.65-6.64 (m, 3H), 5.92-5.85 (m, 1H), 5.71 (d, J = 5.6 Hz, 1H), 5.32-5.25 (m, 1H), 4.85 (d, ² J _H-F = 80 Hz, 1H), 4.05 (m, 1H), 3.85-3.68 (m, 2H), 3.63 (m, 3H), 3.33 (m, 6H), 3.35-2.91 (m, 4H), 2.92-2.82 (m, 3H), 2.80-2.65 (m, 7H), 2.40-2.35 (m, 2H), 2.28 (s, 2H), 2.12 (s, 3H), 2.00- 1.90 (m, 2H), 1.80-1.69 (m, 6H), 1.55 (d, J = 6.8 Hz, 3H) and 1.65-1.41 (m, 4H). LC-MS (ES ⁺ ): m/z 980.0 [M + H] ⁺ . Example 138 N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methy l-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-yl)m ethyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-5-(((3S,4S)-4-fluoropyrrol idin-3-yl)amino)-2- methylbenzamide (Compound 81) Compound 81 was prepared substantially following the synthesis of Compound 80, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 964.3 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 8.90-8.80 (m, 1H), 8.35-8.20 (m, 2H), 7.75-7.50 (m, 5H), 7.01-6.90 (m, 1H), 6.60 (s, 2H), 6.08 (s, 1H), 5.91-5.80 (m, 2H), 5.45-5.32 (m, 1H), 5.17 (d, ² JH-F = 50 Hz, 1H), 4.44-4.30 (m, 1H), 4.35-4.20 (m, 1H), 4.05-3.90 (m, 1H), 3.70-3.55 (m, 4H), 3.50 (m, 3H), 3.30 (s, 3H), 3.06-2.88 (m, 8H), 2.50 (m, 4H), 2.32-2.22 (m, 4H), 2.20 (s, 3H), 2.09-1.90 (m, 5H), 1.90-1.75 (m, 4H), 1.55 (d, J = 6.8 Hz, 3H), (1.30-1.05 (m, 4H). Example 139 N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methy l-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)-4-fluoropiperid in-4-yl)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-5-(((3S,4S)-4-fluoropyrrol idin-3-yl)amino)-2- methylbenzamide (Compound 82) Compound 82 was prepared substantially following the synthesis of Compound 80, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 982.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.07 (s, 1H), 8.84 (d, J = 7.6 Hz, 1H), 8.34-8.29 (m, 2H), 7.67- 7.57 (m, 4H), 6.99-6.93 (m, 2H), 6.84 (s, 1H), 6.65-6.57 (m, 3H), 5.91-5.88 (m, 1H), 5.72-5.71 (m, 1H), 5.30 (dd, J = 5.6, 13 Hz, 1H), 5.00-4.98 (m, 1H), 4.16-4.13 (m, 1H), 3.82-3.76 (m, 2H), 3.64-3.61 (m, 2H), 3.13-2.78 (m, 9H), 2.50 (m, 2H), 2.12 (s, 3H), 2.08 (m, 2H), 2.00-1.84 (m, 9H), 1.73-1.63 (m, 10H), 1.54 (d, J = 6.8 Hz, 3H) and 1.53-1.42 (m, 4H). Example 140 Synthesis of N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methy l-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)-4-hydroxypip eridin-4- yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)-5-(( (3S,4R)-4-fluoropyrrolidin-3- yl)amino)-2-methylbenzamide (Compound 83) Step-1: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (3R,4S)-3-fluoro-4-((3-(((R)-1-(4-((1-((4-hydroxypiperidin-4 -yl)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)pyrrolidine-1-carboxylate (1, 95 mg, 0.129 mmol) and 1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]piperidine-4-carboxylic acid hydrochloride (2, 63.38 mg, 0.142 mmol) in anhydrous DMF (2 mL) were added HATU (73.83 mg, 0.194 mmol) and DIPEA (83.65 mg, 0.647 mmol, 0.112 mL) and the reaction mixture was stirred at ambient temperature for 2 h. After completion of the reaction, the reaction was quenched with cold-water, and the solid precipitate was filtered, washed with water and dried under reduced pressure to afford tert-butyl (3S,4R)-3-((3-(((1R)-1-(4-((1-((1- (1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 H-benzo[d]imidazol-5- yl)piperidine-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pip eridin-4-yl)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)-4-fluoropyrrolidin e-1-carboxylate (3, 108 mg, 0.073 mmol, 57% yield) as a brown solid. LC-MS (ES ⁺ ): m/z 1080.6 [M + H] ⁺ . Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (3S,4R)-3-((3-(((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)-4-hydroxypip eridin-4-yl)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)-4-fluoropyrrolidine-1- carboxylate (3, 108 mg, 0.073 mmol) in anhydrous DCM (0.8 mL) was added 4N HCl in 1,4- dioxane (0.185 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 1 h. After completion of the reaction as indicated by UPLC, excess solvent was removed from the reaction mixture to give the crude product, which was purified by reverse phase prep-HPLC (X SELECT C18 (250 x 19 mm) 5 micron; 0.1% formic acid in water : MeCN) to afford N-((1R)-1-(4-((1-((1- (1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 H-benzo[d]imidazol-5- yl)piperidine-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)pip eridin-4-yl)ethynyl)naphthalen-1- yl)ethyl)-5-(((3S,4R)-4-fluoropyrrolidin-3-yl)amino)-2-methy lbenzamide formate (Compound 83, 16 mg, 0.015 mmol, 21% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 981.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.08 (s, 1H), δ 8.81 (d, J = 8 Hz, 1H), 8.29-8.32 (m, 2H), 7.68- 7.63 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 6.96-6.92 (m, 2H), 6.84 (d, J = 2 Hz, 1H), 6.67-6.62 (m, 3H), 5.88 (m, 1H), 5.69 (m, 1H), 5.32-5.23 (m, 1H), 4.85 (d, ² J H-F= 80 Hz, 1H), 4.10-3.90 (m, 2H), 3.75-3.60 (m, 3H), 3.30 (m, 3H), 3.20-3.10 (m, 3H), 3.05-2.81 (m, 5H), 2.80-2.67 (m, 7H), 2.67-2.59 (m, 2H), 2.42 (m, 2H), 2.34-2.30 (m, 2H), 2.10-2.09 (m, 3H), 1.97-1.93 (m, 3H), 1.75- 1.71 (m, 6H), 1.55 (d, J = 6.8 Hz, 3H) and 1.65-1.41 (m, 4H). Example 141 Synthesis of N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methy l-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)-4-fluoropipe ridin-4-yl)methyl)piperidin- 4-yl)ethynyl)naphthalen-1-yl)ethyl)-5-(((3S,4R)-4-fluoropyrr olidin-3-yl)amino)-2- methylbenzamide (Compound 84) Step-1: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (3R,4S)-3-fluoro-4-((3-(((R)-1-(4-((1-((4-fluoropiperidin-4- yl)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)pyrrolidine-1-carboxylate (1, 100 mg, 0.119 mmol) and 1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]piperidine-4-carboxylic acid hydrochloride (2, 50.86 mg, 0.119 mmol) in DMF (2.5 mL) were added HATU (67.91 mg, 0.178 mmol) and DIPEA (76.94 mg, 0.595 mmol, 0.103 mL) and the reaction mixture was stirred at ambient temperature for 2 h. After completion of the reaction as indicated by UPLC, excess solvent was evaporated under reduced pressure. Ice-cold water was added and the formed solid precipitate was filtered, washed with water (5 mL) and dried in vacuo to afford tert-butyl (3S,4R)-3-((3-(((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin- 3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine -4-carbonyl)-4-fluoropiperidin- 4-yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)car bamoyl)-4-methylphenyl)amino)-4- fluoropyrrolidine-1-carboxylate (3, 100 mg, 0.073 mmol, 61% yield) as an off-white solid. LC- MS (ES ⁺ ): m/z 1084.4 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (3S,4R)-3-((3-(((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)-4-fluoropipe ridin-4-yl)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)-4-fluoropyrrolidine-1- carboxylate (3, 100 mg, 0.073 mmol) in anhydrous DCM (1.5 mL) was added 4N HCl in 1,4- dioxane (182.48 μL) at -78 °C. The resulting mixture was stirred at ambient temperature for 2 h. After completion of the reaction as indicated by UPLC, excess solvent was removed from the reaction mixture under reduced pressure and the crude product was purified by reverse phase prep- HPLC (X-Select C18 (150 x 19) mm 5microns column] Mobile phase: A:0.1% formic acid in MQ- water; B: Acetonitrile; Flow rate: 15 mL/minutes) to afford N-((1R)-1-(4-((1-((1-(1-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidine-4- carbonyl)-4-fluoropiperidin-4-yl)methyl)piperidin-4-yl)ethyn yl)naphthalen-1-yl)ethyl)-5- (((3S,4R)-4-fluoropyrrolidin-3-yl)amino)-2-methylbenzamide formate (Compound 84, 18 mg, 0.017 mmol, 24% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 11.1 (s, 1H), 8.83 (d, J = 7.6 Hz, 1H), 8.29-8.33 (m, 2H), 7.69-7.64 (m, 3H), 7.58 (d, J = 7.6 Hz, 1H), 6.97-6.93 (m, 2H), 6.84 (d, J = 2.4 Hz, 1H), 6.69-6.63 (m, 3H), 5.88-5.80 (m, 2H), 5.31-5.20 (m, 1H), 5.20- 5.10 (m, 1H), 4.20-4.01 (m, 2H), 3.90-3.80 (m, 1H), 3.64-3.61 (m, 2H), 3.30 (s, 3H), 2.90-2.75 (m, 7H), 2.73-2.65 (m, 3H), 2.60-2.55 (m, 2H), 2.50 (m, 2H), 2.45-2.33 (m, 4H), 2.11 (s, 3H), 2.08 (m, 1H), 1.99-1.95 (m, 4H), 1.80 (m, 2H), 1.75-1.73 (m, 6H), 1.56 (m, 2H) and 1.55 (d, J = 6.8 Hz, 3H). LC-MS (ES ⁺ ): m/z 983.4 [M + H] ⁺ . Example 142 Synthesis of N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methy l-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-y l)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-5-(((3S,4R)-4-fluoropyrrol idin-3-yl)amino)-2- methylbenzamide (Compound 85) Step-1: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (3R,4S)-3-fluoro-4-((4-methyl-3-(((R)-1-(4-((1-(piperidin-4- ylmethyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)phenyl)amino)pyrr olidine-1-carboxylate (1, 100 mg, 0.143 mmol) in anhydrous DMF (2.5 mL) were added DIPEA (92.86 mg, 0.718 mmol, 0.12 mL) and HATU (81.96 mg, 0.215 mmol) and 1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]piperidine-4-carboxylic acid hydrochloride (2, 60.76 mg, 0.143 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at this temperature for 2 h. Progress of the reaction was monitored by UPLC. The reaction mixture was concentrated under reduced pressure to give a residue, which was diluted with ice-cold water (20 mL) and the solid precipitate was filtered, washed with water (10 mL) and dried in vacuo to afford tert-butyl (3S,4R)-3-((3-(((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin- 3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine -4-carbonyl)piperidin-4- yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carba moyl)-4-methylphenyl)amino)-4- fluoropyrrolidine-1-carboxylate (3, 125 mg, 0.078 mmol, 55% yield) as an off-white solid. LC- MS (ES ⁺ ): m/z 1065.4 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (3S,4R)-3-((3-(((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-y l)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)-4-fluoropyrrolidine-1- carboxylate (3, 125 mg, 0.078 mmol) in anhydrous DCM (2 mL) was added 4N HCl in 1,4-dioxane (1.3 mL, 0.786 mmol) at -78 °C and the resulting mixture was stirred at ambient temperature for 2 h. The progress of the reaction was monitored by UPLC. Upon completion of the reaction, excess solvent was removed under reduced pressure and the obtained crude was purified by reverse phase column chromatography (C18 column, mobile phase: 10 mm TFA in water : MeCN) to afford N- ((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-yl)m ethyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-5-(((3S,4R)-4-fluoropyrrol idin-3-yl)amino)-2- methylbenzamide di-trifluoroacetate (Compound 85, 30 mg, 0.025 mmol, 32% yield) as an off- white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 8.85 (d, J = 8 Hz, 1H), 8.33-8.28 (m, 2H), 7.76-7.58 (m, 4H), 7.13-7.07 (m, 2H), 6.99 (d, J = 9.2 Hz, 1H), 6.90 (s, 1H), 6.70 (d, J = 6.4 Hz, 2H), 5.92-5.88 (m, 1H), 5.36-5.32 (m, 1H), 5.22 (d, ² J _H-F = 56 Hz, 1H), 4.41-4.20 (m, 2H), 4.04-4.02 (m, 1H), 3.62-3.56 (m, 4H), 3.40 (m, 6H), 3.34 (s, 3H), 3.20-3.00 (m, 7H), 2.94-2.86 (m, 2H), 2.71-2.65 (m, 2H), 2.50 (m, 1H), 2.34-2.31 (m, 2H), 2.20-2.28 (m, 6H), 2.09-2.00 (m, 2H), 1.83 (m, 6H), 1.55 (d, J = 6.8 Hz, 3H) and 1.20-1.00 (m, 2H). LC-MS (ES ⁺ ): m/z 964.0 [M + H] ⁺ . Example 143 Synthesis of N-((1R)-1-(4-((1-(5-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)piperidin-1-yl)-5-oxopentyl)piperid in-4-yl)ethynyl)naphthalen-1- yl)ethyl)-5-(((3S,4R)-4-fluoropyrrolidin-3-yl)amino)-2-methy lbenzamide (Compound 86) Step-1: To a 50 mL sealed tube containing a well-stirred solution of tert-butyl (3S,4S)-3-((3-(((R)-1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)- 4-fluoropyrrolidine-1- carboxylate (1, 180 mg, 0.205 mmol) and ethyl 5-(4-ethynyl-1-piperidyl)pentanoate (2,.17 mg, 0.512 mmol) in anhydrous acetonitrile (6 mL) was added cesium carbonate (200.46 mg, 0.615 mmol) and the resulting mixture was degassed with bubbling nitrogen gas for 10 minutes. Subsequently, XPhos (9.78 mg, 0.020 mmol) and XPhos-Pd-G3 (8.68 mg, 0.010 mmol) were added and the resulting mixture was degassed with nitrogen gas for 5 minutes. The reaction mixture was stirred at 90 °C for 4 h. Progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was passed through a pad of Celite and the Celite bed was washed with EtOAc (200 mL). The filtrate was concentrated combined under reduced pressure and the obtained crude residue was purified by flash column chromatography (230-400 mesh silica gel, 50 g) with 0-15% MeOH/DCM as eluent to afford tert-butyl (3S,4S)-3-((3-(((R)- 1-(4-((1-(5-ethoxy-5-oxopentyl)piperidin-4-yl)ethynyl)naphth alen-1-yl)ethyl)carbamoyl)-4- methylphenyl)amino)-4-fluoropyrrolidine-1-carboxylate (3, 165 mg, 0.200 mmol, 98% yield) as a pale yellow solid. LC-MS (ES ⁺ ): m/z 727.4 [M + H] ⁺ . Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (3S,4S)- 3-((3-(((R)-1-(4-((1-(5-ethoxy-5-oxopentyl)piperidin-4-yl)et hynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)-4-fluoropyrrolidin e-1-carboxylate (3, 185 mg, 0.232 mmol) in a mixture of THF (3.5 mL) and MeOH (1.5 mL) was added lithium hydroxide monohydrate (48.71 mg, 1.16 mmol) in water (1.5 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 h. The reaction was monitored by UPLC. Excess solvent was removed from the reaction mixture under reduced pressure and the crude was dissolved into 10% aqueous citric acid solution. The aqueous phase was extracted with 15%MeOH /DCM (3 × 100 mL) and the organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by reverse phase column chromatography (C18, RediSep Gold (100 g SNAP), Mobile phase A:0.1% formic acid in MQ-water; B: Acetonitrile; Flow rate: 15 mL/minutes) to afford 5-(4-((4-((R)-1-(5-(((3S,4S)-1-(tert- butoxycarbonyl)-4-fluoropyrrolidin-3-yl)amino)-2-methylbenza mido)ethyl)naphthalen-1- yl)ethynyl)piperidin-1-yl)pentanoic acid formate (4, 160 mg, 0.228 mmol, 98% yield) as an off- white solid. LC-MS (ES ⁺ ): m/z 699.4 [M + H] ⁺ . Step-3: To a 8 mL glass vial containing a well-stirred solution of 5-(4-((4-((R)-1-(5-(((3S,4S)-1-(tert- butoxycarbonyl)-4-fluoropyrrolidin-3-yl)amino)-2-methylbenza mido)ethyl)naphthalen-1- yl)ethynyl)piperidin-1-yl)pentanoic acid formate (4, 160 mg, 0.228 mmol) and 3-[3-methyl-2-oxo- 5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione hydrochloride (5, 78.39 mg, 0.171 mmol ) in anhydrous DMF (2.5 mL) were added HATU (130.58 mg, 0.343 mmol) and DIPEA (295.89 mg, 2.29 mmol, 0.399 mL) and the mixture was stirred at ambient temperature under nitrogen atmosphere for 2 h. Progress of the reaction was monitored by UPLC. After completion of the reaction, excess solvent was removed under reduced pressure and the obtained crude product was triturated with ice-cold water (10 mL). The solid precipitate was filtered, washed with water (10 mL) and dried in vacuo to furnish tert-butyl (3S,4S)-3-((3-(((1R)-1-(4-((1-(5-(4-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidin-1-yl)-5- oxopentyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carba moyl)-4-methylphenyl)amino)-4- fluoropyrrolidine-1-carboxylate (6, 65 mg, 0.062 mmol, 26% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 1024.4 [M + H] ⁺ . Step-4: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (3S,4S)- 3-((3-(((1R)-1-(4-((1-(5-(4-(1-(2,6-dioxopiperidin-3-yl)-3-m ethyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-1-yl)-5-oxopentyl)piperidin- 4-yl)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)-4-fluoropyrrolidin e-1-carboxylate (6, 55 mg, 0.052 mmol) in anhydrous DCM (2.5 mL) was added 4N HCl in 1,4-dioxane (0.261 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 2 h and monitored by UPLC. Upon completion of the reaction, excess solvent was removed and the crude residue was washed with MTBE (7 mL). The obtained solid was dissolved in water and lyophilized to afford N-((1R)-1-(4- ((1-(5-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-di hydro-1H-benzo[d]imidazol-5- yl)piperidin-1-yl)-5-oxopentyl)piperidin-4-yl)ethynyl)naphth alen-1-yl)ethyl)-5-(((3S,4S)-4- fluoropyrrolidin-3-yl)amino)-2-methylbenzamide formate (Compound 86, 38 mg, 0.036 mmol, 70% yield) as an off white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 8.89 (d, J = 7.6 Hz, 1H), 8.33-8.30 (m, 2H), 7.74-7.67 (m, 3H), 7.60 (d, J = 7.6 Hz, 1H), 7.12 (s, 1H), 7.03 (d, J = 8 Hz, 2H), 6.93 (d, J = 7.2 Hz, 1H), 6.64-6.62 (m, 2H), 6.10-6.04 (m, 1H), 5.93-5.85 (m, 1H), 5.3653.0 (m, 1H), 5.19 (d, ² JH-F = 75 Hz, 1H), 4.61-4.52 (m, 1H), 4.25-4.16 (m, 1H), 4.09-4.02 (m, 1H), 3.80-3.70 (m, 2H), 3.60-3.48 (m, 4H), 3.52-3.50 (m, 1H), 3.20-2.80 (m, 9H), 2.50-2.45 (m, 4H), 2.30-2.18 (m, 2H), 2.14 (s, 3H), 2.10-1.95 (m, 4H), 1.90-1.70 (m, 5H), 1.68-1.45 (m, 8H). LC-MS (ES ⁺ ): m/z 924.4 [M + H] ⁺ . Example 144 N-((1R)-1-(4-((1-(5-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-1-yl)-5-oxopentyl)piperidin- 4-yl)ethynyl)naphthalen-1- yl)ethyl)-5-(((3S,4R)-4-fluoropyrrolidin-3-yl)amino)-2-methy lbenzamide (Compound 87) Compound 87 was prepared substantially following the synthesis of Compound 86, using the corresponding intermediates. ¹ H NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 8.81 (d, J = 7.6 Hz, 1H), 8.29-8.32 (m, 2H), 7.66- 7.63 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 7.10 (d, J = 1.2 Hz, 1H), 7.01 (d, J = 8 Hz, 1H), 6.96-6.90 (m, 2H), 6.68-6.66 (m, 2H), 5.88-5.86 (m, 1H), 5.79-5.69 (m, 1H), 5.33-5.30 (m, 1H), 5.17 (d, ² J _H- F = 96 Hz,1H), 4.61-4.52 (m, 1H), 4.03-4.00 (m, 2H), 3.32 (s, 6H), 3.30-3.05 (m, 3H), 2.90-2.70 (m, 6H), 2.70-2.60 (m, 2H), 2.50-2.27 (m, 7H), 2.10 (s, 3H), 2.00-1.97 (m, 3H), 1.80-1.73 (m, 4H), 1.56-1.49 (m, 8H). LC-MS (ES ⁺ ): m/z 924.4 [M + H] ⁺ . Example 145 Synthesis of tert-butyl (R)-3,3-difluoro-4-((4-methyl-3-(((R)-1-(4-((1-(piperidin-4- ylmethyl)piperidin-4-yl)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)phenyl)amino)pyrrolidine-1-carboxylate, tert-butyl (S)-3,3-difluoro-4- ((4-methyl-3-(((R)-1-(4-((1-(piperidin-4-ylmethyl)piperidin- 4-yl)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)phenyl)amino)pyrrolidine-1-carboxylate and tert-butyl (S)-3,3-difluoro- 4-((3-(((R)-1-(4-((1-((4-hydroxypiperidin-4-yl)methyl)piperi din-4-yl)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)pyrrolidine-1-carbo xylate

Step-1: To a 40 mL vial containing a well stirred solution of methyl 5-bromo-2-methyl-benzoate (1, 2 g, 8.73 mmol), tert-butyl 4-amino-3,3-difluoro-pyrrolidine-1-carboxylate (2, 1.94 g, 8.73 mmol) in anhydrous 1,4-dioxane (20 mL) was added cesium carbonate (7.11 g, 21.83 mmol) at room temperature. The mixture was purged with nitrogen gas for 10 minutes before X-Phos (416.20 mg, 873.09 μmol) and Pd2(dba)3 (799.51 mg, 873.09 μmol) were added. The reaction was stirred at 110 °C for 6 h. Upon completion of the reaction, the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (230-400 mesh silica gel, 15% EtOAc in pet ether) to afford tert- butyl 3,3-difluoro-4-(3-methoxycarbonyl-4-methyl-anilino)pyrrolidi ne-1-carboxylate (3, 2.2 g, 5.58 mmol, 63.95% yield) as a light brown solid. UPLC (ES ⁺ ): m/z 315.2 [M+H- ^t bu] ⁺ . Step-2: To a 100 mL single-neck round-bottom flask containing a well stirred solution of tert-butyl 3,3- difluoro-4-(3-methoxycarbonyl-4-methyl-anilino)pyrrolidine-1 -carboxylate (3, 2.2 g, 5.58 mmol) in anhydrous THF (20 mL) and methanol (20 mL) was added lithium hydroxide, monohydrate (3.98 g, 94.79 mmol) in water (20 mL) at room temperature. The contents were stirred at room temperature for 16 h. Upon completion of the reaction, the solvent was removed and the resulting crude was acidified with 10% aqueous citric acid solution. The aqueous layer was extracted with EtOAc (3×75 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 5-[(1-tert-butoxycarbonyl-4,4- difluoro-pyrrolidin-3-yl)amino]-2-methyl-benzoic acid (4, 1.9 g, 5.17 mmol, 92.63% yield) as an off-white solid. UPLC (ES-): m/z 355.3 [M-H]-. Step-3: To a 100 mL single-neck round-bottom flask containing well stirred solution of 5-[(1-tert- butoxycarbonyl-4,4-difluoro-pyrrolidin-3-yl)amino]-2-methyl- benzoic acid (4, 1 g, 2.72 mmol), (1R)-1-(4-bromo-1-naphthyl)ethanamine (5, 866.77 mg, 2.99 mmol, HCl salt) in anhydrous DMF (15 mL) were added HATU (1.55 g, 4.08 mmol) and DIPEA (1.76 g, 13.61 mmol, 2.37 mL) at room temperature. The contents were stirred at room temperature for 3 h. Upon completion of the reaction, the reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (3×40 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude, which was purified by flash column chromatography (230-400 mesh silica gel, 30% EtOAc in Pet ether) to afford tert- butyl 3,3-difluoro-4-[4-methyl-3-[[(1R)-1-(4-bromo-1- naphthyl)ethyl]carbamoyl]anilino]pyrrolidine-1-carboxylate (6, 1.4 g, 2.28 mmol, 83.90% yield) as white solid. UPLC (ES ⁺ ): m/z 532.3 [M- ^t bu+H] ⁺ . Step-4: Compound tert-butyl 3,3-difluoro-4-[4-methyl-3-[[(1R)-1-(4-bromo-1- naphthyl)ethyl]carbamoyl]anilino]pyrrolidine-1-carboxylate (6, 1.4 g, 2.28 mmol) was separated by chiral SFC to afford tert-butyl (4R)-3,3-difluoro-4-[4-methyl-3-[[(1R)-1-(4-bromo-1- naphthyl)ethyl]carbamoyl]anilino]pyrrolidine-1-carboxylate (7, early-eluting peak arbitrarily assigned as the R-isomer, 0.55 g, 887.88 μmol, 38.88% yield, 95% purity) and tert-butyl (4S)-3,3- difluoro-4-[4-methyl-3-[[(1R)-1-(4-bromo-1-naphthyl)ethyl]ca rbamoyl]anilino]pyrrolidine-1- carboxylate (8, late-eluting peak arbitrarily assigned as the S-isomer, 0.53 g, 882.61 μmol, 38.65% yield, 98% purity) as off-white solids. 7: UPLC (ES ⁺ ): m/z 590.2 [M+H] ⁺ . SOR [α]D ²⁵ = -29.33 [0.3 concentration, THF] 8: UPLC (ES ⁺ ): m/z 590.2 [M+H] ⁺ . SOR [α] _D ²⁵ ₌ -46.00 [0.3 concentration, THF] SFC Method: Sample preparation: 1.40 g of 6 was dissolved 10 mL of MeCN; Instrument : PIC 100; Column: YMC Cellulose C (250*30)mm, 5μm; Mobile Phase: CO2: IPA (60:40)%; Total Flow: 70 g/min; Back pressure: 100 bar; Wavelength: 220 nm; Cycle time: 6 min; Injection volume: 500 µL Step-5: To 50 mL sealed tube containing a well-stirred solution of tert-butyl (R)-4-((3-(((R)-1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)- 3,3-difluoropyrrolidine-1- carboxylate (7, 250 mg, 0.395 mmol) and 4-ethynyl-1-(4-piperidylmethyl)piperidine hydrochloride (9, 192.59 mg, 0.790 mmol) in anhydrous acetonitrile (6 mL) was added cesium carbonate (321.81 mg, 0.987 mmol) and resulting mixture was degassed with N ₂ for 5 minutes. Subsequently, XPhos (18.83 mg, 0.039 mol) and XPhos-Pd-G3 (33.44 mg, 0.039 mmol) were added and the resulting mixture was heated at 90 °C for 3 h. After completion of the reaction as indicated by TLC, the resulting mixture was filtered through a pad of Celite and Celite bed was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure and the obtained crude was purified by flash column chromatography (230-400 mesh silica gel) with 20% MeOH/DCM as eluent to afford tert-butyl (R)-3,3-difluoro-4-((4-methyl-3-(((R)-1-(4-((1- (piperidin-4-ylmethyl)piperidin-4-yl)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)phenyl)amino)pyrrolidine-1-carboxylate (10, 195 mg, 0.261 mmol, 66% yield) as a brown solid. LC-MS (ES ⁺ ): m/z 714.3 [M + H] ⁺ . Step-6: To a 50 mL sealed tube containing well stirred solution of tert-butyl (4S)-3,3-difluoro-4-[4- methyl-3-[[(1R)-1-(4-bromo-1-naphthyl)ethyl]carbamoyl]anilin o]pyrrolidine-1-carboxylate (8, 260 mg, 384.38 μmol), 4-ethynyl-1-(4-piperidylmethyl)piperidine hydrochloride (9, 187.38 mg, 768.76 μmol) in anhydrous acetonitrile (6 mL) and was added cesium carbonate (313.09 mg, 960.95 μmol) at room temperature. Nitrogen gas was purged through a reaction mixture for 10 minutes. Then XPhos (18.32 mg, 38.44 μmol) and XPhos-Pd-G3 (32.54 mg, 38.44 μmol) were added and the reaction was stirred for 4h at 90 °C and monitored by UPLC. Reaction mixture was passed through a pad of celite bed, filtrate was concentrated under reduced pressure to get crude compound. This reaction crude was purified by flash column chromatography (230-400 mesh silica gel, 30% MeOH in DCM) to afford tert-butyl (4S)-3,3-difluoro-4-[4-methyl-3-[[(1R)-1-[4- [2-[1-(4-piperidylmethyl)-4-piperidyl]ethynyl]-1-naphthyl]et hyl]carbamoyl]anilino]pyrrolidine- 1-carboxylate (11, 200 mg, 265.84 μmol, 69% yield) as off white solid. LC-MS (ES ⁺ ): m/z 714.3 [M + H] ⁺ . Step-7: To a 15 mL sealed tube containing a well-stirred solution of tert-butyl (S)-4-((3-(((R)-1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)- 3,3-difluoropyrrolidine-1- carboxylate (8, 200 mg, 0.336 mmol) and 4-[(4-ethynyl-1-piperidyl)methyl]piperidin-4-ol hydrochloride (12, 359.06 mg, 1.35 mmol) in anhydrous ACN (2.5 mL), THF (2.5 mL) and DMF (1 mL) was added cesium carbonate (274.06 mg, 0.841 mmol) at ambient temperature. Nitrogen gas was purged through the reaction mixture for 10 minutes. Subsequently, XPhos (16.04 mg, 0.033 mmol) and XPhos-Pd-G3 (28.48 mg, 0.033 mmol) were added and the mixture was stirred at 90 °C for 4 h. After completion of the reaction as indicated by UPLC, the reaction mixture was passed through a pad of Celite and the Celite bed was washed with 10% MeOH/DCM (100 mL). The filtrate was concentrated under reduced pressure and the obtained crude was purified by flash column chromatography (230-400 mesh silica gel) with 28% MeOH/ DCM as eluent to afford tert- butyl (S)-3,3-difluoro-4-((3-(((R)-1-(4-((1-((4-hydroxypiperidin-4 -yl)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)pyrrolidine-1-carboxylate (13, 140 mg, 0.183 mmol, 55% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 730.4 [M + H] ⁺ . Targeting ligands (Example 147 and 148) were prepared using the method described in Example 145 for the synthesis of tert-butyl (R)-3,3-difluoro-4-((4-methyl-3-(((R)-1-(4-((1-(piperidin-4- ylmethyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carbam oyl)phenyl)amino)pyrrolidine-1- carboxylate, with the corresponding intermediates in Step-5. Targeting ligands (Example 146 and 146) were prepared using the method described in Example 145 for the synthesis of tert-butyl (S)-3,3-difluoro-4-((4-methyl-3-(((R)-1-(4-((1-(piperidin-4- ylmethyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carbam oyl)phenyl)amino)pyrrolidine-1- carboxylate, with the corresponding intermediates in Step-6.

Example 150 Synthesis of tert-Butyl (R)-4-((3-(((R)-1-(4-((1-(5-ethoxy-5-oxopentyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)-3,3- difluoropyrrolidine-1-carboxylate and tert-Butyl (S)-4-((3-(((R)-1-(4-((1-(5-ethoxy-5- oxopentyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carba moyl)-4- methylphenyl)amino)-3,3-difluoropyrrolidine-1-carboxylate Step-1: To a 100 mL sealed tube containing a well-stirred solution of tert-butyl 4-((3-(((R)-1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)- 3,3-difluoropyrrolidine-1- carboxylate (1, 0.5 g, 0.781 mmol) and ethyl 5-(4-ethynyl-1-piperidyl)pentanoate (2, 383.98 mg, 1.56 mmol) in anhydrous acetonitrile (15 mL) and was added cesium carbonate (254.68 mg, 0.781 mmol) at ambient temperature. Nitrogen gas was purged through the reaction mixture for 10 minutes. Subsequently, XPhos (37.26 mg, 0.078 mmol) and XPhos-Pd-G3 (66.16 mg, 0.078 mmol) were added and stirring was continued at 90 °C for 3 h. Upon completion of the reaction as indicated by UPLC, the reaction mixture was passed through a pad of Celite and the filtrate was concentrated under reduced pressure. The obtained crude was purified by flash column chromatography (230-400 mesh silica gel, 7% MeOH/ DCM) and repurified by reverse phase column chromatography (Redisef-RF C18 column, Mobile phase A: 10 mm NH4HCO3 in water and B : acetonitrile] to afford tert-butyl 4-((3-(((R)-1-(4-((1-(5-ethoxy-5-oxopentyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)-3,3-difluoropyrrolidine-1- carboxylate (3, 260 mg, 0.353 mmol) as an off-white solid. Step-2: Compound tert-Butyl 4-((3-(((R)-1-(4-((1-(5-ethoxy-5-oxopentyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)-3,3-difluoropyrrolidine-1- carboxylate (3, 260 mg, 0.353 mmol) was subjected to chiral SFC separation to separate the diastereomers following a method: YMC Cellulose- SB, Flow rate : 5 mL/min, Co-Solvent : 40%, Co-Solvent Name : 0.5% Isopropyl amine in IPA, Injected Volume : 15μL, Temperature : 35 °C, Outlet Pressure: 100 bar. The early eluting peak at RT = 2.72 minutes was concentrated under reduced pressure to get tert- butyl (R)-4-((3-(((R)-1-(4-((1-(5-ethoxy-5-oxopentyl)piperidin-4-y l)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)-3,3-difluoropyrrol idine-1-carboxylate (4, 120 mg, 153.04 mmol, 20% yield) as an off-white solid. UPLC-MS (ES ⁺ ): m/z 746.1 [M + H] ⁺ . [α] ²⁵ = - 24.8 (c 0.25, THF). The late eluting peak at RT = 4.73 minutes was concentrated under reduced pressure to get tert- butyl (S)-4-((3-(((R)-1-(4-((1-(5-ethoxy-5-oxopentyl)piperidin-4-y l)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)-3,3-difluoropyrrol idine-1-carboxylate (5, 125 mg, 0.156 mmol, 21% yield) as a white solid. UPLC-MS (ES ⁺ ): m/z 746.1 [M + H] ⁺ . [α] ²⁵ = - 42.56 (c 0.25, THF). Note: Configurations are arbitrarily assigned. Example 151 Synthesis of 1-(2-(4-((4-((R)-1-(5-(((S)-1-(tert-butoxycarbonyl)-4,4-difl uoropyrrolidin-3- yl)amino)-2-methylbenzamido)ethyl)naphthalen-1-yl)ethynyl)pi peridin-1-yl)ethyl)-1H- pyrazole-4-carboxylic acid Step-1: To a 40 mL glass-vial containing a well-stirred solution of ethyl 1H-pyrazole-4-carboxylate (1, 1 g, 7.14 mmol) and 2-bromo-1,1-diethoxy-ethane (2, 2.11 g, 10.70 mmol) in anhydrous acetonitrile (10 mL) was added cesium carbonate (4.65 g, 14.27 mmol) at ambient temperature. The resulting mixture was stirred at 90 °C for 8 h. Upon completion of the reaction as indicated by UPLC, the reaction mixture was passed through a pad of Celite and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (230-400 mesh silica gel) with 30% EtOAc in pet ether as eluent to get ethyl 1-(2,2-diethoxyethyl) pyrazole-4- carboxylate (3, 1.5 g, 4.68 mmol, 66% yield) as a colorless liquid. LC-MS (ES ⁺ ): m/z 257.1 [M + H] ⁺ . Step-2: To a 10 mL single-neck round-bottom flask containing a well-stirred solution of ethyl 1-(2,2- diethoxyethyl) pyrazole-4-carboxylate (3, 0.3 g, 0.936 mmol) in anhydrous DCM (5 mL) was added TFA (1.80 g, 15.81 mmol, 1.22 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 h and monitored by UPLC. Excess solvent was then removed from the reaction mixture and the obtained crude was azeotroped with toluene (20 mL) to afford ethyl 1-(2-oxoethyl) pyrazole-4-carboxylate trifluoroacetate (4, 0.32 g, 0.745 mmol, 80% yield) as a colorless syrupy liquid. LC-MS (ES ⁺ ): m/z 181.1 [M + H] ⁺ . Step-3: To a 50 mL sealed tube containing a well-stirred solution of tert-butyl (S)-4-((3-(((R)-1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)- 3,3-difluoropyrrolidine-1- carboxylate (5, 270 mg, 0.449 mmol) and 4-ethynylpiperidine hydrochloride (6, 49.58 mg, 0.337 mmol) in anhydrous acetonitrile (5 mL) and THF (2 mL) was added cesium carbonate (366.25 mg, 1.12 mmol) at ambient temperature. Nitrogen gas was purged through the reaction mixture for 10 minutes. Subsequently, XPhos (42.87 mg, 0.089 mmol) and XPhos-Pd-G3 (76.12 mg, 0.089 mmol) were added and stirring was continued for 3 h at 90 °C. Upon completion of the reaction as confirmed by UPLC, the reaction mixture was passed through a pad of Celite and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (230-400 mesh silica gel) with 30% MeOH in DCM as eluent to afford tert-butyl (S)-3,3-difluoro-4-((4-methyl-3-(((R)-1-(4-(piperidin-4-ylet hynyl)naphthalen-1- yl)ethyl)carbamoyl)phenyl)amino)pyrrolidine-1-carboxylate (7, 0.2 g, 0.304 mmol, 68% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 617.5 [M + H] ⁺ . Note: Configurations are arbitrarily assigned. Step-4: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (S)-3,3- difluoro-4-((4-methyl-3-(((R)-1-(4-(piperidin-4-ylethynyl)na phthalen-1- yl)ethyl)carbamoyl)phenyl)amino)pyrrolidine-1-carboxylate (7, 0.2 g, 0.304 mmol), ethyl 1-(2- oxoethyl)pyrazole-4-carboxylate trifluoroacetate (4, 0.32 g, 1.21 mmol) in anhydrous MeOH (6 mL) were added sodium acetate, anhydrous (125.03 mg, 1.52 mmol) and acetic acid (1.05 g, 17.47 mmol, 1 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 2 h. Subsequently, MP-CNBH ₃ ; (0.4 g, 0.8 mmol; 2mmol\g) was added and stirring was continued for 16 h. Upon completion of the reaction as confirmed by UPLC, the reaction mixture was passed through a sintered funnel and the filtrate was concentrated under reduced pressure. The crude mass was purified by flash column chromatography (230-400 mesh silica gel) with 9% MeOH/DCM as eluent to get ethyl 1-(2-(4-((4-((R)-1-(5-(((S)-1-(tert-butoxycarbonyl)-4,4-difl uoropyrrolidin-3- yl)amino)-2-methylbenzamido)ethyl)naphthalen-1-yl)ethynyl)pi peridin-1-yl)ethyl)-1H-pyrazole- 4-carboxylate (8, 0.3 g, 0.256 mmol, 84% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 783.6 [M + H] ⁺ . Step-5: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of ethyl 1-(2-(4-((4- ((R)-1-(5-(((S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolid in-3-yl)amino)-2- methylbenzamido)ethyl)naphthalen-1-yl)ethynyl)piperidin-1-yl )ethyl)-1H-pyrazole-4- carboxylate (8, 0.3 g, 0.256 mmol) in 1:1 THF/MeOH (4 mL) was added lithium hydroxide, monohydrate (107.73 mg, 2.57 mmol) in water (2 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 4 h. Upon completion of the reaction as confirmed by UPLC, the solvent was removed from the reaction mixture and the crude product was purified by reverse-phase column chromatography (RediSep-Rf Gold C18 column, Mobile phase A: formic acid in water and B : acetonitrile) to afford 1-(2-(4-((4-((R)-1-(5-(((S)-1-(tert- butoxycarbonyl)-4,4-difluoropyrrolidin-3-yl)amino)-2-methylb enzamido)ethyl)naphthalen-1- yl)ethynyl)piperidin-1-yl)ethyl)-1H-pyrazole-4-carboxylic acid formate (9, 0.19 g, 0.232 mmol, 90% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 755.4 [M + H] ⁺ . Example 152 2-methyl-5-[[(3S)-4,4-difluoropyrrolidin-3-yl]amino]-N-[(1R) -1-[4-[2-[1-[[1-[1-[1-(2,6- dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidi ne-4-carbonyl]-4- piperidyl]methyl]-4-piperidyl]ethynyl]-1-naphthyl]ethyl]benz amide (Compound 88) Step-1: To a 25 mL single-neck round-bottom flask containing well stirred solution of 1-[1-(2,6-dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-car boxylic acid hydrochloride (2, 120 mg, 236.96 μmol), tert-butyl (4S)-3,3-difluoro-4-[4-methyl-3-[[(1R)-1-[4-[2-[1-(4- piperidylmethyl)-4-piperidyl]ethynyl]-1-naphthyl]ethyl]carba moyl]anilino]pyrrolidine-1- carboxylate (1, 196.10 mg, 260.65 μmol) in anhydrous DMF (2.84 mL) were added HATU (135.15 mg, 355.44 μmol) and DIPEA (153.13 mg, 1.18 mmol, 206.37 μL) at room temperature. The contents were stirred at room temperature for 1 h. Upon completion of the reaction as indicated by UPLC, the reaction mixture was quenched with water and the off-white precipitate was filtered and dried under reduced pressure to afford tert-butyl (4S)-3,3-difluoro-4-[4-methyl-3-[[(1R)-1-[4- [2-[1-[[1-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzi midazol-5-yl]piperidine-4- carbonyl]-4-piperidyl]methyl]-4-piperidyl]ethynyl]-1- naphthyl]ethyl]carbamoyl]anilino]pyrrolidine-1-carboxylate (3, 200 mg, 133.05 μmol, 56% yield) as an off-white solid. UPLC-MS (ES+): m/z 1082.7 [M + H] ⁺ . Step-2: To a 50 mL single-necked round-bottomed flask containing well stirred solution of tert-butyl (4S)- 3,3-difluoro-4-[4-methyl-3-[[(1R)-1-[4-[2-[1-[[1-[1-[1-(2,6- dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]piperidine-4-carbonyl]-4-piperidyl]methyl] -4-piperidyl]ethynyl]-1- naphthyl]ethyl]carbamoyl]anilino]pyrrolidine-1-carboxylate (3, 200 mg, 133.05 μmol) in anhydrous DCM (4 mL) was added 4 M HCl in 1,4-dioxane (2 mL) at -78 °C. The contents were then stirred at room temperature for 0.5 h. Upon completion of the reaction as indicated by UPLC, the solvent was removed from the reaction mixture and the crude product was purified by reverse phase prep-HPLC [X-Select C18 (150×19)mm 5 microns column, mobile phase: 0.1% FA in water : MeCN] to afford 2-methyl-5-[[(3S)-4,4-difluoropyrrolidin-3-yl]amino]-N-[(1R) -1-[4-[2-[1-[[1- [1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]piperidine-4-carbonyl]-4- piperidyl]methyl]-4-piperidyl]ethynyl]-1-naphthyl]ethyl]benz amide formate (Compound 88, 80 mg, 74.94 μmol, 56.32% yield) as white solid. LCMS (ES ⁺ ): m/z 982.3 [M + H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d6): δ 11.06 (s, 1H), 8.81 (d, J = 8.00 Hz, 1H), 8.34-8.29 (m, 2H), 7.67-7.56 (m, 4H), 6.95-6.93 (m, 2H), 6.84 (s, 1H), 6.65-6.60 (m, 4H), 5.90-5.80 (m, 2H), 5.29 (s, 1H), 4.45- 4.38 (m, 1H), 3.98-3.94 (m, 2H), 3.63-3.60 (m, 2H), 3.04-2.99 (m, 2H), 2.96-2.90 (m, 2H), 2.86- 2.66 (m, 5H), 2.33-2.26 (m, 3H), 2.10 (s, 3H), 1.98-1.81 (m, 3H), 1.78-1.72 (m, 10H), 1.54 (d, J = 8.00 Hz, 3H), 1.08-0.81 (m, 2H).

Example 153 5-[[(3S)-4,4-difluoropyrrolidin-3-yl]amino]-2-methyl-N-[(1R) -1-[4-[2-[1-[[1-[1-[3-methyl-1- (1-methyl-2,6-dioxo-3-piperidyl)-2-oxo-benzimidazol-5-yl]pip eridine-4-carbonyl]-4- piperidyl]methyl]-4-piperidyl]ethynyl]-1-naphthyl]ethyl]benz amide (Compound 89) Step-1: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (S)-3,3- difluoro-4-((4-methyl-3-(((R)-1-(4-((1-(piperidin-4-ylmethyl )piperidin-4-yl)ethynyl)naphthalen- 1-yl)ethyl)carbamoyl)phenyl)amino)pyrrolidine-1-carboxylate (1, 95 mg, 0.119 mmol) and 1-[3- methyl-1-(1-methyl-2,6-dioxo-3-piperidyl)-2-oxo-benzimidazol -5-yl]piperidine-4-carboxylic acid hydrochloride (2, 53.26 mg, 0.119 mmol) in anhydrous DMF (2 mL) were added HATU (68.14 mg, 0.179 mmol) and DIPEA (77.20 mg, 0.559 mmol, 0.104 mL) and the resulting reaction mixture was stirred at ambient temperature for 2 h. After completion of the reaction mixture as indicated by TLC, cold water (50 mL) was added and the solid precipitate was filtered, washed with water and dried in vacuo to afford tert-butyl (4S)-3,3-difluoro-4-((4-methyl-3-(((1R)-1-(4- ((1-((1-(1-(3-methyl-1-(1-methyl-2,6-dioxopiperidin-3-yl)-2- oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-yl)m ethyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)phenyl)amino)pyrr olidine-1-carboxylate (3, 150 mg, 0.097 mmol, 81% yield) as a brown solid. LCMS (ES ⁺ ): m/z 1096.4 [M + H] ⁺ . Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (4S)- 3,3-difluoro-4-((4-methyl-3-(((1R)-1-(4-((1-((1-(1-(3-methyl -1-(1-methyl-2,6-dioxopiperidin-3- yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4- carbonyl)piperidin-4- yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carba moyl)phenyl)amino)pyrrolidine-1- carboxylate (3, 150 mg, 0.097 mmol) in anhydrous DCM (3 mL) was added 4N HCl in 1,4- dioxane (0.242 mL) at 0 °C. The resulting mixture was stirred for 2 h at ambient temperature. After completion of the reaction as confirmed by UPLC, excess solvent was removed from the reaction mixture under reduced pressure and the obtained crude was purified by reverse phase prep- HPLC (X SELECT C18 (250 x 19 mm) 5 micron; Mobile phase A; 0.1% FA in water : MeCN) to afford 5-(((S)-4,4-difluoropyrrolidin-3-yl)amino)-2-methyl-N-((1R)- 1-(4-((1-((1-(1-(3-methyl- 1-(1-methyl-2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-be nzo[d]imidazol-5-yl)piperidine-4- carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)ethynyl)naphth alen-1-yl)ethyl)benzamide formate (Compound 89, 31 mg, 0.028 mmol, 29% yield) as a light pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.83 (d, J = 8 Hz, 1H), 8.33-8.29 (m, 2H), 7.69-7.64 (m, 3H), 7.56 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 2 Hz, 1H), 6.66-6.59 (m, 3H), 5.90-5.82 (m, 2H), 5.38- 5.34 (m, 1H), 4.45-4.35 (m, 1H), 4.05-3.90 (m, 2H), 3.67-3.55 (m, 2H), 3.30 (s, 3H), 3.20 (m, 4H), 3.05 (s, 3H), 3.00-2.90 (m, 4H), 2.80-2.60 (m, 7H), 2.50 (m, 2H), 2.30 (m, 4H), 2.10 (s, 3H), 2.02- 1.98 (m, 3H), 1.90-1.62 (m, 8H), 1.54 (d, J = 6.8 Hz, 3H) and 1.17-0.79 (m, 2H). LCMS (ES ⁺ ): m/z 997.4 [M + H] ⁺ . Example 154 5-(((S)-4,4-difluoropyrrolidin-3-yl)amino)-N-((1R)-1-(4-((1- ((1-(1-(1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pipe ridine-4-carbonyl)-4- hydroxypiperidin-4-yl)methyl)piperidin-4-yl)ethynyl)naphthal en-1-yl)ethyl)-2- methylbenzamide (Compound 90) Step-1: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (S)-3,3- difluoro-4-((3-(((R)-1-(4-((1-((4-hydroxypiperidin-4-yl)meth yl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)pyrrolidine-1-carboxylate (1, 140 mg, 0.182 mmol) and 1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]piperidine-4-carboxylic acid hydrochloride (2, 77.05 mg, 0.182 mmol) in anhydrous DMF (2.5 mL) were added HATU (103.93 mg, 0.273 mmol) and DIPEA (117.75 mg, 0.911 mmol, 0.158 mL) and the reaction mixture was stirred at ambient temperature for 2 h. After completion of the reaction, reaction mixture was quenched with water, and the solid precipitate was filtered, washed with water and dried in vacuo to afford tert-butyl (4S)-4-((3-(((1R)-1-(4-((1-((1-(1-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidine-4- carbonyl)-4-hydroxypiperidin-4-yl)methyl)piperidin-4-yl)ethy nyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)-3,3-difluoropyrrol idine-1-carboxylate (3, 130 mg, 0.104 mmol, 57% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 1099.4 [M + H] ⁺ . Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (4S)-4- ((3-(((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-me thyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)-4-hydroxypiperi din-4-yl)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)-3,3-difluoropyrrolidine-1- carboxylate (3, 130 mg, 0.104 mmol) in anhydrous DCM (2 mL) was added 4N HCl/1,4-dioxane (0.260 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 2 h. After completion of the reaction as indicated by TLC/UPLC, excess solvent was removed from the reaction mixture and the obtained crude was purified by reverse phase prep-HPLC (X SELECT C18 (250 × 19 mm) 5 micron with 0.1% formic acid in water : MeCN) to get 5-(((S)-4,4- difluoropyrrolidin-3-yl)amino)-N-((1R)-1-(4-((1-((1-(1-(1-(2 ,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carbon yl)-4-hydroxypiperidin-4- yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)-2-me thylbenzamide formate (Compound 90, 23 mg, 0.0207 mmol, 20% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 998.9 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO d6): δ 11.07 (s, 1H), 8.83 (d, J = 8 Hz, 1H), 8.33-8.29 (m, 2H), 7.69-7.65 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 6.96-6.93 (m, 2H), 6.83 (d, J = 2 Hz, 1H), 6.66- 6.61 (m, 3H), 5.90-5.88 (m, 2H), 5.29-5.26 (m, 1H), 4.09-4.07 (m, 3H), 3.78-3.75 (m, 1H), 3.63- 3.60 (m, 3H), 3.30 (s, 3H), 3.17-3.10 (m, 3H), 3.05-2.84 (m, 5H), 2.80-2.60 (m, 10H), 2.50 (m, 2H), 2.10 (s, 3H), 2.07 (m, 1H), 2.05-1.8 (m, 3H), 1.71-1.68 (m, 4H), 1.54 (d, J = 6.8 Hz, 3H), 1.52 (m, 2H) and 1.49-1.40 (m, 2H). Example 155 Synthesis of 5-(((R)-4,4-difluoropyrrolidin-3-yl)amino)-N-((1R)-1-(4-((1- ((1-(1-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidine-4- carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)ethynyl)naphth alen-1-yl)ethyl)-2- methylbenzamide (Compound 91) Step-1: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 1-[1-(2,6-dioxo- 3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-c arboxylic acid (2, 120 mg, 0.236 mmol) in anhydrous DMF (3 mL) were added DIPEA (153.13 mg, 1.18 mmol, 0.2 mL) and HATU (135.15 mg, 0.355 mmol) followed by tert-butyl(R)-3,3-difluoro-4-((4-methyl-3-(((R)-1-(4-((1- (piperidin-4-ylmethyl)piperidin-4-yl)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)phenyl)amino)pyrrolidine-1-carboxylate hydrochloride (1, 194.75 mg, 0.260 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 1 h. The progress of the reaction was monitored by UPLC. The reaction mixture was concentrated under reduced pressure to get a crude residue and the latter was diluted with ice-cold water (20 mL) and solid precipitated out was filtered. Solid on the filter was washed with water (10 mL), dried in vacuo to afford tert-butyl (4R)-4-((3-(((1R)-1-(4-((1-((1-(1-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidine-4- carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)ethynyl)naphth alen-1-yl)ethyl)carbamoyl)-4- methylphenyl)amino)-3,3-difluoropyrrolidine-1-carboxylate (3, 210 mg, 0.153 mmol, 65% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 1082.7 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (4R)- 4-((3-(((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-yl)m ethyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)-3,3-difluoropyrrolidine-1- carboxylate (3, 210 mg, 0.153 mmol) in anhydrous DCM (2 mL) was added 4N HCl in 1,4-dioxane (2 mL, 8 mmol) at -78 °C and the resulting mixture was stirred at ambient temperature for 0.5 h. Upon completion of the reaction as indicated by UPLC, excess solvent was removed under reduced pressure and the obtained crude was purified by reverse phase column chromatography (RediSep- RF Gold C18 column, mobile phase: 10 mm HCOOH in water : MeCN) to afford 5-(((R)-4,4- difluoropyrrolidin-3-yl)amino)-N-((1R)-1-(4-((1-((1-(1-(1-(2 ,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carbon yl)piperidin-4- yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)-2-me thylbenzamide formate (Compound 91, 60 mg, 0.057 mmol, 37% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 982.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.06 (s, 1H), 8.82 (d, J = 8 Hz, 1H), 8.34-8.29 (m, 2H), 7.67-7.58 (m, 4H), 6.96-6.93 (m, 2H), 6.84 (s, 1H), 6.66-6.60 (m, 3H), 5.91-5.79 (m, 2H), 5.35-5.28 (m, 1H), 4.45-4.38 (m, 1H), 3.98-3.94 (m, 2H), 3.63-3.60 (m, 3H), 3.30 (m, 2H), 3.03- 2.90 (m, 2H), 2.85-2.50 (m, 11H), 2.34-2.22 (m, 4H), 2.12 (s, 3H), 2.00-1.98 (m, 4H), 1.77-1.72 (m, 11H), 1.54 (d, J = 8 Hz, 3H) and 1.08-0.81 (m, 2H). Example 156 Synthesis of 2-methyl-5-[[(3R)-4,4-difluoropyrrolidin-3-yl]amino]-N-[(1R) -1-[4-[2-[1-[[1-[1- [1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl] piperidine-4-carbonyl]-4- fluoro-4-piperidyl]methyl]-4-piperidyl]ethynyl]-1-naphthyl]e thyl]benzamide (Compound 92) Compound 92 was prepared substantially following the synthesis of Compound 88, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 1001.2 [M + H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 8.84 (d, J = 8.00 Hz, 1H), 8.30-8.32 (m, 2H), 8.14 (s, 1H), 7.62-7.65 (m, 4H), 6.98-6.93 (m, 2H), 6.84 (d, J = 2.00 Hz, 1H), 6.63-6.65 (m, 3H), 5.90-5.87 (m, 2H), 5.29-5.26 (m, 1H), 4.16-4.13 (m, 2H), 3.90-3.80 (m, 1H), 3.63-3.60 (m, 2H), 3.31 (s, 3H), 3.26-3.19 (m, 2H), 2.92-2.82 (m, 6H), 2.80-2.70 (m, 3H), 2.70-2.60 (m, 2H), 2.50- 2.42 (m, 2H), 2.13 (s, 3H), 2.01-1.95 (m, 3H), 1.77-1.72 (m, 6H), 1.54 (d, J = 6.80 Hz, 3H). Example 157 2-methyl-5-[[(3S)-4,4-difluoropyrrolidin-3-yl]amino]-N-[(1R) -1-[4-[2-[1-[[1-[1-[1-(2,6- dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidi ne-4-carbonyl]-4-fluoro-4- piperidyl]methyl]-4-piperidyl]ethynyl]-1-naphthyl]ethyl]benz amide (Compound 93) Compound 93 was prepared substantially following the synthesis of Compound 88, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 1000.1 [M + H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.07 (s, 1H), 8.84 (d, J = 8.00 Hz, 1H), 8.30-8.32 (m, 2H), 8.14 (s, 1H), 7.62-7.65 (m, 4H), 6.98-6.93 (m, 2H), 6.84 (d, J = 2.00 Hz, 1H), 6.63-6.65 (m, 3H), 5.90-5.87 (m, 2H), 5.29-5.26 (m, 1H), 4.16-4.13 (m, 2H), 3.90-3.80 (m, 1H), 3.63-3.60 (m, 2H), 3.31 (s, 3H), 3.26-3.19 (m, 2H), 2.92-2.82 (m, 6H), 2.80-2.70 (m, 3H), 2.70-2.60 (m, 2H), 2.50- 2.42 (m, 2H), 2.13 (s, 3H), 2.01-1.95 (m, 3H), 1.77-1.72 (m, 6H), 1.54 (d, J = 6.80 Hz, 3H). Example 158 5-[[(3S)-4,4-difluoropyrrolidin-3-yl]amino]-2-methyl-N-[(1R) -1-[4-[2-[1-[[1-[1-[1-methyl-3- [(3R)-3-methyl-2,6-dioxo-3-piperidyl]indazol-6-yl]piperidine -4-carbonyl]-4- piperidyl]methyl]-4-piperidyl]ethynyl]-1-naphthyl]ethyl]benz amide (Compound 94) Compound 94 was prepared substantially following the synthesis of Compound 88, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 981.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.82 (s, 1H), 8.82 (d, J = 7.6 Hz, 1H), 8.34-8.28 (m, 2H), 7.67- 7.55 (m, 5H),6.95-6.89 (m, 2H), 6.83 (s, 1H), 6.66 (s,1H), 6.65-6.59 (m, 1H), 5.90-5.80 (m, 2H), 4.41-4.38 (m, 1H), 4.02-3.90 (m, 2H), 3.87 (s, 3H), 3.83-3.80 (m, 2H), 3.38-3.20 (m, 2H), 3.04- 2.93 (m, 3H), 2.93-2.70 (m, 4H), 2.68-2.66 (m, 4H), 2.50 (m, 2H), 2.42-2.41 (m, 1H), 2.30 – 2.14 (m, 4H), 2.13 (s, 3H), 2.08-1.95 (m, 2H), 1.77-1.70 (m, 10H), 1.61 (s, 3H), 1.54 (d, J = 6.8 Hz, 3H) and 0.92 (m, 2H). Example 159 N-((1R)-1-(4-((1-((4-cyano-1-(1-(1-(2,6-dioxopiperidin-3-yl) -3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-y l)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-5-(((S)-4,4-difluoropyrrol idin-3-yl)amino)-2- methylbenzamide (Compound 95) Compound 95 was prepared substantially following the synthesis of Compound 88, using the corresponding intermediates. ¹ H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 8.82 (d, J = 8 Hz, 1H), 8.34-8.29 (m, 2H), 7.69- 7.63 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 6.95-6.93 (m, 2H), 6.84 (d, J = 1.6 Hz, 1H), 6.63-6.59 (m, 3H), 5.90-5.80 (m, 2H), 5.32-5.21 (m, 1H), 4.57-4.48 (m, 1H), 4.11-4.08 (m, 1H), 3.95-3.89 (m, 1H), 3.72-3.60 (m, 2H), 3.51-3.49 (m, 2H), 3.38-3.18 (m, 4H), 2.97-2.90 (m, 3H), 2.85-2.79 (m, 3H), 2.78-2.69 (m, 7H), 2.69-2.66 (m, 3H), 2.10 (s, 3H), 2.08-1.96 (m, 6H), 1.77-1.73 (m, 6H), 1.54 (d, J = 6.8 Hz, 3H) and 1.39-1.24 (m, 2H). LCMS: ES+ (M+H) 1007.4. Example 160 5-(((S)-4,4-difluoropyrrolidin-3-yl)amino)-N-((1R)-1-(4-((1- (2-(4-(4-(1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pi peridine-1-carbonyl)-1H- pyrazol-1-yl)ethyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)et hyl)-2-methylbenzamide (Compound 96) Compound 96 was prepared substantially following the synthesis of Compound 88, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 979.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.09 (s, 1H), 8.82 (d, J = 8 Hz, 1H), 8.31-8.28 (m, 2H), 8.12 (s, 1H), 7.70 (s, 1H), 7.65-7.60 (m, 3H), 7.55 (d, J = 7.6 Hz, 1H), 7.11 (s, 1H), 7.00-6.88 (m, 3H), 6.66-6.62 (m, 2H), 5.97-5.79 (m, 2H), 5.35-5.31 (m, 1H), 4.51-4.38 (m, 2H), 4.28-4.25 (t, J = 6.4 Hz, 2H), 3.93-3.89 (m, 1H), 3.31 (s, 3H), 3.26-3.23 (m, 2H), 3.02-2.92 (m, 2H), 2.81-2.79 (m, 3H), 2.76-2.69 (m, 4H), 2.68-2.50 (m, 5H), 2.38-2.28 (m, 2H), 2.10 (s, 3H), 2.00-1.93 (m, 3H), 1.84-1.82 (m, 2H), 1.73-1.66 (m, 4H) and 1.54 (d, J = 6.8 Hz, 3H). Example 161 N-((1R)-1-(4-((1-((4-cyano-1-(1-(1-(2,6-dioxopiperidin-3-yl) -3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-y l)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-5-(((R)-4,4-difluoropyrrol idin-3-yl)amino)-2- methylbenzamide (Compound 97) Compound 97 was prepared substantially following the synthesis of Compound 88, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 1030.2 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 8.83 (d, J = 7.6 Hz, 1H), 8.34-8.30 (m, 2H), 7.69-7.66 (m, 4H), 6.94 (dd, J = 8.2, 4.4 Hz, 2H), 6.85-6.84 (m, 1H), 6.60-6.66 (m, 3H), 5.91- 5.87 (m, 1H), 5.85-5.75 (m, 1H), 5.34-5.29 (m, 1H), 4.48-4.44 (m, 1H), 4.11-4.08 (m, 1H), 3.97- 3.90 (m, 1H), 3.62 -3.5(m, 2H), 3.64-3.61 (m, 3H), 3.20-3.10 (m, 3H), 2.74-2.66 (m, 5H), 2.75- 2.65 (m, 5H), 2.62-2.49 (m, 5H), 2.12 (s, 3H), 2.10 (m, 1H), 2.19-2.09 (m, 5H), 1.82-1.69 (m, 7H), 1.54 (d, J = 6.8 Hz, 3H) and 1.45-1.35 (m, 2H). Example 162 Synthesis of 5-(((S)-4,4-difluoropyrrolidin-3-yl)amino)-N-((1R)-1-(4-((1- (5-(4-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidin-1-yl)- 5-oxopentyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)-2- methylbenzamide (Compound 98) Step-1: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (S)-4- ((3-(((R)-1-(4-((1-(5-ethoxy-5-oxopentyl)piperidin-4-yl)ethy nyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)-3,3-difluoropyrrol idine-1-carboxylate (1, 125 mg, 0.156 mmol) in THF (1.5 mL) and MeOH (1.5 mL) was added lithium hydroxide, monohydrate (65.49 mg, 1.56 mmol) in water (1.5 mL) at ambient temperature. The resulting mixture was stirred at this temperature for 3 h. Upon completion of the reaction as indicated by UPLC, the solvent was removed from the reaction mixture. The crude product was dissolved into 10% aqueous citric acid solution and extracted with 10% MeOH/ DCM (3 × 50 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 5-(4-((4-((S)-1-(5-(((R)-1-(tert-butoxycarbonyl)-4,4-difluor opyrrolidin-3-yl)amino)-2- methylbenzamido)ethyl)naphthalen-1-yl)ethynyl)piperidin-1-yl )pentanoic acid (2, 115 mg, 0.139 mmol, 89% yield) as an off-white solid. UPLC-MS (ES ⁺ ): m/z 717.6 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 5-(4-((4-((S)-1- (5-(((R)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-3-yl )amino)-2- methylbenzamido)ethyl)naphthalen-1-yl)ethynyl)piperidin-1-yl )pentanoic acid (2, 115 mg, 0.209 mmol) and 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidin e-2,6-dione hydrochloride (3, 106.07 mg, 0.279 mmol) in anhydrous DMF (2 mL) were added HATU (105 mg, 0.279 mmol) and DIPEA (88.28 mg, 0.695 mmol, 0.118 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 2 h. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure. The residue was diluted with ice-cold water (10 mL) and the solid precipitate was filtered, washed with water (10 mL) and dried in vacuo to afford tert-butyl (4S)-4-((3-(((1R)-1-(4-((1-(5-(4-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidin-1-yl)-5- oxopentyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carba moyl)-4-methylphenyl)amino)-3,3- difluoropyrrolidine-1-carboxylate (4, 140 mg, 0.102 mmol, 73% yield) as an off-white solid. UPLC-MS (ES ⁺ ): m/z 1041.6 [M + H] ⁺ . Step-3: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (4S)-4- ((3-(((1R)-1-(4-((1-(5-(4-(1-(2,6-dioxopiperidin-3-yl)-3-met hyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-1-yl)-5-oxopentyl)piperidin- 4-yl)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)-3,3-difluoropyrrol idine-1-carboxylate (4, 140 mg, 0.102 mmol) in anhydrous DCM (2 mL) was added 4N HCl in 1,4-dioxane (1 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 1 h. Upon completion of the reaction as confirmed by UPLC, the solvent was removed and the crude product was purified by reverse phase prep-HPLC (X-SELECT C18 (250 x 19)mm, 5 micron; Mobile phase: A:0.1% formic acid in MQ- water; B: Acetonitrile; Flow rate: 15 mL/minutes) to afford 5-(((S)-4,4-difluoropyrrolidin-3- yl)amino)-N-((1R)-1-(4-((1-(5-(4-(1-(2,6-dioxopiperidin-3-yl )-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-1-yl)-5-oxopentyl)piperidin- 4-yl)ethynyl)naphthalen-1- yl)ethyl)-2-methylbenzamide formic acid (Compound 98, 45 mg, 0.045 mmol, 45% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.08 (s, 1H), 8.81 (d, J = 8 Hz, 1H), 8.33-8.28 (m, 2H), 7.65-7.55 (m, 4H), 7.10 (s, 1H), 7.01 (d, J = 8 Hz, 1H), 6.95-6.91 (m, 2H), 6.66-6.60 (m, 2H), 5.88-5.81 (m, 1H), 5.79-5.75 (m, 1H), 5.34-5.29 (m, 1H), 4.61-4.54 (m, 1H), 4.01-3.93 (m, 1H), 3.95-3.83 (m, 2H), 3.10 (m, 2H), 3.08-2.90 (m, 4H), 2.87-2.71 (m, 7H), 2.52-2.50 (m, 2H), 2.37-2.33 (m, 5H), 2.23-2.18 (m, 2H), 2.10 (s, 3H), 1.99-1.96 (m, 3H), 1.80-1.63 (m, 5H) and1.60- 1.50 (m, 8H). LC-MS (ES ⁺ ): m/z 941.2 [M + H] ⁺ . Example 163 5-(((R)-4,4-difluoropyrrolidin-3-yl)amino)-N-((1R)-1-(4-((1- (5-(4-(1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pipe ridin-1-yl)-5- oxopentyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)-2-me thylbenzamide (Compound 99) Compound 99 was prepared substantially following the synthesis of Compound 98, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 941.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.09 (s, 1H), 8.82 (d, J = 8 Hz, 1H), 8.33-8.28 (m, 2H), 7.66-7.57 (m, 4H), 7.11 (s, 1H), 7.02 (d, J = 8Hz, 1H), 6.96-6.91 (m, 2H), 6.66-6.62 (m, 1H), 6.61-6.55 (m, 1H), 5.91-5.87 (m, 1H), 5.81-5.79 (m, 1H), 5.36-5.31 (m, 1H), 4.61-4.53 (m, 1H), 4.05-4.01 (m, 1H), 3.97-3.89 (m, 1H), 3.14-3.11 (m, 2H), 3.08-2.90 (m, 2H), 2.85-2.71 (m, 4H), 2.68-2.59 (m, 4H), 2.52-2.50 (m, 2H), 2.37-2.34 (m, 5H), 2.28-2.21 (m, 2H), 2.12 (s, 3H), 2.00- 1.96 (m, 4H), 1.80-1.73 (m, 4H), 1.63-1.55 (m, 1H), 1.54-1.49 (m, 9H). Example 164 Synthesis of tert-butyl (S)-3,3-difluoro-4-((4-methyl-3-(((R)-1-(4-((4-(piperidin-4- yloxy)cyclohexyl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)phe nyl)amino)pyrrolidine-1- carboxylate

Step-1: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of methyl 4- hydroxycyclohexanecarboxylate (1, 4 g, 25.29 mmol), pyridin-4-ol (2, 2.40 g, 25.29 mmol) and triphenyl phosphine (7.96 g, 30.34 mmol) in anhydrous THF (40 mL) was added diisopropyl azodicarboxylate (6.65 g, 32.87 mmol, 6.47 mL) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 55 °C for 48 h and the reaction progress was monitored by UPLC. Excess solvent was removed from the reaction mixture under reduced pressure and 1:1 EtOAc\pet-ether (20 mL) was added and resulting mixture was stirred for 16 h. This reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by reverse-phase HPLC (RediSep-Rf Gold C18 column, Mobile phase A: Formic acid in water and B: Acetonitrile) to afford methyl 4-(4- pyridyloxy)cyclohexane carboxylate formate (3, 3 g, 10.56 mmol, 42% yield) as a syrupy liquid. LC-MS (ES ⁺ ): m/z 236.2 [M + H] ⁺ . Step-2: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of methyl 4-(4- pyridyloxy)cyclohexane carboxylate formate (3, 2.7 g, 9.50 mmol) in anhydrous MeOH (30 mL) were added acetic acid (3.15 g, 52.40 mmol, 3 mL) and Palladium hydroxide on carbon, 20 wt.% 50% water (4 g, 5.70 mmol) at ambient temperature. The resulting mixture was stirred for 24 h at ambient temperature under hydrogen atmosphere (~ 1 atm). Upon completion of reaction as confirmed by UPLC, the reaction mixture was passed through a pad of Celite and the filtrate was concentrated under reduced pressure to afford methyl 4-(4-piperidyloxy) cyclohexane carboxylate (4, 2.3 g, 8.95 mmol, 94% yield) as a colorless syrupy liquid. LC-MS (ES ⁺ ): m/z 242.2 [M + H] ⁺ . Step-3: To a 50 mL single-neck round-bottom flask containing well-stirred solution of methyl 4-(4- piperidyloxy) cyclohexane carboxylate (4, 2.3 g, 8.96 mmol) in anhydrous DCM (30 mL) were added TEA (4.53 g, 44.79 mmol, 6.24 mL), DMAP (218.90 mg, 1.79 mmol) and Boc-anhydride (3.91 g, 17.92 mmol) at 0 °C. The resulting mixture was stirred at ambient temperature for 2 h. Upon completion of reaction as confirmed by UPLC, the reaction mixture was diluted with DCM (150 mL). The organic phase was washed with 1.5N HCl (2 × 20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (230-400 mesh silica gel) with 20-30% EtOAc/pet ether as eluent to afford tert- butyl 4-(4-methoxycarbonylcyclohexoxy)piperidine-1-carboxylate (5, 2.5 g, 7.25 mmol, 81% yield) as a colorless syrupy liquid. LC-MS (ES ⁺ ): m/z 242.2 [M - COO ^t Bu + H] ⁺ . Step-4: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-(4- methoxycarbonylcyclohexoxy)piperidine-1-carboxylate (5, 2.5 g, 7.25 mmol) in anhydrous DCM (30 mL) was added 1M diisobutylaluminum hydride in tetrahydrofuran (18.12 mL) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at ambient temperature and monitored by UPLC. The reaction mixture was quenched with brine (20 mL) at 0 °C and stirred for 2 h. The reaction mixture was passed through a pad of Celite, and the aqueous phase was extracted with DCM (2 × 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (230-400 mesh silica gel) with 50- 70% EtOAc/pet ether as eluent to get tert-butyl 4-[4-(hydroxymethyl)cyclohexoxy]piperidine-1- carboxylate (6, 1.8 g, 5.69 mmol, 78% yield) as a colorless syrupy liquid. LC-MS (ES ⁺ ): m/z 214.2 [M - COO ^t Bu + H] ⁺ . Step-5: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[4- (hydroxymethyl) cyclohexoxy]piperidine-1-carboxylate (6, 1.9 g, 6.00 mmol) in anhydrous DCM (15 mL) was added Dess-Martin periodinane (3.82 g, 9.00 mmol) at 0 °C. The resulting mixture was stirred at ambient temperature under nitrogen atmosphere for 2 h. Upon completion of the reaction as confirmed by UPLC, the reaction was quenched with aqueous saturated sodium thiosulfate (5 mL) and aqueous saturated sodium bicarbonate (5 mL) solution. The aqueous layer was extracted with DCM (3 × 40 mL) and the combined organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (230-400 mesh silica gel) with 35-45% EtOAc/pet ether as eluent to afford tert-butyl 4-(4-formylcyclohexoxy)piperidine-1-carboxylate (7, 1.4 g, 4.14 mmol, 69% yield) as a colorless syrupy liquid. LC-MS (ES ⁺ ): m/z 212.2 [M - COO ^t Bu + H] ⁺ . Step-6: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-(4- formylcyclohexoxy)piperidine-1-carboxylate (7, 1.3 g, 3.84 mmol) in anhydrous MeOH (20 mL) was added potassium carbonate, anhydrous, 99% (1.06 g, 7.68 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 15 minutes. Subsequently, dimethyl (1-diazo-2-oxopropyl)phosphonate (8, 1.48 g, 7.68 mmol) was added at 0 °C and the mixture was stirred at ambient temperature for 2 h. Upon completion of the reaction as confirmed by UPLC, the reaction was quenched with aqueous saturated NH4Cl solution. The aqueous phase was extracted with EtOAc (3 × 20 mL) and the combined organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (230-400 mesh silica gel) with 15-20% EtOAc/pet ether as eluent to afford tert-butyl 4-(4-ethynylcyclohexoxy)piperidine-1-carboxylate (9, 0.9 g, 2.92 mmol, 76% yield) as a colorless syrupy liquid. LC-MS (ES ⁺ ): m/z 208.2 [M - Boc + H] ⁺ . Step-7: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-(4- ethynylcyclohexoxy)piperidine-1-carboxylate (9, 0.9 g, 2.92 mmol) in anhydrous DCM (10 mL) was added 4N HCl/1,4-dioxane (5 mL) at ambient temperature. The resulting mixture was stirred at this temperature for 2 h. Upon completion of the reaction as confirmed by UPLC, excess solvent was removed from the reaction mixture. The crude residue was co-distilled with toluene (15 mL) to yield 4-(4-ethynylcyclohexoxy) piperidine hydrochloride (10, 0.65 g, 2.67 mmol, 91% yield) as a white solid. LC-MS (ES ⁺ ): m/z 208.2 [M + H] ⁺ . Step-8: To a 50 mL sealed tube containing a well-stirred solution of tert-butyl (S)-4-((3-(((R)-1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)- 3,3-difluoropyrrolidine-1- carboxylate (11, 0.2 g, 0.333 mmol) and 4-(4-ethynylcyclohexoxy)piperidine hydrochloride (10, 0.2 g, 0.812 mmol) in 1:1 anhydrous acetonitrile/THF (5 mL) was added cesium carbonate (0.35 g, 1.07 mmol) at ambient temperature. Nitrogen gas was purged through the reaction mixture for 10 minutes. Subsequently, XPhos (23.82 mg, 0.049 mmol) and XPhos-Pd-G3 (42.29 mg, 0.049 mol) were added and stirring was continued at 90 °C for 3 h. The reaction mixture was monitored by UPLC. The reaction mixture was passed through a pad of Celite and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (230-400 mesh silica gel) with 50-70% EtOAc/pet ether as eluent to afford tert- butyl (S)-3,3-difluoro-4-((4-methyl-3-(((R)-1-(4-((4-(piperidin-4- yloxy)cyclohexyl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)phe nyl)amino)pyrrolidine-1- carboxylate (12, 200 mg, 0.271 mmol, 81% yield) as a white solid. LC-MS (ES ⁺ ): m/z 716.0 [M + H] ⁺ . Example 165 Synthesis of 5-(((S)-4,4-difluoropyrrolidin-3-yl)amino)-N-((1R)-1-(4-(((1 s,4S)-4-((1-(1-(1- (2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benz o[d]imidazol-5-yl)piperidine- 4-carbonyl)piperidin-4-yl)oxy)cyclohexyl)ethynyl)naphthalen- 1-yl)ethyl)-2- methylbenzamide (Compound 100) and 5-(((S)-4,4-difluoropyrrolidin-3-yl)amino)-N-((1R)- 1-(4-(((1r,4R)-4-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methy l-2-oxo-2,3-dihydro-1H-

benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4- yl)oxy)cyclohexyl)ethynyl)naphthalen-1-yl)ethyl)-2-methylben zamide (Compound 101) Step-1: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (S)-3,3- difluoro-4-((4-methyl-3-(((R)-1-(4-((4-(piperidin-4-yloxy)cy clohexyl)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)phenyl)amino)pyrrolidine-1-carboxylate (1, 200 mg, 0.271 mmol) and 1-(1- (2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benz o[d]imidazol-5-yl)piperidine-4- carboxylic acid hydrochloride (2, 122.08 mg, 0.271 mmol) in anhydrous DMF (3 mL) were added HATU (154.78 mg, 0.407 mmol) and DIPEA (140.29 mg, 1.09 mmol, 0.189 mL) at ambient temperature. The resulting mixture was stirred at this temperature for 1 h. Upon completion of the reaction as indicated by UPLC, the reaction mixture was diluted with water and the formed off-white solid precipitate was filtered and dried in vacuo to afford tert-butyl (4S)-4- ((3-(((1R)-1-(4-((4-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-me thyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-yl)o xy)cyclohexyl)ethynyl)naphthalen- 1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)-3,3-difluoropyrr olidine-1-carboxylate (3; 250 mg, 0.216 mmol, 80% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 1083.6 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (4S)-4- ((3-(((1R)-1-(4-((4-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-me thyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-yl)o xy)cyclohexyl)ethynyl)naphthalen- 1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)-3,3-difluoropyrr olidine-1-carboxylate (3, 250 mg, 0.216 mmol) in anhydrous DCM (3 mL) was added 4M HCl/1,4-dioxane (2 mL) at -78 °C. After completion of the addition the resulting mixture was stirred at ambient temperature for 0.5 h. Upon completion of the reaction as indicated by UPLC, excess solvent was removed from the reaction mixture under reduced pressure to get a crude residue. Crude residue was purified by reverse phase prep-HPLC (X-Select C18 (150 x 19) mm, 5 microns column; Mobile phase A: 0.1% Formic acid in water and B: MeCN) to afford 5-(((S)-4,4-difluoropyrrolidin-3-yl)amino)-N-((1R)-1-(4- (((1s,4S)-4-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-o xo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-yl)o xy)cyclohexyl)ethynyl)naphthalen- 1-yl)ethyl)-2-methylbenzamide formate (Compound 100, early eluting peak, 73 mg, 0.070 mmol, 33% yield) and 5-(((S)-4,4-difluoropyrrolidin-3-yl)amino)-N-((1R)-1-(4-(((1 r,4R)-4-((1-(1-(1- (2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benz o[d]imidazol-5-yl)piperidine-4- carbonyl)piperidin-4-yl)oxy)cyclohexyl)ethynyl)naphthalen-1- yl)ethyl)-2-methylbenzamide formate (Compound 101, late eluting peak, 30 mg, 0.029 mmol, 13% yield) as white solids. Compound 100: ¹ H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 8.81 (d, J = 8 Hz, 1H), 8.31-8.28 (m, 2H), 7.68- 7.61 (m, 3H), 7.56 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 2 Hz, 1H), 6.66-6.59 (m, 3H), 5.90-5.86 (m, 1H), 5.85-5.80 (m, 1H), 5.33-5.28 (m, 1H), 3.95-3.91 (m, 2H), 3.85-3.73 (m, 1H), 3.71-3.68 (m, 1H), 3.64-3.61 (m, 2H), 3.52-3.52 (m, 2H), 3.31 (s, 3H), 3.07-2.87 (m, 5H), 2.76-2.64 (m, 6H), 2.10-2.00 (m, 5H), 1.99-1.97 (m, 3H), 1.87-1.81 (m, 2H), 1.79-1.68 (m, 6H), 1.60-1.53 (m, 5H) and 1.40-1.32 (m, 4H). LC-MS (ES ⁺ ): m/z 983.4 [M + H] ⁺ . Compound 101: ¹ H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 8.82 (d, J = 8 Hz, 1H), 8.34-8.29 (m, 2H), 7.68- 7.64 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 6.95-6.92 (m, 2H), 6.84 (d, J = 2 Hz, 1H), 6.66-6.59 (m, 3H), 5.91-5.87 (m, 1H), 5.83-5.79 (m, 1H), 5.32-5.23 (m, 1H), 3.94-3.90 (m, 2H), 3.83-3.75 (m, 1H), 3.71-3.65 (m, 1H), 3.63-3.57 (m, 3H), 3.39-3.37 (m, 1H), 3.31-3.24 (m, 6H), 3.07-3.00 (m, 1H), 2.98-2.89 (m, 3H), 2.75-2.63 (m, 5H), 2.10 (s, 3H), 2.00-1.97 (m, 1H), 1.90-1.88 (m, 3H), 1.74-1.71 (m, 11H), 1.55 (d, J = 6.8 Hz, 3H) and 1.49-1.38 (m, 2H) and 1.33-1.27 (m, 1H). LC- MS (ES ⁺ ): m/z 983.4 [M + H] ⁺ . Note: Configurations are arbitrarily assigned. Example 166 Synthesis of tert-butyl (3R)-3-((3-((1-(4-bromonaphthalen-1-yl)ethyl)carbamoyl)-4- methylphenyl)amino)pyrrolidine-1-carboxylate To a 20 mL sealed tube containing a well-stirred solution of methyl 5-bromo-2-methyl-benzoate (1, 400 mg, 1.75 mmol) and tert-butyl (R)-3-aminopyrrolidine-1-carboxylate (813.07 mg, 4.37 mmol) in anhydrous 1,4-dioxane (7 mL) was added cesium carbonate (2, 1.42 g, 4.37 mmol) at ambient temperature. Nitrogen gas was purged through the reaction mixture for 10 minutes. Subsequently, XPhos (166.49 mg, 0.349 mmol) and Tris (dibenzylideneacetone)dipalladium (0) (319.80 mg, 349.24 mmol) were added and stirring was continued at 100 °C for 16 h. The reaction was monitored by UPLC. Reaction mixture was passed through a pad of Celite and the Celite bed was washed with EtOAc (300 mL). The combined filtrate was concentrated under reduced pressure to yield a crude residue, which was purified by flash column chromatography (230-400 mesh silica gel) with 70-75% EtOAc/pet ether as eluent to afford tert-butyl (R)-3-((3-(methoxycarbonyl)-4- methylphenyl)amino)pyrrolidine-1-carboxylate (3, 600 mg, 1.71 mmol, 97% yield) as a yellow gum. LC-MS (ES ⁺ ): m/z 279.2 [M – isobutene + H] ⁺ . Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (R)-3- ((3-(methoxycarbonyl)-4-methylphenyl)amino)pyrrolidine-1-car boxylate (3, 600 mg, 1.71 mmol) in 1:1 THF/MeOH (4 mL) was added LiOH.H2O (430.52 mg, 10.26 mmol) in water (2 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 3 h. After completion of the reaction as indicated by UPLC, excess solvent was removed from the reaction mixture under reduced pressure and the crude mass was dissolved in aqueous citric acid solution (50 mL). The aqueous phase was extracted with 10% MeOH/ DCM (2 × 200 mL) and the combined organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to afford (R)-5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)amino)-2-meth ylbenzoic acid (4, 520 mg, 1.52 mmol, 88% yield) as a pale yellow solid. LC-MS (ES-): m/z 319.0 [M - H] -. Step-3: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of (R)-5-((1-(tert- butoxycarbonyl)pyrrolidin-3-yl)amino)-2-methylbenzoic acid (4, 520 mg, 1.52 mmol) and 1-(4- bromonaphthalen-1-yl)ethan-1-amine (5, 426.38 mg, 1.67 mmol) in anhydrous DMF (3 mL) were added DIPEA (980.65 mg, 7.59 mmol, 1.32 mL) and HATU (692.43 mg, 1.82 mmol) at ambient temperature under nitrogen atmosphere, and the resulting mixture was stirred at ambient temperature for 4 h. Progress of the reaction was monitored by UPLC-MS. Upon completion of the reaction, excess solvent was removed from the reaction mixture under reduced pressure. The obtained crude was purified by reverse phase HPLC (RediSep C18 (100 g SNAP) column, Mobile phase: A: 0.1% Formic acid in water and B: Acetonitrile) and fractions having desired product were concentrated under reduced pressure to afford tert-butyl (3R)-3-((3-((1-(4-bromonaphthalen- 1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)pyrrolidine-1-car boxylate formate (6, 300 mg, 0.554 mmol, 36% yield) as a pale yellow solid. LC-MS (ES ⁺ ): m/z 496.0 [M – isobutene + H] ⁺ . The following targeting ligand (Example 167) was prepared using the method described above in Example 166, with the corresponding amine intermediate in Step-1. Example 168 Synthesis of tert-butyl (3S,4R)-3-((3-(((R)-1-(4-bromonaphthalen-1-yl)ethyl)carbamoy l)-4- methylphenyl)amino)-4-hydroxypyrrolidine-1-carboxylate

Step-1: To a 50 mL sealed-tube containing a well-stirred solution of methyl 5-bromo-2-methyl-benzoate (1, 900 mg, 3.93 mmol) and tert-butyl (3S,4R)-3-amino-4-hydroxypyrrolidine-1-carboxylate (2, 794.63 mg, 3.93 mmol) in anhydrous 1,4-dioxane (15 mL) was added cesium carbonate (3.20 g, 9.82 mmol) at ambient temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas into the reaction mixture for 5 minutes. Subsequently, XPhos (374.60 mg, 785.79 μmol) and tris(dibenzylideneacetone)dipalladium (0) (719.56 mg, 785.79 μmol) were added and the resulting mixture was degassed with N2 for another 5 minutes and the reaction mixture was heated to 90 °C for 16 h. The progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was cooled to ambient temperature. The reaction mixture was acidified with 10% citric acid, and the aqueous phase was extracted EtOAc (2 × 150 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (230-400 mesh silica gel) with 0-100% EtOAc/pet ether as eluent to afford tert-butyl (3R,4S)-3-hydroxy-4-((3-(methoxycarbonyl)-4- methylphenyl)amino)pyrrolidine-1-carboxylate (3, 310 mg, 0.659 mmol, 17% yield) as an off- white solid. LC-MS (ES ⁺ ): m/z 295.0 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (3R,4S)-3-hydroxy-4-((3-(methoxycarbonyl)-4-methylphenyl)ami no)pyrrolidine-1-carboxylate (3, 310 mg, 0.663 mmol) in 1:1:1 THF/MeOH/H2O (5 mL) was added lithium hydroxide, monohydrate (417.65 mg, 9.95 mmol) at 0 °C. The reaction mixture was stirred for 12 h at ambient temperature. The progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained crude was diluted with water (50 mL) and extracted with MTBE (2 × 150 mL). The aqueous phase was acidified with citric acid solution (pH=3-4) and extracted with EtOAc (2 × 250 mL). The combined organic phase was concentrated under reduced pressure to afford 5-(((3S,4R)-1-(tert- butoxycarbonyl)-4-hydroxypyrrolidin-3-yl)amino)-2-methylbenz oic acid (4, 315 mg, 0.655 mmol, 99% yield) as a brown liquid. LC-MS (ES ⁺ ): m/z 281.2 [M – isobutene + H] ⁺ . Step-3: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 5-(((3S,4R)-1- (tert-butoxycarbonyl)-4-hydroxypyrrolidin-3-yl)amino)-2-meth ylbenzoic acid (4, 315 mg, 0.655 mmol) in anhydrous DMF (3 mL) were added DIPEA (423.60 mg, 3.28 mmol, 0.57 mL) and HATU (315 mg, 0.655 mmol) at ambient temperature under nitrogen atmosphere. To the flask was added (R)-1-(4-bromonaphthalen-1-yl)ethan-1-amine (5, 195.69 mg, 0.655 mmol). The resulting mixture was stirred at ambient temperature for 4 h. Upon completion of the reaction as confirmed by UPLC, the reaction mixture was diluted with ice-water (5 mL) and the aqueous phase was extracted with EtOAc (2 × 100 mL). The combined organic phase was washed with water followed by brine and dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by flash column chromatography (230-400 mesh silica gel) with 0-60% EtOAc/pet ether as eluent to afford tert-butyl (3S,4R)-3-((3-(((R)-1-(4-bromonaphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)-4-hydroxypyrrolidi ne-1-carboxylate (6, 310 mg, 0.404 mmol, 62% yield) as a brown sticky solid. LC-MS (ES ⁺ ): m/z 512.3 [M + H] ⁺ . The following targeting ligands (Example 169-171) were prepared using the method described above in Example 168, with the corresponding amine intermediate in Step-1.

Example 172 Synthesis of tert-butyl 4-[3-[1-(4-bromo-1-naphthyl)ethylcarbamoyl]-4-methyl- anilino]piperidine-1-carboxylate Step-1: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of 5-amino-2- methyl-benzoic acid (1, 0.6 g, 3.97 mmol) and 1,2-Dichloro ethane (5 mL) in MeOH (5 mL) were added tert-butyl 4-oxopiperidine-1-carboxylate (2, 1.19 g, 5.95 mmol), anhydrous sodium acetate (976.84 mg, 11.91 mmol) and acetic acid (2.10 g, 34.94 mmol, 2 mL) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 2 h under nitrogen atmosphere, then MP-Cyanoborohydride (2 g, 4 mmol) was added, and the resulting suspension was stirred for 16 h. After completion of the reaction as indicated by TLC and LCMS, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford 5-[(1-tert-butoxycarbonyl-4-piperidyl)amino]-2-methyl-benzoi c acid (3, 1.3 g, 3.07 mmol, 77% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 279.4 [M – isobutene + H] ⁺ . Step-2: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of 5-[(1-tert- butoxycarbonyl-4-piperidyl)amino]-2-methyl-benzoic acid (3, 1.2 g, 3.72 mmol) in anhydrous DMF (10 mL) were added HATU (898.25 mg, 2.36 mmol) and DIPEA (1.53 g, 11.81 mmol, 2.06 mL) followed by 1-(4-bromonaphthalen-1-yl)ethan-1-amine (4, 500 mg, 1.18 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 h. After completion of the reaction as shown by TLC, the reaction mixture was diluted with water (150 mL) and extracted with EtOAc (3 × 250 mL). The combined organic phase was dried (Na2SO4), filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by reverse-phase HPLC (Column: RediSep Rf Gold C18 (100 g SNAP), Mobile phase: A: 10 mm NH4HCO3 in MQ-water, B: acetonitrile) to afford tert-butyl 4- [3-[1-(4-bromo-1-naphthyl)ethylcarbamoyl]-4-methyl-anilino]p iperidine-1-carboxylate (5, 300 mg, 0.511 mmol, 43% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 468.0 [M – CO ₂ ^t Bu + H] ⁺ . The following targeting ligand (Example 173) was prepared using the method described above in Example 172, with the corresponding ketone intermediate in Step-1. Example 174 Synthesis of tert-butyl 7-((3-(((R)-1-(4-bromonaphthalen-1-yl)ethyl)carbamoyl)-4- methylphenyl)amino)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carbox ylate Step-1: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 7-oxo- 3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (1, 600 mg, 2.49 mmol) and 5-amino-2-methyl- benzoic acid (2, 375.90 mg, 2.49 mmol) in anhydrous MeOH (10 mL) were added sodium acetate (611.95 mg, 7.46 mmol, 0.4 mL) and AcOH (1.49 g, 24.87 mmol, 1.42 mL) at ambient temperature. The reaction mixture was stirred for 2 h. Subsequently, MP-CNBH3 (2.5 g, 4.97 mmol) was added and the resulting mixture was stirred to ambient temperature for 16 h. After completion of the reaction as indicated by TLC, the reaction mixture was filtered through a pad of Celite and Celite bed was washed with EtOAc (40 mL). The combined filtrate was concentrated under reduced pressure to yield a crude residue which was purified by reverse-phase column chromatography (C-18, 0.1% Formic acid in water and acetonitrile) to afford 5-[(9-tert- butoxycarbonyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)amino]-2- methyl-benzoic acid (3, 365 mg, 0.921 mmol, 37% yield) as a white solid. LC-MS (ES ⁺ ): m/z 377.2 [M + H] ⁺ . Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 5-[(9-tert- butoxycarbonyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)amino]-2- methyl-benzoic acid (3, 365 mg, 0.911 mmol) and (R)-1-(4-bromonaphthalen-1-yl)ethan-1-amine (4, 263.85 mg, 0.911 mmol) in anhydrous DMF (3 mL) were added HATU (519.82 mg, 1.37 mmol) followed by DIPEA (353.38 mg, 2.73 mmol, 0.47 mL) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 2 h. The progress of the reaction mixture was monitored by UPLC. Upon completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phase was washed with brine and evaporated under reduced pressure to obtain a crude residue, which was purified by flash column chromatography (230-400 mesh silica gel) with 0-100% EtOAc/pet ether as eluent to obtain tert-butyl 7-((3-(((R)-1-(4-bromonaphthalen-1-yl)ethyl)carbamoyl)-4- methylphenyl)amino)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carbox ylate (5, 490 mg, 0.764 mmol, 84% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 608.2 [M + H] ⁺ . Example 175 Synthesis of 5-((3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)amino)-N-((1R)-1-(4- ((1-((1-(1-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidine-4- carbonyl)-4-hydroxypiperidin-4-yl)methyl)piperidin-4-yl)ethy nyl)naphthalen-1-yl)ethyl)-2- methylbenzamide (Compound 102) Step-1: To a 20 mL glass-vial containing a solution of tert-butyl 7-((3-(((R)-1-(4-bromonaphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)-3-oxa-9-azabicyclo [3.3.1]nonane-9-carboxylate (1, 200 mg, 0.289 mmol) and 4-[(4-ethynyl-1-piperidyl)methyl]piperidin-4-ol (2, 154.31 mg, 0.578 mmol) in anhydrous acetonitrile (2 mL) was added cesium carbonate (235.57 mg, 0.723.mmol) at ambient temperature. The reaction mixture was purged with N ₂ before X Phos (13.79 mg, 0.0228 mmol) and XPhos-Pd-G3 (24.48 mg, 0.028 mmol) were added at ambient temperature under nitrogen atmosphere. The reaction mixture was stirred for 3 h at 90 °C. After the completion of reaction as confirmed by UPLC, the reaction mixture was filtered through a pad of Celite and the Celite bed was washed with acetonitrile. The combined filtrate was concentrated under reduced pressure and the obtained crude product was purified by reverse-phase prep-HPLC (X-SELECT, C18), 5 micron; Mobile phase: A;10 mm NH ₄ HCO ₃ in MQ-water; B: acetonitrile; Flow rate: 15 mL/minutes) to afford tert-butyl 7-((3-(((R)-1-(4-((1-((4-hydroxypiperidin-4-yl)methyl)piperi din- 4-yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl )amino)-3-oxa-9- azabicyclo[3.3.1]nonane-9-carboxylate (3, 90 mg, 0.097 mmol, 34% yield) as a pale yellow solid. UPLC-MS (ES ⁺ ): m/z 750.5 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 1-[1-(2,6-dioxo- 3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-c arboxylic acid hydrochloride (4, 50.74 mg, 0.120 mmol) and tert-butyl 7-((3-(((R)-1-(4-((1-((4-hydroxypiperidin-4- yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carba moyl)-4-methylphenyl)amino)-3- oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (3, 90 mg, 0.120 mmol) in anhydrous DMF (1 mL) were added HATU (68.44 mg, 0.180 mmol) and DIPEA (77.55 mg, 0.660 mmol, 0.104 mL) at ambient temperature under nitrogen atmosphere .The resulting mixture was stirred at this temperature for 1 h. After completion of the reaction as indicated by UPLC, excess solvent was removed under reduced pressure to give a crude residue which was diluted with ice-cold water (10 mL). The solid precipitate was collected by filtration, washed with water (15 mL) and dried in vacuo to afford tert-butyl 7-((3-(((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3- methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carbon yl)-4-hydroxypiperidin-4- yl)methyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carba moyl)-4-methylphenyl)amino)-3- oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate hydrochloride (5, 100 mg, 0.070 mmol, 59% yield) as a pale yellow solid. UPLC-MS (ES ⁺ ): m/z 1116.7 [M + H] ⁺ . Step-3: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 7-((3- (((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)-4-hydroxypiperi din-4-yl)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)-3-oxa-9- azabicyclo[3.3.1]nonane-9-carboxylate hydrochloride (5, 100 mg, 0.089 mmol) in anhydrous DCM (1 mL) was added 4M HCl in 1,4-dioxane (0.200 mL) at 0 °C. The resulting reaction mixture was stirred at ambient temperature for 1 h. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC (X-SELECT, C18, 5 micron; Mobile phase: A:0.1% formic acid in MQ-water; B: acetonitrile; Flow rate: 15 mL/minutes) to afford 5-((3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)amino)-N-((1R)-1-(4-((1-((1-(1-( 1-(2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine -4-carbonyl)-4- hydroxypiperidin-4-yl)methyl)piperidin-4-yl)ethynyl)naphthal en-1-yl)ethyl)-2-methylbenzamide formate (Compound 102, 13.5 mg, 0.012 mmol, 13% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 8.81-8.77 (m, 1H), 8.34-8.28 (m, 2H), 7.68-7.62 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 6.95-6.90 (m, 2H), 6.84-6.84 (m, 1H), 6.64 (dd, J = 8.4, 2 Hz, 1H), 6.56-6.53 (m, 2H), 5.95-5.81 (m, 1H), 5.80-5.75 (m, 1H), 5.33-5.25 (m, 1H), 4.47-4.12 (bs, 1H), 4.10-4.02 (m, 1H), 3.80-3.65 (m, 2H), 3.64-3.55 (m, 6H), 3.30 (m, 4H), 3.04-2.92 (m, 3H), 2.90-2.81 (m, 3H), 2.79-2.65 (m, 3H), 2.63-2.55 (m, 2H), 2.50 (m, 2H), 2.43-2.35 (m, 2H), 2.30 (m, 2H), 2.20- 2.16 (m, 2H), 2.10 (s, 3H), 2.00-1.90 (m, 3H), 1.8-1.62 (m, 6H) and 1.6-1.33 (m, 9H). LC-MS (ES ⁺ ): m/z 1018.4 [M + H] ⁺ . Example 176 Synthesis of 5-((3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)amino)-N-((1R)-1-(4- ((1-((1-(1-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidine-4-

carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)ethynyl)nap hthalen-1-yl)ethyl)-2- Step-1: To a 100 mL sealed tube containing a well-stirred solution of tert-butyl 7-((3-(((R)-1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)- 3-oxa-9- azabicyclo[3.3.1]nonane-9-carboxylate (1, 240 mg, 0.370 mmol) and 4-ethynyl-1-(4- piperidylmethyl)piperidine hydrochloride (2, 183.68 mg, 741.42 mmol) in anhydrous acetonitrile (5 mL) was added cesium carbonate (301.96 mg, 926.77 mmol) at ambient temperature. The reaction mixture was purged with N ₂ for 10 minutes before X-Phos (17.67 mg, 0.037 mmol) and XPhos-Pd-G3 (31.38 mg, 0.037 mmol) were added at ambient temperature under nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 3 h. Upon completion of the reaction as indicated by UPLC, the reaction mixture was filtered through a pad of Celite and the Celite bed was washed with 10% MeOH/ DCM (200 mL). The combined filtrate was concentrated under reduced pressure and the obtained crude residue was purified by reverse phase column chromatography (Column: RediSep-RF Gold C18 (100 g SNAP), Mobile phase: A: 0.1% Formic acid in water, B: MeCN). The fractions having desired product were concentrated under reduced pressure to remove acetonitrile and then diluted with 10% sodium bicarbonate solution (100 mL) , brine (50 mL) and then extracted with EtOAc (3 × 200 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to afford tert-butyl 7-((4-methyl-3- (((R)-1-(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)ethynyl) naphthalen-1- yl)ethyl)carbamoyl)phenyl)amino)-3-oxa-9-azabicyclo[3.3.1]no nane-9-carboxylate (3, 170 mg, 0.207 mmol, 56% yield) as a pale yellow solid. UPLC-MS (ES ⁺ ): m/z 734.7 [M + H] ⁺ . Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 7-((4- methyl-3-(((R)-1-(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl )ethynyl)naphthalen-1- yl)ethyl)carbamoyl)phenyl)amino)-3-oxa-9-azabicyclo[3.3.1]no nane-9-carboxylate (3, 70 mg, 0.094 mmol) and 1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-y l]piperidine-4- carboxylic acid hydrochloride (4, 48.10 mg, 0.094 mmol) in anhydrous DMF (1.5 mL) were added HATU (53.85 mg, 0.141 mmol) and DIPEA (61.01 mg, 0.447 mmol, 0.082 mL) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at ambient temperature. The reaction progress was monitored by UPLC. Thereafter, the solvent was evaporated under reduced pressure and ice-cold water was added to precipitate a solid that was filtered. The obtained solid was washed with water (10 mL) and dried in vacuo to afford tert-butyl 7-((3-(((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-yl)m ethyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)-3-oxa-9- azabicyclo[3.3.1]nonane-9-carboxylate (5, 100 mg, 0.075 mmol, 80% yield) as a pale yellow solid. UPLC-MS (ES ⁺ ): m/z 1102.7 [M + H] ⁺ . Step-3: To a 100 mL single-neck round-bottom flask containing a solution of tert-butyl 7-((3-(((1R)-1-(4- ((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-d ihydro-1H-benzo[d]imidazol-5- yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-y l)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)-3-oxa-9-azabicyclo [3.3.1]nonane-9-carboxylate (5, 100 mg, 0.074 mmol) in anhydrous DCM (2 mL) was added 4N HCl in 1,4-dioxane (0.186 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at ambient temperature. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure and the obtained crude residue was purified by reverse phase prep-HPLC (X-Select C18 (150 x 19) mm; 5 microns column; Mobile phase: A:0.1% formic acid in MQ- water; B: acetonitrile; Flow rate: 15 mL/minutes) to afford 5-((3-oxa-9-azabicyclo[3.3.1]nonan-7- yl)amino)-N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-y l)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-yl)m ethyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-2-methylbenzamide di-formate (Compound 103, 30 mg, 0.022 mmol, 36% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.06 (s, 1H), 8.78 (d, J = 8 Hz, 1H), 8.35 - 8.25 (m, 2H), 7.69 - 7.61 (m, 4H), 7.59 - 7.54 (m, 1H), 6.96 - 6.89 (m, 2H), 6.67 - 6.60 (m, 1H), 6.55 - 6.49 (m, 2H), 5.91 - 5.83 (m, 1H), 5.80 (d, J = 10.5 Hz, 1H), 5.29 (dd, J = 12.8, 5.2 Hz, 1H),4.40 (d, J = 12 Hz, 1H), 4.03 - 3.96 (m, 1H), 3.80-3.50 (m, 9H), 3.08 - 2.99 (m, 1H), 2.91 - 2.85 (m, 5H), 2.78 - 2.50 (m, 7H), 2.11 - 2.07 (m, 10H), 2.03 - 1.93 (m, 4H), 1.88 - 1.67 (m, 9H) and 1.58 - 1.47 (m, 5H) and 1.10-0.85 (m, 2H). LC-MS (ES ⁺ ): m/z 1002.4 [M + H] ⁺ . Example 177 Synthesis of 5-((3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)amino)-N-((1R)-1-(4- ((1-(5-(4-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidin-1-yl)-

5-oxopentyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl) -2-methylbenzamide (Compound 104) To a 100 mL sealed-tube containing a well-stirred solution of tert-butyl 7-((3-(((R)-1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)- 3-oxa-9- azabicyclo[3.3.1]nonane-9-carboxylate (1, 240 mg, 0.374 mmol) and ethyl 5-(4-ethynyl-1- piperidyl)pentanoate (2, 185.25 mg, 0.749 mmol) in anhydrous Acetonitrile (5 mL) was added Cesium carbonate (305.17 mg, 0.936 mmol) at ambient temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas into the reaction mixture for 5 minutes. Subsequently, XPhos-Pd-G3 (31.71 mg, 0.037 mmol) and dicyclohexyl-[2- (2,4,6-triisopropylphenyl)phenyl]phosphane (17.86 mg, 0.037 mmol) were added and the resulting mixture was degassed further with N2 for 5 minutes. The reaction mixture was stirred for 3 hours at 90°C. After completion of the reaction as indicated by UPLC, the reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (230-400 mesh silica gel) with 0-5% MeOH/DCM as eluent to afford tert-butyl 7-((3-(((R)-1-(4-((1-(5-ethoxy-5-oxopentyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)-3-oxa-9- azabicyclo[3.3.1]nonane-9-carboxylate (3, 190 mg, 0.208 mmol, 56% yield) as a brown solid. LC- MS (ES ⁺ ): m/z 765.2 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 7-((3- (((R)-1-(4-((1-(5-ethoxy-5-oxopentyl)piperidin-4-yl)ethynyl) naphthalen-1-yl)ethyl)carbamoyl)- 4-methylphenyl)amino)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carb oxylate (3, 190 mg, 0.208 mmol) in 1:1:1 THF/MeOH/H ₂ O (5 mL) was added lithium hydroxide, monohydrate (87.55 mg, 2.09 mmol) at 0 °C. The reaction mixture was stirred for 1 h at ambient temperature. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (5 mL) and extracted with MTBE (2 × 10 mL). The aqueous phase was acidified with citric acid solution (pH=3-4) and extracted with 10% MeOH in DCM (3 × 25 mL). The combined organic phase was concentrated under reduced pressure. The obtained crude product was purified by reverse phase column chromatography (C18 column, mobile phase: 10 mm HCOOH in water : MeCN) to afford 5-(4-((4-((1R)-1-(5-((9-(tert- butoxycarbonyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)amino)-2 - methylbenzamido)ethyl)naphthalen-1-yl)ethynyl)piperidin-1-yl )pentanoic acid formate (4, 100 mg, 0.126 mmol, 61% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 737.4 [M + H] ⁺ . Step-3: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 5-(4-((4-((1R)-1- (5-((9-(tert-butoxycarbonyl)-3-oxa-9-azabicyclo[3.3.1]nonan- 7-yl)amino)-2- methylbenzamido)ethyl)naphthalen-1-yl)ethynyl)piperidin-1-yl )pentanoic acid formate (4, 100 mg, 0.134 mmol) in anhydrous DMF (1 mL) were added DIPEA (52.09 mg, 0.403 mmol, 0.070 mL) and HATU (76.62 mg, 0.201 mmol) followed by 3-[3-methyl-2-oxo-5-(4- piperidyl)benzimidazol-1-yl]piperidine-2,6-dione.hydrochlori de (5, 56.55 mg, 0.147 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at this temperature for 2 h. Upon completion of the reaction as confirmed by UPLC, the reaction mixture was concentrated under reduced pressure to give a residue which was diluted with ice- cold water (20 mL). The solid precipitate was collected on filter, and the solid was washed with water (10 mL), dried in vacuo to afford tert-butyl 7-((3-(((1R)-1-(4-((1-(5-(4-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidin-1-yl)-5- oxopentyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carba moyl)-4-methylphenyl)amino)-3- oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (6, 100 mg, 84.80 mmol, 63% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 1062.4 [M + H] ⁺ . Step-4: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 7-((3- (((1R)-1-(4-((1-(5-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-1-yl)-5-oxopentyl)piperidin- 4-yl)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)-3-oxa-9-azabicyclo [3.3.1]nonane-9-carboxylate (6, 100 mg, 0.084 mmol) in anhydrous DCM (1.5 mL) was added 4N HCl in 1,4-dioxane (1.5 mL, 1.7 mmol) at 0 °C and the resulting mixture was stirred at ambient temperature for 1 h. Upon completion of the reaction as confirmed by UPLC, excess solvent was removed under reduced pressure and the crude product was purified by reverse phase column chromatography (RediSep- RF Gold C18 column, mobile phase: 10 mm HCOOH in water : MeCN) to afford 5-((3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)amino)-N-((1R)-1-(4-((1-(5-(4-(1 -(2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin- 1-yl)-5-oxopentyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-2-methylbenzamide di-formate (Compound 104, 42 mg, 0.0.039 mmol, 47% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 11.08 (br s, 1H), 8.77 (d, J = 8 Hz, 1H), 8.38 - 8.25 (m, 2H), 7.68 - 7.60 (m, 3H), 7.60 - 7.54 (m, 1H), 7.10 (s, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.97 - 6.87 (m, 2H), 6.57 - 6.49 (m, 2H), 5.92 - 5.76 (m, 2H), 5.33 (dd, J = 12.6, 5.3 Hz, 1H), 4.58 (d, J = 12.4 Hz, 1H), 4.03 (d, J = 13 Hz, 1H), 3.69 - 3.65 (m, 2H), 3.61 - 3.56 (m, 2H), 3.36 (s, 3H), 3.16 - 3.06 (m, 2H), 2.90 (m, 2H), 2.78 – 2.65 (m, 6H), 2.50 (m, 1H), 2.40 - 2.29 (m, 4H), 2.27 - 2.14 (m, 3H), 2.10 (s, 3H), 2.02 - 1.94 (m, 4H), 1.86 - 1.66 (m, 5H) and 1.64 - 1.45 (m, 12H). LC-MS (ES ⁺ ): m/z 962.4 [M + H] ⁺ . Example 178 N-((1R)-1-(4-((1-(5-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-1-yl)-5-oxopentyl)piperidin- 4-yl)ethynyl)naphthalen-1- yl)ethyl)-5-(((3S,4R)-4-hydroxypyrrolidin-3-yl)amino)-2-meth ylbenzamide (Compound 105) Compound 105 was prepared substantially following the synthesis of Compound 104, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 921.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 8.80 (d, J = 7.6 Hz, 1H), 8.29-8.32 (m, 2H), 7.58- 7.63 (m, 4H), 7.10 (d, J = 1.2 Hz, 1H), 7.01 (d, J = 8 Hz, 1H), 6.95-6.91 (m, 2H), 6.66-6.63 (m, 2H), 5.91-5.80 (m, 1H), 5.48-5.30 (m, 2H), 4.61-4.50 (m, 1H), 4.22 (s, 1H), 4.17-3.85 (m, 3H), 3.32 (s, 3H), 3.15-3.05 (m, 4H), 2.95-2.70 (m, 8H), 2.60-2.58 (m, 3H), 2.41-2.30 (m, 4H), 2.98- 2.20 (m, 2H), 2.11 (s, 3H), 1.99-1.95 (m, 3H), 1.76-1.72 (m, 4H) and 1.56-1.49 (m, 8H). Example 179 N-((1R)-1-(4-((1-(5-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-1-yl)-5-oxopentyl)piperidin- 4-yl)ethynyl)naphthalen-1- yl)ethyl)-5-(((3S,4S)-4-hydroxypyrrolidin-3-yl)amino)-2-meth ylbenzamide (Compound 106) Compound 106 was prepared substantially following the synthesis of Compound 104, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 921.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 8.85-8.83 (m, 1H), 8.34-8.28 (m, 2H), 7.76-7.66 (m, 3H), 7.60-7.57 (m, 1H), 7.10-7.09 (m, 1H), 7.04-6.99 (m, 2H), 6.93-6.90 (m, 1H), 6.62-6.60 (m, 2H), 5.91-5.82 (m, 3H), 5.36-5.33 (m, 1H), 4.61-4.51 (m, 1H), 4.20 (s, 1H), 3.99-3.92 (m, 1H), 3.81-3.75 (m, 1H), 3.58-3.36 (m, 3H), 3.20-3.18 (m, 6H), 3.13-3.02 (m, 2H), 3.00-2.71 (m, 3H), 2.68-2.60 (m, 4H), 2.50-2.49 (m, 6H), 2.34-2.29 (m, 1H), 2.11 (s, 3H), 2.10 (m, 1H), 2.01-1.92 (m, 2H), 1.81-1.70 (m, 2H), 1.69-1.61 (m, 2H) and 1.60-1.54 (m, 7H).

Example 180 5-(azetidin-3-ylamino)-2-methyl-N-((R)-1-(4-((1-(5-(4-(3-met hyl-1-((R)-3-methyl-2,6- dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5 -yl)piperidin-1-yl)-5- oxopentyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)benza mide (Compound 107) Compound 107 was prepared substantially following the synthesis of Compound 104, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 920.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 8.87-8.84 (m, 1H), 8.34-8.28 (m, 2H), 7.79-7.67 (m, 3H), 7.61-7.59 (m, 1H), 7.12-7.11 (m, 1H), 7.09 (m, 1H), 7.04-6.91 (m, 3H), 6.61 (d, J = 8 Hz, 2H), 5.93-5.85 (m, 1H), 5.38 (dd, J = 12.8, 5.2 Hz, 1H), 4.60-4.51 (m, 1H), 4.05-3.97 (m, 1H), 3.40-3.25 (m, 5H), 3.23-2.90 (m, 8H), 2.85-2.70 (m, 3H), 3.60 (m, 3H), 2.49-2.38 (m, 3H), 2.35- 2.19 (m, 2H), 2.15 (m, 5H), 2.10-1.90 (m, 4H), 1.81-1.70 (m, 5H), 1.65-1.41 (m, 8H) and 1.30- 1.20 (m, 1H).

Example 181 N-((1R)-1-(4-((1-(5-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-1-yl)-5-oxopentyl)piperidin- 4-yl)ethynyl)naphthalen-1- yl)ethyl)-2-methyl-5-(((S)-piperidin-3-yl)amino)benzamide (Compound 108) Compound 108 was prepared substantially following the synthesis of Compound 104, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 920.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 8.82 (d, J = 8 Hz, 1H), 8.33-8.28 (m, 2H), 7.66- 7.63 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 7.10 (d, J = 0.8 Hz, 1H), 7.01 (d, J = 8 Hz, 1H), 6.94-6.91 (m, 2H), 6.57 (d, J = 8.4 Hz, 2H), 5.95-5.85 (m, 1H), 5.34 (s, 1H), 5.39-5.31 (m, 1H), 4.61 (m, 1H), 4.05 (m, 1H), 3.32 (s, 3H), 3.27-3.19 (m, 2H), 3.16-3.02 (m, 3H), 3.00-2.51 (m, 10H), 2.50 (m, 1H), 2.40-2.30 (m, 4H), 2.30-2.20 (m, 2H), 2.10 (s, 3H), 2.03-1.90 (m, 4H), 1.85-1.70 (m, 5H) and 1.69-1.45 (m, 10H).

Example 182 N-[1-[4-[2-[1-[5-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-ox o-benzimidazol-5-yl]-1- piperidyl]-5-oxo-pentyl]-4-piperidyl]ethynyl]-1-naphthyl]eth yl]-2-methyl-5-(4- piperidylamino)benzamide (Compound 109) Compound 109 was prepared substantially following the synthesis of Compound 104, except using methyl 5-(4-ethynyl-1-piperidyl)pentanoate in Step-1. LC-MS (ES ⁺ ): m/z 919.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.08 (bs, 1H), 8.79 (d, J = 8 Hz, 1H), 8.33-8.28 (m, 2H), 7.67- 7.62 (m, 3H), 7.56 (d, J = 7.6 Hz 1H), 7.11 (s, 1H), 7.01 (d, J = 8 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.56-6.55 (m, 2H), 5.96-5.86 (m, 1H), 5.61-5.55 (m, 1H), 5.39-5.31 (m, 1H), 4.60 (m, 1H), 4.07 (m, 1H), 3.33 (s, 3H), 3.25-3.11 (m, 4H), 2.95-2.51 (m, 12H), 2.40-2.30 (m, 5H), 2.29-2.15 (m, 2H), 2.09 (s, 3H), 2.00-1.94 (m, 5H), 1.80-1.72 (m, 5H) and 1.55-1.42 (m, 8H).

Example 183 N-(1-(4-((1-(5-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-ox o-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-1-yl)-5-oxopentyl)piperidin- 4-yl)ethynyl)naphthalen-1- yl)ethyl)-2-methyl-5-(((R)-pyrrolidin-3-yl)amino)benzamide (Compound 110) Compound 110 was prepared substantially following the synthesis of Compound 104, except using methyl 5-(4-ethynyl-1-piperidyl)pentanoate in Step-1. LC-MS (ES ⁺ ): m/z 906.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H), 8.82 (d, J = 8 Hz, 1H), 8.32-8.28 (m, 2H), 7.65- 7.63 (m, 3H), 7.57 (d, J = 8 Hz, 1H), 7.11 (s, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.96-0.91 (m, 2H), 6.54 (t, J = 6.8 Hz, 2H), 5.92-5.87 (m, 2H), 5.38-5.31 (m, 1H), 4.58 (d, J = 8 Hz, 1H), 4.15-3.98 (m, 3H), 3.33 (s, 3H), 3.30 (m, 2H), 3.16-3.08 (m, 2H), 2.87-2.74 (m, 7H), 2.68-2.67 (m, 1H), 2.59-2.53 (m, 1H), 2.37-2.31 (m, 5H), 2.22-2.19 (m, 2H), 2.12-2.11 (m, 4H), 1.99-1.96 (m, 3H), 1.75-1.72 (m, 6H) and 1.56-1.49 (m, 7H). Example 184 N-(1-(4-((1-(5-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-ox o-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-1-yl)-5-oxopentyl)piperidin- 4-yl)ethynyl)naphthalen-1- yl)ethyl)-2-methyl-5-(((S)-pyrrolidin-3-yl)amino)benzamide (Compound 111) Compound 111 was prepared substantially following the synthesis of Compound 104, except using methyl 5-(4-ethynyl-1-piperidyl)pentanoate in Step-1. LC-MS (ES ⁺ ): m/z 905.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.08 (s, 1H), 8.81 (d, J = 7.6 Hz, 1H), 8.33-8.28 (m, 2H), 7.66- 7.63 (m, 3H), 7.56 (d, J = 7.6 Hz, 1H), 7.11 (s, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.96-6.91 (m, 2H), 6.55-6.53 (m, 2H), 5.90-5.87 (m, 1H), 5.83-5.81 (m, 1H), 5.34 (dd, J = 12.8, 5.2 Hz, 1H), 4.58 (m, 1H), 4.04-4.01 (m, 1H), 4.00-3.90 (m, 1H), 3.12 (m, 5H), 2.91-2.75 (m, 5H), 2.61-2.51 (m, 3H), 2.48-2.32 (m, 4H), 2.30-2.19 (m, 2H), 2.13-2.02 (m, 5H), 2.01-1.92 (m, 4H), 1.86-1.61 (m, 6H) and 1.52-1.48 (m, 10H). Example 185 5-(2-azaspiro[3.3]heptan-6-ylamino)-N-[1-[4-[2-[1-[5-[4-[1-( 2,6-dioxo-3-piperidyl)-3- methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-5-oxo-pentyl]-4 -piperidyl]ethynyl]-1- naphthyl]ethyl]-2-methyl-benzamide (Compound 112) Compound 112 was prepared substantially following the synthesis of Compound 104, except using methyl 5-(4-ethynyl-1-piperidyl)pentanoate in Step-1. LC-MS (ES ⁺ ): m/z 931.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.08 (bs, 1H), 8.79 (d, J = 8 Hz, 1H), 8.33-8.28 (m, 2H), 7.66- 7.63 (m, 3H), 7.56 (d, J = 7.2 Hz, 1H), 7.11 (s, 1H), 7.03-7.01 (m, 1H), 6.93-6.90 (m, 2H), 6.43- 6.42 (m, 2H), 5.89-5.86 (m, 1H), 5.79 (d, J = 6 Hz, 1H), 5.39-5.31 (m, 1H), 4.59 (m, 1H), 4.11- 4.01 (m, 1H), 3.94 (bs, 2H), 3.83 (bs, 2H), 3.66-3.40 (m, 2H), 3.33 (s, 3H), 3.14-3.08 (m, 2H), 2.83-2.62 (m, 7H), 2.59-2.53 (m, 4H), 2.50 (m, 1H), 2.39-2.31 (m, 2H), 2.25-2.15 (m, 2H), 2.09 (s, 3H), 2.00-1.96 (m, 5H), 1.80-1.72 (m, 5H) and 1.55-1.49 (m, 7H). Example 186 Synthesis of N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methy l-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-y l)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-5-(((3S,4R)-4-hydroxypyrro lidin-3-yl)amino)-2- methylbenzamide (Compound 113) Step-1: To a 25 mL sealed tube containing a well-stirred solution of tert-butyl (3S,4R)-3-((3-(((R)-1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)- 4-hydroxypyrrolidine-1- carboxylate (1, 150 mg, 0.195 mmol) and 4-ethynyl-1-(4-piperidylmethyl)piperidine hydrochloride (2, 145.12 mg, 0.585 mmol) in anhydrous acetonitrile (3 mL) and THF (2.5 mL) was added cesium carbonate (159.04 mg, 0.488 mmol) at ambient temperature. The resulting reaction mixture was degassed by bubbling nitrogen gas for 10 minutes. Subsequently, XPhos (18.62 mg, 0.039 mmol) and XPhos-Pd-G3 (24.79 mg, 0.029 mmol) were added and stirring was continued at 90 °C for 4 h. After completion of the reaction as indicated by UPLC, the reaction mixture was passed through a pad of Celite and the Celite bed was washed with 15% MeOH/ DCM (150 mL). The combined filtrate was concentrated under reduced pressure and the obtained residue was purified by reverse phase prep-HPLC (Red-Sep Gold C18 column, Mobile phase A: 10 mm NH4HCO3 in MQ-water; B: acetonitrile) to afford tert-butyl (3R,4S)-3-hydroxy-4-((4-methyl-3- (((R)-1-(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)ethynyl) naphthalen-1- yl)ethyl)carbamoyl)phenyl)amino)pyrrolidine-1-carboxylate (3, 55 mg, 0.061 mmol, 31% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 694.4 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (3R,4S)-3-hydroxy-4-((4-methyl-3-(((R)-1-(4-((1-(piperidin-4 -ylmethyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)phenyl)amino)pyrr olidine-1-carboxylate (3, 55 mg, 0.061 mmol) and 1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-y l]piperidine-4- carboxylic acid hydrochloride (4, 30.97 mg, 0.073 mmol) in dry DMF (1.5 mL) was added HATU (34.81 mg, 0.091 mmol) and DIPEA (39.44 mg, 0.305 mmol, 0.053 mL) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 h. After completion of reaction mixture as indicated by TLC, excess solvent was concentrated under reduced pressure. Ice-cold water (10 mL) was added to the obtained residue and the solid precipitate was filtered, washed with water (15 mL) and dried in vacuo to afford tert-butyl (3S,4R)-3-((3-(((1R)-1-(4-((1- ((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihyd ro-1H-benzo[d]imidazol-5- yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-y l)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)-4-hydroxypyrrolidi ne-1-carboxylate (5, 70 mg, 0.030 mmol, 49% yield) as a pale yellow solid. UPLC-MS (ES ⁺ ): m/z 1069.4 [M + H] ⁺ . Step-3: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (3S,4R)-3-((3-(((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-y l)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)-4-hydroxypyrrolidine-1- carboxylate (5, 70 mg, 0.030 mmol) in anhydrous DCM (1.55 mL) was added 4N HCl in 1,4- dioxane (0.076 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 2 h. After completion of the reaction as indicated by UPLC, excess solvent was removed from the reaction mixture. The crude product was purified by reverse phase prep-HPLC (X-SELECT, C18 column, 5 micron; Mobile phase: A:0.1% FA in MQ-water; B: acetonitrile; Flow rate: 15 mL/minutes) to afford N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methy l-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piper idin-4-yl)methyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-5-(((3S,4R)-4-hydroxypyrro lidin-3-yl)amino)-2- methylbenzamide formate (Compound 113, 14 mg, 0.013 mmol, 44% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.09 (s, 1H), 8.80 (d, J = 7.6 Hz, 1H), 8.34-8.28 (m, 2H), 7.69- 7.64 (m, 3H), 7.58 (d, J = 7.6 Hz, 1H), 6.94 (dd, J = 8.8, 2.4 Hz, 2H), 6.84 (d, J = 2 Hz, 1H), 6.65- 6.63 (m, 3H), 5.88 (m, 1H), 5.40 (m, 1H), 5.30 (m, 1H), 4.45-4.36 (m, 1H), 4.20 (m, 1H), 4.00- 3.85 (m, 3H), 3.63-3.60 (m, 3H), 3.10-3.04 (m, 3H), 2.96-2.76 (m, 6H), 2.65-2.60 (m, 7H), 2.50 (m, 1H), 2.25-2.19 (m, 4H), 2.17 (s, 3H), 2.00-1.96 (m, 3H), 1.81-1.71 (m, 10H), 1.55 (d, J = 6.8 Hz, 3H) and 1.05-0.85 (m, 2H). LC-MS (ES ⁺ ): m/z 963.4 [M + H] ⁺ . Example 187 N-((1R)-1-(4-((1-((1-(1-(1-(2,6-Dioxopiperidin-3-yl)-3-methy l-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-yl)m ethyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)-5-(((3S,4S)-4-hydroxypyrro lidin-3-yl)amino)-2- methylbenzamide (Compound 116) Compound 116 was prepared substantially following the synthesis of Compound 115, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 963.4 [M + H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.07 (s, 1H), 8.80 (d, J = 8 Hz, 1H), 8.33-8.28 (m, 2H), 7.77- 7.56 (m, 4H), 6.95-6.93 (m, 2H), 6.84 (d, J = 2 Hz, 1H), 6.65-6.56 (m, 3H), 5.90-5.86 (m, 1H), 5.63 (d, J = 8 Hz, 1H), 5.40-5.30 (m, 1H), 4.88-4.87 (m, 1H), 4.42-4.40 (d, J = 6.8 Hz, 1H), 4.12- 4.10 (d, J = 6.8 Hz, 1H), 3.90 (s, 1H), 3.72-3.60 (m, 2H), 3.42 (m, 1H), 3.28 (s, 3H), 3.26-3.20 (m, 2H), 3.10-3.19 (m, 1H), 3.09-3.01 (m, 1H), 2.98-2.90 (m, 3H), 2.89-2.80 (m, 4H), 2.60 (m, 2H), 2.50-2.4 (m, 4H), 2.30-2.22 (m, 3H), 2.15 (s, 3H), 2.08 (m, 3H), 1.85-1.68 (m, 9H), 1.54 (d, J = 6.8 Hz, 3H) and 1.12-0.90 (m, 2H). Example 188 Synthesis of tert-butyl (R)-3-((4-methyl-3-((1-(4-((1-(piperidin-4-ylmethyl)piperidi n-4- yl)ethynyl)-3-(thiophen-2-yl)phenyl)ethyl)carbamoyl)phenyl)a mino)azetidine-1-carboxylate

Step-1: To a 500 mL single-neck round-bottom flask containing a well-stirred solution of 4-bromo-3-iodo- benzoic acid (1, 20 g, 61.18 mmol) and 2-thienylboronic acid (2, 10.18 g, 79.53 mmol) in a mixture of 1,4-dioxane (200 mL) and water (30 mL) was added potassium carbonate (16.91 g, 122.36 mmol) at ambient temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas into the reaction mixture for 10 minutes. Subsequently, Tetrakis(triphenylphosphine)palladium(0) (2.12 g, 1.84 mmol) was added and the resulting mixture was degassed with N2 for another 5 minutes and the reaction mixture was heated to 100 °C for 2 h. The progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was cooled to ambient temperature and filtered through a pad of Celite, Celite bed was washed with EtOAc (200 mL). The combined filtrate was concentrated under reduced pressure, and the residue was diluted with water (50 mL) and washed with EtOAc (50 mL). The aqueous phase was acidified with aqueous 1.5N HCl, and the formed white precipitate was filtered and dried under reduced pressure to afford 4-bromo-3-(2-thienyl)benzoic acid (3, 17 g, 46.23 mmol, 76% yield) as an off-white solid. LC-MS (ES-): m/z 283.1 [M - H] -. Step-2: To a 500 mL single-neck round-bottom flask containing a well-stirred solution of 4-bromo-3-(2- thienyl)benzoic acid (3, 17 g, 46.23 mmol) in anhydrous DMF (170 mL) were added DMAP (16.94 g, 138.69 mmol) and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (17.73 g, 92.46 mmol) followed by N-methoxymethanamine hydrochloride (4, 18.04 g, 184.93 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 3 h. The progress of the reaction was monitored by UPLC. After complete consumption of the starting material, the reaction mixture was diluted with water (700 mL) and extracted with EtOAc (3 × 300 mL). The combined organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to afford 4-bromo-N-methoxy-N- methyl-3-(2-thienyl)benzamide (5, 16 g, 36.79 mmol, 67% yield) as a thick colorless liquid. LC- MS (ES ⁺ ): m/z 328.0 [M + H] ⁺ . Step-3: To a 500 mL three-neck round-bottom flask containing a well-stirred solution of 4-bromo-N- methoxy-N-methyl-3-(2-thienyl)benzamide (5, 16 g, 36.79 mmol) in anhydrous THF (150 mL) were added anhydrous Cerium trichloride (18.13 g, 73.57 mmol) at 0 °C under nitrogen atmosphere. The resulting sparingly soluble reaction was stirred for 1 h at ambient temperature. The resulting solution was cooled to 0 °C and methyl magnesium bromide, 2 M in THF (55.18 mL) was added dropwise to the flask. After addition, the resulting solution was stirred at ambient temperature for 3 h while the progress of the reaction was monitored by UPLC. After complete consumption of starting material, the reaction was slowly quenched with sat NH ₄ Cl solution (500 mL) at 0 °C and the mixture was filtered through a pad of Celite. The solid on the filter was dissolved in water (100 mL) and extracted with EtOAc (2 × 500 mL). The organic phases were combined and washed with brine (150 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The crude residue was purified by column chromatography (230-44 mesh silica gel; 100 g) with 0-10%EtOAc/pet ether as eluent to afford 1-[4-bromo-3-(2- thienyl)phenyl]ethanone (6, 12 g, 34.14 mmol, 93% yield) as a brown syrupy liquid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.04-8.02 (m, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.86-7.83 (m, 1H), 7.75 (d, J = 5.2 Hz, 1H), 7.45-7.42 (m, 1H), 7.22 (t, J = 4.8 Hz, 1H) and 2.62 (s, 3H). Step-4: To a 500 mL single-neck round-bottom flask containing a well stirred solution of 1-[4-bromo-3- (2-thienyl)phenyl]ethanone (6, 10.5 g, 29.88 mmol) in anhydrous THF (60 mL) were added (R)- 2-methylpropane-2-sulfinamide (7, 4.35 g, 35.85 mmol) and Titanium ethoxide (13.63 g, 59.75 mmol, 12.53 mL) at ambient temperature under nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 7 h. The progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was cooled to 0 °C and diluted with water (300 mL), passed through a pad of Celite bed and washed with EtOAc (300 mL) and aqueous phase was extracted with EtOAc (3 × 150 mL). The organic phases were combined and washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to give a crude residue, which was purified by flash column chromatography (230-400 mesh silica gel) with 0-40% EtOAc/pet ether as eluent to afford (R,E)-N-(1-(4-bromo-3-(thiophen-2- yl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (8, 12 g, 23.63 mmol, 79% yield) as a yellow syrupy liquid. LC-MS (ES ⁺ ): m/z 384.0 [M + H] ⁺ . Step-5: To a 500 mL single-neck round-bottom flask containing a well stirred solution of (R,E)-N-(1-(4- bromo-3-(thiophen-2-yl)phenyl)ethylidene)-2-methylpropane-2- sulfinamide (8, 12 g, 23.63 mmol) in anhydrous THF (98 mL) and water (2 mL) was added sodium borohydride (2.68 g, 70.90 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was allowed to stir at ambient temperature for 1 h. The progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was cooled to 0 °C, diluted with ice-cold water (30 mL) then stirred at ambient temperature for 1 h. The aqueous layer was extracted with EtOAc (3 × 50 mL) and the organic phases were combined and washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The crude product was purified by flash column chromatography (230-400 mesh silica gel) with 0-100% EtOAc/pet ether as eluent to afford (R)- N-((R)-1-(4-bromo-3-(thiophen-2-yl)phenyl)ethyl)-2-methylpro pane-2-sulfinamide (9, 10 g, 20.71 mmol, 88% yield) as a colorless syrupy liquid. LC-MS (ES ⁺ ): m/z 386.1 [M + H] ⁺ . Step-6: To a 250 mL single-neck round-bottom flask containing a well-stirred solution of (R)-N-((R)-1-(4- bromo-3-(thiophen-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfi namide (9, 10 g, 20.71 mmol) in anhydrous DCM (50 mL) was added 4N HCl in 1,4-dioxane (4 M, 25 mL) at 0 °C and the reaction mixture was stirred at ambient temperature for 2 h. The progress of the reaction mixture was monitored by UPLC. Upon completion of the reaction, excess solvent was removed under reduced pressure and the obtained crude was washed with MTBE (2 × 50 mL) to afford (R)-1-(4-bromo-3- (thiophen-2-yl)phenyl)ethan-1-amine hydrochloride (10, 6 g, 16.19 mmol, 78% yield) as an off- white solid. LC-MS (ES ⁺ ): m/z 265.0 [M + H] ⁺ . Step-7: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of (R)-1-(4-bromo- 3-(thiophen-2-yl)phenyl)ethan-1-amine hydrochloride (10, 4 g, 10.80 mmol) in anhydrous DMF (60 mL) were added DIPEA (5.58 g, 43.18 mmol, 7.52 mL) and HATU (6.16 g, 16.19 mmol) followed by 5-[(1-tert-butoxycarbonylazetidin-3-yl)amino]-2-methyl-benzo ic acid (11, 4.09 g, 11.87 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 2 h. The progress of the reaction was monitored by UPLC. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ice-cold water (20 mL) and extracted with EtOAc (3 × 30 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (230-400 mesh silica gel) with 0-100% EtOAc/pet ether as eluent to afford tert-butyl (R)-3-((3-((1-(4- bromo-3-(thiophen-2-yl)phenyl)ethyl)carbamoyl)-4-methylpheny l)amino)azetidine-1- carboxylate (12, 2.6 g, 2.99 mmol, 28% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 472.0 [M + H] ⁺ . Step-8: To a 20 mL glass-vial containing a well-stirred solution of tert-butyl (R)-3-((3-((1-(4-bromo-3- (thiophen-2-yl)phenyl)ethyl)carbamoyl)-4-methylphenyl)amino) azetidine-1-carboxylate (12, 0.2 g, 0.210 mmol) and 4-ethynyl-1-(4-piperidylmethyl)piperidine hydrochloride (13, 130.27 mg, 0.525 mmol) in anhydrous acetonitrile (5 mL) was added cesium carbonate (205.59 mg, 0.630 mmol) and reaction mixture was degassed by purging with N2 for 5 minutes. Subsequently, XPhos-Pd-G3 (8.90 mg, 0.010 mmol) and XPhos (10.03 mg, 0.021 mmol) were added and the resulting mixture was heated at 90 °C for 4 h. Upon completion of the reaction, the reaction mixture was passed through a pad of Celite bed and Celite bed was washed with EtOAc (150 mL). The filtrate was concentrated under reduced pressure and the crude residue was purified by reverse phase column chromatography (C18 column, mobile phase: 10 mm HCOOH in water : MeCN) to afford tert-butyl (R)-3-((4-methyl-3-((1-(4-((1-(piperidin-4-ylmethyl)piperidi n-4- yl)ethynyl)-3-(thiophen-2-yl)phenyl)ethyl)carbamoyl)phenyl)a mino)azetidine-1-carboxylate (14, 0.1 g, 0.112 mmol, 53 % yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 696.4 [M + H] ⁺ . The following targeting ligand (Example 189) was prepared using the method described above in Example 188, with the corresponding alkyne intermediate in Step-8. Example 190 Synthesis of tert-butyl (S)-3,3-difluoro-4-((4-methyl-3-(((R)-1-(4-((1-(piperidin-4- ylmethyl)piperidin-4-yl)ethynyl)-3-(thiophen-2- yl)phenyl)ethyl)carbamoyl)phenyl)amino)pyrrolidine-1-carboxy late and tert-butyl (R)-3,3-

difluoro-4-((4-methyl-3-(((R)-1-(4-((1-(piperidin-4-ylmet hyl)piperidin-4-yl)ethynyl)-3- (thiophen-2-yl)phenyl)ethyl)carbamoyl)phenyl)amino)pyrrolidi ne-1-carboxylate Step-1: To a (3 × 20 mL) glass-vial containing a solution of methyl 5-bromo-2-methyl-benzoate (1, 3 g, 13.1 mmol) and tert-butyl 4-amino-3,3-difluoro-pyrrolidine-1-carboxylate (2, 2.9 g, 13.1 mmol) in anhydrous 1,4-dioxane (20 mL) was added cesium carbonate (10.6 g, 32.7 mmol) at ambient temperature and nitrogen gas was purged for five minutes. Subsequently, XPhos (624.33 mg, 1.31 mmol) and Pd2(dba)3 (1.05 g, 1.31 mmol) were added at ambient temperature under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 6 h. After the completion of reaction, the reaction mixture was filtered through a pad of Celite and Celite bed was washed with DCM. The filtrate was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (240-400 mesh silica gel) with 10% EtOAc/pet ether as eluent to afford tert-butyl 3,3-difluoro-4-((3-(methoxycarbonyl)-4-methylphenyl)amino)py rrolidine-1- carboxylate (3, 3.5 g, 8.69 mmol, 66% yield) as a yellow gum. LC-MS (ES ⁺ ): m/z 315.0 [M – isobutene + H] ⁺ . Step-2: To a 250 mL single-neck round-bottom flask containing a solution of tert-butyl 3,3-difluoro-4-((3- (methoxycarbonyl)-4-methylphenyl)amino)pyrrolidine-1-carboxy late (3, 3.5 g, 8.69 mmol) in 1:1:1 anhydrous MeOH/THF/H2O (75 mL) was added lithium hydroxide monohydrate, 98% (5.84 g, 139.10 mmol) at ambient temperature. The reaction mixture was stirred at this temperature for 16 h. After completion of the reaction as indicated by UPLC, excess solvent was removed under reduced pressure and the obtained crude was dissolved with 10% citric acid solution and extracted with EtOAc (2 × 50 mL). The combined organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford 5-((1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-3-yl)amin o)- 2-methylbenzoic acid (4, 3.3 g, 8.6 mmol, 99% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 301.0 [M – isobutene + H] ⁺ . Step-3: To a 50 mL single-neck round-bottom flask containing a well stirred solution of 5-((1-(tert- butoxycarbonyl)-4,4-difluoropyrrolidin-3-yl)amino)-2-methylb enzoic acid (4, 1 g, 2.64 mmol), (R)-1-(4-bromo-3-(thiophen-2-yl)phenyl)ethan-1-amine hydrochloride (5, 1.05 g, 2.90 mmol) in anhydrous DMF (10 mL) were added HATU (1.50 g, 3.96 mmol) and DIPEA (1.70 g, 13.19 mmol, 2.30 mL) and the resulting mixture was stirred at ambient temperature for 4 h. After completion of the reaction as indicated by TLC, the reaction was quenched with ice-water, and extracted with EtOAc (2 × 200 mL). The combined organic phase was washed with water, brine, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The crude product was purified by flash column chromatography (230-400 mesh silica gel) with 50% EtOAc/pet ether as eluent to obtain tert-butyl 4-((3-(((R)-1-(4-bromo-3-(thiophen-2-yl)phenyl)ethyl)carbamo yl)-4- methylphenyl)amino)-3,3-difluoropyrrolidine-1-carboxylate (6, 1.25 g, 1.64 mmol, 62% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 564.0 [M – isobutene + H] ⁺ . Step-4: Compound tert-Butyl 4-((3-(((R)-1-(4-bromo-3-(thiophen-2-yl)phenyl)ethyl)carbamo yl)-4- methylphenyl)amino)-3,3-difluoropyrrolidine-1-carboxylate (6, 1.25 g, 1.65 mmol) was subjected to chiral SFC purification to separate the diastereomers following the method: YMC Cellulose-SJ, Flowrate : 4 mL/minutes, Co-Solvent : 30%, Co-Solvent: MeOH, Injected Volume : 300 μL, Temperature : 35 °C, Outlet Pressure: 100 bar. The early eluting peak at RT = 2.14 minutes was concentrated under reduced pressure to get tert- butyl (R)-4-((3-(((R)-1-(4-bromo-3-(thiophen-2-yl)phenyl)ethyl)car bamoyl)-4- methylphenyl)amino)-3,3-difluoropyrrolidine-1-carboxylate (7, 470 mg, 0.757 mmol, 46% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 564.0 [M – isobutene + H] ⁺ . [α] ^21.7 = 3.6 (c 0.5, MeOH). The late eluting peak at RT = 3.21 minutes was concentrated under reduced pressure to afford tert- butyl (S)-4-((3-(((R)-1-(4-bromo-3-(thiophen-2-yl)phenyl)ethyl)car bamoyl)-4- methylphenyl)amino)-3,3-difluoropyrrolidine-1-carboxylate (8, 495 mg, 0.797 mmol, 48% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 564.0 [M – isobutene + H] ⁺ . [α] ^21.6 = - 8.0 (c 0.5, MeOH). Note: Configurations are arbitrarily assigned. Step-5: To a 10 mL sealed tube containing a well-stirred solution of tert-butyl (S)-4-((3-(((R)-1-(4-bromo- 3-(thiophen-2-yl)phenyl)ethyl)carbamoyl)-4-methylphenyl)amin o)-3,3-difluoropyrrolidine-1- carboxylate (8, 170 mg, 0.271 mmol) and 4-ethynyl-1-(4-piperidylmethyl)piperidine hydrochloride (9, 201.57 mg, 0.813 mmol) in anhydrous acetonitrile (5 mL) was added cesium carbonate (220.92 mg, 0.678 mmol) at ambient temperature. Nitrogen gas was purged through the reaction mixture for 10 minutes. Subsequently, XPhos (25.86 mg, 0.0542 mmol) and XPhos-Pd- G3 (34.44 mg, 0.0406 mmol) were added and stirring was continued at 90 °C for 4 h. After completion of the reaction as indicated by UPLC, the reaction mixture was passed through a pad of Celite and the Celite bed was washed with 15% MeOH/DCM. The filtrate was concentrated under reduced pressure and the obtained crude was purified by flash column chromatography (230- 400 mesh silica gel) with 25% MeOH/DCM as eluent to afford tert-butyl (S)-3,3-difluoro-4-((4- methyl-3-(((R)-1-(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl )ethynyl)-3-(thiophen-2- yl)phenyl)ethyl)carbamoyl)phenyl)amino)pyrrolidine-1-carboxy late (10, 100 mg, 0.118 mmol, 44% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 746.4 [M + H] ⁺ . Step-6: Procedure was identical to that of Step-5. Compound tert-butyl (R)-3,3-difluoro-4-((4-methyl-3- (((R)-1-(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)ethynyl) -3-(thiophen-2- yl)phenyl)ethyl)carbamoyl)phenyl)amino)pyrrolidine-1-carboxy late 11 was obtained as a yellow solid. LC-MS (ES ⁺ ): m/z 746.2 [M + H] ⁺ . Example 191 Synthesis of 1-[4-bromo-3-(2-thienyl)phenyl]ethanamine Step-1: To a sealed tube containing a stirred solution of 4-bromo-3-iodo-benzoic acid (1, 7 g, 21.41 mmol) in toluene (80 mL) and water (8 mL) were added potassium phosphate tribasic (13.64 g, 64.24 mmol) and 2-thienylboronic acid (2, 5.48 g, 42.82 mmol). The reaction mixture was purged with nitrogen gas for 5 minutes before cyclopentyl(diphenyl)phosphane;dichloromethane;dichloropalla dium;iron (174.86 mg, 214.12 μmol) was added. The reaction mixture was purged with N ₂ for another two minutes and then stirred at 115°C for 16 h. Progress of the reaction was monitored by TLC and UPLC. After completion of the reaction, the reaction mixture was diluted with water (100 mL), acidified to pH~1 using 1.5 N HCl solution and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford to give the crude product, which was purified by column chromatography (60-120 mesh silica gel) with 40-50% ethyl acetate in pet ether as eluent to afford 4-bromo-3-(2-thienyl)benzoic acid (3, 5.6 g, 15.69 mmol, 73% yield) as an off-white solid. UPLC-MS (ES-): m/z 281.0 [M - H] -. Step-2: To a stirred solution of 4-bromo-3-(2-thienyl)benzoic acid (3, 5.6 g, 15.69 mmol) in DMF (70 mL) were added N,N-dimethylpyridin-4-amine (1.92 g, 15.69 mmol) and 3- (ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (6.02 g, 31.39 mmol) at room temperature under nitrogen atmosphere. After stirring for 5 minutes, N- methoxymethanamine hydrochloride (4, 6.12 g, 62.78 mmol) was added and the reaction mixture was stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 150 mL). The organic layers were washed with cold water (3 × 70 mL), dried over sodium sulfate and concentrated in vacuo to give the crude product, which was purified by column chromatography (60-120 mesh silica gel) with 30-40% ethyl acetate in pet ether as eluent to afford 4-bromo-N-methoxy-N-methyl-3-(2-thienyl)benzamide (5, 5.2 g, 12.82 mmol, 82% yield) as a colorless gum. UPLC-MS (ES ⁺ ): m/z 326.1 [M + H] ⁺ . Step-3: To a stirred solution of 4-bromo-N-methoxy-N-methyl-3-(2-thienyl)benzamide (5, 6.47 g, 15.94 mmol) in anhydrous THF (70 mL), were added anhydrous trichlorocerium (5.89 g, 23.91 mmol) at 0 °C. The reaction mixture was stirred for 1 h at room temperature under nitrogen atmosphere before 2 M methylmagnesium bromide in THF (23.91 mL) was added by dropwise at 0 °C. The resulting mixture was stirred for 3 h at room temperature. Progress of reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched slowly with saturated ammonium chloride solution (50 mL) at 0°C and extracted with ethyl acetate (3 × 70 mL). The combined organic layers were dried over sodium sulfate and concentrated to give the crude product, which was purified by column chromatography (60-120 mesh silica gel) with 5-10% ethyl acetate in pet ether as eluent to afford 1-[4-bromo-3-(2-thienyl)phenyl]ethanone (6, 4 g, 12.41 mmol, 78% yield) as a light yellow gum. ¹ H NMR (400 MHz, DMSO-d6): δ 8.02 (m, 1H), 7.95- 7.91 (m, 1H), 7.86-7.82 (m, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.43 (m, 1H), 7.23-7.20 (m, 1H) and 2.51 (s, 3H). Step-4: To a stirred solution of 1-[4-bromo-3-(2-thienyl)phenyl]ethanone (6, 3 g, 10.67 mmol) in methanol (40 mL) were added ammonium acetate (8.22 g, 106.70 mmol) and sodium cyanoborohydride (804.59 mg, 12.80 mmol). The reaction mixture was stirred at 75°C for 6 h under nitrogen atmosphere. Progress of the reaction was monitored by TLC and UPLC. After completion of the reaction, the reaction mixture was acidified to pH~2 using trifluoroacetic acid at 0 °C and then concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate and concentrated to give the crude product, which was purified by column chromatography (60-120 mesh silica gel) with 5-10% Methanol in DCM as eluent to afford 1-[4- bromo-3-(2-thienyl)phenyl]ethanamine (7, 1.8 g, 6.38 mmol, 60% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.31 (brs, 2H), 7.85 (d, J = 8.4 Hz, 1H), 7.74-7.66 (m, 2H), 7.45- 7.38 (m, 2H), 7.21 (dd, J = 5.2, 3.6 Hz, 1H), 4.47-4.42 (m, 1H) and 1.51 (d, J = 6.8 Hz, 3H) Example 192 Synthesis of tert-Butyl 3-((4-methyl-3-((1-(4-(piperidin-4-ylethynyl)-3-(thiophen-2- yl)phenyl)ethyl)carbamoyl)phenyl)amino)azetidine-1-carboxyla te Step-1: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 1-[4-bromo-3-(2- thienyl)phenyl]ethanamine (1, 245.75 mg, 0.870 mmol) in anhydrous DMF (5 mL) were added DIPEA (675.29 mg, 5.23 mmol, 0.910 mL) and HATU (397.35 mg, 1.05 mmol) followed by 5- [(1-tert-butoxycarbonylazetidin-3-yl)amino]-2-methyl-benzoic acid (2, 300 mg, 0.870 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 16 h. The progress of the reaction was monitored by UPLC. Upon completion of the reaction, excess solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (230-400 mesh silica gel) with 50% EtOAc/ pet ether as eluent to afford tert-butyl 3-[3-[1-[4-bromo-3-(2-thienyl)phenyl]ethylcarbamoyl]-4-methy l- anilino]azetidine-1-carboxylate (3, 260 mg, 0.364 mmol, 42% yield) as a brown solid. LC-MS (ES ⁺ ): m/z 516.3 [M – isobutene + H] ⁺ . Step-2: To a 20 mL vial containing a well-stirred solution of tert-butyl 3-[3-[1-[4-bromo-3-(2- thienyl)phenyl]ethylcarbamoyl]-4-methyl-anilino]azetidine-1- carboxylate (3, 44.77 mg, 0.369 mmol) and 4-ethynylpiperidine (4, 44.77 mg, 0.369 mmol) in anhydrous acetonitrile (2 mL) was added cesium carbonate (300.67 mg, 0.922 mmol) at ambient temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas into the reaction mixture for 5 minutes. Subsequently, XPhos-Pd-G3 (15.62 mg, 0.018 mmol) and dicyclohexyl-[2- (2,4,6-triisopropylphenyl)phenyl]phosphane (17.60 mg, 0.036 mmol) were added and the resulting mixture was degassed further with N ₂ for an additional 5 minutes before the reaction mixture was heated to 90 °C for 4 h. After completion of the reaction as confirmed by UPLC, the reaction mixture was cooled to ambient temperature, diluted with EtOAc (50 mL) and water (50 mL), and stirred at ambient temperature. The reaction mixture was filtered through a pad of Celite and the Celite bed was washed with EtOAc (100 mL). The filtrate was extracted with EtOAc (2 × 50 mL) and the organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford tert-butyl 3-[4-methyl-3-[1-[4-[2-(4- piperidyl)ethynyl]-3-(2-thienyl)phenyl]ethylcarbamoyl]anilin o]azetidine-1-carboxylate (5, 300 mg, 0.330 mmol, 90% yield) as a brown solid. LC-MS (ES ⁺ ): m/z 599.8 [M – isobutene + H] ⁺ . The following targeting ligand (Example 193) was prepared using the method described above in Example 192, with the corresponding acid intermediate in Step-1. Example 194 Synthesis of 5-(((S)-4,4-difluoropyrrolidin-3-yl)amino)-N-((1R)-1-(4-((1- ((1-(1-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidine-4- carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)ethynyl)-3-(th iophen-2-yl)phenyl)ethyl)-2- methylbenzamide (Compound 115) Step-1: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (S)-3,3- difluoro-4-((4-methyl-3-(((R)-1-(4-((1-(piperidin-4-ylmethyl )piperidin-4-yl)ethynyl)-3- (thiophen-2-yl)phenyl)ethyl)carbamoyl)phenyl)amino)pyrrolidi ne-1-carboxylate (1, 100 mg, 0.118 mmol) and 1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-y l]piperidine-4- carboxylic acid (2, 51.25 mg, 0.129 mmol) in anhydrous DMF (2 mL) were added HATU (67.39 mg, 0.177 mmol) and DIPEA (76.35 mg, 0.590 mmol, 0.103 mL) and the reaction mixture was stirred at ambient temperature for 2 h. After completion of the reaction, the reaction mixture was quenched with water and the solid precipitate was filtered, washed with water and dried in vacuo to afford tert-butyl (4S)-4-((3-(((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-y l)-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl) piperidine-4-carbonyl) piperidin-4- yl)methyl)piperidin-4-yl)ethynyl)-3-(thiophen-2-yl)phenyl)et hyl)carbamoyl)-4- methylphenyl)amino)-3,3-difluoropyrrolidine-1-carboxylate (3, 135 mg, 0.084 mmol, 72% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 1115.4 [M + H] ⁺ . Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (4S)-4- ((3-(((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-me thyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl) piperidine-4-carbonyl) piperidin-4-yl)methyl)piperidin-4-yl)ethynyl)-3- (thiophen-2-yl)phenyl)ethyl)carbamoyl)-4-methylphenyl)amino) -3,3-difluoropyrrolidine-1- carboxylate (3, 135 mg, 0.084 mmol) in anhydrous DCM (2 mL) was added 4M HCl in 1,4- dioxane (0.212 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 1 h. After completion of the reaction as confirmed by UPLC, excess solvent was removed under reduced pressure and the obtained crude was purified by reverse phase prep-HPLC (X SELECT C18(250 x 19 mm) 5 micron; 0.1% formic acid in water : MeCN) to afford 5-(((S)-4,4-difluoropyrrolidin- 3-yl)amino)-N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3 -yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-y l)methyl)piperidin-4-yl)ethynyl)- 3-(thiophen-2-yl)phenyl)ethyl)-2-methylbenzamide formate (Compound 115, 23 mg, 0.021 mmol, 25% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.06 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 7.64-7.61 (m, 3H), 7.45 (d, J = 8 Hz, 1H), 7.31 (dd, J = 8.4, 1.6 Hz, 1H), 7.17- 7.15 (m, 1H), 6.96-6.93 (m, 2H), 6.84 (d, J = 2.4 Hz, 1H), 6.66-6.61 (m, 3H), 5.82-5.80 (m, 1H), 5.32-5.28 (m, 1H), 5.13-5.09 (m, 1H), 4.45-4.35 (m, 1H), 4.01-3.96 (m, 2H), 3.63-3.60 (m, 2H), 3.30-3.20 (m, 4H), 3.10-2.88 (m, 3H), 2.75-2.60 (m, 9H), 2.50 (m, 2H), 2.13-2.11 (m, 6H), 2.05- 1.95 (m, 1H), 1.87-1.84 (m, 2H), 1.76-1.61 (m, 11H), 1.43 (d, J = 7.2 Hz, 3H) and 1.09-0.80 (m, 2H). LC-MS (ES ⁺ ): m/z 1015.4 [M + H] ⁺ . Example 195 5-(((R)-4,4-difluoropyrrolidin-3-yl)amino)-N-((1R)-1-(4-((1- ((1-(1-(1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pipe ridine-4-carbonyl)piperidin- 4-yl)methyl)piperidin-4-yl)ethynyl)-3-(thiophen-2-yl)phenyl) ethyl)-2-methylbenzamide (Compound 116) Compound 116 was prepared substantially following the synthesis of Compound 115, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 1015.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.08 (s, 1H), 8.70 (d, J = 8 Hz, 1H), 8.14 (s, 1H), 7.64-7.61 (m, 3H), 7.46 (d, J = 8 Hz, 1H), 7.32 (dd, J = 8, 1.6 Hz, 1H), 7.18-7.16 (m, 1H), 6.97-6.93 (m, 2H), 6.84 (d, J = 2 Hz, 1H), 6.65-6.61 (m, 3H), 5.83-5.81 (m, 1H), 5.30-5.26 (m, 1H), 5.11-5.09 (m, 1H), 4.45-4.35 (m, 1H), 4.01-3.95 (m, 2H), 3.63-3.60 (m, 2H), 3.30 (s, 3H), 3.29-3.20 (m, 2H), 3.05-2.85 (m, 3H), 2.90 (m, 1H), 2.80-2.64 (m, 9H), 2.60-2.56 (m, 1H), 2.34-2.33 (m, 3H), 2.12 (s, 3H), 2.00-1.86 (m, 3H), 1.82-1.62 (m, 9H), 1.42 (d, J = 6.8 Hz, 3H), 1.45-0.99 (m, 1H) and 0.93-0.83 (m, 1H). Example 196 Synthesis of 5-amino-N-[1-[4-[2-[1-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-met hyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]-4-oxo-butyl]-4-piperidyl]eth ynyl]-3-(2- thienyl)phenyl]ethyl]-2-methyl-benzamide (Compound 117) Step-1: To a 20 mL screw-capped vial containing a well-stirred solution of tert-butyl N-[4-methyl-3-[1- [4-[2-(4-piperidyl)ethynyl]-3-(2-thienyl)phenyl]ethylcarbamo yl]phenyl]carbamate (1, 200 mg, 283.24 μmol) in anhydrous DMF (4 mL) were added potassium carbonate, anhydrous, 99% (117.43 mg, 849.71 μmol) and methyl 4-bromobutanoate (2, 102.55 mg, 566.47 μmol) at room temperature. The reaction mixture was stirred at 80 °C for 3 hours. Afterwards, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get the crude material, which was purified by Biotage® Isolera (230- 400 mesh silica-gel) with the desired compound eluting at 5% -MeOH/DCM to afford methyl 4- [4-[2-[4-[1-[[5-(tert-butoxycarbonylamino)-2-methyl-benzoyl] amino]ethyl]-2-(2- thienyl)phenyl]ethynyl]-1-piperidyl]butanoate (3, 150 mg, 196.17 μmol, 69% yield) as yellow gummy solid. LC-MS (ES ⁺ ): m/z 644.2 [M + H] ⁺ . Step-2: To a 50 mL single neck round-bottom flask containing a stirred solution methyl 4-[4-[2-[4-[1-[[5- (tert-butoxycarbonylamino)-2-methyl-benzoyl]amino]ethyl]-2-( 2-thienyl)phenyl]ethynyl]-1- piperidyl]butanoate (3, 150 mg, 195.70 μmol) in THF (2 mL), methanol (2 mL)and water (1 mL) was added lithium hydroxide monohydrate, 98% (41.06 mg, 978.51 μmol) at ambient temperature and the resulting mixture was stirred for 2 hours. Thereafter, solvent from the reaction mixture was evaporated and the residue was diluted with water (30 mL) and extracted with MTBE (20 mL). The aqueous phase was acidified with 10% citric acid solution to pH=4 and extracted with 10% MeOH-DCM (2 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 4-[4-[2-[4-[1-[[5-(tert- butoxycarbonylamino)-2-methyl-benzoyl]amino]ethyl]-2-(2-thie nyl)phenyl]ethynyl]-1- piperidyl]butanoic acid (4, 100 mg, 146.08 μmol, 75% yield) as an off-white gummy solid. LC- MS (ES ⁺ ): m/z 630.2 [M + H] ⁺ . Step-3: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 4-[4-[2-[4-[1-[[5- (tert-butoxycarbonylamino)-2-methyl-benzoyl]amino]ethyl]-2-( 2-thienyl)phenyl]ethynyl]-1- piperidyl]butanoic acid (4, 100 mg, 146.08 μmol) in anhydrous DMF (3 mL) were added N,N- diisopropylethylamine (18.88 mg, 146.08 μmol, 25.44 μL), HATU (55.54 mg, 146.08 μmol) and 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidin e-2,6-dione (5, 50.02 mg, 146.08 μmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 hours. Thereafter, the solvent was evaporated under reduced pressure and ice-cold water was added. The solid precipitation was washed and dried to afford tert- butyl N-[3-[1-[4-[2-[1-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2 -oxo-benzimidazol-5-yl]-1- piperidyl]-4-oxo-butyl]-4-piperidyl]ethynyl]-3-(2-thienyl)ph enyl]ethylcarbamoyl]-4-methyl- phenyl]carbamate (6, 120 mg, 61.12 μmol, 42% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 954.2 [M + H] ⁺ . Step-4: To a 50 mL single neck round bottom flask containing a well stirred solution of tert-butyl N-[3- [1-[4-[2-[1-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]-4- oxo-butyl]-4-piperidyl]ethynyl]-3-(2-thienyl)phenyl]ethylcar bamoyl]-4-methyl- phenyl]carbamate (6, 120 mg, 61.62 μmol) in dry DCM (2 mL) was added 4 M hydrogen chloride in 1,4-dioxane, 99% (308.12 μL, 1.23 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 2 hours. Thereafter, the solvent was evaporated to get the crude material, which was purified by reverse-phase HPLC (Column: 100 g Redisep C18 column ; Mobile phase A: 0.1% formic acid in Water and Mobile Phase B: Acetonitrile] with the compound eluting at 40% formic acid: CH ₃ CN) to afford 5-amino-N-[1-[4-[2-[1-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3- methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-4-oxo-butyl]-4- piperidyl]ethynyl]-3-(2- thienyl)phenyl]ethyl]-2-methyl-benzamide formate (Compound 117, 50 mg, 54.47 μmol, 88% yield) as a white solid. LC-MS (ES ⁺ ): m/z 854.2 [M + H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.11 (s, 1H), 9.43-9.36 (m, 1H), 8.66 (d, J = 8.00 Hz, 1H), 7.67-7.56 (m, 3H), 7.48 (d, J = 8.00 Hz, 1H), 7.37-7.32 (m, 1H), 7.21-7.17 (m, 1H), 7.10 (s, 1H), 7.03 (d, J = 8.00 Hz, 1H), 6.97-6.87 (m, 2H), 6.58-6.55 (m, 2H), 5.36-5.32 (m, 1H), 5.13-5.09 (m, 1H), 4.60-4.57 (m, 1H), 4.02-3.97 (m, 1H), 3.54-3.45 (m, 2H), 3.18-2.83 (m, 11H), 2.71-2.60 (m, 4H), 2.20-2.17 (m, 1H), 2.09 (s, 3H), 2.02-1.80 (m, 8H), 1.67-1.48 (m, 2H), 1.43 (d, J = 6.80 Hz, 3H). Example 197 5-(azetidin-3-ylamino)-N-[1-[4-[2-[1-[5-[4-[1-(2,6-dioxo-3-p iperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]-5-oxo-pentyl]-4-piperidyl]et hynyl]-3-(2- thienyl)phenyl]ethyl]-2-methyl-benzamide (Compound 118) Compound 118 was prepared substantially following the synthesis of Compound 117, except using 3-[4-methyl-3-[1-[4-[2-(4-piperidyl)ethynyl]-3-(2- thienyl)phenyl]ethylcarbamoyl]anilino]azetidine-1-carboxylat e (1 eq.) and methyl 5- bromopentanoate (2 eq.) in Step-1. LC-MS (ES ⁺ ): m/z 925.2 [M + H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 10.99 (bs, 1H), 8.70 (d, J = 8.40 Hz, 1H), 8.31 (s, 1H), 7.63- 7.62 (m, 3H), 7.46 (d, J = 8.00 Hz, 1H), 7.30 (dd, J = 1.60, 8.00 Hz, 1H), 7.16 (dd, J = 4.00, 4.80 Hz, 1H), 7.10 (s, 1H), 7.03-6.91 (m, 3H), 6.49-6.47 (m, 2H), 6.29 (d, J = 7.20 Hz, 1H), 5.38-5.31 (m, 1H), 5.14-5.07 (m, 1H), 4.61-4.55 (m, 1H), 4.32-4.23 (m, 1H), 4.05-3.98 (m, 3H), 3.62-3.58 (m, 1H), 3.37 (s, 3H), 3.14-3.04 (m, 2H), 2.93-2.72 (m, 2H), 2.71-2.54 (m, 6H), 2.37-2.26 (m, 5H), 2.15-2.07 (m, 5H), 2.01-1.93 (m, 1H), 1.86-1.70 (m, 4H), 1.65-1.46 (m, 8H), 1.43 (d, J = 6.80 Hz, 3H). Example 198 Synthesis of 5-(azetidin-3-ylamino)-N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxo piperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine -4-carbonyl)piperidin-4- yl)methyl)piperidin-4-yl)ethynyl)-3-(thiophen-2-yl)phenyl)et hyl)-2-methylbenzamide (Compound 119) Step-1: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (R)-3- ((4-methyl-3-((1-(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl )ethynyl)-3-(thiophen-2- yl)phenyl)ethyl)carbamoyl)phenyl)amino)azetidine-1-carboxyla te (1, 100 mg, 0.114 mmol) in anhydrous DMF (1.5 mL) were added DIPEA (74.28 mg, 0.574 mmol, 0.1 mL) and HATU (65.56 mg, 0.172 mmol) followed by 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H - benzo[d]imidazol-5-yl)piperidine-4-carboxylic acid (2, 52.32 mg, 0.114 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 4 h. Upon completion of the reaction as indicated by UPLC, excess solvent was removed under reduced pressure and the obtained residue was diluted with ice-cold water (20 mL). The formed solid precipitate was filtered, washed with water (10 mL) and dried in vacuo to afford tert-butyl 3-((3-(((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-yl)m ethyl)piperidin-4-yl)ethynyl)-3- (thiophen-2-yl)phenyl)ethyl)carbamoyl)-4-methylphenyl)amino) azetidine-1-carboxylate (3, 120 mg, 0.090 mmol, 78% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 1064.6 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 3-((3- (((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piperidin-4-yl)m ethyl)piperidin-4-yl)ethynyl)-3- (thiophen-2-yl)phenyl)ethyl)carbamoyl)-4-methylphenyl)amino) azetidine-1-carboxylate (3, 120 mg, 0.090 mmol) in anhydrous DCM (2 mL) was added trifluoroacetic acid (51.42 mg, 0.450 mmol, 0.034 mL) at -78 °C and the resulting mixture was stirred at ambient temperature for 1 h. Upon completion of the reaction as indicated by UPLC, excess solvent was removed under reduced pressure to give a crude residue, which was purified by reverse phase column chromatography (RediSep-RF Gold C18 column, mobile phase: 10 mm HCOOH in water : MeCN) to afford 5- (azetidin-3-ylamino)-N-((1R)-1-(4-((1-((1-(1-(1-(2,6-dioxopi peridin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piper idin-4-yl)methyl)piperidin-4- yl)ethynyl)-3-(thiophen-2-yl)phenyl)ethyl)-2-methylbenzamide formate (Compound 119, 15 mg, 0.014 mmol, 16% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.12 (bs, 1H), 8.69 (d, J = 7.6 Hz, 1H), 8.29 (s, 1H), 7.65-7.62 (m, 2H), 7.47 (d, J = 8 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.18 (dd, J = 5, 4 Hz, 1H), 6.97-6.93 (m, 2H), 6.84 (s, 1H), 6.64 (d, J = 6.8 Hz, 1H), 6.49-6.47 (m, 2H), 6.21 (d, J = 6.8 Hz, 1H), 5.30 (dd, J = 13, 5.6 Hz, 1H), 5.13-5.09 (m, 1H), 4.43-4.35 (m, 1H), 4.30-4.19 (m, 1H), 4.12-3.85 (m, 3H), 3.68-3.55 (m, 3H), 3.30 (s, 3H; merged with solvent), 3.10-2.80 (m, 2H), 2.66-2.50 (m, 14H), 2.12-1.85 (m, 6H), 2.00 (m, 1H), 1.85-1.61 (m, 9H), 1.43 (d, J = 7.2 Hz, 3H) and 1.02-0.87 (m, 2H). LC-MS (ES ⁺ ): m/z 964.2 [M + H] ⁺ . Example 199 Synthesis of 5-(azetidin-3-ylamino)-N-((1R)-1-(4-((1-(5-(1-(1-(2,6-dioxop iperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin- 4-yl)pentyl)piperidin-4- yl)ethynyl)-3-(thiophen-2-yl)phenyl)ethyl)-2-methylbenzamide (Compound 120) Step-1: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 5-(1-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidin-4- yl)pentanal (2, 110 mg, 0.227 mmol) and tert-butyl (R)-3-((4-methyl-3-((1-(4-(piperidin-4- ylethynyl)-3-(thiophen-2-yl)phenyl)ethyl)carbamoyl)phenyl)am ino)azetidine-1-carboxylate (1, 121.44 mg, 0.192 mmol) in dry DMSO (2 mL) at ambient temperature under nitrogen atmosphere. Subsequently, anhydrous sodium acetate (93.09 mg, 1.13 mmol) and acetic acid (136.29 mg, 2.27 mmol, 0.129 mL) were added. The mixture was stirred at this temperature for 4 h, MP-CNBH3 (190 mg, 0.381 mmol; 2 mmol/g) added to the flask. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to give a crude product, which was purified by reverse phase column chromatography (Purification method: Column : Redisef-RF C18120 g, Mobile phase A: 0.1% formic acid in water and B: acetonitrile) to afford tert-butyl 3- ((3-(((1R)-1-(4-((1-(5-(1-(1-(2,6-dioxopiperidin-3-yl)-3-met hyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-4-yl)pentyl)piperidin-4-yl)e thynyl)-3-(thiophen-2- yl)phenyl)ethyl)carbamoyl)-4-methylphenyl)amino)azetidine-1- carboxylate (3, 90 mg, 0.080 mmol, 35% yield) as a brown gummy liquid. LC-MS (ES ⁺ ): m/z 1009.4 [M + H] ⁺ . Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 3-((3- (((1R)-1-(4-((1-(5-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-4-yl)pentyl)piperidin-4-yl)e thynyl)-3-(thiophen-2- yl)phenyl)ethyl)carbamoyl)-4-methylphenyl)amino)azetidine-1- carboxylate (3, 90 mg, 0.080 mmol) in anhydrous DCM (1 mL) was added 4N HCl/1,4-dioxane (0.020 mL) at 0 °C. After completion of the addition the contents were stirred at ambient temperature for 2 h. The reaction was monitored by UPLC. After completion of the reaction, excess solvent was removed from the reaction mixture to get a crude residue which was purified by reverse phase prep-HPLC (Column : X Select C18 (250 x 19)mm, 5 micron; Mobile phase A: 0.1% formic acid in water and B: Acetonitrile) to afford 5-(azetidin-3-ylamino)-N-((1R)-1-(4-((1-(5-(1-(1-(2,6-dioxop iperidin-3- yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pipe ridin-4-yl)pentyl)piperidin-4- yl)ethynyl)-3-(thiophen-2-yl)phenyl)ethyl)-2-methylbenzamide formate (Compound 120, 15.5 mg, 0.015 mmol, 19% yield) as an white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.15 (s, 1H), 8.71 (d, J = 10.4 Hz, 1H), 7.64-7.61 (m, 3H), 7.48 (d, J = 5.6 Hz, 1H), 7.31 (d, J = 6.8 Hz, 1H), 7.19-7.16 (m, 1H), 6.98-6.91 (m, 2H), 6.82 (d, J = 2 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H), 6.51-6.49 (m, 2H),6.30-6.25 (m, 1H), 5.29 (dd, J = 12.8, 5.2 Hz, 1H), 5.13-5.09 (m, 1H), 4.32-4.25 (m, 1H), 4.03-3.91 (m, 2H), 3.62-3.35 (m, 3H), 3.30 (s, 3H), 2.93-2.85 (m, 1H), 2.67-2.61 (m, 7H), 2.34- 2.25 (m, 3H), 2.16-2.05 (m, 5H), 2.01-1.98 (m, 2H), 1.90-1.84 (m, 2H), 1.76-1.70 (m, 2H), 1.63- 1.55 (m, 2H), 1.49-1.38 (m, 5H) and 1.38-1.19 (m, 9H). LC-MS (ES ⁺ ): m/z 909.4 [M + H] ⁺ . Example 200 Synthesis of 5-(azetidin-3-ylamino)-N-(1-(4-((1-(6-(4-(1-(2,6-dioxopiperi din-3-yl)-3-methyl- 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)-6 -oxohexanoyl)piperidin-4- yl)ethynyl)-3-(thiophen-2-yl)phenyl)ethyl)-2-methylbenzamide (Compound 121) Step-1: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 6-(4-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidin-1-yl)-6- oxohexanoic acid (2, 56.37 mg, 0.110 mmol) in anhydrous DMF (3 mL) were added DIPEA (71.23 mg, 0.551 mmol, 0.095 mL) and HATU (50.29 mg, 0.132 mmol) followed by tert-butyl 3-[4- methyl-3-[1-[4-[2-(4-piperidyl)ethynyl]-3-(2-thienyl)phenyl] ethylcarbamoyl]anilino]azetidine-1- carboxylate hydrochloride (1, 100 mg, 0.110 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 3 h. The progress of the reaction was monitored by UPLC. The reaction mixture was concentrated under reduced pressure to get a crude residue and the latter was diluted with ice-cold water (20 mL) and solid precipitated out was filtered. Solid on the filter was washed with water (10 mL) and dried in vacuo to afford tert-butyl 3-[3-[1-[4-[2-[1-[6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2 -oxo- benzimidazol-5-yl]-1-piperidyl]-6-oxo-hexanoyl]-4-piperidyl] ethynyl]-3-(2- thienyl)phenyl]ethylcarbamoyl]-4-methyl-anilino]azetidine-1- carboxylate (3, 80 mg, 0.030 mmol, 28% yield) as a brown solid. LC-MS (ES ⁺ ): m/z 1051.7 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 3-[3- [1-[4-[2-[1-[6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]-6- oxo-hexanoyl]-4-piperidyl]ethynyl]-3-(2-thienyl)phenyl]ethyl carbamoyl]-4-methyl- anilino]azetidine-1-carboxylate (3, 80 mg, 0.030 mmol) in anhydrous DCM (2 mL) was added 4N HCl in 1,4-dioxane (0.152 mmol, 0.038 mL) at 0 °C and the resulting mixture was stirred at ambient temperature for 1 h. The progress of the reaction was monitored by UPLC. Excess solvent was then removed under reduced pressure and the obtained crude was purified by reverse phase HPLC (RediSep-RF Gold C18 column, mobile phase A: 10 mm NH4HCO3 in water B: acetonitrile) to afford 5-(azetidin-3-ylamino)-N-[1-[4-[2-[1-[6-[4-[1-(2,6-dioxo-3-p iperidyl)-3- methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-6-oxo-hexanoyl] -4-piperidyl]ethynyl]-3-(2- thienyl)phenyl]ethyl]-2-methyl-benzamide (Compound 121, 16 mg, 0.015 mmol, 50% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 7.64- 7.59 (m, 3H), 7.48 (d, J = 8 Hz, 1H), 7.32 (d, J = 6.8 Hz, 1H), 7.16 (dd, J = 5, 3.6, 5 Hz, 1H), 7.11 (s, 1H), 7.01 (d, J = 8 Hz, 1H), 6.96-6.91 (m, 2H), 6.47-6.47 (m, 2H), 6.17 (d, J = 6.8 Hz, 1H), 5.34-5.31 (m, 1H), 5.17-5.10 (m, 1H), 4.60-4.52 (m, 1H), 4.30-4.20 (m, 1H), 4.08-3.98 (m, 1H), 3.95-3.79 (m, 3H), 3.70-3.62 (m, 2H), 3.55-3.45 (m, 2H), 3.28-3.05 (m, 2H), 3.00-2.85 (m, 2H), 2.85-2.71 (m, 2H), 2.65 (m, 1H), 2.35 (m, 2H), 2.11 (s, 3H), 2.02-1.93 (m, 2H), 1.90-1.69 (m, 5H), 1.70-1.40 (m, 12H), 1.30-1.10 (m, 4H). LC-MS (ES ⁺ ): m/z 952.2 [M + H] ⁺ . Example 201 5-(azetidin-3-ylamino)-N-(1-(4-((1-(2-(4-(1-(2,6-dioxopiperi din-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)acetyl)piper idin-4-yl)ethynyl)-3- (thiophen-2-yl)phenyl)ethyl)-2-methylbenzamide (Compound 122) Compound 122 was prepared substantially following the synthesis of Compound 121, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 883.2 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 8.68 (d, J = 8 Hz, 1H), 7.62-7.57 (m, 3H), 7.50- 7.48 (d, J = 8 Hz, 1H), 7.32 (d, J = 6.8 Hz, 1H), 7.15-7.13 (m, 1H), 7.07 (s, 1H), 7.0-7.02 (d, J = 8 Hz, 1H), 6.93-6.90 (m, 2H), 6.47-6.43 (m, 2H), 6.17 (d, J = 6.80 Hz, 1H), 5.34-5.31 (m, 1H), 5.13-5.10 (m, 1H), 4.26-4.20 (m, 1H), 3.90-3.80 (m, 4H), 3.50-3.35 (m, 4H), 3.31 (s, 3H), 3.23- 3.12 (m, 4H), 2.99-2.90 (m, 4H), 2.68-2.63 (m, 2H), 2.14-2.11 (m, 4H), 2.01-1.90 (m, 2H), 1.88- 1.60 (m, 7H), 1.52-1.46 (m, 1H), 1.43 (d, J = 6.8 Hz, 3H).

Example 202 Synthesis of 5-(azetidin-3-ylamino)-N-((1S)-1-(4-((1-(5-(4-(1-(2,6-Dioxop iperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin- 1-yl)-5-oxopentyl)piperidin- 4-yl)ethynyl)-3-(thiophen-2-yl)phenyl)ethyl)-2-methylbenzami de (Compound 123)

Step-1: To a 25 mL sealed tube containing a well-stirred solution of tert-butyl 3-[3-[1-[4-bromo-3-(2- thienyl)phenyl]ethylcarbamoyl]-4-methyl-anilino]azetidine-1- carboxylate (1, 700 mg, 0.797 mmol) and ethyl 5-(4-ethynyl-1-piperidyl)pentanoate (2, 259.28 mg, 0.797 mmol) in anhydrous Acetonitrile (5 mL) was added Cesium carbonate (649.60 mg, 1.99 mmol) at ambient temperature and the resulting mixture was degassed by bubbling nitrogen gas for 5 minutes. Subsequently, XPhos (38.02 mg, 0.079 mmol) and XPhos-Pd-G3 (33.75 mg, 0.039 mmol) were added, and the resulting mixture was degassed with nitrogen gas for additional 5 minutes. The reaction mixture was stirred at 90 °C for 4 h. Progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was passed through a pad of Celite and the Celite bed was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure and the obtained crude was purified by reverse phase column chromatography (RediSep-RF Gold C18 column, mobile phase A: 10 mm HCOOH in water B: MeCN) to afford tert-butyl 3-[3-[1-[4- [2-[1-(5-ethoxy-5-oxo-pentyl)-4-piperidyl]ethynyl]-3-(2-thie nyl)phenyl]ethylcarbamoyl]-4- methyl-anilino]azetidine-1-carboxylate formate (3, 270 mg, 0.342 mmol, 43% yield) as an off- white solid. LC-MS (ES ⁺ ): m/z 727.6 [M + H] ⁺ . Step-2: Compound tert-Butyl 3-[3-[1-[4-[2-[1-(5-ethoxy-5-oxo-pentyl)-4-piperidyl]ethynyl ]-3-(2- thienyl)phenyl]ethylcarbamoyl]-4-methyl-anilino]azetidine-1- carboxylate formate (3, 270 mg, 0.349 mmol) was subjected to chiral SFC separation to separate the diastereomers following the method: YMC Cellulose-SZ, Flowrate : 4 mL/minutes, Co-Solvent : 50 %, Co-Solvent: 0.1% Isopropyl amine in IPA, Temperature : 35 °C, Outlet Pressure: 100 bar. The late eluting peak at RT = 2.6 minutes was concentrated under reduced pressure to afford tert-butyl (S)-3-((3-((1-(4- ((1-(5-ethoxy-5-oxopentyl)piperidin-4-yl)ethynyl)-3-(thiophe n-2-yl)phenyl)ethyl)carbamoyl)-4- methylphenyl)amino)azetidine-1-carboxylate (4, 100 mg, 0.131 mmol, 38% yield, 99.7% chiral purity) as an off-white solid. LC-MS (ES ⁺ ): m/z 727.3 [M + H] ⁺ . Step-3: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (S)-3- ((3-((1-(4-((1-(5-ethoxy-5-oxopentyl)piperidin-4-yl)ethynyl) -3-(thiophen-2- yl)phenyl)ethyl)carbamoyl)-4-methylphenyl)amino)azetidine-1- carboxylate (4, 100 mg, 0.131 mmol) in 1:1 THF/MeOH (4 mL) was added lithium hydroxide, monohydrate (11.01 mg, 0.262 mmol) in water (1 mL) at ambient temperature. The resulting solution was stirred at this temperature for 2 h. Upon completion of the reaction as indicated by UPLC, the solvent was removed from the reaction mixture. The crude product was acidified with 1.5 N HCl and extracted with 10% MeOH/DCM (2 × 25 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford (S)-5-(4-((4-(1-(5-((1-(tert- butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenzamido)ethyl) -2-(thiophen-2- yl)phenyl)ethynyl)piperidin-1-yl)pentanoic acid hydrochloride (5, 100 mg, 0.125 mmol, 96% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 699.2 [M + H] ⁺ . Step-4: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of (S)-5-(4-((4-(1- (5-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-2-methylben zamido)ethyl)-2-(thiophen-2- yl)phenyl)ethynyl)piperidin-1-yl)pentanoic acid hydrochloride (5, 100 mg, 0.125 mmol) in anhydrous DMF (3 mL) were added DIPEA (48.51 mg, 0.375 mmol, 0.065 mL), HATU (57.08 mg, 0.150 mmol), and 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidin e-2,6-dione trifluoroacetate (6, 57.51 mg, 0.125 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 2 h. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure and ice-cold water (10 mL) was added to the obtained crude residue. The solid precipitate was filtered, washed with water (10 mL) and dried in vacuo to afford tert-butyl 3-((3-(((1S)-1-(4-((1-(5-(4-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidin-1-yl)-5- oxopentyl)piperidin-4-yl)ethynyl)-3-(thiophen-2-yl)phenyl)et hyl)carbamoyl)-4- methylphenyl)amino)azetidine-1-carboxylate (7, 140 mg, 0.088 mmol, 71% yield) as an off- white solid. LC-MS (ES-): m/z 1022.4 [M - H] -. Step-5: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 3-((3- (((1S)-1-(4-((1-(5-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-1-yl)-5-oxopentyl)piperidin- 4-yl)ethynyl)-3-(thiophen-2- yl)phenyl)ethyl)carbamoyl)-4-methylphenyl)amino)azetidine-1- carboxylate (7, 140 mg, 0.088 mmol) in anhydrous DCM (3 mL) was added TFA (101.45 mg, 0.889 mmol, 0.068 mL) at 0 °C and the resulting mixture was stirred at ambient temperature for 1 h. Upon completion of the reaction as indicated by UPLC, excess solvent was removed under reduced pressure and the crude product was purified by reverse phase HPLC (RediSep-RF Gold C18 column, mobile phase A: 10 mm TFA in water and B: MeCN) to afford 5-(azetidin-3-ylamino)-N-((1S)-1-(4-((1-(5-(4-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidin-1-yl)-5- oxopentyl)piperidin-4-yl)ethynyl)-3-(thiophen-2-yl)phenyl)et hyl)-2-methylbenzamide di- trifluoroacetate (Compound 123, 60 mg, 0.051 mmol, 58% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 9.30 (bs, 1H), 8.72 (d, J = 8.4 Hz, 1H), 7.67-7.56 (m, 3H), 7.49 (d, J = 8 Hz, 1H), 7.37-7.32 (m, 1H), 7.19-7.15 (m, 1H), 7.10 (s, 1H), 7.19-7.00 (m, 2H), 6.95-6.90 (m, 1H), 6.52-6.49 (m, 2H), 5.38-5.31 (m, 1H), 5.15-5.08 (m, 1H), 4.63-4.55 (m, 1H), 4.38-4.20 (m, 3H), 4.03-3.95 (m, 1H), 3.90-3.75 (m, 3H), 3.33 (s, 3H), 3.25-3.05 (m, 4H), 3.00- 2.75 (m, 7H), 2.7-2.6 (m, 2H), 2.50 (m, 1H), 2.44-2.41 (m, 2H), 2.20-2.15 (m, 1H), 2.12 (s, 3H), 2.05-1.9 (m, 3H), 1.90-1.76 (m, 3H), 1.721-1.51 (m, 6H), 1.43 (d, J = 7.20 Hz, 3H). LC-MS (ES ⁺ ): m/z 923.4 [M + H] ⁺ . Example 203 Synthesis of tert-butyl (3-(((R)-1-(4-(((3R,4S)-3-fluoro-1-(piperidin-4-ylmethyl)pip eridin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)c arbamate Step-1: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 7-oxa- 3-azabicyclo[4.1.0]heptane-3-carboxylate (1, 3.0 g, 15.06 mmol) in dry DMSO (30 mL) was added lithium acetylide (2.71 g, 30.11 mmol) under nitrogen atmosphere at 10 °C. The resulting mixture was stirred at ambient temperature for 16 h. Thereafter, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 100 mL). The organic phases were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (230-400 mesh silica gel) with 50% EtOAc/pet ether as eluent to afford tert-butyl (3S,4S)-4-ethynyl-3-hydroxypiperidine-1- carboxylate (2, 2.2 g, 8.52 mmol, 57% yield) as a colorless liquid. LC-MS (ES ⁺ ): m/z 170.0 [M – isobutene + H] ⁺ . Step-2: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (3S,4S)-4-ethynyl-3-hydroxypiperidine-1-carboxylate (2, 1.00 g, 3.86 mmol) in anhydrous DCM (10 mL) was added N-ethyl-N-(trifluoro-sulfanyl)ethanamine, DAST (2.49 g, 15.45 mmol, 2.04 mL) at 0 °C under nitrogen atmosphere and the resulting mixture was stirred for 4 h at ambient temperature. After completion of the reaction as indicated by TLC, the reaction was quenched with saturated NaHCO3 (30 mL) at 0 °C and the aqueous phase was extracted with DCM (2 × 200 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The crude mass was purified by flash column chromatography (230-400 mesh silica gel) with 15% EtOAc/pet ether as eluent to afford tert-butyl (3R,4S)-4-ethynyl-3-fluoropiperidine-1-carboxylate (3, 680 mg, 2.33 mmol, 60% yield) as a yellow liquid. LC-MS (ES ⁺ ): m/z 128.2 [M – COO ^t Bu + H] ⁺ . Step-3: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (3R,4S)-4-ethynyl-3-fluoropiperidine-1-carboxylate (3, 650 mg, 2.52 mmol) in dry DCM (5 mL) was added 4N HCl in 1,4-dioxane (3.15 mL) at 0 °C. The resulting reaction mixture was stirred at ambient temperature for 2 h. Progress of the reaction was monitored by UPLC. Thereafter, excess solvent was evaporated under reduced pressure and the obtained residue was washed with MTBE (10 mL) to afford (3R,4S)-4-ethynyl-3-fluoropiperidine hydrochloride (4, 400 mg, 2.42 mmol, 96% yield) as a white solid. LC-MS (ES ⁺ ): m/z 128.2 [M + H] ⁺ . Step-4: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of (3R,4S)-4- ethynyl-3-fluoropiperidine (4, 300 mg, 1.71 mmol) and tert-butyl 4-formylpiperidine-1- carboxylate (5, 436.40 mg, 2.05 mmol) in MeOH (10 mL) were added sodium acetate, anhydrous (279.75 mg, 3.41 mmol) and acetic acid (1.02 g, 17.05 mmol, 0.976 mL) and the reaction mixture was stirred at ambient temperature for 1 h. Subsequently, MP-CNBH ₃ (600 mg, 1.23 mmol; 2 mmol/g) was added in one portion and stirring was continued for another 16 h at ambient temperature. After completion of the reaction as confirmed by UPLC, excess solvent was evaporated under reduced pressure. Water was then added to the residue and the resulting aqueous phase was basified with aq. NaHCO3 solution and extracted with DCM (2 × 150 mL). The combined organic phase was dried over anhydrous Na2SO4, and concentrated in vacuo to afford tert-butyl 4-(((3R,4S)-4-ethynyl-3-fluoropiperidin-1-yl)methyl)piperidi ne-1-carboxylate (6, 500 mg, 1.22 mmol, 71% yield) as a red gum. LC-MS (ES ⁺ ): m/z 325.2 [M + H] ⁺ . Step-5: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4- (((3R,4S)-4-ethynyl-3-fluoropiperidin-1-yl)methyl)piperidine -1-carboxylate (6, 500 mg, 1.22 mmol) in anhydrous DCM (5 mL) was added 4N HCl/1,4-dioxane, 99% (0.304 mL) at 0 °C. The resulting reaction mixture was stirred at ambient temperature for 2 h. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated under vacuum to give the crude product, which was washed with MTBE and dried to afford (3R,4S)-4-ethynyl-3-fluoro-1- (piperidin-4-ylmethyl)piperidine hydrochloride (7, 310 mg, 1.19 mmol, 98% yield) as a white solid. LC-MS (ES ⁺ ): m/z 225.2 [M + H] ⁺ . Step-6: To a 50 mL sealed tube containing a well-stirred solution of (3R,4S)-4-ethynyl-3-fluoro-1- (piperidin-4-ylmethyl)piperidine hydrochloride (7, 206.19 mg, 0.790 mmol) and tert-butyl (R)-(3- ((1-(4-bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl) carbamate (8, 350 mg, 0.608 mmol) in a mixture of anhydrous acetonitrile (25 mL) and THF (5 mL) was added cesium carbonate (1.19 g, 3.65 mmol) and the resulting mixture was degassed by bubbling N ₂ for 10 minutes. Thereafter, XPhos (57.92 mg, 0.121 mmol) and XPhos-Pd-G3 (102.96 mg, 0.121 mmol) were added and the resulting mixture was degassed with N2 for an additional 3 minutes. The reaction mixture was stirred at 90 °C for 4 h. Progress of the reaction mass was monitored by UPLC-MS. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and the Celite bed and washed with EtOAc (200 mL). The combined filtrate was concentrated under reduced pressure give the crude product, which was purified by reverse- phase column chromatography (RediSep-Rf Gold C18 column -100 g, Mobile phase: A: 0.1% Formic acid in water, B: Acetonitrile). Fractions having desired product were concentrated under reduced pressure to remove acetonitrile and then diluted with 10% sodium bicarbonate solution (100 mL) and brine (25 mL) and then extracted with EtOAc (2 × 100 mL). The organic phases were dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to afford tert-butyl (3-(((R)-1-(4-(((3R,4S)-3-fluoro-1-(piperidin-4-ylmethyl)pip eridin-4-yl)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)carbamate (9, 210 mg, 0.331 mmol, 54% yield) as a pale yellow solid. LC-MS (ES ⁺ ): m/z 627.2 [M + H] ⁺ . Example 204 Synthesis of tert-butyl (S)-3,3-difluoro-4-((3-(((R)-1-(4-(((3R,4S)-3-fluoro-1-((4- fluoropiperidin-4-yl)methyl)piperidin-4-yl)ethynyl)naphthale n-1-yl)ethyl)carbamoyl)-4- methylphenyl)amino)pyrrolidine-1-carboxylate Step-1: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of (3R,4S)-4- ethynyl-3-fluoropiperidine hydrochloride (1, 200 mg, 1.21 mmol) and tert-butyl 4-fluoro-4- formyl-piperidine-1-carboxylate (2, 363.81 mg, 1.57 mmol) in MeOH (5 mL) were added anhydrous sodium acetate (297.81 mg, 3.63 mmol) and acetic acid (436.02 mg, 7.26 mmol, 0.415 mL) and the resulting mixture was stirred at ambient temperature for 1 hour. Subsequently, MP-CNBH ₃ (2 mmol \ 1 g) (901 mg, 1.82 mmol) was added in one portion and stirring was continued for another 16 h at ambient temperature. After completion of reaction as confirmed by LCMS, the reaction mixture was filtered through a cotton plug and excess solvent was evaporated under reduced pressure. The obtained crude was purified by flash column chromatography (230-400 mesh silica gel) with desired compound eluting at 20% EtOAc in pet ether to afford tert-butyl 4-(((3R,4S)-4-ethynyl-3-fluoropiperidin-1-yl)methyl)-4- fluoropiperidine-1-carboxylate (3, 250 mg, 0.546 mmol, 45% yield) as a colorless liquid. LC-MS (ES ⁺ ): m/z 343.2 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing to a well-stirred solution of tert-butyl 4- (((3R,4S)-4-ethynyl-3-fluoropiperidin-1-yl)methyl)-4-fluorop iperidine-1-carboxylate (3, 250 mg, 0.547 mmol) in anhydrous DCM (2 mL) was added 4M HCl in 1,4-dioxane, 99% (1.37 mL) at 0 °C. the resulting mixture was stirred for 2 h at ambient temperature. After completion of the reaction as indicated by UPLC, excess solvent was removed and the crude was triturated with MTBE to afford (3R,4S)-4-ethynyl-3-fluoro-1-((4-fluoropiperidin-4-yl)methyl )piperidine hydrochloride (4, 150 mg, 0.511 mmol, 93% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 243.2 [M + H] ⁺ . Step-3: To 50 mL sealed tube containing a well-stirred solution of tert-butyl (S)-4-((3-(((R)-1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)- 3,3-difluoropyrrolidine-1- carboxylate (5, 100 mg, 0.168 mmol) and (3R,4S)-4-ethynyl-3-fluoro-1-((4-fluoropiperidin-4- yl)methyl)piperidine hydrochloride (4, 52.11 mg, 0.185 mmol) in anhydrous acetonitrile (2 mL) was added cesium carbonate (137.03 mg, 0.420 mmol) and reaction mixture was degassed with N2 for 5 minutes. Subsequently, XPhos (8.02 mg, 0.0168 mmol) and XPhos-Pd-G3 (7.12 mg, 0.0084 mmol) were added and the resulting mixture was heated at 90 °C for 4 h. After completion of the reaction as indicated by TLC, the reaction mixture was filtered through a pad of Celite and the Celite bed was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure. The crude residue was purified with flash column chromatography (230-400 mesh silica gel) with 20% MeOH/DCM as eluent to afford tert-butyl (S)-3,3-difluoro-4-((3-(((R)-1-(4- (((3R,4S)-3-fluoro-1-((4-fluoropiperidin-4-yl)methyl)piperid in-4-yl)ethynyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)pyrrolidine-1-carbo xylate (6, 140 mg, 0.100 mmol, 60% yield) as a brown solid. LC-MS (ES ⁺ ): m/z 750.4 [M + H] ⁺ . Example 205 Synthesis of tert-butyl (R)-3,3-difluoro-4-((3-(((R)-1-(4-(((3R,4S)-3-fluoro-1-(pipe ridin-4- ylmethyl)piperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)carbam oyl)-4- methylphenyl)amino)pyrrolidine-1-carboxylate Step-1, Step-2, and Step-3: Procedures were identical to those of Step-1 to Step-3 in Example 204. Compound tert-butyl (R)- 3,3-difluoro-4-((3-(((R)-1-(4-(((3R,4S)-3-fluoro-1-(piperidi n-4-ylmethyl)piperidin-4- yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)a mino)pyrrolidine-1-carboxylate was obtained as a brown solid. LC-MS (ES ⁺ ): m/z 732.4 [M + H] ⁺ . The following targeting ligand (Example 206) was prepared using the method described above in Example 205, with the corresponding bromide intermediate in Step-3.

Example 207 Synthesis of tert-butyl (S)-3,3-difluoro-4-((3-(((R)-1-(4-(((3R,4S)-3-fluoro-1-((4- hydroxypiperidin-4-yl)methyl)piperidin-4-yl)ethynyl)naphthal en-1-yl)ethyl)carbamoyl)-4- methylphenyl)amino)pyrrolidine-1-carboxylate

Step-1: To a 20 mL glass-vial containing a well-stirred solution of (3R,4S)-4-ethynyl-3-fluoropiperidine hydrochloride (1, 200 mg, 1.21 mmol) in EtOH (2 mL) was added tert-butyl 1-oxa-6- azaspiro[2.5]octane-6-carboxylate (2, 258.09 mg, 1.21 mmol) and the resulting mixture was stirred at 70 °C for 16 h. Progress of the reaction mass was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water and the aqueous phase was extracted with EtOAc (3 × 150 mL). The combined organic phase was washed with water (25 mL), brine (25 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography (230-400 mesh silica gel) with 15% EtOAc/pet ether as eluent to afford tert-butyl 4-(((3R,4S)-4-ethynyl-3-fluoropiperidin-1-yl)methyl)-4- hydroxypiperidine-1-carboxylate (3, 280 mg, 0.797 mmol, 66% yield) as a colorless liquid. LC- MS (ES ⁺ ): m/z 341.2 [M + H] ⁺ . Step-2: To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4- (((3R,4S)-4-ethynyl-3-fluoropiperidin-1-yl)methyl)-4-hydroxy piperidine-1-carboxylate (3, 300 mg, 0.854 mmol) in dry DCM (3 mL) was added 4N HCl/1,4-dioxane (1.07 mL) at 0 °C and the reaction mixture was stirred at 25 °C for 1 h. After completion of the reaction as indicated by TLC, excess solvent was removed under reduced pressure. The obtained crude mass was washed with MTBE to afford 4-(((3R,4S)-4-ethynyl-3-fluoropiperidin-1-yl)methyl)piperidi n-4-ol hydrochloride (4, 230 mg, 0.822 mmol, 96% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 241.2 [M + H] ⁺ . Step-3: To a 25 mL sealed tube containing a well-stirred solution of tert-butyl (S)-4-((3-(((R)-1-(4- bromonaphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)- 3,3-difluoropyrrolidine-1- carboxylate (5, 140 mg, 0.235 mmol) and 4-(((3R,4S)-4-ethynyl-3-fluoropiperidin-1- yl)methyl)piperidin-4-ol hydrochloride (4, 131.69 mg, 0.471 mmol) in anhydrous acetonitrile (15 mL) was added cesium carbonate (191.84 mg, 0.589 mmol) at ambient temperature. Nitrogen gas was purged through the reaction mixture for 10 minutes. Subsequently, XPhos (11.23 mg, 0.023 mmol) and XPhos-Pd-G3 (19.94 mg, 0.023 mmol) were added and stirring was continued for 4 h at 90 °C. The reaction was monitored by LCMS. Reaction mixture was passed through a Celite bed and the Celite bed was washed with EtOAc (50 mL). The filtrate was concentrated under vacuum to give the crude product which was purified by flash column chromatography (230-400 mesh silica gel) with 25% MeOH/DCM as eluent to afford tert-butyl (S)-3,3-difluoro-4-((3-(((R)- 1-(4-(((3R,4S)-3-fluoro-1-((4-hydroxypiperidin-4-yl)methyl)p iperidin-4-yl)ethynyl)naphthalen- 1-yl)ethyl)carbamoyl)-4-methylphenyl)amino)pyrrolidine-1-car boxylate (6, 55 mg, 0.068 mmol, 29% yield) as a brown solid. LC-MS (ES ⁺ ): m/z 748.5 [M + H] ⁺ . Example 208 Synthesis of 5-(((S)-4,4-difluoropyrrolidin-3-yl)amino)-N-((1R)-1-(4-(((3 R,4S)-1-((1-(1-(1- (2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydro-3l2-benzo[d]imid azol-5-yl)piperidine-4- carbonyl)-4-fluoropiperidin-4-yl)methyl)-3-fluoropiperidin-4 -yl)ethynyl)naphthalen-1-

yl)ethyl)-2-methylbenzamide (Compound 124) Step-1: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 1-[1-(2,6-dioxo- 3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-c arboxylic acid hydrochloride (2, 50 mg, 0.112 mmol) in anhydrous DMF (2 mL) were added DIPEA (72.59 mg, 0.561 mmol, 0.098 mL), HATU (64.07 mg, 0.168 mmol) and tert-butyl (S)-3,3-difluoro-4-((3-(((R)-1-(4-(((3R,4S)-3- fluoro-1-((4-fluoropiperidin-4-yl)methyl)piperidin-4-yl)ethy nyl)naphthalen-1- yl)ethyl)carbamoyl)-4-methylphenyl)amino)pyrrolidine-1-carbo xylate (1, 140.39 mg, 0.101 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at this temperature for 4 h. After completion of the reaction as indicated by UPLC, excess solvent was evaporated under reduced pressure and ice-cold water was added to precipitate a solid that was filtered, washed with water (5 mL) and dried in vacuo to afford tert-butyl (4S)-4-((3-(((1R)-1-(4- (((3R,4S)-1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-o xo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)-4-fluoropiperid in-4-yl)methyl)-3-fluoropiperidin- 4-yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl )amino)-3,3-difluoropyrrolidine- 1-carboxylate (3, 100 mg, 0.036 mmol, 32% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 1118.7 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (4S)-4- ((3-(((1R)-1-(4-(((3R,4S)-1-((1-(1-(1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbonyl)-4-fluoropiperid in-4-yl)methyl)-3-fluoropiperidin- 4-yl)ethynyl)naphthalen-1-yl)ethyl)carbamoyl)-4-methylphenyl )amino)-3,3-difluoropyrrolidine- 1-carboxylate (3, 100 mg, 0.036 mmol) in dry DCM (2 mL)was added 4N HCl in 1,4-dioxane (0.091 mL) at 0 °C. The resulting reaction mixture was stirred at ambient temperature for 2 h. After completion of the reaction as indicated by UPLC, excess solvent was evaporated under reduced pressure to give the crude product which was purified by reverse phase column chromatography (C18 column, 60 g, mobile phase: 0.1% formic acid in water:MeCN) to afford 5- (((S)-4,4-difluoropyrrolidin-3-yl)amino)-N-((1R)-1-(4-(((3R, 4S)-1-((1-(1-(1-(2,6-dioxopiperidin- 3-yl)-2-oxo-1,2-dihydro-3l2-benzo[d]imidazol-5-yl)piperidine -4-carbonyl)-4-fluoropiperidin-4- yl)methyl)-3-fluoropiperidin-4-yl)ethynyl)naphthalen-1-yl)et hyl)-2-methylbenzamide formate (Compound 124, mg, 0.011 mmol, 31% yield) as a white solid. LC-MS (ES ⁺ ): m/z 1018.2 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 8.83 (d, J = 8 Hz, 1H), 8.34-8.30 (m, 2H), 7.69-7.66 (m, 3H), 7.58 (d, J = 7.6 Hz, 1H), 6.96-6.93 (m, 2H), 6.84 (d, J = 1.6 Hz, 1H), 6.66-6.60 (m, 3H), 5.91-5.86 (m, 2H), 5.29 (dd, J = 13, 5.6 Hz, 1H), 4.81-4.51 (m, 1H), 4.15 (d, J = 14.4 Hz, 1H), 4.10-3.91 (m, 1H), 3.90-3.81 (m, 1H), 3.62 (d, J = 11.6 Hz, 2H), 3.45-3.42 (m, 2H), 3.40- 3.33 (m, 3H), 3.10 (m, 2H), 3.01-2.97 (m, 3H), 2.82-2.72 (m, 3H), 2.50 (m, 10H), 2.20-2.10 (m, 1H), 2.01 (s, 3H), 2.00-1.85 (m, 2H), 1.81-1.73 (m, 6H), 1.56 (m, 2H) and 1.55 (d, J = 6.8 Hz, 3H). Example 209 5-amino-N-((1R)-1-(4-(((3R,4S)-1-((1-(1-(1-(2,6-dioxopiperid in-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carbonyl)piper idin-4-yl)methyl)-3- fluoropiperidin-4-yl)ethynyl)naphthalen-1-yl)ethyl)-2-methyl benzamide (Compound 125) Compound 125 was prepared substantially following the synthesis of Compound 124, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 895.3 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 8.78 (d, J = 7.6 Hz, 1H), 8.34-8.30 (m, 2H), 7.69- 7.64 (m, 3H), 7.59 (d, J = 3.6 Hz, 1H), 6.96-6.93 (m, 1H), 6.85 (d, J = 7.6 Hz, 2H), 6.64 (d, J = 9.2 Hz, 1H), 6.55-6.51 (m, 2H), 5.92-5.81 (m, 1H), 5.30-5.27 (m, 1H), 5.00 (bs, 2H), 4.80-4.61 (m, 1H), 4.40 (d, J = 12.8 Hz, 1H), 4.00 (d, J = 11.2 Hz, 1H), 3.62 (d, J = 11.6 Hz, 2H), 3.36 (s, 3H), 3.35-3.32 (m, 1H), 3.15-2.95 (m, 3H), 2.91-2.86 (m, 1H), 2.85-2.62 (m, 7H), 2.61-2.35 (m, 2H), 2.30-2.10 (m, 3H), 2.09 (s, 3H), 2.05-1.90 (m, 1H), 1.89-1.60 (m, 7H) and 1.54 (d, J = 6.8 Hz, 3H) and 1.10 -0.80 (m, 2H). Example 210 5-(((R)-4,4-difluoropyrrolidin-3-yl)amino)-N-((1R)-1-(4-(((3 R,4S)-1-((1-(1-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidine-4-

carbonyl)piperidin-4-yl)methyl)-3-fluoropiperidin-4-yl)et hynyl)naphthalen-1-yl)ethyl)-2- methylbenzamide (Compound 126) Compound 126 was prepared substantially following the synthesis of Compound 124, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 1000.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.07 (s, 1H), 8.84 (d, J = 8 Hz, 1H), 8.34-8.32 (m, 2H), 7.68- 7.58 (m, 4H), 6.96-6.93 (m, 2H), 6.84 (d, J = 2 Hz, 1H), 6.66-6.60 (m, 3H), 5.90 (quin, J = 8 Hz, 1H ), 5.89-5.80 (m, 1H), 5.39-5.31 (m, 1H), 4.70-4.60 (m, 1H), 4.52-4.42 (m, 1H), 4.10-3.90 (m, 2H), 3.62 (d, J = 12 Hz, 2H), 3.43-3.40 (m, 2H), 3.38-3.33 (m, 3H), 3.27-3.26 (m, 1H), 3.03-2.95 (m, 6H), 2.68-2.61 (m, 5H), 2.59-2.53 (m, 2H), 2.34-2.34 (m, 3H), 2.25 (m, 1H), 2.12 (s, 3H), 2.05-1.98 (m, 2H), 1.77-1.71 (m, 8H), 1.55-1.53 (d, J = 6.8 Hz, 3H) and 1.10-0.80 (m, 2H). Example 211 5-(((S)-4,4-difluoropyrrolidin-3-yl)amino)-N-((1R)-1-(4-(((3 R,4S)-1-((1-(1-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidine-4- carbonyl)piperidin-4-yl)methyl)-3-fluoropiperidin-4-yl)ethyn yl)naphthalen-1-yl)ethyl)-2- methylbenzamide (Compound 127) Compound 127 was prepared substantially following the synthesis of Compound 124, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 1000.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.06 (s, 1H), 8.82 (d, J = 10.8 Hz, 1H), 8.42-8.29 (m, 2H), 7.68-7.65 (m, 3H), 7.59-7.56 (m, 1H), 6.94 (d, J = 10.8 Hz, 2H), 6.84 (d, J = 2.8 Hz, 1H), 6.65- 6.58 (m, 3H), 5.91-5.86 (m, 2H), 5.38-5.14 (m, 1H), 4.68 (d, ² J H-F= 57 Hz, 1H ),4.45-4.35 (m, 1H), 4.05-3.85 (m, 2H), 3.63-3.59 (m, 2H), 3.30 (s, 3H), 3.25-3.15 (m, 2H), 3.07-2.93 (m, 6H), 2.72-2.64 (m, 4H), 2.50 (m, 5H), 2.28-2.13 (m, 3H), 2.12 (s, 3H), 2.00-1.98 (m, 2H), 1.77-1.71 (m, 8H), 1.71-1.53 (m, 3H) and 1.10-0.08 (m, 2H). Example 212 5-(((S)-4,4-difluoropyrrolidin-3-yl)amino)-N-((1R)-1-(4-(((3 R,4S)-1-((1-(1-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidine-4- carbonyl)-4-hydroxypiperidin-4-yl)methyl)-3-fluoropiperidin- 4-yl)ethynyl)naphthalen-1- Compound 128 was prepared substantially following the synthesis of Compound 124, using the corresponding intermediates. LC-MS (ES ⁺ ): m/z 1016.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 8.83 (d, J = 8 Hz, 1H), 8.34-8.30 (m, 2H), 7.69- 7.64 (m, 3H), 7.58 (d, J = 7.6 Hz, 1H), 6.94 (dd, J = 8.6, 2.8 Hz, 2H), 6.84-6.84 (m, 1H), 6.72- 6.59 (m, 3H), 5.91-5.80 (m, 2H), 5.31-5.22 (m, 1H), 4.67 ( ² J _HF = 52 Hz, 1H), 4.34 (s, 1H), 4.11- 4.00 (m, 1H), 3.98-3.87 (m, 1H), 3.77-3.66 (m, 1H), 3.64-3.56 (m, 2H), 3.52 (m, 4H), 3.31 (s, 3H), 3.05-2.80 (m, 5H), 2.72-2.65 (m, 3H), 2.62-2.5 (m, 6H), 32.45-2.30 (m, 2H), 2.10 (m, 1H), 2.09 (s, 3H), 2.00-1.91 (m, 2H), 1.83-1.62 (m, 5H) and 1.60-1.32 (m, 6H). Example 213 Synthesis of tert-butyl 3-((3-(((R)-1-(3-(5-(((S)-3-aminopyrrolidin-1-yl)methyl)thio phen-2- yl)phenyl)ethyl)carbamoyl)-4-methylphenyl)amino)azetidine-1- carboxylate Step-1: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of 5-[(1-tert- butoxycarbonylazetidin-3-yl)amino]-2-methyl-benzoic acid (1, 0.7 g, 2.18 mmol) and (R)-1-(3- bromophenyl)ethan-1-amine (2, 436.63 mg, 2.18 mmol) in anhydrous DMF (10 mL) were added HATU (1.24 g, 3.27 mmol) and DIPEA (846.15 mg, 6.55 mmol, 1.14 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 3 h. The reaction was monitored by UPLC. Upon completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc (3 × 40 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (230-400 mesh silica gel) with 50% EtOAc/pet ether as eluent to afford tert-butyl (R)-3-((3-((1-(3-bromophenyl)ethyl)carbamoyl)-4- methylphenyl)amino)azetidine-1-carboxylate (3, 0.9 g, 1.81 mmol, 83% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 432.2 [M – isobutene + H] ⁺ . Step-2: To a 20 mL glass-vial containing a well-stirred solution of tert-butyl (R)-3-((3-((1-(3- bromophenyl)ethyl)carbamoyl)-4-methylphenyl)amino)azetidine- 1-carboxylate (3, 0.9 g, 1.81 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-c arbaldehyde (4, 644.98 mg, 2.71 mmol) in anhydrous 1,4-dioxane (8 mL) and water (2 mL) was added sodium carbonate (478.50 mg, 4.51 mmol) at ambient temperature. Nitrogen gas was purged through the reaction mixture for 10 minutes. Then, PdCl ₂ (dppf). DCM complex (147.46 mg, 0.180 mmol) was added and the reaction mixture was stirred for 6 h at 90 °C and monitored by UPLC. Upon completion of the reaction, the reaction mixture was passed through a pad of Celite and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by flash column chromatography (230-400 mesh silica gel) with 55% EtOAc/pet ether as eluent to afford tert-butyl (R)-3-((3-((1-(3-(5-formylthiophen-2-yl)phenyl)ethyl)carbamo yl)-4- methylphenyl)amino)azetidine-1-carboxylate (5, 0.6 g, 1.10 mmol, 61% yield) as a light yellow solid. LC-MS (ES ⁺ ): m/z 520.3 [M + H] ⁺ . Step-3: To a 500 mL single-neck round-bottom flask containing a well-solution of tert-butyl (R)-3-((3-((1- (3-(5-formylthiophen-2-yl) phenyl)ethyl)carbamoyl)-4-methylphenyl)amino)azetidine-1- carboxylate (5, 6.2 g, 10.74 mmol) and (S)-2,2,2-trifluoro-N-(pyrrolidin-3-yl)acetamide hydrochloride (6, 2.82 g, 12.89 mmol) in anhydrous MeOH (100 mL) were added sodium acetate, anhydrous (3.52 g, 42.95 mmol) and acetic acid (12.25 g, 204.02 mmol, 11.68 mL) at ambient temperature. The reaction mixture was stirred for 1 h at ambient temperature. Then MP-CNBH ₃ (16 g, 32.21 mmol; 2 mmol/g) was added at ambient temperature and the reaction mixture was stirred at ambient temperature for 16 h. After completion of reaction as indicated by UPLC, the reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. Water (500 mL) was added to the residue and the aqueous phase was extracted with EtOAc (2 × 300 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford tert-butyl 3-((4-methyl-3-(((R)-1-(3-(5-(((S)-3- (2,2,2-trifluoroacetamido)pyrrolidin-1-yl)methyl)thiophen-2- yl)phenyl)ethyl)carbamoyl)phenyl)amino)azetidine-1-carboxyla te (7, 7 g, 7.66 mmol, 71% yield) as a yellow solid. LC-MS (ES ⁺ ): m/z 686.2 [M + H] ⁺ . Step-4: To a 250 mL single-neck round-bottom flask containing a well-solution of tert-butyl 3-((4-methyl- 3-(((R)-1-(3-(5-(((S)-3-(2,2,2-trifluoroacetamido)pyrrolidin -1-yl)methyl)thiophen-2- yl)phenyl)ethyl)carbamoyl)phenyl)amino)azetidine-1-carboxyla te (7, 7 g, 7.55 mmol) in THF (50 mL) and water (15 mL) was added lithium hydroxide, monohydrate (3.17 g, 75.53 mmol) at ambient temperature. The reaction mixture was stirred for 16 h at this temperature. After the completion of reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure and the crude compound was purified by reverse-phase column chromatography (RediSep-Rf Gold C18 column, Mobile phase A : 0.1% Ammonium bicarbonate in water and B = Acetonitrile). Fractions having desired product were lyophilized to afford tert-butyl 3-((3-(((R)-1- (3-(5-(((S)-3-aminopyrrolidin-1-yl)methyl)thiophen-2-yl)phen yl)ethyl)carbamoyl)-4- methylphenyl)amino)azetidine-1-carboxylate (8, 1.5 g, 2.31 mmol, 31% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 590.4 [M + H] ⁺ . Example 214 Synthesis of 5-(azetidin-3-ylamino)-N-((1R)-1-(3-(5-(((3S)-3-(10-(4-(1-(2 ,6-dioxopiperidin-3- yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pipe ridin-1-yl)-10-

oxodecanamido)pyrrolidin-1-yl)methyl)thiophen-2-yl)phenyl )ethyl)-2-methylbenzamide (Compound 129) Step-1: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 10-(4-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperidin-1-yl)-10- oxodecanoic acid hydrochloride (2, 60 mg, 0.106 mmol), tert-butyl 3-((3-(((R)-1-(3-(5-(((S)-3- aminopyrrolidin-1-yl)methyl)thiophen-2-yl)phenyl)ethyl)carba moyl)-4- methylphenyl)amino)azetidine-1-carboxylate formate (1, 60 mg, 0.092 mmol) in anhydrous DMF (2 mL) were added HATU (60.77 mg, 0.159 mmol) and DIPEA (55.09 mg, 0.426 mmol, 0.074 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 2 h. The reaction was monitored by UPLC. The reaction mixture was then diluted with water while stirring and an off-white solid was formed. The solid precipitate was collected on filter and dried in vacuo to afford tert-butyl 3-((3-(((1R)-1-(3-(5-(((3S)-3-(10-(4-(1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)-10- oxodecanamido)pyrrolidin-1- yl)methyl)thiophen-2-yl)phenyl)ethyl)carbamoyl)-4-methylphen yl)amino)azetidine-1- carboxylate (3; 90 mg, 0.058 mmol, 55% yield) as an off-white solid. LC-MS (ES ⁺ ): m/z 1098.5 [M + H] ⁺ . Step-2: To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 3-((3- (((1R)-1-(3-(5-(((3S)-3-(10-(4-(1-(2,6-dioxopiperidin-3-yl)- 3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-1-yl)-10-oxodecanamido)pyrro lidin-1-yl)methyl)thiophen-2- yl)phenyl)ethyl)carbamoyl)-4-methylphenyl)amino)azetidine-1- carboxylate (3, 90 mg, 0.058 mmol) in anhydrous DCM (1 mL) was added 4M HCl in 1,4-dioxane (0.7 mL) at -78 °C. The resulting mixture was stirred at ambient temperature for 0.5 h. Upon completion of the reaction as indicated by UPLC, the solvent was removed from the reaction mixture and the obtained crude was purified by reverse phase prep-HPLC (X-Select C18 (150 × 19) mm, 5 microns column; Mobile phase A: 0.1% formic acid in water: B : acetonitrile) to afford 5-(azetidin-3-ylamino)-N- ((1R)-1-(3-(5-(((3S)-3-(10-(4-(1-(2,6-dioxopiperidin-3-yl)-3 -methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-1-yl)-10-oxodecanamido)pyrro lidin-1-yl)methyl)thiophen-2- yl)phenyl)ethyl)-2-methylbenzamide formate (Compound 129, 37 mg, 0.034 mmol, 60% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 8.66 (d, J = 8.4 Hz, 1H), 8.35 (s, 1H), 7.93 (d, J = 6.8 Hz, 1H), 7.62 (s, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.38-7.29 (m, 3H), 7.10 (d, J = 1.20 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.96-6.90 (m, 3H), 6.48-6.46 (m, 2H), 6.21 (d, J = 6.8 Hz, 1H), 5.39-5.31 (m, 1H), 5.13-5.09 (m, 1H), 4.61-4.51 (m, 1H), 4.31-4.28 (m, 1H), 4.19-4.11 (m, 1H), 3.94-3.92 (m, 3H), 3.77-3.77 (m, 2H), 3.55-3.51 (m, 2H), 3.33 (s, 3H), 3.28- 3.23 (m, 2H), 3.13-3.05 (m, 1H), 2.95-2.83 (m, 1H), 2.77-2.75 (m, 3H), 2.69-2.60 (m, 3H), 2.36- 2.30 (m, 4H), 2.12 (s, 3H), 2.04-2.00 (m, 3H), 1.83-1.71 (m, 2H), 1.62-1.52 (m, 2H), 1.49-1.42 (m, 8H) and 1.29-1.13 (m, 8H). LC-MS (ES ⁺ ): m/z 998.4 [M + H] ⁺ . Example 215 Generation of 239T cell lines stably expressing NSP3 Ubl-2_PLpro-HA-HiBiT For quantitative cellular^degradation^of the target^protein^degradation^mediated by the bi functional degraders described here,^HA and HiBiT^was appended to the C-terminus of the human codon optimized gene sequence of amino acids 1564-1878 of ORF1a polyprotein from Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) and an NSP3 UBL2_PLpro-HA-HiBiT expressing 293T (ATCC ^® ,^CRL-3216) cell line was generated in house. Expression of the NSP3 UBL2_PLpro-HA-HiBiT was confirmed with an HA antibody at the expected molecular weight. A NSP3 UBL2_PLpro-HA-HiBiT 293T CRBN ^-/- cell line was generated using a CRISPR/Cas9 edited CRBN ^-/- 293T cell line in a similar way. Materials^ NSP3 UBL2_PLpro-HA-HiBiT 293T line were generated in house as described herein. The parental 293T cell line, as well as NSP3 UBL2_PLpro-HA-HiBiT 293T CRBN ^+/+ and CRBN ^-/- cell lines were routinely cultured in the following medium: DMEM (Thermo Fisher, 11965092) containing 10% serum (Thermo Fisher, 10437036) and to no more than 20 passages. For the assay, NSP3 UBL2_PLpro-HA-HiBiT cells were plated for treatment in DMEM no- Phenol Red (Thermo Fisher, 21063045 or alternative no phenol red DMEM) containing 10% serum (Thermo Fisher, 10437036). Assay were performed in Corning ^® 384 Well Low Flange Black Flat Bottom Polystyrene TC-Treated Microplates (Corning, 3571). Cells were lysed in Nano-Glo ^® HiBiT Lytic Assay System (Promega, N3050). Example 216 NSP3 UBL2_PLpro-HA-HiBiT degradation^assay (cellular) Test compounds were added to the 384-well plate from a top concentration of 10 mM with 10 points, half-log titration in duplicates and stored at -20 °C until use. Briefly, on the day of compound treatment, cells were seeded onto 384-well plate containing test compounds at the density of 2,500 cell per well in a volume resulting in the top dose of the test compounds as 10 mM. Additionally, the negative control cells were treated with vehicle alone. The plates were incubated at 37 °C with 5% CO2 for duration of the assay (6 or 24 hours). After the desired incubation time, cells were lysed by addition of Nano-Glo ^® HiBiT Lytic Assay System (prepared according to the manufacture recommendations and added to the cells in ratio 1:1, v/v). Microplates were agitated on an orbital plate shaker at 300-600 rpm for 10 minutes and incubated for another 60 minutes at room temperature. Luminescence was acquired on EnVision ^® Multilabel Reader (PerkinElmer, Santa Clara, Calif., USA). Quantification of luminescence responses measured in the presence of compound were normalized to a high signal/no^degradation control (untreated cells + lytic detection reagent) and a low signal/full^degradation^control (untreated cells, no lytic detection reagent). Data were analyzed with a 4-parameter logistic fit to generate sigmoidal dose-response curves. The DC50 is the concentration of compound at which exactly 50% of the total cellular NSP3 UBL2_PLpro- HA-HiBiT has been degraded. The E _max , or maximum effect of each compound, represents the amount of residual^protein^remaining in the cell following compound treatment. The IP, or inflection point, represents the concentration of compound at which the sigmoidal curve changes sign. The results of this assay are shown in Table 1, Figure 1, and Figure 4. When the duration of assay was 6 hours, ΔEmax [CRBN ^null - CRBN ^WT ] was 18 % for Compound 27 and 25 % for Compound 5. When the duration of the assay was 24 hours, ΔEmax [CRBN ^null - CRBN ^WT ] was 12 % for Compound 27 and 16 % for Compound 5. Representative Compounds of the Present Invention Table 1

As used in Table 1 above for DC50 values, +++ = DC50 < 500 nM, ++ = 500 nM ≤ DC50 < 10,000 nM, + = DC50 ≥ 10,000 nM, and NA= Emax > 50%. For inflection point (IP) values, +++ = IP < 500 nM, ++ = 500 nM ≤ IP < 10,000 nM, and + = IP ≥10,000 nM. For Emax values, ++++ = Emax < 45%, +++ = 45% ≤ Emax < 60%, ++ = 60% ≤ Emax < 95%, and + = Emax ≥ 95%. Example 217 CRBN+ and CRBN- Cell Viability Analysis 293T parental and NSP3 UBL2_PLpro-HA-HiBiT 293T CRBN ^+/+ and CRBN ^-/- cell viability was determined based on quantification of ATP using CellTiter-Glo ^® 2.0 luminescent Assay kit (Promega, which signals the presence of metabolically active cells). Briefly, test compound was added to 384-well plates at a top concentration of 20 μΜ with 10-points, half-log titration in duplicates. Cells were seeded into the 384-well plates in DMEM medium containing 10% FBS at a cell density of 2,500 cells per well. Cells treated in the absence of the test compound were the negative control, normalized to 100% viability, and cells treated in the absence of CellTiter-Glo® 2.0 were the positive control, normalized to 0% viability. Cells were incubated at 37 °C with 5% CO ₂ for 6 or 24 hr. CellTiter-Glo reagent was then added to the cells and Luminescence was acquired on EnVision ^® Multilabel Reader (PerkinElmer, Santa Clara, CA, USA). The results of this assay are shown in Figures 2A and 2B. Example 218 Ternary Complex Formation Assay Ternary complex formation between NSP3 PLpro, compound and CRBN was characterized using AlphaLISA ^® (PerkinElmer) assay. In this study His (6x) tag on the CRBN was labeled with Ni donor beads, and biotinylated NSP3 PLpro was labeled with streptavidin acceptor beads. Ternary complex formation was monitored via changes in the chemiluminescence signal from the beads. In the absence of the ternary complex the average distance between donor and acceptor beads is too large to elicit a signal. Complex formation promoted by the test compound brings the beads in close proximity giving a rise to the Alpha-signal. To convert the luminescence signal into the molar concentration of the ternary complex we used the signal generated by a negative and positive controls samples located in wells 23 and 24 respectively. Maltose-binding protein (MBP) modified with a histidine and biotin tags on the N- and C- terminus respectively is used as a positive control. This construct is capable of binding both donor and acceptor beads and yields maximum possible signal per concentration unit, which was used to normalize the signal from the compound treated samples. The results of this assay are shown in Figure 3. Example 219 Pharmacokinetics (PK) in Male ICR-C1 Mice The pharmacokinetic (PK) profile in plasma of two compounds of the present invention, Compound 92 described in Example 156 and Compound 93 in Example 157, was determined in male ICR-CD1 mice following single dose IV (1 mg/kg) and PO (10 mg/kg) administration. This study was performed under non-GLP conditions, and unless otherwise stated, all analytical reagents were standard laboratory reagent grade. Compound 92 and Compound 93 were each formulated in 20% PEG 400, 20% sulfobutylether-b-cyclodextrin (SBECD, Captisol ^® , CyDex Pharmaceuticals, Inc., San Diego, CA), and 60% water. The IV and PO formulations for each compound are described in Table 2 below. Table 2 After addition of PEG 400, each formulation was kept for sonification for twenty minutes with intermittent stirring. Formulations were freshly prepared on of the day of dosing and stored at room temperature until used. All animals were weighed prior to drug administration, and the standard weight of the animals used was 30 grams. The animals were divided into two groups, intravenous (IV) group and per os (PO) group, for each compound tested, with each group containing 3 animals each. The IV dose was administered by intravenous injection into the tail vein and PO dose was administered via oral gavage. The dosing volume was 5 mL/kg body weight for IV groups and 10 mL/kg body weight PO groups. The dosing concentration was 0.2 mg/mL for IV groups and 1.00 mg/mL for PO groups respectively. The animals were in fasted stated during the study. For both tested compounds, for the IV dosing groups, blood was collected from the saphenous vein (serial sampling) for plasma isolation at pre-dose (0.00 hours), and 0.033, 0.33, 1, 2, 4, 6, 8, and 24 hour timepoints, and for the PO dosing groups, whole blood was collected from the saphenous vein (serial sampling) for plasma isolation at pre-dose (0.00 hours), and 0.25, 0.50, 1, 2, 4, 6, 8, and 24 hour timepoints . The anti-coagulant solution used was 6% (v/v) Sodium citrate (200 mM, pH 4.79). For sample preparation, 5 µl of plasma samples was precipitated with 150 µl of acetonitrile containing internal standard (VERAPAMIL 50 ng/mL). Samples were vortexed at 1000 rpm and centrifuged for 10 minutes at 4000 rpm. 120 µl of supernatant was transferred to 96-well plate and analyzed using LC-MS/MS. For sample dilution, 2 µl of sample was diluted with 18 µl of blank plasma. After vortexing, 5 µl was aliquoted from the sample and regular processing procedures continued. A 10X dilution factor was applied to IV-0.033 hour samples while processing. Samples were analyzed by Shimadzu NexeraX2 (Shimadzu Corp., Kyoto, Japan) high- pressure liquid chromatography (HPLC) system followed by tandem mass spectroscopy analysis (MS/MS) with SCIEX Triple Quad™ 4500 (AB Sciex LLC, Framingham, MA). The samples were resolved on a Kinetex ^® (Phenomenex, Inc., Torrance, CA) 5 µm C18100Å, 100*2.1mm column. For Compound 92, 0.1% formic acid in Milli-Q ^® water (EMD Millipore, Burlington, MA) was used as an aqueous (A) mobile phase and 0.1% formic acid in acetonitrile as an organic (B) mobile phase. The flow rate was set at 0.8 mL/min. Injection volume was 8 µl, Column oven was 40°C and autosampler temperature was 8°C. The LC gradient program included initial conditions of 90% A at 0.5 min, with switch to 60% A at 1 min., switch to 5% at 1.5 min and hold until 2.5 min before returning to initial conditions of 90% A at 2.7 min. with a hold until 3.5 min at 90% A. For Compound 93, 0.1% Formic acid in Milli-Q ^® water (EMD Millipore, Burlington, MA) was used as an aqueous (A) mobile phase and 0.1% formic acid in methanol as an organic (B) mobile phase. The flow rate was set at 0.8 mL/min. Injection volume was 8 µl, Column oven was 40°C and autosampler temperature was 8°C. The LC gradient program included initial conditions of 90% A at 0.01 min, with switch to 50% A at 1 min., switch to 5% at 1.5 min and hold until 2.5 min before returning to initial conditions of 90% A at 2.7 min. with a hold till 3.5 min at 90% A. A positive electrospray ionization (ESI) method was used for detecting analytes and internal standard by mass spectroscopy. The MRM conditions for Compound 92 were Q1 m/z of 501.047, Q3 m/z 373.200, declustering potential (DP) 86 V, collision energy (CE) 21 eV, and Collision Cell Exit Potential (CXP) 6. The MRM conditions for Compound 93 were Q1 m/z 501.082, Q3 m/z 373.2, DP 81 V and CE of 21 eV, and Collision Cell Exit Potential (CXP) 6. For both compounds, internal standard MEM conditions were Q1 m/z of 455.10, Q3 m/z 165.10, declustering potential (DP) 80 V, collision energy (CE) 44 eV, and Collision Cell Exit Potential (CXP) 8. Other MS/MS conditions for test compounds and internal standard included Collision Gas (CAD) 10, Curtain Gas (CUR) 40, Ion spray voltage (V) 5500, Temperature (TEM) 550, GS155, GS250 and EP 10. Pharmacokinetic parameters like AUClast, T1/2, Tmax, C0, Vdss, Cl, Cmax, and %F were calculated for individual animal by non-compartmental model with Phoenix software version 8.1. The results of this PK study in male ICR-CD1 mice for Compound 92 are shown in Tables 3-6 below and FIG.5, and the results for Compound 93 are shown in Tables 7-10 below and FIG.6.

Table 3 Plasma Concentration Time Profile following 1 mg/kg IV dosing of Compound 92 in Male ICR-CD1 Mice BQL- below quantitation limit; NC- not calculated; NA- not applicable Table 4 Plasma Concentration Time Profile following 10 mg/kg PO dosing of Compound 92 in Male ICR-CD1 Mice BQL- below quantitation limit; NC- not calculated; NA- not applicable Table 5 Calculated pharmacokinetic parameters following 1 mg/kg IV dosing of Compound 92 in Male ICR-CD1 Mice Table 6 Calculated pharmacokinetic parameters following 10 mg/kg PO dosing of Compound 92 in Male ICR-CD1 Mice

Table 7 Plasma Concentration Time Profile following 1 mg/kg IV dosing of Compound 93 in Male ICR-CD1 Mice BQL- below quantitation limit; NC- not calculated; NA- not applicable *-Concentration observed pre-dose sample might be due to contamination Table 8 Plasma Concentration Time Profile following 10 mg/kg PO dosing of Compound 93 in Male ICR-CD1 Mice BQL- below quantitation limit; NC- not calculated; NA- not applicable Table 9 Calculated pharmacokinetic parameters following 1 mg/kg IV dosing of Compound 93 in Male ICR-CD1 Mice Table 10 Calculated pharmacokinetic parameters following 10 mg/kg PO dosing of Compound 93 in Male ICR-CD1 Mice Compound 92 showed moderate clearance of hepatic blood flow in mice (Qh= 25%) and volume of distribution at steady state was approximately 7-fold higher than total body water in mice with elimination half-life of 2.78 hours following IV administration of 1 mg/kg in mice. Compound 92 showed rapid oral absorption (Tmax: 1 hour) with oral bioavailability of 33.48% following oral administration at 10 mg/kg in mice. Compound 93 showed a low clearance of hepatic blood flow in mice (Qh= 13.9%) and volume of distribution at steady state was approximately 6.9-fold higher than total body water in mice with elimination half-life of 6.72 hours following IV administration of 1 mg/kg in mice. Some variability in C0 (~3.7-fold variation) was observed. Compound 93 showed rapid oral absorption (Tmax: 0.5-1 hour) with oral bioavailability of 15.89% following oral administration at 10 mg/kg in mice. Example 220 Solubility of Compound 92 and Compound 93 Kinetic solubility of Compound 92 and Compound 93 was determined using standard procedures. The results of this assay showed that at pH 6.5, the solubility of Compound 92 was 6.98 µM and the solubility of Compound 93 was 3.14 µM. Example 221 Cytopathic Effect (CPE) Protection Assay A549-ACE2 cells (obtained from Dr. Benjamin tenOever of the tenOever Lab and colleagues) (Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Møller R, Jordan TX, Oishi K, Panis M, Sachs D, Wang TT, Schwartz RE, Lim JK, Albrecht RA, tenOever BR. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell.2020 May 28;181(5):1036-1045.e9. doi: 10.1016/j.cell.2020.04.026. Epub 2020 May 15. PMID: 32416070; PMCID: PMC7227586) were grown in culturing media comprised of DMEM media (Fischer 11995073) supplemented with 10% FBS (Heat Treated FBS 100-106 BenchMark ^TM Fetal Bovine Serum), 1% Pen-Strep (15-140-122 Fisher Scientific), and 1% NEAA (Non-Essential Amino Acid, 11-140-050 Fisher Scientific) in 182 cm ² Flasks (GenClone 25-211). Twenty-four hours prior to infection, cells were seeded in to 96-well plates (GenClone 25-109) at a density of 10,000 cells per well in 100 ^L of culturing media. Drug dilutions were made in infection media that is the same as culturing media but with only 2% FBS added instead of 10%. Culturing media was removed from cells and replaced with drug dilutions and incubated for 2 hours prior to infection. Drug dilutions were made by diluting 10mM drug stock solutions 1:1000 for an initial concentration of 10 ^M with subsequent serial dilutions occurring at 1:4 dilution ratio. Seven dilutions were made in total with each drug being represented in triplicate. The final row of each plate was left without any drug concentration and served as Negative and Positive infection controls for the experiment. Following a 2-hour drug incubation, cells were infected with 0.5 MOI (multiplicity of infection) of SARS-CoV-2 Washington strain [novel coronavirus [(nCoV)/Washington/1/2020] provided by N. Thornburg (CDC) via the World Reference Center for Emerging Viruses and Arboviruses (World Reference Center for Emerging Viruses and Arboviruses https://www.utmb.edu/wrceva, Galveston, TX). Virus was cultured using the infection media described above. One-half of the No Drug wells in the final row were infected with 0.5 MOI of SARS-CoV-2 and served as the Positive Control. The other half of the wells were mock-infected with virus-free infection media and served as the Negative Control. Cells were incubated with virus for at least 72-hours to allow for cytopathic effect (CPE) to be observed in Positive Control wells. At this point the infection media was removed and 100 ^l of Formalin solution (10% Formalin, Fisher 23305510) was added to each well to fix the cells and inactivate the virus. Cells were incubated at room temperature with Formalin solution for at least 15 minutes to ensure viral inactivation. Then formalin media was removed, and 0.25% Crystal Violet solution was added (0.25% w/v Crystal Violet, Sigma C0775, in 20% EtOH). Cells were stained in the Crystal Violet solution for 15-30 minutes, after which the Crystal violet was washed off under gently flowing tap water. Plates were then allowed to dry uncovered on the benchtop for at least 24 hours prior to analysis by plate reader. Dry plates were analyzed without their lids on an Infinite ^® 200 Pro TECAN plate reader (Tecan Trading AG, Männedorf, Switzerland) with the following settings: The gathered absorbance data for each well was organized in an EXCEL file (Microsoft Corporation, Redmond, WA, USA), where it was arranged to match the 96-well format of the plate. The data was subjected to the following analyses. 1. The absorbance values for the wells corresponding to the Positive Control were averaged. This average was then subtracted from all other absorbance values for the corresponding plate (each drug dilution treatment as well as the Negative Control wells). The percent cell survival in each of the drug dilution wells was calculated then by finding the ration between that well and the average of the Negative Control wells and multiplying by 100. The formula below outlines the process. (Sample Well − Average Positive Control) % Cell Survival = × 100 (Average Negative Control − Average Positive Control) 2. The % Cell Survival for the drug dilution series where then input into Graph Pad Prism 9.3.1 (GraphPad by Dotmatics, San Diego, CA, USA) and dose response curve and EC50 values were calculated using the XY: Log-dose vs. response (nonlinear.reg.) analysis function of the program. The compounds in Table 11 below were tested in this cytopathic effect (CPE) protection assay to evaluate in vitro antiviral activities against SARS-CoV-2. Table 11 As used in Table 11 above, A = EC ₅₀ < 1 µM, B = 1 µM ≤ EC ₅₀ < 10 µM, and C = EC ₅₀ ≥ 10 µM. All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for the purposes of clarity of understanding, it will be readily apparent to one of ordinary skill in the art in light of the teaching of this invention that certain changes and modification may be made thereto without departing from the spirit or scope of the invention as defined in the embodiments and claims of the present invention.