INHIBITORS OF CYSTEINE PROTEASES AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The application claims priority to U.S.S.N.63/175,338, filed April 15, 2021, the contents of which are incorporated herein by reference. BACKGROUND [0002] The Coronaviridae family of viruses are enveloped, single-stranded, positive- sense RNA viruses and include 141 species that are classified into four genera according to their phylogenetic relationships: α-, β-, γ-, and δ-coronavirus. Coronaviruses (CoVs) are zoonotic viruses that infect a variety of animals from whales to birds, bats, cats, and humans. Typically, CoV infection results in mild to moderate respiratory tract infections; however, some CoV species are extremely virulent and can result in widespread fatality. Severe acute respiratory syndrome coronavirus (SARS-CoV) is a human CoV that was responsible for the first pandemic of the 21 ^st century, infecting over 8,000 people with a 10% mortality rate. Middle East respiratory syndrome coronavirus (MERS-CoV) was identified in November 2012 and had since infected over 1,600 people in 26 countries with 36% mortality rate. More recently, COVID-19 (SARS CoV2) coronaviruses have raised a global pandemic since they had been first identified in late 2019. Therefore, it is important to identify coronavirus drug targets that can be utilized for the development of broad-spectrum anti-coronaviral therapeutics to combat infections of existing and emerging coronaviruses. [0003] All CoVs express a >800 kDa replicase polyprotein that contains either two or three cysteine proteases, the papain-like protease(s) (PLPpro, or PLP1 and PLP2) and the 3C- like protease (3CLpro, nsp5, or Mpro). These proteases process the CoV replicase polyprotein by cleaving it into 16 non-structural proteins, which are responsible for a variety of aspects of CoV replication. The CoV 3CLpro is responsible for processing 11 cleavage sites of within the replicase polyprotein and is essential for CoV replication, making it a highly valuable target for therapeutic development. The overall active site architecture and substrate recognition pockets are structurally conserved across CoV 3CLpros, increasing its attractiveness as a target for the development of broad-spectrum anti-CoV therapeutics. Moreover, high sequence conservation in the vicinity of active site among CoV 3CLpros from different coronavirus subclasses make them an excellent target for the development of broad-spectrum therapeutics for coronavirus infections. Accordingly, the development of CoV 3CLpro inhibitors is a promising path for the treatment of respiratory tract infections and related diseases. [0004] Numerous studies on targeting the immediate zoonotic reservoirs of coronaviruses with small molecule inhibitors have helped inform structure-based design strategies aimed at creating molecular scaffolds that may aid in the development of therapeutic against coronaviral infection; however, small molecule antiviral agents nor effective commercially available broad-spectrum therapeutics have not yet been identified. There is a critical need for the development of broad-spectrum CoV therapeutics to overcome the challenges of traditional anti-CoV therapeutic development, as broad-spectrum therapeutics can be rapidly implemented upon zoonotic disease outbreak. SUMMARY [0005] The disclosure is directed to, in part, viral protease inhibitor compounds. Also provided are pharmaceutical compositions comprising at least one disclosed compound and a pharmaceutically acceptable carrier. [0006] In an embodiment, provided herein are compounds represented by Formula I: (Formula I), wherein: Y is selected from -C(O)-, -S(O)-, and -S(O) ₂ -; R ^W is selected from N(R ^U1 R ^U2 ) and a 3-10 membered N-heterocyclyl, wherein R ^W is optionally substituted by one, two or three substituents each selected from R ^a , or R ^W is a warhead; R ² is selected from the group consisting of C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl, wherein R ² is optionally substituted by one, two or three substituents each selected from the group consisting of halogen, -C(O)-N(R ^b R ^c ), and R ⁵ ; R ³ is selected from the group consisting of C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 3-10 membered heterocyclyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl, wherein the heteroaryl contains at least one ring nitrogen and may have one, two or three optional substituents each selected from R ^a ; R ^3a is selected from the group consisting of hydrogen, deuterium, halogen, C ₁ -C ₆ alkyl, and C ₁ -C ₆ haloalkyl; or R ³ and R ^3a may be joined together to form, together with the carbon to which they are attached, a 3-10 membered heterocyclyl; or R ^3a and R ^4a may form, together with the carbon and nitrogen to which they are attached, respectively, a 5-10 membered heterocycle, wherein the heterocycle is optionally substituted by one, two or three substituents each selected from R ^a ; R ⁴ is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl-N(R ^b R ^c ), C ₁ -C ₆ alkyl-(C ₆ - C ₁₄ aryl), C ₁ -C ₆ alkyl-(3-10 membered heterocyclyl), C ₁ -C ₆ alkyl-(5-9 membered heteroaryl), C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein the aryl, heteroaryl, alkyl, alkoxy, or cycloalkyl is optionally substituted by one, two or three substituents each selected from R ^a ; R ^4a is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl, wherein the aryl, heteroaryl, alkyl, alkoxy, or cycloalkyl is optionally substituted by one, two or three substituents each selected from R ^a ; or R ⁴ and R ^4a may form, together with the nitrogen to which they are attached, a 4-10 membered heterocycle, wherein the heterocycle is optionally substituted by one, two or three substituents each selected from R ^a ; R ⁵ is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, SF ₅ , cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ - C ₆ alkoxy, C ₆ -C ₁₄ aryl, C ₁ -C ₆ alkyl-phenyl, C ₁ -C ₆ alkenyl-phenyl, C ₁ -C ₆ alkoxy-phenyl, C ₃ - C ₁₀ cycloalkyl, and 5-9 membered heteroaryl; wherein R ⁵ is optionally substituted by one, two or three substituents each selected from R ^a ; R ^a is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, SF ₅ , -OR ^aa , S(O) ₂ -(C1-C ₆ alkyl), C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, -C(O)-O-C(CH ₃ ) ₃ , -C(O)-O-(CH ₂ )- (C ₁₃ H ₉ ), -C(O)-O-(CH ₂ )-(phenyl), -C(O)-N(R ^b R ^c ), and -N(R ^b R ^c ), wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted by one, two, or three substituents of halogen; and R ^aa is selected from the group consisting of C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl-phenyl and C ₆ -C ₁₄ aryl; R ^b and R ^c are independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₆ alkyl, and C ₃ -C ₁₀ cycloalkyl; wherein the alkyl or cycloalkyl may optionally be substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, and hydroxyl; or R ^b and R ^c may form, together with the nitrogen to which they are attached, a 4-6 membered heterocycle, wherein the heterocycle is optionally substituted by one, two or three substituents each selected from R ^a ; R ^U1 and R ^U2 are independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ - C ₆ alkyl, and C ₃ -C ₁₀ cycloalkyl; wherein the alkyl or cycloalkyl may optionally be substituted by one or more substituents selected from the group consisting of halogen, -CF ₃ , cyano, oxo, and hydroxyl; and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof. [0007] Also provided herein are compounds represented by Formula II: (Formula II), wherein: Y is selected from -C(O)-, -S(O)-, and -S(O) ₂ -; R ^6a is selected from the group consisting of hydrogen, halogen, cyano, SF ₅ , C ₁ -C ₆ alkyl, and C ₃ -C ₁₀ cycloalkyl; R ^6b is selected from the group consisting of hydrogen, halogen, cyano, SF ₅ , C ₁ -C ₆ alkyl, and C ₃ - C ₁₀ cycloalkyl; R ^7a is selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl, and C ₁ -C ₆ haloalkyl; R ^7b is selected from the group consisting of hydrogen, halogen, C ₁ - C ₆ alkyl, and C ₁ -C ₆ haloalkyl; R ⁸ is selected from the group consisting of hydrogen, deuterium, halogen, C ₁ -C ₆ alkyl, and C ₁ -C ₆ haloalkyl; R ^W is selected from the group consisting of:

pharmaceutically acceptable salts thereof. [0008] Also provided herein are methods of ameliorating or treating a viral infection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of any of the compounds described herein. [0009] In some embodiments, provided herein are methods of inhibiting transmission of a virus, a method of inhibiting viral replication, a method of minimizing expression of viral proteins, or a method of inhibiting virus release, comprising administering a therapeutically effective amount of a compound described herein to a patient suffering from the virus, and/or contacting an effective amount of a compound described herein with a virally infected cell. BRIEF DESCRIPTION OF THE DRAWINGS [00010] The Figure illustrates a 2D depiction of the interactions of compound 10 with the SARS-CoV2 main protease showing formation of a thioimidate adduct. DETAILED DESCRIPTION [00011] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. Definitions [00012] The term “treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like, including a reduction of viral shedding in asymptomatic individuals and prophylaxis of exposed individuals, independent of symptoms. [00013] The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as C ₁ -C ₅ alkenyl, C ₂ -C ₆ alkenyl, and C ₃ -C ₄ alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc. [00014] The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as C ₁ -C ₅ alkoxy, C ₁ -C ₆ alkoxy, and C ₂ -C ₆ alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc. [00015] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C _1-6 alkyl, C _1-4 alkyl, and C _1-3 alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1- butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc. [00016] The term "alkylene bridge" refers to a straight or branched divalent hydrocarbon bridge, linking two different carbons of the same ring structure. The alkylene bridge may link any two carbons within the ring structure. In some embodiments, alkylene bridges can be an indicated number of carbon atoms, for example, C ₁ -C ₆ alkylene bridge, C ₁ -C ₅ alkylene bridge, C ₁ -C ₄ alkylene bridge, C ₁ -C ₃ alkylene bridge, or C ₁ -C ₂ alkylene bridge. Unless otherwise specified, each instance of an alkylene bridge is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkylene bridge”) or substituted (a “substituted alkylene bridge”) with one or more substituents (for instance from 1 to 4 substituents, 1 to 3 substituents, or 1 substituent) which may be halo, -NO ₂ , -OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, or C ₁ -C ₆ cycloalkyl. Examples of alkylene bridge include, but are not limited to, methylene, ethylene, propylene, tetramethylene, and n-butylene. [00017] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, 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 six ring carbon atoms (“C ₆ aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C ₁₀ aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl 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. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. [00018] Examples of representative substituted aryls include the following wherein one of R ⁵⁶ and R ⁵⁷ may be hydrogen and at least one of R ⁵⁶ and R ⁵⁷ is each independently selected from C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C ₁ -C ₈ alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR ⁵⁸ COR ⁵⁹ , NR ⁵⁸ SOR ⁵⁹ NR ⁵⁸ SO ₂ R ⁵⁹ , COOalkyl, COOaryl, CONR ⁵⁸ R ⁵⁹ , CONR ⁵⁸ OR ⁵⁹ , NR ⁵⁸ R ⁵⁹ , SO ₂ NR ⁵⁸ R ⁵⁹ , S-alkyl, SOalkyl, SO ₂ alkyl, Saryl, SOaryl, SO ₂ aryl; or R ⁵⁶ and R ⁵⁷ may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R ⁶⁰ and R ⁶¹ are each independently hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₄ haloalkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, substituted C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, or substituted 5- 10 membered heteroaryl. [00019] The term “carbonyl” as used herein refers to the radical -C(O)-. [00020] The term “cyano” as used herein refers to the radical -CN. [00021] The terms “cycloalkyl” or a “carbocyclic group” as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as C ₃ -C ₁₀ cycloalkyl, C _3-6 cycloalkyl or C _4-6 cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl. [00022] The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I. [00023] The terms “haloalkyl” as used herein refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl (i.e. CF ₃ ), difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like. Exemplary haloalkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms substituted with a halogen (i.e. Cl, F, Br and I), referred to herein as C _1-6 haloalkyl, C _1-4 haloalkyl, and C _1-3 haloalkyl, respectively. [00024] The term “hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g,. heteroaryl, cycloalkenyl, e.g,. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms. [00025] The terms “heteroaryl” or “heteroaromatic group” as used herein refers to an aromatic 5-10 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. The term may also be used to refer to a 5-7 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine or pyrimidine etc. [00026] Examples of representative heteroaryls include the following: wherein each Z is selected from carbonyl, N, NR ⁶⁵ , O, and S; and R ⁶⁵ is each independently hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, and 5-10 membered heteroaryl. [00027] The terms “heterocyclyl,” “heterocycle,” or “heterocyclic group” are art- recognized and refer to saturated or partially unsaturated 4-10 membered ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran or dihydrofuran etc. In some embodiments, the heterocyclyl group is a bridged heterocyclyl, a bicyclic heterocyclyl, or a spirocyclic heterocyclyl. In some embodiments, the heterocycle is a spiro heterocycle (e.g.2,8-diazaspiro[4.5]decane). In some embodiments, the heterocycle is a bridged heterocycle (e.g. octahydro-1H-4,7-methanoisoindole). "Spiro heterocyclyl," or “spiro heterocycle” refers to a polycyclic heterocyclyl with rings connected through one common atom (called a spiro atom), wherein the rings have one or more heteroatoms selected from the group consisting of N, O, and S(O) _m (wherein m is an integer of 0 to 2) as ring atoms. Representative examples of heterocyclyl include, for example: , , , , , In some embodiments, the heterocycle is a N-heterocyclyl. “N-heterocyclyl” or “N-linked heterocyclyl” refers to a heterocyclyl group as defined above containing at least one nitrogen, wherein the point of attachment of the heterocyclyl group to the rest of the molecule is the nitrogen atom of the heterocyclyl group. [00028] The terms “hydroxy” and “hydroxyl” as used herein refers to the radical -OH. [00029] The term “oxo” as used herein refers to the radical =O. [00030] “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards. [00031] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions. [00032] The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. [00033] “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). “Modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism. [00034] In the present specification, the term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g. mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds of the disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect. [00035] The term "pharmaceutically acceptable salt(s)" as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt. [00036] The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. [00037] The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond. [00038] Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a carbocyclic or heterocyclic rings may also be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.” [00039] Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations, and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009. [00040] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form. [00041] The disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium. [00042] Certain isotopically-labeled disclosed compounds (e.g., those labeled with ³ H and ¹⁴ C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ² H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. [00043] The term “prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255). For example, if a compound of the disclosure or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C _1-8 )alkyl, (C _2-12 )alkylcarbonyloxymethyl, 1- (alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkylcarbonyloxy)- ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C _{1- 2} )alkylamino(C _2-3 )alkyl (such as β-dimethylaminoethyl), carbamoyl-(C _1-2 )alkyl, N,N-di(C _{1- 2} )alkylcarbamoyl-(C _1-2 )alkyl and piperidino-, pyrrolidino- or morpholino(C _2-3 )alkyl. [00044] Similarly, if a compound of the disclosure contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C _1-6 )alkylcarbonyloxymethyl, 1-((C _1-6 )alkylcarbonyloxy)ethyl, 1-methyl-1-((C _1-6 )alkylcarbonyloxy)ethyl (C _1-6 )alkoxycarbonyloxymethyl, N-(C _{1- 6} )alkoxycarbonylaminomethyl, succinoyl, (C _1-6 )alkylcarbonyl, α-amino(C _1-4 )alkylcarbonyl, arylalkylcarbonyl and α-aminoalkylcarbonyl, or α-aminoalkylcarbonyl-α- aminoalkylcarbonyl, where each α-aminoalkylcarbonyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) ₂ , -P(O)(O(C _1-6 )alkyl) ₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate). [00045] If a compound of the disclosure incorporates an amine functional group, a prodrug can be formed, for example, by creation of an amide or carbamate, an N- alkylcarbonyloxyalkyl derivative, an (oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine. In addition, a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine. For examples, see Simplício, et al., Molecules 2008, 13, 519 and references therein. [00046] The term "warhead" or "warhead group" as used herein refers to a functional group present on a compound wherein that functional group is capable of reversibly or irreversibly participating in a reaction with a protein, e.g., 3C or 3CL protease (e.g., with a cysteine on the protease such as Cys 145). Warheads may, for example, form covalent bonds with the protein, or may create stable transition states, or be a reversible or an irreversible alkylating agent. For example, the warhead moiety can be a functional group on an inhibitor that can participate in a bond-forming reaction, wherein a new covalent bond is formed between a portion of the warhead and a donor, for example an amino acid residue of a protein. In embodiments, the warhead is an electrophile and the “donor” is a nucleophile such as the side chain of a cysteine residue. As provided herein, a warhead may include a nitrile or halo group. As also provided herein, a warhead may include an aldehyde, ketoamides, hydroxybisulfite salts, heterocyclic moieties, aziridine, oxirane, epoxy ketones, halomethyl ketones, hydroxymethyl ketones, electrophilic ketones (e.g. trifluoromethyl ketones), acyloxymethyl ketones, benzothiazolyl ketones and a Michael acceptor. For example, nitriles may be reversible covalent warheads for cysteine protease inhibition., for example, where the mechanism of action may involve aformation of reversible covalent bond between the nitrile and the active cysteine to form a thioimidate adduct. Reaction of cysteine of glutathione or other proteins is generally reversible, while the reaction with cysteine or aminoethylthiols generally irreversibly forms a thiazolidine adduct. It can be appreciated that contemplated compounds herein may be a reversible or an irreversible inhibitor. [00047] Examples of exemplary warheads include, but not limited to, a moiety with a cyano or halo moiety, e.g.: independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, -SO ₂ , -SF ₅ , and R ^13a ; R ^13a is selected from the group consisting of -OR ^13b , C ₁ - C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, -N(R ^e R ^f ), -N(R ^e )-C(O)-(R ^f ), 3-10 membered heterocyclyl, C ₆ -C ₁₄ aryl and 5-10 membered heteroaryl; wherein R ^13a may be optionally substituted by one, two or three substituents each selected from R ^h ; R ^e and R ^f are each selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl; wherein C ₁ -C ₆ alkyl may optionally be substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, hydroxyl, 3-10 membered heterocyclyl, C ₆ -C ₁₄ aryl, and 5-10 membered heteroaryl; or R ^e and R ^f may form, together with the nitrogen to which they are attached, a 4- 6 membered heterocycle; R ^h , for each occurrence, is selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, and C ₁ -C ₆ alkoxy; R ^13b is selected from the group consisting of C ₁ -C ₆ alkyl-(3-10 membered heterocyclyl), C ₁ -C ₆ alkyl-(5-10 membered heteroaryl), C ₁ -C ₆ alkyl-(C ₆ -C ₁₄ aryl), C ₁ -C ₆ haloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl; and p is 0, 1, 2, 3, or 4, as valency permits. [00048] It will be appreciated to one of skilled in the art that the compounds disclosed herein that include the warheads above also contemplate the precursors to those compounds, for example, where a cyano moiety involved in a warheads may be replaced with e.g., a halo moiety. [00049] It will be appreciated to one of skilled in the art that the compounds disclosed herein can also irreversibly bind, or may otherwise inhibit e.g., a virus protein via any other mechanism of action. [00050] The term "inhibitor" as used herein refers to a compound that binds to and /or inhibits a target protease with measurable affinity. [00051] The term “reversible” or "reversible inhibitor" as used herein refers to a protease inhibitor that associates with a protease in such a way as to inhibit the activity of the protease while the protease and inhibitor are bound, but does not associate with a protease in such a way as to inhibit the activity of the protease when the protease and inhibitor are no longer bound. Reversible inhibitors can effect inhibition by competing with substrate for binding to the active site of the protease (competitive reversible inhibitor), or by associating with the protease bound to its substrate in a way to make the complex inactive (uncompetitive reversible inhibitor), or by associating with the protease and/or protease-substrate complex in a way that inhibits the activity of either and/or both. [00052] As used herein, the term “irreversible” or “irreversible inhibitor” refers to an inhibitor (i.e. a compound) that is able to be covalently bonded to a target protease in a substantially non-reversible manner. An irreversible inhibitor will remain substantially bound to the target protease once covalent bond formation has occurred. Irreversible inhibitors usually display time dependency, whereby the degree of inhibition increases with the time with which the inhibitor is in contact with the enzyme. In certain embodiments, an irreversible inhibitor will remain substantially bound to target protease once covalent bond formation has occurred and will remain bound for a time period that is longer than the life of the protein. I. Reversible or Irreversible Viral Protease Inhibitor Compounds [00053] The disclosure is directed to, in part, compounds that inhibit a viral protease. Examples of viral proteases include, but not limited to, Cathepsin K, coronavirus main protease (Mpro), Caspase 3, Calpain 1, and Cathepsin S. Accordingly, in various embodiments, a compound of the present disclosure (e.g. a compound of Formula I, I-B, I-C, I-D, I-E, I-F, II, etc.) is a viral protease inhibitor, wherein the viral protease is selected from the group consisting of Cathepsin K, coronavirus main protease (Mpro), Caspase 3, Calpain 1, and Cathepsin S. In certain embodiments, the viral protease is a coronavirus main protease (Mpro). In some embodiments, the viral protease is Cathepsin K. In some embodiments, the viral protease is Caspase 3. In some embodiments, the viral protease is Calpain 1. In some embodiments, the viral protease is Cathepsin S. [00054] In an embodiment, provided herein are compounds represented by Formula I: wherein: Y is selected from -C(O)-, -S(O)-, and -S(O) ₂ -; R ^W is selected from N(R ^U1 R ^U2 ) and a 3-10 membered N-heterocyclyl, wherein R ^W is optionally substituted by one, two or three substituents each selected from R ^a , or R ^W is a warhead; R ² is selected from the group consisting of C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl, wherein R ² is optionally substituted by one, two or three substituents each selected from the group consisting of halogen, -C(O)-N(R ^b R ^c ), and R ⁵ ;mR ³ is selected from the group consisting of C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 3-10 membered heterocyclyl, 5-6 membered monocyclic heteroaryl and 8-10 membered bicyclic heteroaryl, wherein the heteroaryl contains at least one ring nitrogen and may have one, two or three optional substituents each selected from R ^a ; R ^3a is selected from the group consisting of hydrogen, deuterium, halogen, C ₁ -C ₆ alkyl, and C ₁ -C ₆ haloalkyl; or R ³ and R ^3a may be joined together to form, together with the carbon to which they are attached, a 3-10 membered heterocyclyl; or R ^3a and R ^4a may form, together with the carbon and nitrogen to which they are attached, respectively, a 5-10 membered heterocycle, wherein the heterocycle is optionally substituted by one, two or three substituents each selected from R ^a ; R ⁴ is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl-N(R ^b R ^c ), C ₁ -C ₆ alkyl-(C ₆ - C ₁₄ aryl), C ₁ -C ₆ alkyl-(3-10 membered heterocyclyl), C ₁ -C ₆ alkyl-(5-9 membered heteroaryl), C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein the aryl, heteroaryl, alkyl, alkoxy, or cycloalkyl is optionally substituted by one, two or three substituents each selected from R ^a ; R ^4a is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl, wherein the aryl, heteroaryl, alkyl, alkoxy, or cycloalkyl is optionally substituted by one, two or three substituents each selected from R ^a ; or R ⁴ and R ^4a may form, together with the nitrogen to which they are attached, a 4-10 membered heterocycle, wherein the heterocycle is optionally substituted by one, two or three substituents each selected from R ^a ; R ⁵ is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, SF ₅ , cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ - C ₆ alkoxy, C ₆ -C ₁₄ aryl, C ₁ -C ₆ alkyl-phenyl, C ₁ -C ₆ alkenyl-phenyl, C ₁ -C ₆ alkoxy-phenyl, C ₃ - C ₁₀ cycloalkyl, and 5-9 membered heteroaryl; wherein R ⁵ is optionally substituted by one, two or three substituents each selected from R ^a ; R ^a is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, SF ₅ , -OR ^aa , S(O) ₂ -(C1-C ₆ alkyl), C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, -C(O)-O-C(CH ₃ ) ₃ , -C(O)-O-(CH ₂ )- (C ₁₃ H ₉ ), -C(O)-O-(CH ₂ )-(phenyl), -C(O)-N(R ^b R ^c ), and -N(R ^b R ^c ), wherein the aryl, heteroaryl, or heterocyclyl is optionally substituted by one, two, or three substituents of halogen; and R ^aa is selected from the group consisting of C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl-phenyl and C ₆ -C ₁₄ aryl; R ^b and R ^c are independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₆ alkyl, and C ₃ -C ₁₀ cycloalkyl; wherein the alkyl or cycloalkyl may optionally be substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, and hydroxyl; or R ^b and R ^c may form, together with the nitrogen to which they are attached, a 4-6 membered heterocycle, wherein the heterocycle is optionally substituted by one, two or three substituents each selected from R ^a ; R ^U1 and R ^U2 are independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ - C ₆ alkyl, and C ₃ -C ₁₀ cycloalkyl; wherein the alkyl or cycloalkyl may optionally be substituted by one or more substituents selected from the group consisting of halogen, -CF ₃ , cyano, oxo, and hydroxyl; and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof. [00055] In some embodiments, the compound of Formula I is represented by: (Formula I-A). [00056] In some embodiments, the compound of Formula I is represented by: (Formula I-B). [00057] In some embodiments, the compound of Formula I is represented by: (Formula I-C). [00058] In some embodiments, the compound of Formula I is represented by: (Formula I-D), wherein: Y ¹ , Y ² and Y ³ are independently selected, for each occurrence, from the group consisting of C(R ^Y1 R ^Y2 ), N(R ^Y1 R ^Y2 ), O, S(O) and S(O) ₂ , or two of Y ¹ , Y ² and Y ³ may form, together with the carbons to which they are attached, a C ₁ -C ₃ alkylene bridge, wherein the alkylene bridge may optionally be substituted by one, two or three substituents selected from the group consisting of halogen, hydroxyl, oxo, C ₁ -C ₆ alkyl, and C ₁ -C ₆ haloalkyl; R ^Y1 and R ^Y2 are independently selected, for each occurrence, from the group consisting of R ^13aa , hydrogen, cyano, halogen, hydroxyl, oxo, -CH(CN)(OH), -SR ^13ee , -S(R ^13ee ) ₅ , -S(O)R ^13ee , and - S(O) ₂ R ^13ee , as valency permits; R ^13aa is selected from the group consisting of -OR ^13bb , - N(R ^ee R ^ff ), -N(R ^ee )-C(O)-(R ^ff ), C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, 3- 10 membered heterocyclyl, C ₆ -C ₁₄ aryl, and 5-10 membered heteroaryl; wherein R ^13aa may be optionally substituted by one, two or three substituents each selected from R ^hh ; R ^13ee is independently selected, for each occurrence, from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₁₀ cycloalkyl, and C ₁ -C ₆ alkoxy; R ^13bb is selected from the group consisting of C ₁ -C ₆ alkyl-(3-10 membered heterocyclyl), C ₁ -C ₆ alkyl-(5-10 membered heteroaryl), C ₁ -C ₆ alkyl-(C ₆ -C ₁₄ aryl), C ₁ -C ₆ haloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl; R ^ee and R ^ff are independently selected, for each occurrence, from the group consisting of hydrogen and C ₁ -C ₆ alkyl; wherein the alkyl may optionally be substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, hydroxyl, 3-10 membered heterocyclyl, C ₆ -C ₁₄ aryl, and 5- 10 membered heteroaryl; or R ^ee and R ^ff may form, together with the nitrogen to which they are attached, a 4-6 membered heterocycle; R ^hh is independently selected, for each occurrence, from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, and C ₁ -C ₆ alkoxy; and n is selected from 1, 2, 3 and 4. [00059] In some embodiments, the compound of Formula I is represented by: wherein: Y ¹ , Y ² and Y ³ are independently selected, for each occurrence, from the group consisting of C(R ^Y1 R ^Y2 ), N(R ^Y1 R ^Y2 ), O, S(O), and S(O) ₂ ; or two of Y ¹ , Y ² and Y ³ may form, together with the carbons to which they are attached, a C ₁ -C ₃ alkylene bridge, wherein the alkylene bridge may optionally be substituted by one, two or three substituents selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, oxo, hydroxyl, and halogen; R ^Y1 and R ^Y2 are independently selected, for each occurrence, from the group consisting of R ^13aa , hydrogen, cyano, halogen, hydroxyl, oxo, -CH(CN)(OH), -SR ^13ee , -S(R ^13ee ) ₅ , -S(O)R ^13ee , and - S(O) ₂ R ^13ee , and as valency permits; R ^13aa is selected from the group consisting of -OR ^13bb , - N(R ^ee R ^ff ), -N(R ^ee )-C(O)-(R ^ff ), C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, 3- 10 membered heterocyclyl, C ₆ -C ₁₄ aryl, and 5-10 membered heteroaryl; wherein R ^13aa may be optionally substituted by one, two or three substituents each selected from R ^hh ; R ^13ee is independently selected, for each occurrence, from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₁₀ cycloalkyl, and C ₁ -C ₆ alkoxy; R ^13bb is selected from the group consisting of C ₁ -C ₆ alkyl-(3-10 membered heterocyclyl), C ₁ -C ₆ alkyl-(5-10 membered heteroaryl), C ₁ -C ₆ alkyl-(C ₆ -C ₁₄ aryl), C ₁ -C ₆ haloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl; R ^ee and R ^ff are independently selected, for each occurrence, from the group consisting of hydrogen and C ₁ -C ₆ alkyl; wherein C ₁ -C ₆ alkyl may optionally be substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, hydroxyl, 3-10 membered heterocyclyl, C ₆ -C ₁₄ aryl, and 5- 10 membered heteroaryl; or R ^ee and R ^ff may form, together with the nitrogen to which they are attached, a 4-6 membered heterocycle; R ^hh is independently selected, for each occurrence, from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, and C ₁ -C ₆ alkoxy; and n is selected from 1, 2, 3 and 4. [00060] In some embodiments, wherein Y ^{1 2 3} , Y and Y are independently selected, for each occurrence, from the group consisting of C(R ^Y1 R ^Y2 ), N(R ^Y1 R ^Y2 ), O, S(O), and S(O) ₂ ; or two of Y ¹ , Y ² and Y ³ may form, together with the carbons to which they are attached, a C ₁ -C ₃ alkylene bridge, wherein the alkylene bridge may optionally be substituted by one, two or three substituents selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, oxo, hydroxyl and halogen; R ^Y1 and R ^Y2 are independently selected, for each occurrence, from the group consisting of R ^13aa , hydrogen, cyano, halogen, hydroxyl, oxo, -CH(CN)(OH), -SR ^13ee , -S(R ^13ee ) ₅ , -S(O)R ^13ee , and -S(O) ₂ R ^13ee , and as valency permits; R ^13aa is selected from the group consisting of -OR ^13bb , -N(R ^ee R ^ff ), -N(R ^ee )-C(O)-(R ^ff ), C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ - C ₁₄ aryl and 5-10 membered heteroaryl; wherein R ^13aa may be optionally substituted by one, two or three substituents each selected from R ^hh ; R ^13ee is independently selected, for each occurrence, from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ - C ₁₀ cycloalkyl, and C ₁ -C ₆ alkoxy; R ^13bb is selected from the group consisting of C ₁ -C ₆ alkyl-(3- 10 membered heterocyclyl), C ₁ -C ₆ alkyl-(5-10 membered heteroaryl), C ₁ -C ₆ alkyl-(C ₆ - C ₁₄ aryl), C ₁ -C ₆ haloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl; R ^ee and R ^ff are independently selected, for each occurrence, from the group consisting of hydrogen and C ₁ -C ₆ alkyl; wherein the alkyl may optionally be substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, hydroxyl, 3-10 membered heterocyclyl, C ₆ -C ₁₄ aryl, and 5-10 membered heteroaryl; or R ^ee and R ^ff may form, together with the nitrogen to which they are attached, a 4-6 membered heterocycle; R ^hh is independently selected, for each occurrence, from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, and C ₁ -C ₆ alkoxy; and n is selected from 1, 2, 3 and 4. [00061] In some embodiments, Y ¹ , Y ² and Y ³ are each independently C(R ^Y1 R ^Y2 ), wherein each R ^Y1 and R ^Y2 is independently hydrogen or cyano. In some embodiments, Y ¹ is O, and Y ² and Y ³ are each independently C(R ^Y1 R ^Y2 ), wherein each R ^Y1 and R ^Y2 is independently hydrogen or cyano. In some embodiments, n is 1, 2 or 3. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1. [00062] In some embodiments, R ^W is an optionally substituted 3-10 membered N- heterocyclyl. In some embodiments, R ^W is a 3-10 membered N-heterocyclyl, wherein R ^W is optionally substituted by one, two or three substituents each independently selected from R ^a . In some embodiments, R ^a is cyano. In some embodiments, R ^a is halogen. [00063] In some embodiments, R ^W is optionally substituted N(R ^U1 R ^U2 ). In some embodiments, R ^W is N(R ^U1 R ^U2 ), wherein R ^W is optionally substituted by one, two or three substituents each independently selected from R ^a . In some embodiments, R ^a is cyano. In some embodiments, R ^a is halogen. In some embodiments, R ^U1 is hydrogen or C _1- C ₃ alkyl, wherein the C _1- C ₃ alkyl is optionally substituted with one, two or three substituents each independently selected from R ^a , wherein R ^a is cyano, -CF ₃ or halogen. In some embodiments, R ^U2 is C ₃ -C ₆ cycloalkyl optionally substituted with one, two or three substituents each independently selected from R ^a , wherein R ^a is cyano or halogen. [00064] In some embodiments, R ^W is a warhead selected from the group consisting of: , [00065] In some embodiments, R ^W is a warhead selected from the group consisting of: . [00066] In some embodiments, R ² is selected from C ₃ -C ₆ cycloalkyl and C ₆ -C ₈ aryl, wherein the cycloalkyl or aryl is optionally substituted by one, two or three substituents each independently selected from R ^a . In some embodiments, R ^a is selected from the group consisting of SF ₅ , halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ haloalkyl, and C ₁ -C ₆ alkoxy. In some embodiments, R ^a is selected from the group consisting of SF ₅ , halogen, C ₁ -C ₆ alkyl, and C ₃ -C ₆ cycloalkyl. [00067] In some embodiments, R ² is selected from the group consisting of: [00068] In some embodiments, R ³ is 5-6 membered heteroaryl optionally substituted by one, two or three substituents each independently selected from R ^a . In some embodiments, R ³ is pyridyl optionally substituted by one, two or three substituents each independently selected from R ^a . In some embodiments, R ^a is selected from the group consisting of halogen, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, and C ₃ -C ₁₀ cycloalkyl. In some embodiments, R ^a is halogen or C ₁ -C ₆ haloalkyl. In some embodiments, R ^a is -CF ₃ . [00069] In some embodiments, R ³ is selected from the group consisting of: [00070] In some embodiments, R ^3a is selected from the group consisting of hydrogen, deuterium, and C ₁ -C ₃ alkyl. In some embodiments, R ^3a is selected from the group consisting of hydrogen and methyl. In some embodiments, R ^3a is hydrogen. In some embodiments, R ^3a is deuterium. In some embodiments, R ^3a is methyl. [00071] In some embodiments, R ⁴ is C ₃ -C ₆ cycloalkyl optionally substituted by one, two or three substituents each independently selected from R ^a . In some embodiments, R ^a is selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, and C ₃ -C ₁₀ cycloalkyl. In some embodiments, R ^a is halogen. In some embodiments, R ^a is F. [00072] In some embodiments, [00073] In some embodiments, R ^4a is hydrogen. [00074] In some embodiments, R ⁵ is selected from the group consisting of halogen, SF ₅ , C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, and C ₃ -C ₆ cycloalkyl. In some embodiments, R ⁵ is selected from the group consisting of halogen, SF ₅ , C ₁ -C ₆ alkyl, and C ₃ -C ₆ cycloalkyl. In some embodiments, R ⁵ is selected from the group consisting of F, SF ₅ , tert-butyl, and cyclopropyl. [00075] In some embodiments, Y is -C(O)-. In some embodiments, Y is -S(O)-. In some embodiments, Y is -S(O) ₂ -. [00076] In some embodiments, R ^a is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, cyano, SF ₅ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ - C ₆ alkoxy, and C ₃ -C ₁₀ cycloalkyl. In some embodiments, R ^a is independently selected, for each occurrence, from the group consisting of halogen, cyano, and C ₁ -C ₆ haloalkyl. In some embodiments, R ^a is halogen or cyano. [00077] Also provided herein are compounds represented by Formula II: (Formula II), wherein: Y is selected from -C(O)-, -S(O)-, and -S(O) ₂ -; R ^6a is selected from the group consisting of hydrogen, halogen, cyano, SF ₅ , C ₁ -C ₆ alkyl, and C ₃ -C ₁₀ cycloalkyl; R ^6b is selected from the group consisting of hydrogen, halogen, cyano, SF ₅ , C ₁ -C ₆ alkyl, and C ₃ - C ₁₀ cycloalkyl; R ^7a is selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl, and C ₁ -C ₆ haloalkyl; R ^7b is selected from the group consisting of hydrogen, halogen, C ₁ - C ₆ alkyl, and C ₁ -C ₆ haloalkyl; R ⁸ is selected from the group consisting of hydrogen, deuterium, halogen, C ₁ -C ₆ alkyl, and C ₁ -C ₆ haloalkyl; R ^W is selected from the group pharmaceutically acceptable salts thereof. [00078] In some embodiments, R ^6a is selected from the group consisting of hydrogen, [00079] In some embodiments, R ^6b is selected from hydrogen and halogen. [00080] In some embodiments, R ^7a is selected from hydrogen and -CF ₃ . [00081] In some embodiments, R ^7b is selected from hydrogen and halogen. [00082] In some embodiments, Y is -C(O)-. In some embodiments, Y is -S(O)-. In some embodiments, Y is -S(O) ₂ -. [00083] In some embodiments, the compound is selected from the group consisting of the compounds identified in Table 1 below: Table 1. Exemplary compounds.

II. Methods [00084] Another aspect of the disclosure provides methods of treating patients suffering from a viral infection, e.g., a coronaviral infection. In particular, in certain embodiments, the disclosure provides a method of treating the below medical indications comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, I-B, I-C, I-D, I-E, I-F, or II. [00085] In certain embodiments, the disclosure provides a method of ameliorating or treating a viral infection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of any of the compounds described herein. In some embodiments, the viral infection is from a virus selected from the group consisting of an RNA virus, a DNA virus, a coronavirus, a papillomavirus, a pneumovirus, a picornavirus, an influenza virus, an adenovirus, a cytomegalovirus, a polyomavirus, a poxvirus, a flavivirus, an alphavirus, an ebola virus, a morbillivirus, an enterovirus, an orthopneumovirus, a lentivirus, arenavirus, a herpes virus, and a hepatovirus. In certain embodiments, the viral infection is a coronavirus infection. In some embodiments, the viral infection is a coronavirus selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus,

OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), severe acute respiratory syndrome (SARS) coronavirus (SARS- CoV), and SARS-CoV-2 (COVID-19). In embodiments, the viral infection is SARS-CoV-2.

[00086] In some embodiments, the viral infection is from a virus selected from the group consisting of caliciviruses, MD145, murine norovirus, vesicular exanthema of swine virus, abbit hemorrhagic disease virus, porcine teschovirus, bovine coronavirus, feline infectious peritonitis virus, EV-68 virus, EV-71 virus, poliovirus, norovirus, human rhinovirus (HRV), hepatitis A virus (HAV) and foot-and-mouth disease virus (FMDV).

[00087] In embodiments, the viral infection is an arenovirus infection. In some embodiments, the arenovirus is selected from the group consisting of: Junin virus, Lassa virus, Lujo virus, Machupo virus, and Sabia virus. In some embodiments, the viral infection is an influenza infection. In some embodiments, the influenza is influenza H1N1, H3N2 or H5N1.

[00088] Another aspect of the disclosure provides methods of treating patients suffering from a viral infection, e.g., a noroviral infection. In some embodiments, the disclosure provides a method of treating a viral infection from a norovirus in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of any of the compounds described herein.

[00089] Also provided herein, in certain embodiments, is a method of inhibiting transmission of a virus, a method of inhibiting viral replication, a method of minimizing expression of viral proteins, or a method of inhibiting virus release, comprising administering a therapeutically effective amount of a compound described herein to a patient suffering from the virus, and/or contacting an effective amount of a compound described herein with a virally infected cell. In some embodiments, the method further comprises administering another therapeutic. In some embodiments, the method further comprises administering an additional anti-viral therapeutic. In embodiments, the anti-viral therapeutic is selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, simeprevir, daclatasvir, grazoprevir, pibrentasvir, adefovir, amprenavir, ampligen, aplaviroc, anti-caprine antibody, balavir, cabotegravir, cytarabine, ecoliever, epigallocatechin gallate, etravirine, fostemsavir, gemcitabine, griffithsin, imunovir, indinavir, maraviroc, methisazone, MK-2048, nelfmavir, nevirapine, nitazoxanide, norvir, plerixafor, PRO 140, raltegravir, pyramidine, saquinavir, telbivudine, TNX-355, valacyclovir, VIR- 576, and zalcitabine. In some embodiments, the another therapeutic is selected from the group consisting of protease inhibitors, fusion inhibitors, M2 proton channel blockers, polymerase inhibitors, 6- endonuclease inhibitors, neuraminidase inhibitors, reverse transcriptase inhibitor, aciclovir, acyclovir, protease inhibitors, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, darunavir, docosanol, edoxudine, entry inhibitors, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, immunovir, idoxuridine, imiquimod, inosine, integrase inhibitor, interferons, lopinavir, loviride, moroxydine, nexavir, nucleoside analogues, penciclovir, pleconaril, podophyllotoxin, ribavirin, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, and zodovudine. In embodiments, the additional anti-viral therapeutic is selected from the group consisting of lamivudine, an interferon alpha, a VAP anti -idiotypic antibody, enfuvirtide, amantadine, rimantadine, pleconaril, aciclovir, zidovudine, fomivirsen, a morpholino, a protease inhibitor, double-stranded RNA activated caspase oligomerizer (DRACO), rifampicin, zanamivir, oseltamivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, simeprevir, daclatasvir, grazoprevir, pibrentasvir, adefovir, amprenavir, ampligen, aplaviroc, anti-caprine antibody, balavir, cabotegravir, cytarabine, ecoliever, epigallocatechin gallate, etravirine, fostemsavir, gemcitabine, griffithsin, imunovir, indinavir, maraviroc, methisazone, MK-2048, nelfmavir, nevirapine, nitazoxanide, norvir, plerixafor, PRO 140, raltegravir, pyramidine, saquinavir, telbivudine, TNX-355, valacyclovir, VIR- 576, and zalcitabine.

[00090] Contemplated patients include not only humans, but other animals such as companion animals (e.g. dogs, cats), domestic animals (e.g. cow, swine), and wild animals (e.g. monkeys, bats, snakes).

[00091] Accordingly, in one embodiment, described herein is a method of ameliorating or treating a viral infection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of a compound of Formula I, I-B, I-C, I-D, I-E, I-F, or II, described herein) or a pharmaceutically acceptable salt thereof.

[00092] Other contemplated methods of treatment include method of treating or ameliorating a virus infection condition or co-morbidity, by administering a compound disclosed herein to a subject.

[00093] Exemplary co-morbidities include lung diseases, cardiac disorders, endocrine disorders, respiratory disorders, hepatic disorders, skeletal disorders, psychiatric disorders, metabolic disorders, and reproductive disorders.

[00094] In some embodiments, the viral infection is from a virus selected from the group consisting of an RNA virus, a DNA virus, a coronavirus, a papillomavirus, a pneumovirus, a picomavirus, an influenza virus, an adenovirus, a cytomegalovirus, a polyomavirus, a poxvirus, a flavivirus, an alphavirus, an ebola virus, a morbillivirus, an enterovirus, an orthopneumovirus, a lentivirus, arenovirus, a herpes virus, and a hepatovirus. In some embodiments, the viral infection is a coronavirus infection. In some embodiments, the viral infection is a coronavirus selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and SARS-CoV-2 (COVID-19). In some embodiments, the viral infection is SARS-CoV-2. In some embodiments, the viral infection is an arenovirus infection. In some embodiments, the arenovirus is selected from the group consisting of: Junin virus, Lassa virus, Lujo virus, Machupo virus, and Sabia virus. In some embodiments, the viral infection is an influenza infection. In some embodiments, the influenza is influenza H1N1, H3N2 or H5N1. In some embodiments, the viral infection is a respiratory viral infection. In some embodiments, the viral infection is an upper respiratory viral infection or a lower respiratory viral infection. In some embodiments, the method further comprises administering another therapeutic.

[00095] In certain embodiments, the virus is selected from the group consisting of a retrovirus ( e.g ., human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV), human T-cell lymphotropic virus (HTLV)-l, HTLV-2, HTLV-3, HTLV-4), Ebola virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, a herpes simplex virus (HSV)

(e.g., HSV-1, HSV-2, varicella zoster virus, cytomegalovirus), an adenovirus, an orthomyxovirus (e.g, influenza virus A, influenza virus B, influenza virus C, influenza virus D, thogotovirus), a flavivirus (e.g, dengue virus, Zika virus), West Nile virus, Rift Valley fever virus, an arenavirus, Crimean-Congo hemorrhagic fever virus, an echovirus, a rhinovirus, coxsackie virus, a coronavirus (e.g, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19), a respiratory syncytial virus, a mumps virus, a rotavirus, measles virus, rubella virus, a parvovirus (e.g, an adeno- associated virus), a vaccinia virus, a variola virus, a molluscum virus, bovine leukemia virus, bovine diarrhea virus, a poliovirus, St. Louis encephalitis virus, Japanese encephalitis virus, a tick-borne encephalitis virus, Murray Valley virus, Powassan virus, Rocio virus, louping-ill virus, Banzi virus, Ilheus virus, Kokobera virus, Kunjin virus, Alfuy virus, a rabies virus, a polyomavirus (e.g, JC virus, BK virus), an alphavirus, and a rubivirus (e.g, rubella virus).

[00096] In certain embodiments, the disease or disorder is a viral infection, e.g, a disease or disorder selected from the group consisting of acquired immune deficiency syndrome (AIDS), HTLV-1 associated myelopathy/tropical spastic paraparesis, Ebola virus disease, hepatitis A, hepatitis B, hepatitis C, herpes, herpes zoster, acute varicella, mononucleosis, respiratory infections, pneumonia, influenza, dengue fever, encephalitis (e.g, Japanese encephalitis, St. Louis encephalitis, or tick-borne encephalitis such as Powassan encephalitis), West Nile fever, Rift Valley fever, Crimean-Congo hemorrhagic fever, Kyasanur Forest disease, Yellow fever, Zika fever, aseptic meningitis, myocarditis, common cold, lung infections, molloscum contagiosum, enzootic bovine leucosis, coronavirus disease 2019 (COVID-19), mumps, gastroenteritis, measles, rubella, slapped-cheek disease, smallpox, warts (e.g, genital warts), molluscum contagiosum, polio, rabies, and pityriasis rosea. [00097] In some embodiments, the vims is an RNA vims (having a genome that is composed of RNA). RNA vimses may be single-stranded RNA (ssRNA) or double-stranded RNA (dsRNA). RNA vimses have high mutation rates compared to DNA vimses, as RNA polymerase lacks proofreading capability (see Steinhauer DA, Holland JJ (1987). "Rapid evolution of RNA viruses". Annu. Rev. Microbiol. 41: 409 33). In some embodiments, the RNA vims is a positive-strand RNA vims (e.g., a SARS-CoV vims, polio vims, Coxsackie vims, Enterovims, Human rhinovims, Foot/Mouth disease vims, encephalomyocarditis vims, Dengue vims, Zika vims, Hepatitis C vims, or New Castle Disease vims).

[00098] RNA vimses are classified by the type of genome (double-stranded, negative (-), or positive (+) single-stranded). Double-stranded RNA vimses contain a number of different RNA molecules, each coding for one or more viral proteins. Positive-sense ssRNA vimses utilize their genome directly as mRNA; ribosomes within the host cell translate mRNA into a single protein that is then modified to form the various proteins needed for viral replication. One such protein is RNA-dependent RNA polymerase (RNA replicase), which copies the viral RNA in order to form a double-stranded, replicative form. Negative-sense ssRNA vimses have their genome copied by an RNA replicase enzyme to produce positive- sense RNA for replication. Therefore, the vims comprises an RNA replicase enzyme. The resultant positive-sense RNA then acts as viral mRNA and is translated by the host ribosomes. In some embodiments, the vims is a dsRNA vims. In some embodiments, the vims is a negative ssRNA vims. In some embodiments, the vims is a positive ssRNA vims. In some embodiments, the positive ssRNA vims is a coronavims.

[00099] SARS-CoV2, also sometimes referred to as the novel coronavims of 2019 or 2019-nCoV, is a positive-sense single-stranded RNA vims. SARS-CoV-2 has four stmctural proteins, known as the S (spike), E (envelope), M (membrane), and N (nucleocapsid) proteins. The N protein holds the RNA genome together; the S, E, and M proteins form the viral envelope. Spike allows the vims to attach to the membrane of a host cell, such as the ACE2 receptor in human cells (Kmse R.L. (2020), Therapeutic strategies in an outbreak scenario to treat the novel coronavims originating in Wuhan, China (version 2). FlOOOResearch , 9:72). SARS-CoV2 is the highly contagious, causative viral agent of coronavims disease 2019 (COVID19), a global pandemic.

[000100] In some embodiments, the vims is a DNA vims (having a genome that is composed of DNA). Exemplary DNA vimses include, without limitation, parvoviruses (e.g., adeno-associated viruses), adenoviruses, asfarviruses, herpesviruses ( e.g ., herpes simplex virus 1 and 2 (HSV-1 and HSV-2), Epstein-Barr virus (EBV), cytomegalovirus (CMV)), papillomoviruses (e.g., HPV), polyomaviruses (e.g, simian vacuolating virus 40 (SV40)), and poxviruses (e.g, vaccinia virus, cowpox virus, smallpox virus, fowlpox virus, sheeppox virus, myxoma virus). Exemplary RNA viruses include, without limitation, bunyaviruses (e.g, hantavirus), coronaviruses, flaviviruses (e.g, yellow fever virus, west nile virus, dengue virus), hepatitis viruses (e.g, hepatitis A virus, hepatitis C virus, hepatitis E virus), influenza viruses (e.g, influenza virus type A, influenza virus type B, influenza virus type C), measles virus, mumps virus, noroviruses (e.g, Norwalk virus), poliovirus, respiratory syncytial virus (RSV), retroviruses (e.g, human immunodeficiency virus- 1 (HIV-1)) and toroviruses.

[000101] The methods described herein may inhibit viral replication transmission, replication, assembly, or release, or minimize expression of viral proteins. In one embodiment, described herein is a method of inhibiting transmission of a virus, a method of inhibiting viral replication, a method of minimizing expression of viral proteins, or a method of inhibiting virus release, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to a patient suffering from the virus, and/or contacting an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, with a virally infected cell.

[000102] Also described herein is a method of treating a respiratory disorder in a subject in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I, I-B, I-C, I-D, I-E, I-F, II, etc. described herein) or a pharmaceutically acceptable salt thereof. In embodiments, the respiratory disorder is selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, fibrosis, chronic asthma, acute asthma, lung disease secondary to environmental exposures, acute lung infection, chronic lung infection, al antitrypsin disease, cystic fibrosis and an autoimmune disease. In some embodiments, the respiratory disorder is associated with a heart attack.

[000103] Also described herein is a method of treating a disorder associated with cathepsin (e.g. Cathepsin K) in a subject in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I, I-B, I-C, I-D, I-E, I-F, II, etc. described herein) or a pharmaceutically acceptable salt thereof. In some embodiments, the disorder is a cathepsin dependent condition or disease. In embodiments, the disorder is selected from the group consisting of breast cancer, pycnodysostosis, glioblastoma, osteosclerosis, osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, atherosclerosis, obesity, glaucoma, chronic obstructive pulmonary disease, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma.

[000104] Compounds described herein, e.g., a compound of Formula I, I-B, I-C, I-D, I-E, I-F, II, etc. as defined herein, can be administered in combination with one or more additional therapeutic agents to treat a disorder described herein, such as an infection by a pathogen described herein, e.g., a virus, fungus, or protozoan. For clarity, contemplated herein are both a fixed composition comprising a disclosed compound and another therapeutic agent such as disclosed herein, and methods of administering, separately a disclosed compound and a disclosed therapeutic. For example, provided in the present disclosure is a pharmaceutical composition comprising a compound described herein, e.g., a compound of Formula I as defined herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient. In some embodiments, a compound of Formula I, I-B, I-C, I-D, I-E, I-F, II, as defined herein and one additional therapeutic agent is administered. In some embodiments, a disclosed compound as defined herein and two additional therapeutic agents are administered. In some embodiments, a disclosed compound as defined herein and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. For example, a compound of Formula I, I-B, I-C, I-D, I-E, I-F, II, etc. as defined herein and an additional therapeutic agent can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, for example a pharmaceutical composition comprising a compound of Formula I as one therapeutic agent and one or more additional therapeutic agents such as an antibiotic, a viral protease inhibitor, or an anti -viral nucleoside anti -metabolite. For example, a compound of Formula I as defined herein and an additional therapeutic agent can be administered in a single formulation. Other combinations are also encompassed by combination therapy.

While the two or more agents in the combination therapy can be administered simultaneously, they need not be. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient's body at the same time, this need not be so.

[000105] Combination therapy can also include two or more administrations of one or more of the agents used in the combination using different sequencing of the component agents. For example, if agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y-X, X-X-Y, Y- X-Y, Y-Y-X, X-X-Y- Y, etc.

[000106] In some embodiments, the one or more additional therapeutic agents that may be administered in combination with a compound provided herein can be an antibiotic, a viral protease inhibitor, an anti-viral anti-metabolite, a lysosomotropic agent, a M2 proton channel blocker, a polymerase inhibitor (e.g., EIDD-2801, which is also known as MOLNUPIRAVIR), aneuraminidase inhibitor, a reverse transcriptase inhibitor, a viral entry inhibitor, an integrase inhibitor, interferons (e.g., types I, II, and III), or a nucleoside analogue. In some embodiments, the one or more additional therapeutic agents that may be administered in combination wiht a compounds provided herein can be a steroid (e.g., corticosteroids, such as bethamethasone, prednisone, prednisolone, triamcinolone, methylprednisolone, dexamethasone; mineralcorticoid such as fludrocortisone; glucocorticoids, such as hydrocortisone, cortisone, ethamethasoneb, prednisone, prednisolone, triamcinolone, dexamethasone; vitamin D such as dihydrotachysterol; androgens such as apoptone, oxandrolone, oxabolone, testosterone, nandrolone (also known as anabolic steroids), oestrogens such as diethylstilbestrol, progestins such as danazol, norethindrone, medroxyprogesterone acetate, 17-Hydroxyprogesterone caproate; and progestins such as mifepristone and gestrinone) or an immunomodulator (e.g., 6Mercaptopurine, 6MP, Alferon N, anakinra, Arcalyst, Avonex, AVOSTARTGRIP, Bafiertam, Berinert, Betaseron, BG-12, Cl esterase inhibitor recombinant, Cl inhibitor human, Cinryze, Copaxone, dimethyl fumarate, diroximel fumarate, ecallantide, emapalumab, emapalumab-lzsg, Extavia, fmgolimod, Firazyr, Gamifant, Gilenya, glatiramer, Glatopa, Haegarda, icatibant, Infergen, interferon alfa n3, interferon alfacon 1, interferon beta la, interferon beta lb, Kalbitor, Kineret, mercaptopurine, monomethyl fumarate, peginterferon beta- la, Plegridy, Purinethol, Purixan, Rebif, Rebif Rebidose, remestemcel-L, rilonacept, ropeginterferon alfa 2b, Ruconest, Ryoncil, siltuximab, sutimlimab, Sylvant, Tecfidera, and Vumerity). In some embodiments, the one or more additional therapeutic agent is Cathepsin L. In some embodiments, the one or more additional therapeutic agent is dehydrodidemnin B (also known as Plitidepsin or APLIDIN) or Zotatifm (eFT226).

[000107] In some embodiments, methods described herein further comprise administering an additional anti-viral therapeutic. In some embodiments, the anti-viral therapeutic is selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, simeprevir, daclatasvir, grazoprevir, pibrentasvir, adefovir, amprenavir, ampligen, aplaviroc, anti-caprine antibody, balavir, cabotegravir, cytarabine, ecoliever, epigallocatechin gallate, etravirine, fostemsavir, gemcitabine, griffithsin, imunovir, indinavir, maraviroc, methisazone, MK- 2048, nelfmavir, nevirapine, nitazoxanide, norvir, plerixafor, PRO 140, raltegravir, pyramidine, saquinavir, telbivudine, TNX-355, valacyclovir, VIR- 576, and zalcitabine. In some embodiments, the another therapeutic is selected from the group consisting of protease inhibitors (e.g., nafamostat, camostat, gabexate, epsilon-aminocapronic acid and aprotinin), fusion inhibitors (e.g., BMY-27709, CL 61917, and CL 62554), M2 proton channel blockers (e.g., amantadine and rimantadine), polymerase inhibitors (e.g., 2-deoxy-2'fluoroguanosides (2'-fluoroGuo), 6- endonuclease inhibitors (e.g., L-735,822 and flutamide) neuraminidase inhibitors (e.g., zanamivir (Relenza), oseltamivir, peramivir and ABT-675 (A-315675), reverse transcriptase inhibitor (e.g., abacavir, adefovir, delavirdine, didanosine, efavirenz, emtricitabine, lamivudine, nevirapine, stavudine, tenofovir, tenofovir disoproxil, and zalcitabine), acyclovir, acyclovir, protease inhibitors (e.g., amprenavir, indinavir, nelfmavir, ritonavir, and saquinavir), arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, darunavir, docosanol, edoxudine, entry inhibitors (e.g., enfuvirtide and maraviroc), entecavir, famciclovir, fomivirsen, fosamprenavir, foscamet, fosfonet, ganciclovir, ibacitabine, immunovir, idoxuridine, imiquimod, inosine, integrase inhibitor (e.g., raltegravir), interferons (e.g., types I, II, and III), lopinavir, loviride, moroxydine, nexavir, nucleoside analogues (e.g., aciclovir), penciclovir, pleconaril, podophyllotoxin, ribavirin, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, and zodovudine. In some embodiments, the additional anti-viral therapeutic is selected from the group consisting of lamivudine, an interferon alpha, a VAP anti-idiotypic antibody, enfuvirtide, amantadine, rimantadine, pleconaril, aciclovir, zidovudine, fomivirsen, a morpholino, a protease inhibitor, double-stranded RNA activated caspase oligomerizer (DRACO), rifampicin, zanamivir, oseltamivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, simeprevir, daclatasvir, grazoprevir, pibrentasvir, adefovir, amprenavir, ampligen, aplaviroc, anti-caprine antibody, balavir, cabotegravir, cytarabine, ecoliever, epigallocatechin gallate, etravirine, fostemsavir, gemcitabine, griffithsin, imunovir, indinavir, maraviroc, methisazone, MK-2048, nelfmavir, nevirapine, nitazoxanide, norvir, plerixafor, PRO 140, raltegravir, pyramidine, saquinavir, telbivudine, TNX-355, valacyclovir, VIR- 576, and zalcitabine. In some embodiments, the another therapeutic is selected from the group consisting of quinine (optionally in combination with clindamycin), chloroquine, amodiaquine, artemisinin and its derivatives (e.g., artemether, artesunate, dihydroartemisinin, arteether), doxycycline, pyrimethamine, mefloquine, halofantrine, hydroxychloroquine, eflomithine, nitazoxanide, ornidazole, paromomycin, pentamidine, primaquine, pyrimethamine, proguanil (optionally in combination with atovaquone), a sulfonamide (e.g., sulfadoxine, sulfamethoxypyridazine), tafenoquine, tinidazole and aPPTl inhibitor (including Lys05 and DC661). In some embodiments, the another therapeutic is an antibiotic. In some embodiments, the antibiotic is a penicillin antibiotic, a quinolone antibiotic, a tetracycline antibiotic, a macrolide antibiotic, a lincosamide antibiotic, a cephalosporin antibiotic, or an RNA synthetase inhibitor. In some embodiments, the antibiotic is selected from the group consisting of azithromycin, vancomycin, metronidazole, gentamicin, colistin, fidaxomicin, telavancin, oritavancin, dalbavancin, daptomycin, cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, ceftobiprole, cipro, Levaquin, floxin, tequin, avelox, norflox, tetracycline, minocycline, oxytetracycline, doxycycline, amoxicillin, ampicillin, penicillin V, dicloxacillin, carbenicillin, methicillin, ertapenem, doripenem, imipenem/cilastatin, meropenem, amikacin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefoxotin, and streptomycin. In some embodiments, the antibiotic is azithromycin. [000108] In some embodiments, the one or more additional therapeutic agents that may be administered in combination with a compound provided herein can be selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, simeprevir, daclatasvir, grazoprevir, pibrentasvir, adefovir, amprenavir, ampligen, aplaviroc, anti-caprine antibody, balavir, cabotegravir, cytarabine, ecoliever, epigallocatechin gallate, etravirine, fostemsavir, gemcitabine, griffithsin, imunovir, indinavir, maraviroc, methisazone, MK-2048, nelfmavir, nevirapine, nitazoxanide, norvir, plerixafor, PRO 140, raltegravir, pyramidine, saquinavir, telbivudine, TNX-355, valacyclovir, VIR- 576, and zalcitabine.

[000109] In some embodiments, the compounds described herein (e.g. a compound of Formula I, I-B, I-C, I-D, I-E, I-F, II, etc.) and pharmaceutically acceptable salts thereof may be used in combination with one or more other agents which may be useful in the prevention or treatment of respiratory disease, inflammatory disease, autoimmune disease, for example; anti-histamines, corticosteroids, (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), NSAIDs, leukotriene modulators (e.g., montelukast, zafirlukast.pranlukast), tryptase inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors such as elastase inhibitors, integrin antagonists (e.g., beta-2 integrin antagonists), adenosine A2a agonists, mediator release inhibitors such as sodium chromoglycate, 5 -lipoxygenase inhibitors (zyflo), DPI antagonists, DP2 antagonists, PI3K delta inhibitors, ITK inhibitors,

LP (lysophosphatidic) inhibitors or FLAP (5 -lipoxygenase activating protein) inhibitors (e.g., sodium 3-(3-(tert-butylthio)-l -(4-(6- ethoxypyridin-3-yl)benzyl)-5-((5-ethylpyridin-2- yl)methoxy)-l H-indol-2-yl)-2,2- dimethylpropanoate), bronchodilators (e.g.. muscarinic antagonists, beta-2 agonists), methotrexate, and similar agents; monoclonal antibody therapy such as anti-lgE, anti- TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents; cytokine receptor therapies e.g. etanercept and similar agents; antigen non-specific immunotherapies (e.g. interferon or other cytokines/chemokines, chemokine receptor modulators such as CCR3, CCR4 or CXCR2 antagonists, other cytokine/chemokine agonists or antagonists, TLR agonists and similar agents), suitable anti-infective agents including antibiotic agents, antifungal agents, anthelmintic agents, antimalarial agents, antiprotozoal agents and antituberculosis agents. [000110] In some embodiments, the additional therapeutic agents can be kinase inhibitors including but not limited to erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatanib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, temsirolimus, abemaciclib, LEE011, palbociclib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, dasatinib, imatinib, nilotinib, ponatinib, idelalisib, ibrutinib, Loxo 292, larotrectinib, and quizartinib. [000111] In some embodiments, the additional therapeutic agents can be therapeutic anti- viral vaccines. [000112] In some embodiments, the additional therapeutic agents can be immunomodulatory agents including but not limited to anti-PD-1or anti-PDL-1 therapeutics including pembrolizumab, nivolumab, atezolizumab, durvalumab, BMS-936559, or avelumab, anti-TIM3 (anti-HAVcr2) therapeutics including but not limited to TSR-022 or MBG453, anti-LAG3 therapeutics including but not limited to relatlimab, LAG525, or TSR- 033, anti-4-1BB (anti-CD37, anti-TNFRSF9), CD40 agonist therapeutics including but not limited to SGN-40, CP-870,893 or RO7009789, anti-CD47 therapeutics including but not limited to Hu5F9-G4, anti-CD20 therapeutics, anti-CD38 therapeutics, STING agonists including but not limited to ADU-S100, MK-1454, ASA404, or amidobenzimidazoles, anthracyclines including but not limited to doxorubicin or mitoxanthrone, hypomethylating agents including but not limited to azacytidine or decitabine, other immunomodulatory therapeutics including but not limited to epidermal growth factor inhibitors, statins, metformin, angiotensin receptor blockers, thalidomide, lenalidomide, pomalidomide, prednisone, or dexamethasone. In some embodiments, the additional therapeutic agent is a p2-adrenoreceptor agonist including, but not limited to, vilanterol, salmeterol, salbutamol.formoterol, salmefamol, fenoterol carmoterol, etanterol, naminterol, clenbuterol, pirbuterol.flerbuterol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for example the xinafoate (1 -hydroxy-2- naphthalenecarboxylate) salt of salmeterol, the sulphate salt of salbutamol or the fumarate salt of formoterol. In some embodiments, the additional therapeutic agent is an anticholinergic agent, including, but not limited to, umeclidinium (for example, as the bromide), ipratropium (for example, as the bromide), oxitropium (for example, as the bromide) and tiotropium (for example, as the bromide). [000113] In particular, in certain embodiments, the disclosure provides a method of treating the above medical indications comprising administering a subject in need thereof a therapeutically effective amount of a compound described herein, such as a disclosed compound. [000114] The term "boosting amount" or "boosting dose" is the amount of a compound needed to improve the pharmacokinetics of a second compound (or increase availability or exposure). The boosting amount or boosting dose may improve the pharmacokinetics (or increase availability or exposure) of the second compound to a level to therapeutic levels in a subject. [000115] In one embodiment, the disclosure provides for a disclosed compound to be administered together with an antiviral therapeutic such as disclosed herein, and e.g., thereby boosting the dose of the anti-viral therapeutic or therapeutics. Such a boost combination may be used, e.g., as prophylactic or therapeutic treatment of a viral infection in a subject in need thereof. In one embodiment, the protease inhibitor is a compound described herein (e.g. a compound of Formula I, I-B, I-C, I-D, I-E, I-F, II, etc. III. Pharmaceutical Compositions and Kits [000116] Another aspect of the disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration. [000117] Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compound of the disclosure, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non- toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease. [000118] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the disclosure, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. [000119] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. [000120] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. [000121] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof. [000122] Suspensions, in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. [000123] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent. [000124] Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required. [000125] The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. [000126] Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. [000127] Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions. [000128] Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. [000129] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants [000130] In another aspect, the disclosure provides enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate- chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e. g. , Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives of the present disclosure. [000131] Advantageously, the disclosure also provides kits for use by a e.g. a consumer in need of 3CL inhibitor. Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening. [000132] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, ... etc.... Second Week, Monday, Tuesday, ... “ etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this. [000133] Also contemplated herein are methods and compositions that include a second active agent, or administering a second active agent. For example, in addition to having a viral infection, a subject or patient can further have viral infection- or virus-related co- morbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being infected by a virus. Contemplated herein are disclosed compounds in combination with at least one other agent that has previously been shown to treat these virus-related conditions. EXAMPLES [000134] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials. [000135] The compounds described herein can be synthesized using methods disclosed in Tanaka, Y.; Hasui, T.; Suginome, M. Organic Letters 20079(22), 4407-4410, and Pan, S. C.; List, B. Angew. Chem. Int. Ed.2008, 47, 3622-3625, which are incorporated herein by reference. [000136] At least some of the compounds identified as “Intermediates” herein are contemplated as compounds of the disclosure. [000137] ¹ H NMR spectra are recorded at ambient temperature using e.g., a Varian Unity Inova (400MHz) spectrometer with a triple resonance 5mm probe for Example compounds, and either a Bruker Avance DRX (400MHz) spectrometer or a Bruker Avance DPX (300MHz) spectrometer for Intermediate compounds. Chemical shifts are expressed in ppm relative to tetramethylsilane. The following abbreviations have been used: br = broad signal, s = singlet, d = doublet, dd = double doublet, dt = double triplet, ddd = double double doublet, t = triplet, td = triple doublet, tdd = triple double doublet, q = quartet, m = multiplet. [000138] Abbreviations: ACN acetonitrile BPO benzoyl peroxide DCC N,N-dicyclohexylcarbodiimide DCE dichloroethane DCM dichloromethane DIEA N,N-diisopropylethylamine DIPEA N,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DMF dimethylformamide DMP Dess-Martin periodinane EA ethyl acetate EDCI 1-ethyl-3- (3-dimethylaminopropyl)carbodiimide EtOAc ethyl acetate EtOH ethanol HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyr idinium 3-oxid hexafluorophosphate MS mass spectrometry MeCN acetonitrile NBS N-bromosuccinimide NMR nuclear magnetic resonance PE petroleum ether t-BuOH tert-butyl alcohol T3P propanephosphonic acid anhydride TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin-layer chromatography TMSCl trimethylsilyl chloride TMSCN trimethylsilyl cyanide General Chemistry [000139] Exemplary compounds described herein are available by the general synthetic method(s) illustrated in the Scheme(s) below, including preparations of Intermediates and preparation of accompanying Examples. Synthetic Scheme(s) Scheme 1 A-I B-I C-I D-I E-I [000140] Scheme 1 illustrates an exemplary preparation of ureido-acetamide E-I. Reacting a solution of aldehyde C-I and amine A-I with a catalyst/reagent, for example a propylphosphonic anhydride solution, and then reacting the solution with isocyanide B-I in the presence of a solvent affords amino acetamide D-I. Then, adding a solution of the amino acetamide D-I to a solution of triphosgene with amine F-I affords ureido-acetamide E-I. [000141] In Scheme 1, examples of R ^1a include optionally substituted phenyl, and examples of R ^1b include optionally substituted cycloalkyl, and R ^1c include optionally substituted heteroaryl. Examples of each R ^1d and R ^1e include hydrogen, optionally substituted alkyl, optionally substitued cycloalkyl, or R ^1d and R ^1e may form, together with the nitrogen to which they are attached, a heterocyclyl. Scheme 2 base G-I H-I I-I [000142] Scheme 2 illustrates an exemplary preparation of ureido-acetamide I-I. Reacting a solution of nitrile G-I and triphosgene affords isocyanate H-I. Then, reacting a solution of H-I in the presensce of, for example, Hunig’s base affords ureido-acetamide I-I. [000143] In Scheme 2, examples of each of R ^1f and R ^1g , independently, include optionally substituted alkyl and optionally substitued cycloalkyl, and examples of R ^1a include optionally substituted phenyl. Examples of R ^1b include optionally substituted cycloalkyl, and examples of R ^1c include optionally substituted heteroaryl. Scheme 3 O-I P-I [000144] Scheme 3 illustrates an exemplary prepartion of ureido-acetamide P-I. Reacting a solution of BnO ester J-I with triphosgene affords carbamaic chloride K-I. Then, reacting K-I with a heterocyclic ester (wherein the heterocyle moiety contains NH) in the presence of, for example, a Hunigs base provides BnO ester L-I. Reducing L-I in the presence of H ₂ and Pd/C affords M-I, which then undergoes amidation with R-I in the presence of a coupling reagent (for example, N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate) affords N-I. Adding NH _3· MeOH to N-I affords amide O-I, and then reacting the amide O-I with Burgess reagent affords the ureido-acetamide P-I. [000145] Compounds of Table 1 can be prepared following general Scheme 1, Scheme 2, or Scheme 3, which follows examples described below. Example 1: Synthesis of compound 10

Step 1: 2-(4-tert-butylanilino)-N-(4,4-difluorocyclohexyl)-2-(5-fluo ro-3-pyridyl)acetamide [000146] To a solution of 5-fluoropyridine-3-carbaldehyde (838.29 mg, 6.70 mmol, 1 eq) in EtOAc (15 mL) was added 4-tert-butylaniline (1 g, 6.70 mmol, 1.06 mL, 1 eq) and T3P (2.13 g, 3.35 mmol, 1.99 mL, 50% purity, 0.5 eq), and then the solution was stirred at 20 °C for 0.5 h. After the addition of 1,1-difluoro-4-isocyano-cyclohexane (972.64 mg, 6.70 mmol, 1 eq), the mixture was stirred at 20 °C for 0.5 h. Upon completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 2/1) to give 2-(4-tert-butylanilino)-N-(4,4-difluorocyclohexyl)-2- (5-fluoro-3-pyridyl)acetamide (2 g, 4.29 mmol, 64.04% yield, 90% purity) as a yellow solid. MS (ESI) m/z 420.2 [M+H] ⁺ . [000147] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.59 (s, 1H), 8.49 (d, J = 2.9 Hz, 1H), 8.39 (d, J = 7.7 Hz, 1H), 7.80 (td, J = 2.1, 9.9 Hz, 1H), 7.09 (d, J = 8.6 Hz, 2H), 6.59 (d, J = 8.6 Hz, 2H), 6.17 (d, J = 8.3 Hz, 1H), 5.11 (d, J = 8.6 Hz, 1H), 3.84 - 3.64 (m, 1H), 2.04 - 1.75 (m, 5H), 1.64 (br dd, J = 3.8, 12.8 Hz, 1H), 1.59 - 1.48 (m, 1H), 1.47 - 1.32 (m, 1H), 1.18 (s, 9H). Step 2: 2-[4-tert-butyl-N-[(1-cyanocyclopropyl)carbamoyl]anilino]-N- (4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide [000148] A solution of triphosgene (113.19 mg, 381.42 umol, 0.8 eq) in DCM (3 mL) was cooled to 0 °C, and then 1-aminocyclopropanecarbonitrile (169.59 mg, 1.43 mmol, 3 eq, HCl) and DIEA (369.71 mg, 2.86 mmol, 498.27 uL, 6 eq) in DCM (2 mL) was added drop- wise. The solution was stirred at 0 °C for 1 h, and then 2-(4-tert-butylanilino)-N-(4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide (0.2 g, 476.78 umol, 1 eq) and DIEA (184.86 mg, 1.43 mmol, 249.13 uL, 3 eq) in DCM (2 mL) was added. After stirring the solution at 20 °C for 13 h under N ₂ atmosphere, the reaction mixture was diluted with sat. NaHCO ₃ (20 mL), and then extracted with DCM (10 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 35%-65%,8min) to give 2-[4-tert-butyl-N-[(1-cyanocyclopropyl)carbamoyl]anilino]-N- (4,4-difluorocyclohexyl)- 2-(5-fluoro-3-pyridyl)acetamide (0.13 g, 246.41 umol, 51.68% yield) as a white solid. MS (ESI) m/z 528.2 [M+H] ⁺ . Step 3: 2-[4-tert-butyl-N-[(1-cyanocyclopropyl)carbamoyl]anilino]-N- (4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide [000149] 2-[4-tert-butyl-N-[(1-cyanocyclopropyl)carbamoyl]anilino]-N- (4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide (0.1 g, 189.54 umol, 1 eq) was separated by SFC (column: DAICEL CHIRALCEL OD(250mm*30mm,10um); mobile phase: [0.1%NH ₃ H ₂ O ETOH];B%: 36%-36%,8min) to give 2-[4-tert-butyl-N-[(1- cyanocyclopropyl)carbamoyl]anilino]-N-(4,4-difluorocyclohexy l)-2-(5-fluoro-3- pyridyl)acetamide Isomer 1 (47.86 mg, 90.72 umol, 47.86% yield, 100% purity) as a white solid. MS (ESI) m/z 528.1 [M+H] ⁺ . [000150] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.26 (d, J = 2.7 Hz, 1H), 8.19 (s, 1H), 7.40 - 7.22 (m, 3H), 7.08 (br d, J = 8.2 Hz, 2H), 5.99 (s, 1H), 3.86 (br s, 1H), 2.12 - 1.76 (m, 6H), 1.62 (br dd, J = 3.8, 11.1 Hz, 1H), 1.50 - 1.34 (m, 3H), 1.31 - 1.21 (m, 9H), 1.20 - 1.10 (m, 2H). [000151] 2-[4-tert-butyl-N-[(1-cyanocyclopropyl)carbamoyl]anilino]-N- (4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide Isomer 2 (42.05 mg, 79.70 umol, 42.05% yield, 100% purity) was obtained as a white solid. MS (ESI) m/z 528.2 [M+H] ⁺ . [000152] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.26 (d, J = 2.8 Hz, 1H), 8.19 (s, 1H), 7.36 - 7.21 (m, 3H), 7.08 (d, J = 8.2 Hz, 2H), 5.99 (s, 1H), 3.86 (br s, 1H), 2.10 - 1.76 (m, 6H), 1.68 - 1.54 (m, 1H), 1.52 - 1.33 (m, 3H), 1.25 (s, 9H), 1.19 - 1.07 (m, 2H). Example 2: (2S)-N-(4-(tert-butyl)phenyl)-2-cyano-N-(2-((4,4-difluorocyc lohexyl)amino)- 1-(5-fluoropyridin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxamid e (Compound 18) and (2S)-N1-(4-(tert-butyl)phenyl)-N1-(2-((4,4-difluorocyclohexy l)amino)-1-(5- fluoropyridin-3-yl)-2-oxoethyl)pyrrolidine-1,2-dicarboxamide (Compound 57) Step 1: 2-((4-(tert-butyl)phenyl)amino)-2-(5-fluoropyridin-3-yl)acet onitrile [000153] To a mixture of 4-tert-butylaniline (5 g, 33.50 mmol, 5.29 mL, 1 eq) and 5- fluoropyridine-3-carbaldehyde (4.19 g, 33.50 mmol, 1 eq) in DCM (70 mL) was added PdCl ₂ (1.19 g, 6.70 mmol, 0.2 eq) and Na ₂ SO ₄ (9.52 g, 67.01 mmol, 6.80 mL, 2 eq) at 0 °C, the solution was stirred at 0 °C for 0.5 h, then TMSCN (6.65 g, 67.01 mmol, 8.38 mL, 2 eq) was added drop-wise, the solution was stirred at 40 °C for 1.5 h under N ₂ atmosphere. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 1/1) to give 2-(4-tert-butylanilino)-2-(5-fluoro-3-pyridyl)acetonitrile (5 g, 15.88 mmol, 47.40% yield, 90% purity) as a white solid. MS (ESI) m/z 454.2 [M+H] ⁺ . [000154] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.66 (s, 1H), 8.52 (d, J = 2.6 Hz, 1H), 7.86 (br d, J = 9.3 Hz, 1H), 7.34 - 7.19 (m, 2H), 6.91 - 6.68 (m, 2H), 5.93 (s, 1H), 1.28 (s, 9H). Step 2: methyl 2-((4-(tert-butyl)phenyl)amino)-2-(5-fluoropyridin-3-yl)acet ate [000155] A mixture of 2-(4-tert-butylanilino)-2-(5-fluoro-3-pyridyl)acetonitrile (5 g, 17.65 mmol, 1 eq) in HCl/MeOH (70 mL) was stirred at 50 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure and washed with DCM (30 mL * 3) and concentrated in vacuo to give methyl 2-(4-tert-butylanilino)-2-(5-fluoro-3- pyridyl)acetate (5 g, crude) as a yellow solid. MS (ESI) m/z 317.1 [M+H] ⁺ . Step 3: methyl 2-((S)-N-(4-(tert-butyl)phenyl)-2-cyanopyrrolidine-1-carboxa mido)-2-(5- fluoropyridin-3-yl)acetate [000156] To a solution of methyl 2-(4-tert-butylanilino)-2-(5-fluoro-3-pyridyl)acetate (0.5 g, 1.58 mmol, 1 eq, HCl) in DCM (7 mL) was added DIEA (612.77 mg, 4.74 mmol, 825.83 uL, 3 eq), then triphosgene (468.99 mg, 1.58 mmol, 1 eq) in DCM (3 mL) was added drop- wise at 0 °C, the solution was stirred at 0 °C for 1 h under N ₂ atmosphere. And (2S)- pyrrolidine-2-carbonitrile (209.55 mg, 1.58 mmol, 1 eq, HCl) and DIEA (612.77 mg, 4.74 mmol, 825.83 uL, 3 eq) in DCM (3 mL) was added, the solution was stirred at 20 °C for 12 h under N ₂ atmosphere. Upon completion, the reaction mixture was diluted with sat. NaHCO ₃ (50 mL) and extracted with DCM (30 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH = 1:1) and re-purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [water(10mM NH ₄ HCO ₃ )- ACN];B%: 45%-70%,8min) to give methyl 2-(4-tert-butyl-N-[(2S)-2-cyanopyrrolidine-1- carbonyl]anilino)-2-(5-fluoro-3-pyridyl)acetate (0.1 g, 209.81 umol, 13.28% yield, 92% purity) as a white solid. MS (ESI) m/z 439.2 [M+H] ⁺ . Step 4: 2-((S)-N-(4-(tert-butyl)phenyl)-2-cyanopyrrolidine-1-carboxa mido)-2-(5- fluoropyridin-3-yl)acetic acid [000157] To a solution of methyl 2-(4-tert-butyl-N-[(2S)-2-cyanopyrrolidine-1- carbonyl]anilino)-2-(5-fluoro-3-pyridyl)acetate (0.05 g, 114.03 umol, 1 eq) in DCM (2 mL) was added BBr ₃ (57.13 mg, 228.05 umol, 21.97 uL, 2 eq) at -78 °C, the solution was stirred at 20 °C for 0.5 h under N2 atmosphere. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (5 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was diluted with sat. NaHCO ₃ (2 mL) and stirred for 10 min, concentrated under reduced pressure to give a residue to give the mixture of 2-(4-tert-butyl-N-[(2S)-2- cyanopyrrolidine-1-carbonyl]anilino)-2-(5-fluoro-3-pyridyl)a cetic acid (0.05 g, crude) and 2- (4-tert-butyl-N-[(2S)-2-carbamoylpyrrolidine-1-carbonyl]anil ino)-2-(5-fluoro-3- pyridyl)acetic acid (0.05 g, crude) as a white solid. Step 5: (2S)-N-(4-(tert-butyl)phenyl)-2-cyano-N-(2-((4,4-difluorocyc lohexyl)amino)-1-(5- fluoropyridin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxamide [000158] To a solution of 2-(4-tert-butyl-N-[(2S)-2-cyanopyrrolidine-1-carbonyl]anilin o)- 2-(5-fluoro-3-pyridyl)acetic acid (0.05 g, 58.90 umol, 50% purity, 1 eq) and 2-(4-tert-butyl- N-[(2S)-2-carbamoylpyrrolidine-1-carbonyl]anilino)-2-(5-fluo ro-3-pyridyl)acetic acid (0.05 g, 56.50 umol, 50% purity, 9.59e-1 eq) in ACN (2 mL) was added 4,4- difluorocyclohexanamine (7.96 mg, 58.90 umol, 1 eq), 1-methylimidazole (14.51 mg, 176.69 umol, 14.08 uL, 3 eq) and [chloro(dimethylamino)methylene]-dimethyl- ammonium;hexafluorophosphate (24.79 mg, 88.35 umol, 1.5 eq), the solution was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with EA (5 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Waters Xbridge BEH C18100*25mm*5um;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 40%-70%,10min) to give (2S)-N-(4-tert-butylphenyl)-2-cyano-N-[2- [(4,4-difluorocyclohexyl)amino]-1-(5-fluoro-3-pyridyl)-2-oxo -ethyl]pyrrolidine-1- carboxamide (1.21 mg, 2.10 umol, 11.75% yield, 94% purity) as a white solid. MS (ESI) m/z 542.2 [M+H] ⁺ . [000159] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.33 (dd, J = 2.6, 13.8 Hz, 1H), 8.27 - 8.15 (m, 1H), 7.62 - 7.45 (m, 1H), 7.40 - 7.27 (m, 2H), 7.10 - 6.95 (m, 2H), 5.77 (d, J = 18.9 Hz, 1H), 4.65 - 4.54 (m, 1H), 3.92 - 3.68 (m, 1H), 3.05 - 2.93 (m, 1H), 2.83 - 2.64 (m, 1H), 2.15 (dd, J = 6.5, 13.3 Hz, 1H), 2.08 - 1.74 (m, 9H), 1.69 - 1.41 (m, 2H), 1.27 (d, J = 8.6 Hz, 9H). [000160] (2S)-N1-(4-tert-butylphenyl)-N1-[2-[(4,4-difluorocyclohexyl) amino]-1-(5- fluoro-3-pyridyl)-2-oxo-ethyl]pyrrolidine-1,2-dicarboxamide (1.12 mg, 1.98 umol, 11.09% yield, 99% purity) was obtained as a white solid. MS (ESI) m/z 560.2 [M+H] ⁺ . [000161] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.29 (dd, J = 2.7, 11.3 Hz, 1H), 8.16 (d, J = 10.7 Hz, 1H), 7.75 - 7.23 (m, 3H), 7.12 - 7.00 (m, 2H), 5.90 - 5.47 (m, 1H), 4.16 - 3.71 (m, 2H), 3.28 - 2.76 (m, 2H), 2.21 - 1.95 (m, 4H), 1.93 - 1.55 (m, 8H), 1.27 (d, J = 12.3 Hz, 9H). Example 3: (2S)-N-(4-(tert-butyl)phenyl)-2-cyano-N-(2-((4,4-difluorocyc lohexyl)amino)- 1-(5-fluoropyridin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxamid e (Compound 18) Step 1: methyl ((2-(benzyloxy)-1-(5-fluoropyridin-3-yl)-2-oxoethyl)(4-(tert - butyl)phenyl)carbamoyl)-L-prolinate [000162] To a solution of benzyl 2-(4-tert-butylanilino)-2-(5-fluoro-3-pyridyl)acetate (0.3 g, 764.40 umol, 1 eq) in DCM (5 mL) was added DIEA (296.37 mg, 2.29 mmol, 399.42 uL, 3 eq), then triphosgene (226.84 mg, 764.40 umol, 1 eq) in DCM (1 mL) was added drop-wise at 0 °C, the solution was stirred at 0 °C for 1 h under N ₂ . And methyl (2S)-pyrrolidine-2- carboxylate (632.99 mg, 3.82 mmol, 5 eq, HCl) and DIEA (296.38 mg, 2.29 mmol, 399.43 uL, 3 eq) in DCM (1 mL) was added, the solution was stirred at 20 °C for 12 h under N ₂ . Upon completion, the reaction mixture was diluted with sat. NaHCO ₃ (20 mL) and extracted with DCM (10 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 15/1 to 0/1) to give methyl (2S)-1- [[2-benzyloxy-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl]-(4-tert- butylphenyl)carbamoyl]pyrrolidine-2-carboxylate (0.4 g, 472.59 umol, 61.83% yield, 64.7% purity) was obtained as a yellow oil. MS (ESI) m/z 548.3 [M+H] ⁺ Step 2: methyl ((2-(benzyloxy)-1-(5-fluoropyridin-3-yl)-2-oxoethyl)(4-(tert - butyl)phenyl)carbamoyl)-L-prolinate [000163] To a solution of methyl (2S)-1-[[2-benzyloxy-1-(5-fluoro-3-pyridyl)-2-oxo- ethyl]-(4-tert-butylphenyl)carbamoyl]pyrrolidine-2-carboxyla te (0.4 g, 730.44 umol, 1 eq) in ethyl acetate (4 mL) was added Pd/C (0.4 g, 10% purity, 1.00 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give methyl ((2-(benzyloxy)-1-(5-fluoropyridin-3-yl)-2-oxoethyl)(4-(tert - butyl)phenyl)carbamoyl)-L-prolinate (370 mg, crude) and used directly next step. MS (ESI) m/z 458.2 [M+H] ⁺ Step 3: methyl ((4-(tert-butyl)phenyl)(2-((4,4-difluorocyclohexyl)amino)-1- (5-fluoropyridin- 3-yl)-2-oxoethyl)carbamoyl)-L-prolinate [000164] To a solution of 2-(4-tert-butyl-N-[(2S)-2-methoxycarbonylpyrrolidine-1- carbonyl]anilino)-2-(5-fluoro-3-pyridyl)acetic acid (370 mg, 808.75 umol, 1 eq) and 4,4- difluorocyclohexanamine (109.31 mg, 808.75 umol, 1 eq) in ACN (4 mL) was added 1- methylimidazole (132.80 mg, 1.62 mmol, 128.94 uL, 2 eq) and [chloro(dimethylamino)methylene]-dimethyl-ammonium;hexafluor ophosphate (453.84 mg, 1.62 mmol, 2 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (6 mL * 2). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 20/1 to 1/1) to give methyl (2S)-1- [(4-tert-butylphenyl)-[2-[(4,4-difluorocyclohexyl)amino]-1-( 5-fluoro-3-pyridyl)-2-oxo- ethyl]carbamoyl]pyrrolidine-2-carboxylate (0.3 g, 325.77 umol, 40.28% yield, 62.4% purity) was obtained as a yellow oil. MS (ESI) m/z 575.3 [M+H] ⁺ Step 4: (2S)-N1-(4-(tert-butyl)phenyl)-N1-(2-((4,4-difluorocyclohexy l)amino)-1-(5- fluoropyridin-3-yl)-2-oxoethyl)pyrrolidine-1,2-dicarboxamide [000165] To a solution of methyl (2S)-1-[(4-tert-butylphenyl)-[2-[(4,4- difluorocyclohexyl)amino]-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl ]carbamoyl]pyrrolidine-2- carboxylate (300 mg, 522.07 umol, 1 eq) was added NH ₃ .MeOH (7 M, 7.5 mL, 100.56 eq). The mixture was stirred at 60 °C for 48 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent. Then the mixture was dissolved in DCM (5 mL) and concentrated under reduced pressure for two times to give (2S)-N1-(4-tert- butylphenyl)-N1-[2-[(4,4-difluorocyclohexyl)amino]-1-(5-fluo ro-3-pyridyl)-2-oxo- ethyl]pyrrolidine-1,2-dicarboxamide (250 mg, 260.59 umol, 71.8% yield, 70% purity) and used directly next step. MS (ESI) m/z 560.2 [M+H] ⁺ Step 5: (2S)-N-(4-(tert-butyl)phenyl)-2-cyano-N-(2-((4,4-difluorocyc lohexyl)amino)-1-(5- fluoropyridin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxamide [000166] To a solution of (2S)-N1-(4-tert-butylphenyl)-N1-[2-[(4,4- difluorocyclohexyl)amino]-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl ]pyrrolidine-1,2-dicarboxamide (240 mg, 428.86 umol, 1 eq) in DCM (7 mL) was added burgess reagent (306.60 mg, 1.29 mmol, 3 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was quenched by H ₂ O (0.5 mL) at 20 °C, and then the mixture was dried with N ₂ . The crude product was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40 mm * 10 um; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B%: 45% - 75%, 8min) to give (2S)-N-(4-tert-butylphenyl)-2-cyano-N-[2-[(4,4-difluorocyclo hexyl)amino]-1-(5-fluoro-3- pyridyl)-2-oxo-ethyl]pyrrolidine-1-carboxamide (100 mg, 184.64 umol, 43.05% yield) as a white solid. Step 6: (2S)-N-(4-(tert-butyl)phenyl)-2-cyano-N-(2-((4,4-difluorocyc lohexyl)amino)-1-(5- fluoropyridin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxamide [000167] (2S)-N-(4-(tert-butyl)phenyl)-2-cyano-N-(2-((4,4-difluorocyc lohexyl)amino)-1- (5-fluoropyridin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxamide (100 mg) was purified by chiral separation (column: REGIS(S,S)WHELK-O1(250mm * 25mm, 10 um); mobile phase: [0.1% NH ₃ H ₂ O IPA];B%: 38%-38%, 4min) to give (2S)-N-(4-(tert-butyl)phenyl)-2-cyano-N-(2- ((4,4-difluorocyclohexyl)amino)-1-(5-fluoropyridin-3-yl)-2-o xoethyl)pyrrolidine-1- carboxamide (Isomer 1) (20.8 mg, 38.40 umol, 20.80% yield, 100% purity) as a white solid. MS (ESI) m/z 542.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 8.40 (d, J =2.6 Hz, 1H), 8.22 - 8.17 (m, 2H), 7.38 - 7.31 (m, 1H), 7.27 (d, J =8.3 Hz, 2H), 6.97 (d, J =8.3 Hz, 2H), 5.79 (s, 1H), 4.68 (dd, J =5.4, 7.1 Hz, 1H), 3.77 (br d, J =5.0 Hz, 1H), 2.84 - 2.75 (m, 1H), 2.69 - 2.59 (m, 1H), 2.05 - 1.86 (m, 6H), 1.78 - 1.70 (m, 4H), 1.54 - 1.36 (m, 2H), 1.21 (s, 9H). [000168] (2S)-N-(4-(tert-butyl)phenyl)-2-cyano-N-(2-((4,4-difluorocyc lohexyl)amino)-1- (5-fluoropyridin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxamide (Isomer 2) (12.3 mg, 22.71 umol, 12.30% yield, 100% purity) was obtained as a white solid. MS (ESI) m/z 542.2 [M+H]+. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 8.43 (d, J =2.6 Hz, 1H), 8.27 (s, 1H), 8.12 (d, J =7.5 Hz, 1H), 7.52 (br d, J =10.1 Hz, 1H), 7.31 (d, J =8.6 Hz, 2H), 7.04 (d, J =8.6 Hz, 2H), 5.76 (s, 1H), 4.61 (t, J =6.9 Hz, 1H), 3.64 (br s, 1H), 3.05 - 2.96 (m, 1H), 2.46 - 2.41 (m, 1H), 2.14 - 1.59 (m, 10H), 1.54 - 1.36 (m, 2H), 1.23 (s, 9H). Example 4: (2R)-N-(4-(tert-butyl)phenyl)-2-cyano-N-(2-((4,4-difluorocyc lohexyl)amino)- 1-(5-fluoropyridin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxamid e (Compound 19) Step 1: 2-((4-(tert-butyl)phenyl)amino)-2-(5-fluoropyridin-3-yl)acet onitrile [000169] To a mixture of 4-tert-butylaniline (5 g, 33.50 mmol, 5.29 mL, 1 eq) and 5- fluoropyridine-3-carbaldehyde (4.19 g, 33.50 mmol, 1 eq) in DCM (70 mL) was added PdCl ₂ (1.19 g, 6.70 mmol, 0.2 eq) and Na ₂ SO ₄ (9.52 g, 67.01 mmol, 6.80 mL, 2 eq) at 0 °C, the solution was stirred at 0 °C for 0.5 h, then TMSCN (6.65 g, 67.01 mmol, 8.38 mL, 2 eq) was added drop-wise, the solution was stirred at 40 °C for 2.5 h under N ₂ atmosphere. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 20/1 to 1/1) to give 2-(4-tert-butylanilino)-2-(5-fluoro-3-pyridyl)acetonitrile (5 g, 15.88 mmol, 47.40% yield, 90% purity) as a white solid. ¹ H NMR (400 MHz, MeOD-d4) δ = 8.66 (s, 1H), 8.52 (d, J = 2.6 Hz, 1H), 7.86 (br d, J = 9.3 Hz, 1H), 7.34 - 7.19 (m, 2H), 6.91 - 6.68 (m, 2H), 5.93 (s, 1H), 1.28 (s, 9H). Step 2: methyl 2-((4-(tert-butyl)phenyl)amino)-2-(5-fluoropyridin-3-yl)acet ate [000170] A mixture of 2-(4-tert-butylanilino)-2-(5-fluoro-3-pyridyl)acetonitrile (5 g, 17.65 mmol, 1 eq) in HCl/MeOH (4M, 70 mL) was stirred at 50 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure and washed with DCM (30 mL * 3) and concentrated in vacuo to give methyl 2-(4-tert-butylanilino)-2-(5-fluoro-3- pyridyl)acetate (5 g, crude, HCl) as a yellow solid. MS (ESI) m/z 317.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.66 (s, 1H), 8.61 (d, J = 2.8 Hz, 1H), 8.01 - 7.93 (m, 1H), 7.10 (d, J = 8.6 Hz, 2H), 6.65 (d, J = 8.8 Hz, 2H), 5.52 (s, 1H), 3.67 (s, 3H), 1.18 (s, 9H). Step 3: 2-((4-(tert-butyl)phenyl)amino)-2-(5-fluoropyridin-3-yl)acet ic acid [000171] To a mixture of methyl 2-(4-tert-butylanilino)-2-(5-fluoro-3-pyridyl)acetate (2 g, 6.32 mmol, 1 eq) in THF (20 mL) and H ₂ O (7 mL) was added LiOH.H ₂ O (397.89 mg, 9.48 mmol, 1.5 eq), the solution was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was acide with HCl (1M) to adjust pH=4, and then diluted with water (50 mL) and extracted with EA (20 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 2-(4-tert-butylanilino)-2-(5-fluoro-3- pyridyl)acetic acid (1.9 g, crude) as a yellow solid. Step 4: benzyl 2-((4-(tert-butyl)phenyl)amino)-2-(5-fluoropyridin-3-yl)acet ate [000172] To a mixture of 2-(4-tert-butylanilino)-2-(5-fluoro-3-pyridyl)acetic acid (1.5 g, 4.96 mmol, 1 eq) and phenylmethanol (3.22 g, 29.77 mmol, 3.10 mL, 6 eq) in DCM (20 mL) was added DMAP (1.21 g, 9.92 mmol, 2 eq) and DCC (2.05 g, 9.92 mmol, 2.01 mL, 2 eq). The resulting solution was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with EA (10 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 30/1 to 10/1) and re-purified by prep-HPLC(column: Waters Xbridge C18 150*50mm* 10um;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 65%-95%,10min) to give benzyl 2-(4-tert-butylanilino)-2-(5-fluoro-3-pyridyl)acetate (0.8 g, 1.94 mmol, 39.03% yield, 95% purity) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.70 - 8.60 (m, 1H), 8.53 (d, J = 2.7 Hz, 1H), 7.90 - 7.79 (m, 1H), 7.42 - 7.27 (m, 3H), 7.26 - 7.15 (m, 2H), 7.09 (d, J = 8.7 Hz, 2H), 6.65 (d, J = 8.8 Hz, 2H), 6.39 (d, J = 9.2 Hz, 1H), 5.55 (d, J = 9.0 Hz, 1H), 5.17 (d, J = 1.5 Hz, 2H), 1.19 (s, 9H). Step 5: (2R)-methyl 1-((2-(benzyloxy)-1-(5-fluoropyridin-3-yl)-2-oxoethyl)(4-(te rt- butyl)phenyl)carbamoyl)pyrrolidine-2-carboxylate [000173] To a solution of benzyl 2-(4-tert-butylanilino)-2-(5-fluoro-3-pyridyl)acetate (0.3 g, 764.40 umol, 1 eq) in DCM (5 mL) was added DIEA (296.37 mg, 2.29 mmol, 399.42 uL, 3 eq), then triphosgene (226.84 mg, 764.40 umol, 1 eq) in DCM (1 mL) was added drop-wise at 0 °C, and then the solution was stirred at 0 °C for 1 h under N ₂ atmosphere. Then methyl (2R)-pyrrolidine-2-carboxylate (632.99 mg, 3.82 mmol, 5 eq, HCl) and DIEA (296.37 mg, 2.29 mmol, 399.42 uL, 3 eq) in DCM (1 mL) was added at 0 °C, and the solution was stirred at 20 °C for 12 h under N ₂ atmosphere. Upon completion, the reaction mixture was diluted with sat. NaHCO ₃ (20 mL) and extracted with DCM (10 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 10/1 to 2/1) to give methyl (2R)-1-[[2-benzyloxy-1-(5-fluoro-3-pyridyl)-2-oxo- ethyl]-(4-tert-butylphenyl)carbamoyl]pyrrolidine-2-carboxyla te (0.22 g, 381.65 umol, 49.93% yield, 95% purity) as a yellow oil. MS (ESI) m/z 548.2 [M+H] ⁺ . Step 6: 2-((R)-N-(4-(tert-butyl)phenyl)-2-(methoxycarbonyl)pyrrolidi ne-1-carboxamido)-2- (5-fluoropyridin-3-yl)acetic acid [000174] To a solution of methyl (2R)-1-[[2-benzyloxy-1-(5-fluoro-3-pyridyl)-2-oxo- ethyl]-(4-tert-butylphenyl)carbamoyl]pyrrolidine-2-carboxyla te (0.2 g, 365.22 umol, 1 eq) in EtOAc (3 mL) was added Pd/C (365.22 umol, 10% purity, 1 eq), the solution was stirred at 20 °C for 1 h under H ₂ (737.74 ug, 365.22 umol, 1 eq) at 15 Psi. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give 2-(4-tert-butyl- N-[(2R)-2-methoxycarbonylpyrrolidine-1-carbonyl]anilino)-2-( 5-fluoro-3-pyridyl)acetic acid (0.16 g, crude) as a yellow oil. MS (ESI) m/z 458.2 [M+H] ⁺ . Step 7: 2-((R)-N-(4-(tert-butyl)phenyl)-2-(methoxycarbonyl)pyrrolidi ne-1-carboxamido)-2- (5-fluoropyridin-3-yl)acetic acid [000175] A solution of 2-(4-tert-butyl-N-[(2R)-2-methoxycarbonylpyrrolidine-1- carbonyl]anilino)-2-(5-fluoro-3-pyridyl)acetic acid (0.16 g, 349.73 umol, 1 eq) and 4,4- difluorocyclohexanamine (47.27 mg, 349.73 umol, 1 eq) in ACN (3 mL) was added 1- methylimidazole (57.43 mg, 699.46 umol, 55.75 uL, 2 eq) and [chloro(dimethylamino)methylene]-dimethyl-ammonium;hexafluor ophosphate (196.25 mg, 699.46 umol, 2 eq) was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with EA (5 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 20/1 to 1/1) to give methyl (2R)-1-[(4-tert-butylphenyl)-[2-[(4,4-difluorocyclohexyl)ami no]- 1-(5-fluoro-3-pyridyl)-2-oxo-ethyl]carbamoyl]pyrrolidine-2-c arboxylate (0.2 g, 295.84 umol, 84.59% yield, 85% purity) as a yellow oil. MS (ESI) m/z 575.4 [M+H] ⁺ . Step 8: (2R)-methyl 1-((4-(tert-butyl)phenyl)(2-((4,4-difluorocyclohexyl)amino)- 1-(5- fluoropyridin-3-yl)-2-oxoethyl)carbamoyl)pyrrolidine-2-carbo xylate [000176] A solution of methyl (2R)-1-[(4-tert-butylphenyl)-[2-[(4,4- difluorocyclohexyl)amino]-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl ]carbamoyl]pyrrolidine-2- carboxylate (0.2 g, 348.05 umol, 1 eq) in NH ₃ .MeOH (7M, 4 mL, 80.45 eq) was stirred at 50 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure and washed with DCM (3 mL * 3) and concentrated under reduced pressure to give (2R)-N1-(4-tert-butylphenyl)-N1-[2-[(4,4-difluorocyclohexyl) amino]-1-(5-fluoro-3-pyridyl)- 2-oxo-ethyl]pyrrolidine-1,2-dicarboxamide (0.2 g, crude) as a yellow solid. MS (ESI) m/z 560.3 [M+H] ⁺ . Step 9: (2R)-N1-(4-(tert-butyl)phenyl)-N1-(2-((4,4-difluorocyclohexy l)amino)-1-(5- fluoropyridin-3-yl)-2-oxoethyl)pyrrolidine-1,2-dicarboxamide [000177] To a solution of (2R)-N1-(4-tert-butylphenyl)-N1-[2-[(4,4- difluorocyclohexyl)amino]-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl ]pyrrolidine-1,2-dicarboxamide (0.16 g, 285.91 umol, 1 eq) in DCM (3 mL) was added burgess reagent (204.40 mg, 857.72 umol, 3 eq), and then the solution was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was quenched by addition water (0.5 mL) at 20 °C, and then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [water(10mM NH ₄ HCO ₃ )- ACN];B%: 45%-75%,8min) to give (2R)-N-(4-tert-butylphenyl)-2-cyano-N-[2-[(4,4- difluorocyclohexyl)amino]-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl ]pyrrolidine-1-carboxamide (0.05 g, 87.70 umol, 30.67% yield, 95% purity) as a yellow solid. MS (ESI) m/z 542.3 [M+H] ⁺ . Step 10: (2R)-N-(4-(tert-butyl)phenyl)-2-cyano-N-(2-((4,4-difluorocyc lohexyl)amino)-1-(5- fluoropyridin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxamide [000178] (2R)-N-(4-tert-butylphenyl)-2-cyano-N-[2-[(4,4-difluorocyclo hexyl)amino]-1-(5- fluoro-3-pyridyl)-2-oxo-ethyl]pyrrolidine-1-carboxamide (0.05 g, 92.32 umol, 1 eq) was separated by SFC (column: DAICEL CHIRALCEL OD(250mm*30mm,10um);mobile phase: [Neu-ETOH];B%: 25%-25%,12min) to give (2R)-N-(4-tert-butylphenyl)-2-cyano-N-[2-[(4,4- difluorocyclohexyl)amino]-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl ]pyrrolidine-1-carboxamide (Isomer 1) (18.29 mg, 33.77 umol, 36.58% yield, 100% purity) as a white solid. MS (ESI) m/z 542.2 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.31 (d, J = 2.6 Hz, 1H), 8.19 (s, 1H), 7.48 (br d, J = 9.6 Hz, 1H), 7.31 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 5.80 (s, 1H), 4.63 (dd, J = 5.8, 7.3 Hz, 1H), 3.86 (br s, 1H), 3.00 (br d, J = 9.9 Hz, 1H), 2.68 (br d, J = 10.0 Hz, 1H), 2.23 - 2.12 (m, 1H), 2.11 - 1.90 (m, 5H), 1.90 - 1.76 (m, 4H), 1.69 - 1.46 (m, 2H), 1.34 - 1.20 (m, 9H). [000179] (2R)-N-(4-tert-butylphenyl)-2-cyano-N-[2-[(4,4-difluorocyclo hexyl)amino]-1-(5- fluoro-3-pyridyl)-2-oxo-ethyl]pyrrolidine-1-carboxamide (Isomer 2) (13.18 mg, 24.34 umol, 26.36% yield, 100% purity) was obtained as a white solid. MS (ESI) m/z 542.2 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.34 (d, J = 2.6 Hz, 1H), 8.25 (s, 1H), 7.63 - 7.52 (m, 1H), 7.35 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 5.75 (s, 1H), 4.56 (dd, J = 5.5, 7.3 Hz, 1H), 3.77 (br s, 1H), 3.05 - 2.93 (m, 1H), 2.87 - 2.73 (m, 1H), 2.15 (br dd, J = 7.1, 12.9 Hz, 1H), 2.06 - 1.93 (m, 3H), 1.92 - 1.72 (m, 6H), 1.56 - 1.42 (m, 2H), 1.28 (s, 9H). Example 5: N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-2-(4-methox y-1H-indole-2- carbonyl)-2-aza-5-silaspiro[4.4]nonane-3-carboxamide (Compound 20)

Step 1: methyl 1-[[2-benzyloxy-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl]-(4-tert- butylphenyl)carbamoyl]azetidine-2-carboxylate [000180] A solution of benzyl 2-(4-tert-butylanilino)-2-(5-fluoro-3-pyridyl)acetate (300 mg, 764.40 umol, 1 eq) and DIEA (296.37 mg, 2.29 mmol, 399.42 uL, 3 eq) in DCM (5 mL) was cooled to 0 °C and triphosgene (680.51 mg, 2.29 mmol, 3 eq) in DCM (2 mL) was added drop-wise at 0 °C, the solution was stirred at 0 °C for 1 h under N ₂ . And methyl azetidine-2- carboxylate (579.38 mg, 3.82 mmol, 5 eq, HCl) and DIEA (296.37 mg, 2.29 mmol, 399.42 uL, 3 eq) in DCM (1 mL) was added, the solution was stirred at 20 °C for 13 h under N ₂ . Upon completion, the reaction mixture was diluted with NaHCO ₃ (30 mL) and extracted with DCM (10 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column (SiO ₂ , Petroleum ether/Ethyl acetate = 5/1~3/1) to get product methyl 1-[[2-benzyloxy-1-(5- fluoro-3-pyridyl)-2-oxo-ethyl]-(4-tert-butylphenyl)carbamoyl ]azetidine-2-carboxylate (420 mg, 629.70 umol, 82.38% yield, 80% purity) as yellow oil. MS (ESI) m/z 534.3 [M+H] ⁺ . Step 2: 2-(4-tert-butyl-N-(2-methoxycarbonylazetidine-1-carbonyl)ani lino)-2-(5-fluoro-3- pyridyl)acetic acid [000181] To a solution of methyl 1-[[2-benzyloxy-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl]-(4- tert-butylphenyl)carbamoyl]azetidine-2-carboxylate (410 mg, 768.38 umol, 1 eq) in EA (6 mL) was added Pd/C (906.69 mg, 768.38 umol, 10% purity, 1 eq). The mixture was stirred under H ₂ (15 Psi) at 20 °C for 1 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to get the product 2-(4-tert-butyl-N-(2- methoxycarbonylazetidine-1-carbonyl)anilino)-2-(5-fluoro-3-p yridyl)acetic acid (310 mg, crude) as yellow oil. MS (ESI) m/z 444.2 [M+H] ⁺ . Step 3: methyl 1-[(4-tert-butylphenyl)-[2-[(4,4-difluorocyclohexyl)amino]-1 -(5-fluoro-3- pyridyl)-2-oxo-ethyl]carbamoyl]azetidine-2-carboxylate [000182] A mixture of 2-(4-tert-butyl-N-(2-methoxycarbonylazetidine-1- carbonyl)anilino)-2-(5-fluoro-3-pyridyl)acetic acid (260 mg, 586.29 umol, 1 eq) and 4,4- difluorocyclohexanamine (158.48 mg, 1.17 mmol, 2 eq) in DCM (8 mL) was added TEA (355.96 mg, 3.52 mmol, 489.63 uL, 6 eq) and T3P (932.73 mg, 1.47 mmol, 871.71 uL, 50% purity, 2.5 eq), the mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (25 mL) and extracted with DCM (10 mL * 5). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure and was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 9/1 to 5/1 to 4/1 to 3/1) to give methyl 1-[(4-tert-butylphenyl)-[2-[(4,4- difluorocyclohexyl)amino]-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl ]carbamoyl]azetidine-2- carboxylate (0.26 g, 431.32 umol, 73.57% yield, 93% purity) as white solid. MS (ESI) m/z 561.3 [M+H] ⁺ Step 4: N1-(4-tert-butylphenyl)-N1-[2-[(4,4-difluorocyclohexyl)amino ]-1-(5-fluoro-3- pyridyl)-2-oxo-ethyl]azetidine-1,2-dicarboxamide [000183] The methyl 1-[(4-tert-butylphenyl)-[2-[(4,4-difluorocyclohexyl)amino]-1 -(5- fluoro-3-pyridyl)-2-oxo-ethyl]carbamoyl]azetidine-2-carboxyl ate (240 mg, 428.11 umol, 1 eq) in NH ₃ /MeOH (7M, 4 mL) was stirred at 30 °C for 20 h. Upon completion, the reaction was concentrated under pressure reduced to give crude product N1-(4-tert-butylphenyl)-N1- [2-[(4,4-difluorocyclohexyl)amino]-1-(5-fluoro-3-pyridyl)-2- oxo-ethyl]azetidine-1,2- dicarboxamide (198 mg, crude) as yellow oil. MS (ESI) m/z 546.3 [M+H] ⁺ Step 5: N-(4-tert-butylphenyl)-2-cyano-N-[2-[(4,4-difluorocyclohexyl )amino]-1-(5-fluoro-3- pyridyl)-2-oxo-ethyl]azetidine-1-carboxamide [000184] To a solution of N1-(4-tert-butylphenyl)-N1-[2-[(4,4-difluorocyclohexyl)amino ]- 1-(5-fluoro-3-pyridyl)-2-oxo-ethyl]azetidine-1,2-dicarboxami de (190 mg, 348.24 umol, 1 eq) in DCM (5 mL) was added burgess reagent (248.97 mg, 1.04 mmol, 3 eq), the mixture was stirred at 30 °C for 1 h. Upon completion, the mixture were quenched with water (0.5 mL) and blow-dried with N ₂ and was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875*30mm*3um;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 35%-50%,10min) to give the product N-(4-tert-butylphenyl)-2-cyano-N-[2-[(4,4-difluorocyclohexyl )amino]-1- (5-fluoro-3-pyridyl)-2-oxo-ethyl]azetidine-1-carboxamide (60 mg, 113.73 umol, 20.33% yield, 100% purity) as white solid. MS (ESI) m/z 528.2 [M+H] ⁺ Step 6: N-(4-tert-butylphenyl)-2-cyano-N-[2-[(4,4-difluorocyclohexyl )amino]-1-(5-fluoro-3- pyridyl)-2-oxo-ethyl]azetidine-1-carboxamide [000185] The N-(4-tert-butylphenyl)-2-cyano-N-[2-[(4,4-difluorocyclohexyl )amino]-1-(5- fluoro-3-pyridyl)-2-oxo-ethyl]azetidine-1-carboxamide (60 mg, 113.73 umol, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); mobile phase: [Neu-ETOH]; B%: 25% - 25%, 25 min) to get the product N-(4-tert-butylphenyl)-2- cyano-N-[2-[(4,4-difluorocyclohexyl)amino]-1-(5-fluoro-3-pyr idyl)-2-oxo-ethyl]azetidine-1- carboxamide_(Isomer 1) (11 mg, 20.85 umol, 18.33% yield, 100% purity) as white solid. MS (ESI) m/z 528.3 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.34 (d, J = 2.9 Hz, 1H), 8.23 (s, 1H), 7.32 (d, J = 8.8 Hz, 3H), 7.14 - 7.02 (m, 2H), 5.85 (s, 1H), 4.78 - 4.68 (m, 1H), 3.80 (br t, J = 10.9 Hz, 1H), 3.51 - 3.41 (m, 1H), 2.94 - 2.83 (m, 1H), 2.45 - 2.32 (m, 1H), 2.29 - 2.19 (m, 1H), 2.10 - 1.74 (m, 6H), 1.61 - 1.41 (m, 2H), 1.27 (s, 9H). [000186] N-(4-tert-butylphenyl)-2-cyano-N-[2-[(4,4-difluorocyclohexyl )amino]-1-(5- fluoro-3-pyridyl)-2-oxo-ethyl]azetidine-1-carboxamide (Isomer 2) (13 mg, 24.64 umol, 21.67% yield, 100% purity) was obatined as white solid. MS (ESI) m/z 528.3 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.29 - 8.21 (m, 1H), 8.20 - 8.14 (m, 1H), 7.39 - 7.25 (m, 3H), 7.18 - 7.09 (m, 2H), 6.11 - 6.07 (m, 1H), 4.85 - 4.79 (m, 1H), 3.98 - 3.86 (m, 1H), 3.51 - 3.41 (m, 1H), 2.92 - 2.82 (m, 1H), 2.46 - 2.34 (m, 1H), 2.29 - 2.18 (m, 1H), 2.14 - 1.83 (m, 6H), 1.73 - 1.59 (m, 1H), 1.56 - 1.44 (m, 1H), 1.24 (s, 9H) [000187] N-(4-tert-butylphenyl)-2-cyano-N-[2-[(4,4-difluorocyclohexyl )amino]-1-(5- fluoro-3-pyridyl)-2-oxo-ethyl]azetidine-1-carboxamide (Isomer 3) (12 mg, 22.75 umol, 20.00% yield, 100% purity) was obtained as white solid. MS (ESI) m/z 528.3 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.37 - 8.32 (m, 1H), 8.25 - 8.19 (m, 1H), 7.42 - 7.26 (m, 3H), 7.14 - 7.03 (m, 2H), 5.88 - 5.82 (m, 1H), 4.78 - 4.68 (m, 1H), 3.86 - 3.74 (m, 1H), 3.53 - 3.39 (m, 1H), 2.97 - 2.84 (m, 1H), 2.45 - 2.33 (m, 1H), 2.31 - 2.18 (m, 1H), 2.08 - 1.73 (m, 6H), 1.61 - 1.38 (m, 2H), 1.27 (s, 9H) [000188] To get the product N-(4-tert-butylphenyl)-2-cyano-N-[2-[(4,4- difluorocyclohexyl)amino]-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl ]azetidine-1-carboxamide (Isomer 4) (7 mg, 13.27 umol, 11.67% yield, 100% purity) was obtained as white solid. MS (ESI) m/z 528.3 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.28 - 8.22 (m, 1H), 8.21 - 8.11 (m, 1H), 7.28 (s, 3H), 7.18 - 7.06 (m, 2H), 6.09 (s, 1H), 4.84 - 4.77 (m, 1H), 3.83 (s, 1H), 3.53 - 3.36 (m, 1H), 2.92 - 2.81 (m, 1H), 2.46 - 2.34 (m, 1H), 2.30 - 2.16 (m, 1H), 2.14 - 1.79 (m, 6H), 1.74 - 1.58 (m, 1H), 1.57 - 1.43 (m, 1H), 1.24 (s, 9H). Example 6: 2-(4-tert-butyl-N-[(2R)-2-cyanopyrrolidin-1-yl]sulfonyl-anil ino)-N-(4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide (Compound 31)

Step 1: methyl (2R)-1-chlorosulfonylpyrrolidine-2-carboxylate [000189] DMAP (2.50 g, 20.46 mmol, 1.69e-1 eq) and TEA (12.70 g, 125.51 mmol, 17.47 mL, 1.04 eq) were added to a stirred solution of methyl (2R)-pyrrolidine-2-carboxylate (20 g, 120.76 mmol, 1 eq, HCl) in dry toluene (200 mL) at 20 °C and the resulting mixture was stirred for 10 mins. The reaction mixture was cooled to -20 ° C, followed by dropwise addition of sulfuryl chloride (16.50 g, 122.25 mmol, 12.22 mL, 1.01 eq) over a period of 30 mins and the stirring was continued for 1 hr at -10 °C. and for a further 2 h at 20 °C. Upon completion, the reaction mass was diluted with DCM (300 mL) and washed with aqueous NH ₄ Cl solution (200 mL * 2). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to dryness give methyl (2R)-1-chlorosulfonylpyrrolidine-2-carboxylate (8 g, crude) as a yellow solid. Step 2: methyl (2R)-1-[(4-tert-butylphenyl)sulfamoyl]pyrrolidine-2-carboxyl ate [000190] To a solution of methyl (2R)-1-chlorosulfonylpyrrolidine-2-carboxylate (2 g, 8.78 mmol, 1 eq) in lutidine (5 mL) was added 4-tert-butylaniline (1.40 g, 9.40 mmol, 1.48 mL, 1.07 eq) in DCM (5 mL). Then the reaction was stirred at 50 °C for 16 h. Upon completion, the reaction mass was diluted with DCM (40 mL) and washed with 1 M HCl (20 mL * 3) solution. The organic layer was, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 50/1 to 1/1), give methyl (2R)-1-[(4-tert-butylphenyl)sulfamoyl]pyrrolidine-2-carboxyl ate (1.2 g, 3.52 mmol, 40.12% yield, assumed 100% purity) as a light yellow solid. Step 3: bromo-(2-tert-butoxy-2-oxo-ethyl)zinc [000191] Under N ₂ atmosphere, to a 500 mL round-bottom flask were added Zn (16.71 g, 255.57 mmol, 1.99 eq), dry THF (160 mL), and TMSCl (1.39 g, 12.82 mmol, 1.63 mL, 0.1 eq). The suspension was warmed to 75 °C, and tert-butyl 2-bromoacetate (25 g, 128.17 mmol, 18.94 mL, 1 eq) in THF (100 mL) was added dropwise to the suspension. After insoluble matter precipitated, the gray solution was stirred at 75 °C for 16 h. Upon completion, give the solution of bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (33 g, 126.71 mmol, 98.86% yield, N/A purity) as a gray liquid in 260 mL THF, the solution was used directly in next step. Step 4: tert-butyl 2-(5-fluoro-3-pyridyl)acetate [000192] To a solution of 3-bromo-5-fluoro-pyridine (10 g, 56.82 mmol, 1 eq) in THF (50 mL) was added Pd(dba) ₂ (653.47 mg, 1.14 mmol, 0.02 eq) and ditert- butyl(cyclopentyl)phosphane;iron;(2,3,4,5-tetraphenylcyclope ntyl)benzene (807.68 mg, 1.14 mmol, 0.02 eq). Bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (0.5 M, 256.00 mL, 2.25 eq) was added to the solution at 20 °C under N ₂ , and the reaction was stirred at 40 °C for 16 h under N ₂ . Upon completion, the reaction mixture was quenched by addition sat. NH ₄ Cl 300 mL at 0 °C, and then diluted with EA 100 mL and extracted with EA 300 mL (100 mL * 3). The combined organic layers were washed with sat. NaCl 300 mL (150 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 50 g SepaFlash® Silica Flash Column, Eluent of 0~100% ethyl acetate/petroleum ether gradient @ 75 mL/min). Then the reasidue was trituried with petroleum ether/ethyl acetate = 3/1, filtered. The filter cake was concentrated in vacuo to dryness give tert-butyl 2-(5-fluoro-3-pyridyl)acetate (8 g, 37.87 mmol, 66.65% yield, assumed 100% purity) as a white solid. Step 5: 2-bromo-2-(5-fluoro-3-pyridyl)acetate [000193] To a solution of tert-butyl 2-(5-fluoro-3-pyridyl)acetate (2 g, 9.47 mmol, 1 eq) in CCl ₄ (20 mL) were added NBS (3.37 g, 18.94 mmol, 2 eq) and BPO (229.35 mg, 946.83 umol, 0.10 eq). The reaction mixture was heated to 80 °C and stirred for 16 h. Upon completion, the resulting mixture was filtered and evaporated in vacuo. The residue purified by silica gel column chromatography (SiO ₂ , PE:EA = 50:1 to 3:1) give tert-butyl 2-bromo-2- (5-fluoro-3-pyridyl)acetate (0.5 g, 1.72 mmol, 18.20% yield) as a light yellow oil. Step 6: (2R)-1-[[2-tert-butoxy-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl]-( 4-tert- butylphenyl)sulfamoyl]pyrrolidine-2-carboxylate [000194] To a solution of tert-butyl 2-bromo-2-(5-fluoro-3-pyridyl)acetate (500 mg, 1.72 mmol, 1.47 eq) in MeCN (10 mL) was added methyl (2R)-1-[(4-tert- butylphenyl)sulfamoyl]pyrrolidine-2-carboxylate (400 mg, 1.17 mmol, 1 eq) and K ₂ CO ₃ (194.86 mg, 1.41 mmol, 1.2 eq). Then the reaction was stirred at 20 °C for 24 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 40 mL at 20 °C, and extracted with EtOAc 60 mL (20 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 50/1 to 1/1) give methyl (2R)-1-[[2-tert-butoxy-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl]-( 4-tert- butylphenyl)sulfamoyl]pyrrolidine-2-carboxylate (200 mg, 363.87 umol, 30.97% yield, assumed 100% purity) as a black brown oil. Step 7: 2-(4-tert-butyl-N-[(2R)-2-methoxycarbonylpyrrolidin-1-yl]sul fonyl-anilino)-2-(5- fluoro-3-pyridyl)acetic acid [000195] To a solution of methyl (2R)-1-[[2-tert-butoxy-1-(5-fluoro-3-pyridyl)-2-oxo- ethyl]-(4-tert-butylphenyl)sulfamoyl]pyrrolidine-2-carboxyla te (200 mg, 363.87 umol, 1 eq) in DCM (2 mL) was added TFA (0.4 mL). Then the reaction was stirred at 20 °C for 16 h. Upon completion, the reaction was concentrated in vacuo to dryness give the crude of 2-(4- tert-butyl-N-[(2R)-2-methoxycarbonylpyrrolidin-1-yl]sulfonyl -anilino)-2-(5-fluoro-3- pyridyl)acetic acid (145 mg, crude) as a brown oil. Step 8: methyl (2R)-1-[(4-tert-butylphenyl)-[2-[(4,4-difluorocyclohexyl)ami no]-1-(5-fluoro- 3-pyridyl)-2-oxo-ethyl]sulfamoyl]pyrrolidine-2-carboxylate [000196] To a solution of 2-(4-tert-butyl-N-[(2R)-2-methoxycarbonylpyrrolidin-1- yl]sulfonyl-anilino)-2-(5-fluoro-3-pyridyl)acetic acid (145 mg, 293.79 umol, 1 eq) in MeCN (4 mL) was added 4,4-difluorocyclohexanamine (59.56 mg, 440.69 umol, 1.5 eq), 1- methylimidazole (72.36 mg, 881.37 umol, 70.25 uL, 3 eq) and [chloro(dimethylamino)methylene]-dimethyl-ammonium;hexafluor ophosphate (164.86 mg, 587.58 umol, 2 eq). Then the reaction was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with H ₂ O 20 mL and extracted with EtOAc 30 mL (10 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , PE:EA = 1:1) give compound methyl (2R)-1-[(4-tert-butylphenyl)-[2-[(4,4-difluorocyclohexyl)ami no]- 1-(5-fluoro-3-pyridyl)-2-oxo-ethyl]sulfamoyl]pyrrolidine-2-c arboxylate (110 mg, 180.13 umol, 61.31% yield, assumed 100% purity) was obtained as a white gum. Step 9: (2R)-1-[(4-tert-butylphenyl)-[2-[(4,4-difluorocyclohexyl)ami no]-1-(5-fluoro-3- pyridyl)-2-oxo-ethyl]sulfamoyl]pyrrolidine-2-carboxylic acid [000197] To a solution of methyl (2R)-1-[(4-tert-butylphenyl)-[2-[(4,4- difluorocyclohexyl)amino]-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl ]sulfamoyl]pyrrolidine-2- carboxylate (60.00 mg, 98.25 umol, 1 eq) in dioxane (0.6 mL) was added 4 M of HCl aq. (0.6 mL). Then the reaction was stirred at 70 °C for 16 h. Upon completion, the reaction mixture was diluted with H ₂ O 10 mL and extracted with EtOAc 20 mL (10 mL * 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue of (2R)-1-[(4-tert-butylphenyl)-[2-[(4,4-difluorocyclohexyl)ami no]-1-(5- fluoro-3-pyridyl)-2-oxo-ethyl]sulfamoyl]pyrrolidine-2-carbox ylic acid (60 mg, crude) as a white solid. The crude product was used directly in next step. Step 10: (2R)-1-[(4-tert-butylphenyl)-[2-[(4,4-difluorocyclohexyl)ami no]-1-(5-fluoro-3- pyridyl)-2-oxo-ethyl]sulfamoyl]pyrrolidine-2-carboxamide [000198] To a solution of (2R)-1-[(4-tert-butylphenyl)-[2-[(4,4- difluorocyclohexyl)amino]-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl ]sulfamoyl]pyrrolidine-2- carboxylic acid (50.00 mg, 83.80 umol, 1 eq) in DCM (2.5 mL) was added ammonium;1- oxidobenzotriazole (25.50 mg, 167.60 umol, 2 eq), DIPEA (32.49 mg, 251.40 umol, 43.79 uL, 3 eq) and EDCI (32.13 mg, 167.60 umol, 2 eq). The resulting reaction mixture was stirred at 25 °C for 16 h. Upon completion, the reaction mixture was diluted with H ₂ O 40 mL and extracted with EtOAc 40 mL (20 mL * 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , PE/EtOAc = 0/1) give compound (2R)-1-[(4-tert-butylphenyl)- [2-[(4,4-difluorocyclohexyl)amino]-1-(5-fluoro-3-pyridyl)-2- oxo- ethyl]sulfamoyl]pyrrolidine-2-carboxamide (Isomer 1) (20 mg, 33.58 umol, 40.07% yield, assumed 100% purity) and (2R)-1-[(4-tert-butylphenyl)-[2-[(4,4-difluorocyclohexyl)ami no]- 1-(5-fluoro-3-pyridyl)-2-oxo-ethyl]sulfamoyl]pyrrolidine-2-c arboxamide (Isomer 2) (15 mg, 25.18 umol, 30.05% yield, assumed 100% purity) as a white solid. Step 11: 2-(4-tert-butyl-N-[(2R)-2-cyanopyrrolidin-1-yl]sulfonyl-anil ino)-N-(4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide [000199] To a solution of (2R)-1-[(4-tert-butylphenyl)-[2-[(4,4- difluorocyclohexyl)amino]-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl ]sulfamoyl]pyrrolidine-2- carboxamide (Isomer 1) (15 mg, 25.18 umol, 1 eq) in DCM (0.6 mL) was added Burgess reagenT (12.00 mg, 50.35 umol, 2.00 eq). The resulting reaction mixture was stirred at 25 °C for 16 h. Upon completion, the reaction was blow-dried by N ₂ . The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [water(NH ₄ HCO ₃ )-ACN];B%: 45%-75%,10min) to give 2-(4-tert-butyl-N-[(2R)-2- cyanopyrrolidin-1-yl]sulfonyl-anilino)-N-(4,4-difluorocycloh exyl)-2-(5-fluoro-3- pyridyl)acetamide (Isomer 1) (10 mg, 17.31 umol, 68.75% yield, 100% purity) as white solid. MS (ESI) m/z 578.1 [M+H] ⁺ . [000200] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.30 (d, J = 2.7 Hz, 1H), 8.26 (s, 1H), 7.36 (td, J = 2.2, 9.3 Hz, 1H), 7.28 (s, 4H), 5.88 (s, 1H), 4.41 - 4.31 (m, 1H), 3.85 (br t, J = 9.8 Hz, 1H), 3.55 - 3.39 (m, 2H), 2.16 - 1.75 (m, 10H), 1.71 - 1.55 (m, 1H), 1.53 - 1.38 (m, 1H), 1.24 (s, 9H). [000201] 2R)-1-[(4-tert-butylphenyl)-[2-[(4,4-difluorocyclohexyl)amin o]-1-(5-fluoro-3- pyridyl)-2-oxo-ethyl]sulfamoyl]pyrrolidine-2-carboxamide (Isomer 2) (15 mg, 25.18 umol, 1 eq) in DCM (0.6 mL) was added with Burgess reagent (12.00 mg, 50.35 umol, 2.00 eq). Then the reaction was stirred at 25 °C for 16 h. Upon completion, the reaction was blow-dried by N ₂ . The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [water(NH ₄ HCO ₃ )-ACN];B%: 45%-75%,10min) to give 2- (4-tert-butyl-N-[(2R)-2-cyanopyrrolidin-1-yl]sulfonyl-anilin o)-N-(4,4-difluorocyclohexyl)-2- (5-fluoro-3-pyridyl)acetamide (Isomer 2) (10 mg, 17.31 umol, 68.75% yield, 100% purity) as white solid. MS (ESI) m/z 578.1 [M+H] ⁺ . [000202] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.36 - 8.18 (m, 2H), 7.36 (td, J = 2.1, 9.4 Hz, 1H), 7.33 - 7.21 (m, 4H), 5.90 (s, 1H), 4.83 - 4.75 (m, 1H), 3.88 (br t, J = 9.7 Hz, 1H), 3.36 (ddd, J = 3.8, 7.7, 9.2 Hz, 1H), 3.05 (dt, J = 7.2, 8.8 Hz, 1H), 2.26 - 2.14 (m, 2H), 2.12 - 1.75 (m, 8H), 1.72 - 1.56 (m, 1H), 1.53 - 1.40 (m, 1H), 1.23 (s, 8H). Example 7: 2-[4-tert-butyl-N-[(1-cyano-1-methyl-ethyl)carbamoyl]anilino ]-N-(4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide (Compound 33) Step 1: 2-[4-tert-butyl-N-[(1-cyano-1-methyl-ethyl)carbamoyl]anilino ]-N-(4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide [000203] A solution of triphosgene (212.23 mg, 715.17 umol, 1.5 eq) in DCM (3 mL) was cooled to 0 °C, and then 2-amino-2-methyl-propanenitrile (200.53 mg, 2.38 mmol, 5 eq) and DIEA (369.71 mg, 2.86 mmol, 498.27 uL, 6 eq) in DCM (2 mL) was added drop-wise, the solution was stirred at 0 °C for 1 h. Then 2-(4-tert-butylanilino)-N-(4,4-difluorocyclohexyl)- 2-(5-fluoro-3-pyridyl)acetamide (0.2 g, 476.78 umol, 1 eq) and DIEA (184.86 mg, 1.43 mmol, 249.13 uL, 3 eq) in DCM (2 mL) was added drop-wise at 0 °C, and then the solution was stirred at 20 °C for 12 h under N2 atmosphere. Upon completion, the reaction mixture was diluted with sat. NaHCO ₃ (20 mL) and extracted with DCM (10 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*40mm*3um;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 30%-60%,8min) to give 2-[4-tert-butyl-N-[(1-cyano-1-methyl-ethyl)carbamoyl]anilino ]-N-(4,4-difluorocyclohexyl)- 2-(5-fluoro-3-pyridyl)acetamide (0.05 g, 93.47 umol, 19.60% yield, 99% purity) as a yellow solid. MS (ESI) m/z 530.2 [M+H] ⁺ . Step 2: 2-[4-tert-butyl-N-[(1-cyano-1-methyl-ethyl)carbamoyl]anilino ]-N-(4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide [000204] 2-[4-tert-butyl-N-[(1-cyano-1-methyl-ethyl)carbamoyl]anilino ]-N-(4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide (0.05 g, 94.41 umol, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [0.1%NH ₃ H ₂ O ETOH];B%: 23%-23%,6min) to give 2-[4-tert-butyl-N-[(1-cyano-1- methyl-ethyl)carbamoyl]anilino]-N-(4,4-difluorocyclohexyl)-2 -(5-fluoro-3-pyridyl)acetamide (Isomer 1) (8.7 mg, 16.10 umol, 17.05% yield, 98% purity) as a white solid. MS (ESI) m/z 530.2 [M+H] ⁺ . [000205] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.28 (d, J = 2.7 Hz, 1H), 8.21 (s, 1H), 7.38 - 7.28 (m, 3H), 7.14 (d, J = 8.6 Hz, 2H), 6.00 (s, 1H), 3.94 - 3.76 (m, 1H), 2.12 - 1.79 (m, 6H), 1.67 - 1.44 (m, 8H), 1.26 (s, 9H). [000206] 2-[4-tert-butyl-N-[(1-cyano-1-methyl-ethyl)carbamoyl]anilino ]-N-(4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide (Isomer 2) (12.93 mg, 24.17 umol, 25.60% yield, 99% purity) was obtained as a white solid. MS (ESI) m/z 530.2 [M+H] ⁺ . [000207] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.28 (d, J = 2.8 Hz, 1H), 8.21 (s, 1H), 7.37 - 7.28 (m, 3H), 7.14 (d, J = 8.6 Hz, 2H), 6.00 (s, 1H), 3.94 - 3.78 (m, 1H), 2.12 - 1.73 (m, 6H), 1.66 - 1.42 (m, 8H), 1.26 (s, 9H). Example 8: 2-[4-tert-butyl-N-[(1-cyanocyclopropyl)carbamoyl]anilino]-N- (4,4- difluorocyclohexyl)-2-[4-(trifluoromethyl)-3-pyridyl]acetami de (Compound 34) Step 1: 2-(4-tert-butylanilino)-N-(4,4-difluorocyclohexyl)-2-[4-(tri fluoromethyl)-3- pyridyl]acetamide [000208] To a solution of 4-tert-butylaniline (1000 mg, 6.70 mmol, 1.06 mL, 1 eq) in EtOAc (15 mL) was added 4-(trifluoromethyl)pyridine-3-carbaldehyde (1.17 g, 6.70 mmol, 1 eq) and T3P (2.13 g, 3.35 mmol, 1.99 mL, 50% purity, 0.5 eq), and then the solution was stirred at 20 °C for 1 h, then 1,1-difluoro-4-isocyano-cyclohexane (972.64 mg, 6.70 mmol, 1 eq) was added. The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with EA (30 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 10/1 to 7/3) to get product 2-(4-tert-butylanilino)-N-(4,4- difluorocyclohexyl)-2-[4-(trifluoromethyl)-3-pyridyl]acetami de (2.0 g, 4.26 mmol, 63.57% yield) as yellow oil. MS (ESI) m/z 470.2 [M+H] ⁺ . Step 2: 2-[4-tert-butyl-N-[(1-cyanocyclopropyl)carbamoyl]anilino]-N- (4,4- difluorocyclohexyl)-2-[4-(trifluoromethyl)-3-pyridyl]acetami de [000209] A solution of triphosgene (474.05 mg, 1.60 mmol, 1.5 eq) in DCM (5 mL) was cooled to 0 °C, and then 1-aminocyclopropanecarbonitrile (631.35 mg, 5.32 mmol, 5 eq, HCl) and DIEA (412.93 mg, 3.19 mmol, 556.50 uL, 3 eq) in DCM (2 mL) was added drop- wise, the solution was stirred at 0 °C for 1 h. Then 2-(4-tert-butylanilino)-N-(4,4- difluorocyclohexyl)-2-[4-(trifluoromethyl)-3-pyridyl]acetami de (500 mg, 1.06 mmol, 1 eq) and DIEA (412.93 mg, 3.19 mmol, 556.50 uL, 3 eq) in DCM (5 mL) was added, and the solution was stirred at 20 °C for 13 h under N ₂ . Upon completion, the reaction mixture was diluted with NaHCO ₃ (50 mL) and extracted with DCM (20 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters X bridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B%: 40% - 75%, 8 min) to get the product 2-[4-tert-butyl-N-[(1-cyanocyclopropyl)carbamoyl]anilino]-N- (4,4- difluorocyclohexyl)-2-[4-(trifluoromethyl)-3-pyridyl]acetami de (28.3 mg, 45.57 umol, 10.70% yield, 93% purity) as white solid. MS (ESI) m/z 578.1 [M+H] ⁺ . [000210] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.58 (d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 7.68 (d, J = 5.3 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H), 7.12 (br d, J = 7.6 Hz, 2H), 6.45 (s, 1H), 3.80 (br t, J = 11.1 Hz, 1H), 2.05 - 1.76 (m, 6H), 1.56 - 1.44 (m, 2H), 1.43 - 1.36 (m, 2H), 1.25 (s, 9H), 1.20 - 1.15 (m, 1H), 1.11 - 1.04 (m, 1H). Example 9: (2R)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]azetidine-1- carboxamide (Compound 58) Step 1: methyl (2R)-1-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3-pyridyl] ethyl]-(4- cyclopropyl-2-fluoro-phenyl)carbamoyl]azetidine-2-carboxylat e [000211] A solution of benzyl 2-(4-cyclopropyl-2-fluoro-anilino)-2-[4-(trifluoromethyl)-3- pyridyl]acetate (0.35 g, 787.54 umol, 1 eq) and DIEA (305.35 mg, 2.36 mmol, 411.52 uL, 3 eq) in DCE (7 mL) was cooled to 0 °C, and then triphosgene (701.11 mg, 2.36 mmol, 3 eq) in DCE (2 mL) was added drop-wise. The resulting solution was stirred at 70 °C for 13 h under N ₂ and then cooled to 0 °C. Methyl (2R)-azetidine-2-carboxylate (596.92 mg, 3.94 mmol, 5 eq, HCl) and DIEA (610.69 mg, 4.73 mmol, 823.03 uL, 6 eq) in DCE (2 mL) was added drop-wise, and then the solution was stirred at 20 °C for another 16 h under N ₂ . Upon completion, the reaction mixture was diluted with sat. NaHCO ₃ (100 mL) and extracted with DCM (50 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 10/1 to 1/1) to give methyl (2R)-1- [[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]- (4-cyclopropyl-2-fluoro- phenyl)carbamoyl]azetidine-2-carboxylate (0.12 g, 184.44 umol, 23.42% yield, 90% purity) as a yellow oil. MS (ESI) m/z 586.2 [M+H] ⁺ . Step 2: 2-(4-cyclopropyl-2-fluoro-N-[(2R)-2-methoxycarbonylazetidine -1-carbonyl]anilino)- 2-[4-(trifluoromethyl)-3-pyridyl]acetic acid [000212] To a solution of methyl (2R)-1-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]-(4-cyclopropyl-2-fluoro-phenyl)carbamoyl]azet idine-2-carboxylate (0.1 g, 170.78 umol, 1 eq) in EA (3 mL) was added Pd/C (170.78 umol, 10% purity, 1 eq), and then the solution was stirred at 20 °C for 1 h under H ₂ (344.98 ug, 170.78 umol, 1 eq) at 15 Psi. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give 2-(4-cyclopropyl-2-fluoro-N-[(2R)-2-methoxycarbonylazetidine -1-carbonyl]anilino)- 2-[4-(trifluoromethyl)-3-pyridyl]acetic acid (0.07 g, crude) as a yellow oil. MS (ESI) m/z 496.1 [M+H] ⁺ . Step 3: methyl (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4-difluorocyc lohexyl)amino]- 2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]carbamoyl]azeti dine-2-carboxylate [000213] To a solution of 2-(4-cyclopropyl-2-fluoro-N-[(2R)-2-methoxycarbonylazetidine - 1-carbonyl]anilino)-2-[4-(trifluoromethyl)-3-pyridyl]acetic acid (0.07 g, 141.29 umol, 1 eq) and 4,4-difluorocyclohexanamine (38.19 mg, 282.59 umol, 2 eq) in ACN (2 mL) was added 1-methylimidazole (23.20 mg, 282.59 umol, 22.52 uL, 2 eq) and [chloro(dimethylamino)methylene]-dimethyl-ammonium;hexafluor ophosphate (79.29 mg, 282.59 umol, 2 eq), and then the solution was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with EA (5 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , Petroleum ether/Ethyl acetate = 1/1) to give methyl (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]carbamoyl]azetidine-2-carboxylate (0.07 g, 102.85 umol, 72.79% yield, 90% purity) as a yellow oil. MS (ESI) m/z 613.1 [M+H] ⁺ . Step 4: (2R)-N1-(4-cyclopropyl-2-fluoro-phenyl)-N1-[2-[(4,4-difluoro cyclohexyl)amino]-2- oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]azetidine-1,2-dic arboxamide [000214] A solution of methyl (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]carbamoyl]azetidine-2-carboxylate (0.06 g, 97.95 umol, 1 eq) in NH ₃ .MeOH (7 M, 2 mL, 142.93 eq) was stirred at 65 °C for 13 h. Upon completion, the reaction mixture was concentrated under reduced pressure and washed with DCM (1 mL * 2) and concentrated under reduced pressure to give (2R)-N1-(4-cyclopropyl-2-fluoro-phenyl)-N1-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]azetidine-1,2- dicarboxamide (0.06 g, crude) as a yellow oil. MS (ESI) m/z 598.2 [M+H] ⁺ . Step 5: (2R)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]azetidine-1- carboxamide [000215] To a solution of (2R)-N1-(4-cyclopropyl-2-fluoro-phenyl)-N1-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]azetidine-1,2- dicarboxamide (0.06 g, 100.41 umol, 1 eq) in DCM (1 mL) was added burgess reagent (71.79 mg, 301.23 umol, 3 eq), the solution was stirred at 25 °C for 1 h. Upon completion, water (0.2 mL) was added to the reaction solution at 20 °C, and then dried by blowing N ₂ to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 35%-65%,8min) to give (2R)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4-di fluorocyclohexyl)amino]- 2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]azetidine-1-car boxamide (0.035 g, 60.39 umol, 60.15% yield) as a yellow solid. MS (ESI) m/z 580.1 [M+H] ⁺ . Step 6: (2R)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]azetidine-1- carboxamide [000216] (2R)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]azetidine-1- carboxamide (0.035 g, 60.39 umol, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm,10um);mobile phase: [Neu-ETOH];B%: 45%-45%,10min) to give (2R)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]azetidine-1- carboxamide (Isomer 1) (8.7 mg, 15.01 umol, 24.86% yield, 100% purity) as a white solid. MS (ESI) m/z 580.1 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.61 (d, J = 5.3 Hz, 1H), 8.33 (td, J = 4.7, 6.6 Hz, 1H), 7.67 (d, J = 5.3 Hz, 1H), 6.88 (br d, J = 8.2 Hz, 1H), 6.67 (br dd, J = 1.3, 3.3 Hz, 1H), 6.46 (br dd, J = 0.7, 2.2 Hz, 1H), 4.84 (dd, J = 6.2, 9.3 Hz, 1H), 4.62 (s, 1H), 3.99 - 3.78 (m, 1H), 3.50 - 3.37 (m, 1H), 3.20 - 3.02 (m, 1H), 2.56 - 2.35 (m, 1H), 2.33 - 2.18 (m, 1H), 2.13 - 1.96 (m, 2H), 1.95 - 1.78 (m, 4H), 1.72 - 1.41 (m, 2H), 1.36 - 1.27 (m, 1H), 1.04 - 0.86 (m, 2H), 0.71 - 0.60 (m, 2H). [000217] (2R)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]azetidine-1- carboxamide (Isomer 2) (9.97 mg, 17.20 umol, 28.49% yield, 100% purity) was obtained as a white solid. MS (ESI) m/z 580.1 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.68 (br d, J = 2.2 Hz, 1H), 8.61 - 8.11 (m, 1H), 7.71 (d, J = 5.3 Hz, 1H), 7.06 - 6.87 (m, 1H), 6.84 - 6.47 (m, 1H), 6.41 - 6.06 (m, 1H), 4.83 (br s, 1H), 4.61 (s, 1H), 3.89 - 3.46 (m, 2H), 3.10 - 2.65 (m, 1H), 2.49 - 2.38 (m, 1H), 2.36 - 2.25 (m, 1H), 1.96 (br s, 4H), 1.75 (br dd, J = 1.4, 11.4 Hz, 2H), 1.52 - 1.42 (m, 1H), 1.39 - 1.24 (m, 2H), 1.08 - 0.88 (m, 2H), 0.69 (br d, J = 5.3 Hz, 2H). Example 10: (2S)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]pyrrolidine-1- carboxamide (Compound 15)

Step 1: benzyl 2-(N-[(2S)-2-cyanopyrrolidine-1-carbonyl]-4-cyclopropyl-2-fl uoro-anilino)-2- [4-(trifluoromethyl)-3-pyridyl]acetate [000218] A solution of benzyl 2-(4-cyclopropyl-2-fluoro-anilino)-2-[4-(trifluoromethyl)-3- pyridyl]acetate (0.4 g, 900.05 umol, 1 eq) and DIEA (348.97 mg, 2.70 mmol, 470.31 uL, 3 eq) in DCE (5 mL) was cooled to 0 °C, and then triphosgene (801.27 mg, 2.70 mmol, 3 eq) in DCE (1 mL) was added drop-wise, the solution was stirred at 70 °C for 13 h. (2S)- pyrrolidine-2-carbonitrile (596.69 mg, 4.50 mmol, 5 eq, HCl) and DIEA (348.97 mg, 2.70 mmol, 470.31 uL, 3 eq) in DCE (1 mL) were added at 20 °C, and then the solution was stirred at 20 °C for 13 h under N ₂ atmosphere. Upon completion, the reaction mixture was diluted with sat. NaHCO ₃ (100 mL) and extracted with DCM (50 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 20/1 to 2/1) to give benzyl 2-(N-[(2S)-2-cyanopyrrolidine-1-carbonyl]- 4-cyclopropyl-2-fluoro-anilino)-2-[4-(trifluoromethyl)-3-pyr idyl]acetate (0.12 g, 169.45 umol, 18.83% yield, 80% purity) as a yellow oil. Step 2: 2-(4-cyclopropyl-2-fluoro-N-[(2S)-2-methoxycarbonylpyrrolidi ne-1- carbonyl]anilino)-2-[4-(trifluoromethyl)-3-pyridyl]acetic acid [000219] A solution of methyl (2S)-1-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]-(4-cyclopropyl-2-fluoro-phenyl)carbamoyl]pyrr olidine-2-carboxylate (120 mg, 200.14 umol, 1 eq) in EA (3 mL) was added Pd/C (236.17 mg, 200.14 umol, 10% purity, 1 eq), and then the mixture was stirred under H ₂ (15 Psi ) at 20 °C for 1 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give crude product 2-(4-cyclopropyl-2-fluoro-N-[(2S)-2-methoxycarbonylpyrrolidi ne-1- carbonyl]anilino)-2-[4-(trifluoromethyl)-3-pyridyl]acetic acid (115 mg, crude) as yellow oil. MS (ESI) m/z 510.1 [M+H] ⁺ Step 3: methyl (2S)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4-difluorocyc lohexyl)amino]- 2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]carbamoyl]pyrro lidine-2-carboxylate [000220] To a solution of 2-(4-cyclopropyl-2-fluoro-N-[(2S)-2- methoxycarbonylpyrrolidine-1-carbonyl]anilino)-2-[4-(trifluo romethyl)-3-pyridyl]acetic acid (115 mg, 225.73 umol, 1 eq) in ACN (3 mL) was added 4,4-difluorocyclohexanamine (61.02 mg, 451.47 umol, 2 eq), 1-methylimidazole (37.07 mg, 451.47 umol, 35.99 uL, 2 eq) and [chloro(dimethylamino)methylene]-dimethyl-ammonium; hexafluorophosphate (126.67 mg, 451.47 umol, 2 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction was quenched by addition H ₂ O (25 mL) and extracted with DCM (8 mL * 5). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get crude product. The rsidue was purified by prep-TLC (SiO ₂ , Petroleum ether:Ethyl acetate = 1:1) to give methyl (2S)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]carbamoyl]pyrrolidine-2-carboxylate (85 mg, 135.66 umol, 60.10% yield) as yellow oil. MS (ESI) m/z 627.2 [M+H] ⁺ Step 4: (2S)-N1-(4-cyclopropyl-2-fluoro-phenyl)-N1-[2-[(4,4-difluoro cyclohexyl)amino]-2- oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]pyrrolidine-1,2-d icarboxamide [000221] The methyl (2S)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]carbamoyl]pyrrolidine-2-carboxylate (85.00 mg, 135.66 umol, 1 eq) in NH ₃ /MeOH (3 mL) was stirred at 80 °C for 96 h. Upon completion, the reaction mixture was concentrated under pressure reduced to get the crude product (2S)-N1-(4-cyclopropyl-2- fluoro-phenyl)-N1-[2-[(4,4-difluorocyclohexyl)amino]-2-oxo-1 -[4-(trifluoromethyl)-3- pyridyl]ethyl]pyrrolidine-1,2-dicarboxamide (49 mg, crude) as yellow oil. MS (ESI) m/z 612.2 [M+H] ⁺ Step 5: (2S)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]pyrrolidine-1- carboxamide [000222] To a solution of (2S)-N1-(4-cyclopropyl-2-fluoro-phenyl)-N1-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl] pyrrolidine-1,2- dicarboxamide (49 mg, 80.12 umol, 1 eq) in DCM (3 mL) was added burgess reagent (57.28 mg, 240.36 umol, 3 eq), the mixture was stirred at 30 °C for 0.5 h. Upon completion, the mixture were quenched with water (0.1 mL) and blow-dried with N ₂ and purified by prep- HPLC (column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [water( NH ₄ HCO ₃ )-ACN];B%: 40%-80%,8min) to give the product N-[(1S)-2-amino-2-oxo- 1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-2-(4-methoxy-1H-ind ole-2-carbonyl)-2-aza-5- silaspiro[4.4]nonane-3-carboxamide (0.03 g, 41.85 umol, 50.02% yield, 96% purity) as white solid. MS (ESI) m/z 594.1 [M+H] ⁺ Step 6: (2S)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]pyrrolidine-1- carboxamide [000223] N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-2-(4-methox y-1H-indole-2- carbonyl)-2-aza-5-silaspiro[4.4]nonane-3-carboxamide was separated by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [0.1%NH ₃ H ₂ O ETOH];B%: 33%-33%,8min) to give (2S)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2- [(4,4-difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl) -3-pyridyl]ethyl]pyrrolidine-1- carboxamide (Isomer 1) (7.5 mg, 12.51 umol, 15.61% yield, 99% purity) as white solid. MS (ESI) m/z 594.1 [M+H] ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ = 8.85 (s, 1H), 8.75 (d, J = 5.0 Hz, 1H), 7.60 (d, J = 5.1 Hz, 1H), 6.82 - 6.78 (m, 1H), 6.68 (br d, J = 11.7 Hz, 1H), 6.20 (s, 1H), 4.68 (t, J = 7.2 Hz, 1H), 3.87 (br d, J = 4.5 Hz, 1H), 3.05 - 2.95 (m, 1H), 2.46 (br d, J = 9.8 Hz, 1H), 2.27 - 2.16 (m, 1H), 1.99 (br s, 3H), 1.90 - 1.78 (m, 5H), 1.65 - 1.54 (m, 5H), 1.08 - 1.00 (m, 2H), 0.74 - 0.65 (m, 2H) [000224] (2S)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]pyrrolidine-1- carboxamide (Isomer 2) (4.5 mg, 7.58 umol, 9.46% yield, 100% purity) was obtained as white solid. MS (ESI) m/z 594.1 [M+H] ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ = 8.83 (s, 1H), 8.72 (br d, J = 4.2 Hz, 1H), 7.58 (br d, J = 3.8 Hz, 1H), 6.78 (br d, J = 7.5 Hz, 1H), 6.64 (br d, J = 11.6 Hz, 1H), 6.03 (s, 1H), 4.59 - 4.53 (m, 1H), 3.90 (br s, 1H), 2.82 (br dd, J = 4.8, 6.6 Hz, 1H), 2.75 - 2.67 (m, 1H), 2.12 - 2.00 (m, 5H), 1.92 - 1.77 (m, 5H), 1.61 (br s, 4H), 1.06 - 0.99 (m, 2H), 0.70 - 0.64 (m, 2H) Example 11: (2R)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]piperidine-1- carboxamide (Compound 16) Step 1: benzyl 2-(N-[(2R)-2-cyanopyrrolidine-1-carbonyl]-4-cyclopropyl-2-fl uoro-anilino)-2- [4-(trifluoromethyl)-3-pyridyl]acetate [000225] A solution of benzyl 2-(4-cyclopropyl-2-fluoro-anilino)-2-[4-(trifluoromethyl)-3- pyridyl]acetate (0.4 g, 900.05 umol, 1 eq) and DIEA (348.97 mg, 2.70 mmol, 470.31 uL, 3 eq) in DCE (5 mL) was cooled to 0 °C, and then triphosgene (801.27 mg, 2.70 mmol, 3 eq) in DCE (1 mL) was added drop-wise, the solution was stirred at 70 °C for 13 h. Then (2R)- pyrrolidine-2-carbonitrile (596.69 mg, 4.50 mmol, 5 eq, HCl) and DIEA (348.97 mg, 2.70 mmol, 470.31 uL, 3 eq) in DCE (1 mL) was added at 20 °C, the solution was stirred at 20 °C for 13 h under N2 atmosphere. Upon completion, the reaction mixture was diluted with sat. NaHCO ₃ (100 mL) and extracted with DCM (50 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 20/1 to 2/1) to give benzyl 2-(N-[(2R)-2-cyanopyrrolidine-1-carbonyl]-4-cyclopropyl-2-fl uoro- anilino)-2-[4-(trifluoromethyl)-3-pyridyl]acetate (0.23 g, 365.37 umol, 40.59% yield, 90% purity) as a yellow oil. Step 2: 2-(4-cyclopropyl-2-fluoro-N-[(2R)-2-methoxycarbonylpyrrolidi ne-1- carbonyl]anilino)-2-[4-(trifluoromethyl)-3-pyridyl]acetic acid [000226] To a solution of methyl (2R)-1-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]-(4-cyclopropyl-2-fluoro-phenyl)carbamoyl]pyrr olidine-2-carboxylate (200 mg, 333.57 umol, 1 eq) in EA (5 mL) was added Pd/C (393.61 mg, 333.57 umol, 10% purity, 1 eq) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 Psi) at 20 °C for 1 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give crude product 2-(4-cyclopropyl- 2-fluoro-N-[(2R)-2-methoxycarbonylpyrrolidine-1-carbonyl]ani lino)-2-[4-(trifluoromethyl)- 3-pyridyl]acetic acid (217 mg, crude) as yellow oil. MS (ESI) m/z 510.2 [M+H] ⁺ Step 3: methyl (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4-difluorocyc lohexyl)amino]- 2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]carbamoyl]pyrro lidine-2-carboxylate [000227] To a solution of 2-(4-cyclopropyl-2-fluoro-N-[(2R)-2- methoxycarbonylpyrrolidine-1-carbonyl]anilino)-2-[4-(trifluo romethyl)-3-pyridyl]acetic acid (217 mg, 425.95 umol, 1 eq) in ACN (3 mL) was added 4,4-difluorocyclohexanamine (115.14 mg, 851.90 umol, 2 eq), 1-methylimidazole (69.94 mg, 851.90 umol, 67.91 uL, 2 eq) and [chloro(dimethylamino)methylene]-dimethyl-ammonium;hexafluor ophosphate (239.03 mg, 851.90 umol, 2 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction was quenched by addition H ₂ O (30 mL) and extracted with DCM (10 mL * 5), the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure and then was purified by prep-TLC (SiO ₂ , Petroleum ether:Ethyl acetate = 1:1) to get product methyl (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]carbamoyl]pyrrolidine-2-carboxylate (205 mg, 327.17 umol, 76.81% yield) as yellow oil. MS (ESI) m/z 627.3 [M+H] ⁺ Step 4: (2R)-N1-(4-cyclopropyl-2-fluoro-phenyl)-N1-[2-[(4,4-difluoro cyclohexyl)amino]-2- oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]pyrrolidine-1,2-d icarboxamide [000228] Methyl (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]carbamoyl]pyrrolidine-2-carboxylate (205 mg, 327.17 umol, 1 eq) in NH ₃ /MeOH (7 M, 3 mL) was stirred at 80 °C for 16 h. Upon completion, the reaction was concentrated under pressure reduced to get the crude product and was purified by prep-TLC (SiO ₂ , Petroleum ether:Ethyl acetate = 0:1) to give (2R)-N1-(4-cyclopropyl-2-fluoro-phenyl)- N1-[2-[(4,4-difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluorom ethyl)-3- pyridyl]ethyl]pyrrolidine-1,2-dicarboxamide (88 mg, 122.31 umol, 37.38% yield, 85% purity) as yellow oil. MS (ESI) m/z 612.2 [M+H] ⁺ Step 5: (2R)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]pyrrolidine-1- carboxamide [000229] The (2R)-N1-(4-cyclopropyl-2-fluoro-phenyl)-N1-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]pyrrolidine-1,2- dicarboxamide (88 mg, 143.89 umol, 1 eq) in DCM (5 mL) was added with burgess reagent (102.87 mg, 431.67 umol, 3 eq), and the mixture was stirred at 20 °C for 0.5 h. Upon completion, the mixture were quenched with water (0.1 mL) and blow-dried with N ₂ and was purified by prep-HPLC(column: Waters Xbridge BEH C18100*25mm*5um;mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 35%-65%,8 min) to get the product (2R)-2-cyano-N-(4- cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4-difluorocyclohexyl)a mino]-2-oxo-1-[4- (trifluoromethyl)-3-pyridyl]ethyl]pyrrolidine-1-carboxamide (51 mg, 30.57 umol, 34.73% yield, 96% purity) as white solid. MS (ESI) m/z 594.1 [M+H] ⁺ Step 6: (2R)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]pyrrolidine-1- carboxamide [000230] (2R)-N1-(4-cyclopropyl-2-fluoro-phenyl)-N1-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]pyrrolidine-1,2- dicarboxamide (51 mg, 30.57 umol, 1 eq.) was separated by SFC (column: DAICEL CHIRALPAK AD-H(250mm*30mm,5um);mobile phase: [Neu-ETOH];B%: 12%- 12%,15min) to give product (2R)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]pyrrolidine-1- carboxamide (Isomer 1) (11 mg, 18.35 umol, 12.75% yield, 99% purity) as white solid. MS (ESI) m/z 594.1 [M+H] ⁺ [000231] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.90 (br s, 1H), 8.67 (d, J = 5.2 Hz, 1H), 7.66 (d, J = 5.2 Hz, 1H), 7.27 (t, J = 8.2 Hz, 1H), 6.86 (dd, J = 1.9, 8.3 Hz, 1H), 6.73 (dd, J = 1.8, 11.9 Hz, 1H), 6.11 (s, 1H), 4.63 - 4.60 (m, 1H), 3.71 (br t, J = 10.6 Hz, 1H), 3.00 - 2.93 (m, 1H), 2.71 - 2.63 (m, 1H), 2.08 - 2.03 (m, 2H), 2.02 - 1.92 (m, 3H), 1.92 - 1.83 (m, 3H), 1.81 - 1.70 (m, 3H), 1.55 - 1.43 (m, 2H), 1.02 - 0.97 (m, 2H), 0.67 - 0.63 (m, 2H) [000232] (2R)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]pyrrolidine-1- carboxamide (Isomer 2) (13 mg, 21.90 umol, 15.22% yield, 100% purity) was obtained as white solid. MS (ESI) m/z 594.1 [M+H] ⁺ [000233] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 9.02 (br s, 1H), 8.70 (d, J = 5.2 Hz, 1H), 7.69 (d, J = 5.1 Hz, 1H), 7.43 - 7.40 (m, 1H), 7.30 (t, J = 8.2 Hz, 1H), 7.04 - 7.00 (m, 1H), 6.92 (dd, J = 1.8, 8.3 Hz, 1H), 6.81 (dd, J = 1.3, 11.7 Hz, 1H), 6.11 (s, 1H), 4.60 (t, J = 7.5 Hz, 1H), 3.60 (br t, J = 10.5 Hz, 1H), 3.24 - 3.17 (m, 1H), 2.53 - 2.46 (m, 1H), 2.30 - 2.20 (m, 1H), 2.01 - 1.89 (m, 5H), 1.88 - 1.81 (m, 2H), 1.80 - 1.70 (m, 4H), 1.55 - 1.45 (m, 2H), 1.06 - 1.00 (m, 2H), 0.71 - 0.66 (m, 2H) Example 12: (2R)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]piperidine-1- carboxamide (Compound 59)

Step 1: methyl (2R)-1-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3-pyridyl] ethyl]-(4- cyclopropyl-2-fluoro-phenyl)carbamoyl]piperidine-2-carboxyla te [000234] A solution of benzyl 2-(4-cyclopropyl-2-fluoro-anilino)-2-[4-(trifluoromethyl)-3- pyridyl]acetate (0.4 g, 900.05 umol, 1 eq) and DIEA (348.97 mg, 2.70 mmol, 470.31 uL, 3 eq) in DCE (7 mL) was cooled to 0 °C, and then triphosgene (1.07 g, 3.60 mmol, 4 eq) in DCE (3 mL) was added drop-wise. The resulting solution was stirred at 70 °C for 13 h, and then cooled to 0 °C. Methyl (2R)-piperidine-2-carboxylate (808.44 mg, 4.50 mmol, 5 eq, HCl) and DIEA (348.97 mg, 2.70 mmol, 470.31 uL, 3 eq) in DCE (3 mL) were added, and then the solution was stirred at 20 °C for 13 h under N ₂ atmosphere. Upon completion, the reaction mixture was diluted with sat. NaHCO ₃ (100 mL) and extracted with DCM (50 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=20/1 to 1/1) to give methyl (2R)-1-[[2-benzyloxy-2- oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]-(4-cyclopropyl-2 -fluoro- phenyl)carbamoyl]piperidine-2-carboxylate (0.14 g, 205.35 umol, 22.82% yield, 90% purity) as a yellow oil. Step 2: 2-(4-cyclopropyl-2-fluoro-N-[(2R)-2-methoxycarbonylpiperidin e-1- carbonyl]anilino)-2-[4-(trifluoromethyl)-3-pyridyl]acetic acid [000235] To a solution of methyl (2R)-1-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]-(4-cyclopropyl-2-fluoro-phenyl)carbamoyl]pipe ridine-2-carboxylate (130 mg, 211.87 umol, 1 eq) in EA (2 mL) was added Pd/C (250.00 mg, 211.87 umol, 10% purity, 1 eq) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 Psi) at 20 °C for 1 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give crude product 2-(4-cyclopropyl- 2-fluoro-N-[(2R)-2-methoxycarbonylpiperidine-1-carbonyl]anil ino)-2-[4-(trifluoromethyl)-3- pyridyl]acetic acid (91 mg, crude) as yellow oil. MS (ESI) m/z 524.1 [M+H] ⁺ Step 3: methyl (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4-difluorocyc lohexyl)amino]- 2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]carbamoyl]piper idine-2-carboxylate [000236] To a solution of 2-(4-cyclopropyl-2-fluoro-N-[(2R)-2- methoxycarbonylpiperidine-1-carbonyl]anilino)-2-[4-(trifluor omethyl)-3-pyridyl]acetic acid (91 mg, 173.84 umol, 1 eq) in ACN (2 mL) was added 4,4-difluorocyclohexanamine (46.99 mg, 347.68 umol, 2 eq), 1-methylimidazole (28.54 mg, 347.68 umol, 27.71 uL, 2 eq) and [chloro(dimethylamino)methylene]-dimethyl-ammonium;hexafluor ophosphate (97.55 mg, 347.68 umol, 2 eq), and then the mixture was stirred at 20 °C for 1 h. Upon completion, the reaction was quenched by addition H ₂ O (30 mL) and extracted with DCM (10 mL * 5). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure and purified by prep-TLC (SiO ₂ , Petroleum ether:Ethyl acetate = 1:1) to give the product methyl (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4-difluorocyc lohexyl)amino]- 2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]carbamoyl]piper idine-2-carboxylate (84 mg, 110.14 umol, 63.36% yield, 84% purity) as yellow oil. MS (ESI) m/z 641.3 [M+H] ⁺ Step 4: (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4-difluorocyc lohexyl)amino]-2-oxo- 1-[4-(trifluoromethyl)-3-pyridyl]ethyl]carbamoyl]piperidine- 2-carboxylic acid [000237] To a solution of methyl (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]carbamoyl]piperidine-2-carboxylate (74 mg, 115.51 umol, 1 eq) in THF (3 mL) was added LiOH.H ₂ O (14.54 mg, 346.54 umol, 3 eq) and H ₂ O (1 mL). The mixture was stirred at 20 °C for 3 h. Upon completion, the reaction mixture was acidic at pH of 1 with 1 M HCl (1.5 mL) and extracted with EA (3 mL * 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get the crude product (2S)-N1-(4-cyclopropyl-2-fluoro-phenyl)-N1-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]pyrrolidine-1,2- dicarboxamide (65 mg, crude) as white solid. MS (ESI) m/z 627.3 [M+H] ⁺ Step 5: (2R)-N1-(4-cyclopropyl-2-fluoro-phenyl)-N1-[2-[(4,4-difluoro cyclohexyl)amino]-2- oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]piperidine-1,2-di carboxamide [000238] A mixture of (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]carbamoyl]piperidine-2-carboxylic acid (65 mg, 103.74 umol, 1 eq), NH ₄ Cl (11.10 mg, 207.47 umol, 2 eq), HATU (78.89 mg, 207.47 umol, 2 eq) and DIEA (26.81 mg, 207.47 umol, 36.14 uL, 2 eq) in DMF (1 mL) was stirred at 20 °C for 3 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (25 mL) and extracted with DCM (8 mL * 5). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get crude product (2R)-N1-(4-cyclopropyl-2-fluoro-phenyl)-N1-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]piperidine-1,2- dicarboxamide (60 mg, crude) as yellow oil. MS (ESI) m/z 626.3 [M+H] ⁺ Step 6: (2R)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]piperidine-1- carboxamide [000239] To a solution of (2R)-N1-(4-cyclopropyl-2-fluoro-phenyl)-N1-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]piperidine-1,2- dicarboxamide (55 mg, 87.92 umol, 1 eq) in DCM (3 mL) was added burgess reagent (62.85 mg, 263.75 umol, 3 eq). The mixture was stirred at 20 °C for 0.5 h. Upon completion, the mixture were quenched with water (0.1 mL) and blow-dried with N ₂ and was purified by prep-HPLC (column: Waters Xbridge BEH C18100*25 mm*5 um; mobile phase: [water ( NH ₄ HCO ₃ )-ACN]; B%: 40%-75%, 10 min) to give the product (2R)-2-cyano-N-(4- cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4-difluorocyclohexyl)a mino]-2-oxo-1-[4- (trifluoromethyl)-3-pyridyl]ethyl]piperidine-1-carboxamide (33 mg, 54.31 umol, 61.78% yield) as white solid. MS (ESI) m/z 608.1 [M+H] ⁺ Step 7: (2R)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]piperidine-1- carboxamide [000240] The (2R)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]piperidine-1- carboxamide (30 mg, 49.38 umol, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK AD(250 mm*30 mm, 10 um); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; B%: 30%-30%, 10 min) to give (2R)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]piperidine-1- carboxamide (Isomer 1) (6 mg, 9.84 umol, 19.92% yield, 99.6% purity) as white solid. MS (ESI) m/z 608.1 [M+H] ⁺ [000241] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 9.03 (s, 1H), 8.71 (d, J = 5.1 Hz, 1H), 7.69 (d, J = 5.3 Hz, 1H), 7.22 (t, J = 8.3 Hz, 1H), 6.90 (br d, J = 8.4 Hz, 1H), 6.82 (br d, J = 12.1 Hz, 1H), 5.97 (s, 1H), 4.95 (br s, 1H), 3.72 - 3.60 (m, 2H), 2.86 (br t, J = 12.3 Hz, 1H), 1.77 (br d, J = 3.2 Hz, 6H), 1.67 - 1.47 (m, 6H), 1.37 - 1.28 (m, 3H), 1.01 (br dd, J = 1.7, 8.2 Hz, 2H), 0.68 - 0.64 (m, 2H). [000242] (2R)-2-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]piperidine-1- carboxamide (Isomer 2) (5 mg, 8.16 umol, 16.52% yield, 99.1% purity) was obtained as white solid. MS (ESI) m/z 608.1 [M+H] ⁺ [000243] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 9.03 (s, 1H), 8.70 (d, J = 5.1 Hz, 1H), 7.66 (d, J = 5.3 Hz, 1H), 7.19 (t, J = 8.3 Hz, 1H), 6.87 (dd, J = 1.9, 8.3 Hz, 1H), 6.81 (dd, J = 1.8, 12.2 Hz, 1H), 6.05 (s, 1H), 5.13 - 5.09 (m, 1H), 3.73 - 3.63 (m, 2H), 2.75 - 2.61 (m, 1H), 2.00 - 1.84 (m, 4H), 1.81 - 1.74 (m, 3H), 1.70 - 1.61 (m, 2H), 1.58 - 1.33 (m, 3H), 1.04 - 0.97 (m, 2H), 0.69 - 0.61 (m, 2H). Example 13: (3S)-3-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]morpholine-4- carboxamide (Compound 60)

Step 1: methyl (3R)-4-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3-pyridyl] ethyl]-(4- cyclopropyl-2-fluoro-phenyl)carbamoyl]morpholine-3-carboxyla te [000244] A solution of benzyl 2-(4-cyclopropyl-2-fluoro-anilino)-2-[4-(trifluoromethyl)-3- pyridyl]acetate (0.35, 787.54 umol, 1 eq) and DIEA (305.35 mg, 2.36 mmol, 411.52 uL, 3 eq) in DCE (7 mL) was cooled to 0 °C, and then triphosgene (934.81 mg, 3.15 mmol, 4 eq) in DCE (3 mL) was added drop-wise, the solution was stirred at 70 °C for 13 h. Then methyl (3R)-morpholine-3-carboxylate (715.15 mg, 3.94 mmol, 5 eq, HCl) and DIEA (305.35 mg, 2.36 mmol, 411.52 uL, 3 eq) in DCE (3 mL) was added, the solution was stirred at 70 °C for 13 h under N ₂ atmosphere. Upon completion, the reaction mixture was diluted with sat. NaHCO ₃ (100 mL) and extracted with DCM (50 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 20/1 to 1/1) to give methyl (3R)-4-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3-pyridyl] ethyl]-(4- cyclopropyl-2-fluoro-phenyl)carbamoyl]morpholine-3-carboxyla te (0.12 g, 185.19 umol, 23.52% yield, 95% purity) as a yellow oil. Step 2: 2-(4-cyclopropyl-2-fluoro-N-[(3R)-3-methoxycarbonylmorpholin e-4- carbonyl]anilino)-2-[4-(trifluoromethyl)-3-pyridyl]acetic acid [000245] To a solution of methyl (3R)-4-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]-(4-cyclopropyl-2-fluoro-phenyl)carbamoyl]morp holine-3-carboxylate (104 mg, 168.95 umol, 1 eq) in EA (1 mL) was added Pd/C (199.36 mg, 168.95 umol, 10% purity, 1 eq) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 Psi) at 20 °C for 1 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give crude product 2-(4- cyclopropyl-2-fluoro-N-[(3R)-3-methoxycarbonylmorpholine-4-c arbonyl]anilino)-2-[4- (trifluoromethyl)-3-pyridyl]acetic acid (86 mg, crude) as yellow oil. MS (ESI) m/z 526.1 [M+H] ⁺ Step 3: methyl (3R)-4-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4-difluorocyc lohexyl)amino]- 2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]carbamoyl]morph oline-3-carboxylate [000246] A mixture of 2-(4-cyclopropyl-2-fluoro-N-[(3R)-3-methoxycarbonylmorpholin e- 4-carbonyl]anilino)-2-[4-(trifluoromethyl)-3-pyridyl]acetic acid (86 mg, 163.67 umol, 1 eq), 4,4-difluorocyclohexanamine (44.24 mg, 327.34 umol, 2 eq), 1-methylimidazole (26.88 mg, 327.34 umol, 26.09 uL, 2 eq), [chloro(dimethylamino)methylene]-dimethyl- ammonium;hexafluorophosphate (91.84 mg, 327.34 umol, 2 eq) in ACN (10 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 20 °C for 1 h under N ₂ atmosphere. Upon completion, the reaction was quenched by addition H ₂ O (20 mL) and extracted with DCM (8 mL * 5). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure and was purified by prep-TLC (SiO ₂ , Petroleum ether:Ethyl acetate = 1:1) to get methyl (3R)-4-[(4-cyclopropyl-2-fluoro-phenyl)- [2-[(4,4-difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluorometh yl)-3- pyridyl]ethyl]carbamoyl]morpholine-3-carboxylate (91 mg, 109.04 umol, 66.62% yield, 77% purity) as yellow oil. MS (ESI) m/z 643.2 [M+H] ⁺ Step 4: (3R)-4-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4-difluorocyc lohexyl)amino]-2-oxo- 1-[4-(trifluoromethyl)-3-pyridyl]ethyl]carbamoyl]morpholine- 3-carboxylic acid [000247] To a solution of methyl (3R)-4-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]carbamoyl]morpholine-3-carboxylate (80 mg, 124.50 umol, 1 eq) in THF (3 mL) and H ₂ O (1 mL) were added LiOH.H ₂ O (15.67 mg, 373.49 umol, 3 eq). The mixture was stirred at 20 °C for 3 h. Upon completion, the reaction mixture was acidic at pH of 1 with 1 M HCl (2.5 mL) and extracted with EA (5 mL * 5). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get (3R)-4-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4-difluorocyc lohexyl)amino]-2-oxo-1-[4- (trifluoromethyl)-3-pyridyl]ethyl]carbamoyl]morpholine-3-car boxylic acid (75 mg, crude) as yellow oil. MS (ESI) m/z 629.1 [M+H] ⁺ Step 5: (3R)-N4-(4-cyclopropyl-2-fluoro-phenyl)-N4-[2-[(4,4-difluoro cyclohexyl)amino]-2- oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]morpholine-3,4-di carboxamide [000248] To a solution of (3R)-4-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]carbamoyl]morpholine-3-carboxylic acid (75 mg, 119.32 umol, 1 eq) in DMF (3 mL) was added NH ₄ Cl (12.76 mg, 238.64 umol, 2 eq) and HATU (90.74 mg, 238.64 umol, 2 eq), DIEA (30.84 mg, 238.64 umol, 41.57 uL, 2 eq). The mixture was stirred at 20 °C for 12 h. Upon completion, the mixture were quenched by addition H ₂ O (10 mL) and extracted with DCM (5 mL * 4). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give (3R)-N4-(4-cyclopropyl-2-fluoro-phenyl)-N4-[2- [(4,4-difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl) -3-pyridyl]ethyl]morpholine- 3,4-dicarboxamide (70 mg, crude) as yellow oil. MS (ESI) m/z 628.2 [M+H] ⁺ Step 6: (3S)-3-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]morpholine-4- carboxamide [000249] To a solution of (3R)-N4-(4-cyclopropyl-2-fluoro-phenyl)-N4-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]morpholine-3,4- dicarboxamide (65 mg, 103.57 umol, 1 eq) in DCM (5 mL) was added burgess reagent (74.05 mg, 310.72 umol, 3 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the mixture were quenched with water (0.3 mL) and blow-dried with N ₂ and was purified by prep-HPLC (column: Waters Xbridge BEH C18100*25mm*5um;mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 30%-60%, 10 min) to give (3S)-3-cyano-N-(4-cyclopropyl-2- fluoro-phenyl)-N-[2-[(4,4-difluorocyclohexyl)amino]-2-oxo-1- [4-(trifluoromethyl)-3- pyridyl]ethyl]morpholine-4-carboxamide (51 mg, 81.99 umol, 79.16% yield, 98% purity) as white solid. MS (ESI) m/z 610.2 [M+H] ⁺ Step 7: (3S)-3-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]morpholine-4- carboxamide [000250] The (3S)-3-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]morpholine-4- carboxamide (51 mg, 83.67 umol, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: [Neu-ETOH]; B%: 45%-45%, 10 min) to give (3S)-3-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]morpholine-4- carboxamide (Isomer 1) (12 mg, 19.53 umol, 23.34% yield, 99.2% purity) as a white solid. MS (ESI) m/z 610.2 [M+H] ⁺ [000251] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 9.00 (s, 1H), 8.72 (d, J = 5.1 Hz, 1H), 7.69 (d, J = 5.1 Hz, 1H), 7.21 (t, J = 8.3 Hz, 1H), 6.92 - 6.87 (m, 1H), 6.83 (dd, J = 1.7, 12.2 Hz, 1H), 6.00 (s, 1H), 4.75 (br s, 1H), 3.93 (d, J = 12.1 Hz, 1H), 3.71 - 3.62 (m, 1H), 3.61 - 3.55 (m, 1H), 3.50 - 3.43 (m, 2H), 3.14 - 3.02 (m, 1H), 2.82 (dt, J = 2.2, 11.6 Hz, 1H), 2.03 - 1.71 (m, 6H), 1.64 (br d, J = 12.3 Hz, 1H), 1.55 - 1.44 (m, 1H), 1.43 - 1.32 (m, 1H), 1.05 - 0.95 (m, 2H), 0.72 - 0.59 (m, 2H). [000252] (3S)-3-cyano-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]morpholine-4- carboxamide (Isomer 2) (7 mg, 11.44 umol, 13.67% yield, 99.6% purity) was obtained as a white solid. MS (ESI) m/z 610.2 [M+H] ⁺ [000253] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 9.02 (s, 1H), 8.70 (d, J = 5.0 Hz, 1H), 7.67 (d, J = 5.1 Hz, 1H), 7.20 (t, J = 8.3 Hz, 1H), 6.94 - 6.77 (m, 2H), 6.08 (s, 1H), 4.95 (br s, 1H), 3.87 (d, J = 12.0 Hz, 1H), 3.74 - 3.64 (m, 2H), 3.45 (br d, J = 13.4 Hz, 1H), 3.38 - 3.34 (m, 1H), 3.17 (dt, J = 2.4, 11.7 Hz, 1H), 2.92 - 2.83 (m, 1H), 2.02 - 1.72 (m, 6H), 1.68 - 1.58 (m, 1H), 1.56 - 1.45 (m, 1H), 1.44 - 1.33 (m, 1H), 1.05 - 0.95 (m, 2H), 0.71 - 0.61 (m, 2H). Example 14: (2R)-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]-2-formyl- azetidine-1-carboxamide (Compound 62) and (2R)-N-(4-cyclopropyl-2-fluoro-phenyl)- N-[2-[(4,4-difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluorome thyl)-3-pyridyl]ethyl]-2- (hydroxymethyl)azetidine-1-carboxamide (Compound 61) Step 1: benzyl 2-(N-chlorocarbonyl-4-cyclopropyl-2-fluoro-anilino)-2-[4-(tr ifluoromethyl)-3- pyridyl]acetate [000254] A solution of benzyl 2-(4-cyclopropyl-2-fluoro-anilino)-2-[4-(trifluoromethyl)-3- pyridyl]acetate (0.35 g, 787.54 umol, 1 eq) and DIEA (610.69 mg, 4.73 mmol, 823.03 uL, 6 eq) in DCE (7 mL) was cooled to 0 °C, and then triphosgene (934.81 mg, 3.15 mmol, 4 eq) in DCE (2 mL) was added drop-wise at 0 °C, the solution was stirred at 70 °C for 12 h under N ₂ atmosphere. Upon completion, the solution of benzyl 2-(N-chlorocarbonyl-4-cyclopropyl-2- fluoro-anilino)-2-[4-(trifluoromethyl)-3-pyridyl]acetate (0.4 g, crude) in DCE (7 mL) was obtained as a yellow liquid and was used to the next step directly. Step 2: methyl (2R)-1-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3-pyridyl] ethyl]-(4- cyclopropyl-2-fluoro-phenyl)carbamoyl]azetidine-2-carboxylat e [000255] A solution of benzyl 2-(N-chlorocarbonyl-4-cyclopropyl-2-fluoro-anilino)-2-[4- (trifluoromethyl)-3-pyridyl]acetate (0.4 g, 789.15 umol, 1 eq) in DCE (9 mL) was cooled to 0 °C, and then methyl (2R)-azetidine-2-carboxylate (598.14 mg, 3.95 mmol, 5 eq, HCl) and DIEA (611.94 mg, 4.73 mmol, 824.71 uL, 6 eq) in DCE (7 mL) was added drop-wise. The resulting solution was stirred at 25 °C for another 12 h under N ₂ atmosphere. Upon completion, the reaction mixture was diluted with sat. NaHCO ₃ (100 mL) and extracted with DCM (50 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 10/1 to 1/1) to give methyl (2R)-1- [[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]- (4-cyclopropyl-2-fluoro- phenyl)carbamoyl]azetidine-2-carboxylate (0.17 g, 261.30 umol, 33.11% yield, 90% purity) as a yellow oil. MS (ESI) m/z 586.2 [M+H] ⁺ . Step 3: 2-(4-cyclopropyl-2-fluoro-N-[(2R)-2-methoxycarbonylazetidine -1-carbonyl]anilino)- 2-[4-(trifluoromethyl)-3-pyridyl]acetic acid [000256] To a solution of methyl (2R)-1-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]-(4-cyclopropyl-2-fluoro-phenyl)carbamoyl]azet idine-2-carboxylate (0.17 g, 290.33 umol, 1 eq) in EA (3 mL) was aaded Pd/C (290.33 umol, 10% purity, 1 eq), and the solution was stirred at 25 °C for 1 h under H ₂ (586.46 ug, 290.33 umol, 1 eq) at 15 Psi. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give 2-(4-cyclopropyl-2-fluoro-N-[(2R)-2-methoxycarbonylazetidine -1-carbonyl]anilino)-2-[4- (trifluoromethyl)-3-pyridyl]acetic acid (0.15 g, crude) as a yellow oil. Step 4: methyl (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4-difluorocyc lohexyl)amino]- 2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]carbamoyl]azeti dine-2-carboxylate [000257] A solution of 2-(4-cyclopropyl-2-fluoro-N-[(2R)-2-methoxycarbonylazetidine -1- carbonyl]anilino)-2-[4-(trifluoromethyl)-3-pyridyl]acetic acid (0.15 g, 302.77 umol, 1 eq) in ACN (3 mL) was aaded 4,4-difluorocyclohexanamine (81.84 mg, 605.54 umol, 2 eq), 1- methylimidazole (49.72 mg, 605.54 umol, 48.27 uL, 2 eq) and [chloro(dimethylamino)methylene]-dimethyl-ammonium;hexafluor ophosphate (169.90 mg, 605.54 umol, 2 eq) was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with EA (20 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , Petroleum ether/Ethyl acetate = 1/1 to 1/1) to give methyl (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4-difluorocyc lohexyl)amino]-2- oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]carbamoyl]azetidi ne-2-carboxylate (Isomer 1) (0.07 g, 102.85 umol, 33.97% yield, 90% purity) as a yellow oil. [000258] Methyl (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]carbamoyl]azetidine-2-carboxylate (Isomer 2) (0.07 g, 102.85 umol, 33.97% yield, 90% purity) was obtained as a yellow oil. Step 5: (2R)-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4-difluorocy clohexyl)amino]-2- oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]-2-(hydroxymethyl )azetidine-1-carboxamide [000259] To a solution of methyl (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]carbamoyl]azetidine-2-carboxylate (Isomer 1) (0.07 g, 114.27 umol, 1 eq) in EtOH (3 mL) was aaded CaCl ₂ (12.68 mg, 114.27 umol, 1 eq) and the solution was cooled to 0 °C and NaBH4 (21.61 mg, 571.37 umol, 5 eq) was added, the solution was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with sat. NH ₄ Cl (20 mL) and extracted with EA (10 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , Petroleum ether/Ethyl acetate = 0/1) and re-purified by prep-HPLC (column: Phenomenex Luna C1875*30mm*3um;mobile phase: [water(FA)-ACN];B%: 40%-70%,8min) to give (2R)-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]-2- (hydroxymethyl)azetidine-1-carboxamide (Isomer 1) (0.03 g, 51.32 umol, 44.91% yield, 100% purity) as a white solid. MS (ESI) m/z 585.0 [M+H] ⁺ . [000260] ¹ H NMR (400 MHz, CDCl ₃ -d) δ = 8.66 (d, J = 5.0 Hz, 1H), 8.59 (s, 1H), 7.52 (d, J = 5.1 Hz, 1H), 7.02 (br dd, J = 2.4, 10.0 Hz, 1H), 6.73 (br d, J = 8.2 Hz, 1H), 6.59 (br d, J = 11.5 Hz, 1H), 6.52 - 6.41 (m, 1H), 6.28 (s, 1H), 4.73 - 4.59 (m, 1H), 4.56 - 4.42 (m, 1H), 4.01 - 3.85 (m, 1H), 3.80 - 3.72 (m, 1H), 3.71 - 3.61 (m, 1H), 3.11 (dt, J = 5.6, 8.8 Hz, 1H), 3.06 - 2.96 (m, 1H), 2.17 - 1.75 (m, 8H), 1.72 - 1.63 (m, 2H), 1.58 - 1.48 (m, 1H), 1.09 - 0.93 (m, 2H), 0.74 - 0.57 (m, 2H). [000261] To a solution of methyl (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]carbamoyl]azetidine-2-carboxylate (Isomer 2) (0.07 g, 114.27 umol, 1 eq) in EtOH (3 mL) was aaded CaCl ₂ (12.68 mg, 114.27 umol, 1 eq) and the solution was cooled to 0 °C and NaBH ₄ (21.61 mg, 571.37 umol, 5 eq) was added, the solution was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with sat. NH ₄ Cl (20 mL) and extracted with EA (10 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , Petroleum ether/Ethyl acetate = 0/1) and re-purified by prep-HPLC (column: Phenomenex Luna C1875*30mm*3um;mobile phase: [water(FA)-ACN];B%: 20%-70%,8min) to give (2R)-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]-2- (hydroxymethyl)azetidine-1-carboxamide (Isomer 2) (0.035 g, 58.68 umol, 51.35% yield, 98% purity) as a white solid. MS (ESI) m/z 585.0 [M+H] ⁺ . [000262] ¹ H NMR (400 MHz, CDCl ₃ -d) δ = 8.69 (d, J = 5.1 Hz, 1H), 8.59 (br s, 1H), 7.55 (d, J = 5.1 Hz, 1H), 7.19 - 6.89 (m, 1H), 6.77 (br d, J = 7.3 Hz, 1H), 6.63 - 6.55 (m, 1H), 6.51 - 6.30 (m, 1H), 6.22 (s, 1H), 4.52 (br d, J = 6.7 Hz, 1H), 4.06 - 3.81 (m, 2H), 3.75 - 3.62 (m, 2H), 3.32 (q, J = 8.2 Hz, 1H), 2.82 - 2.62 (m, 1H), 2.15 - 2.04 (m, 2H), 2.01 - 1.72 (m, 8H), 1.50 (br d, J = 2.6 Hz, 1H), 1.06 - 0.94 (m, 2H), 0.75 - 0.56 (m, 2H). Step 6: (2R)-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4-difluorocy clohexyl)amino]-2- oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]-2-formyl-azetidi ne-1-carboxamide [000263] To a solution of (2R)-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]-2- (hydroxymethyl)azetidine-1-carboxamide (Isomer 1) (0.03 g, 51.32 umol, 1 eq) in DCM (2 mL) was added DMP (43.53 mg, 102.64 umol, 31.78 uL, 2 eq), and the solution was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with Na ₂ S ₂ O ₃ (aq, 10 %) and NaHCO ₃ (aq, sat) and extracted with EA (5 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water( NH ₄ HCO ₃ )-ACN];B%: 30%-60%,8min) to give (2R)-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4-difluorocy clohexyl)amino]-2-oxo-1-[4- (trifluoromethyl)-3-pyridyl]ethyl]-2-formyl-azetidine-1-carb oxamide (Isomer 1) (2.01 mg, 3.45 umol, 6.72% yield, 100% purity) as a white solid. MS (ESI) m/z 583.1 [M+H] ⁺ . [000264] ¹ H NMR (400 MHz, CDCl ₃ -d) δ = 9.39 (s, 1H), 8.58 (d, J = 5.1 Hz, 1H), 8.40 (br s, 1H), 7.46 (d, J = 5.0 Hz, 1H), 7.03 - 6.65 (m, 2H), 6.63 - 6.48 (m, 2H), 4.12 - 3.82 (m, 2H), 3.69 (br d, J = 7.4 Hz, 1H), 3.56 (br d, J = 4.2 Hz, 1H), 2.44 - 2.26 (m, 1H), 2.20 - 1.70 (m, 10H), 1.07 - 0.94 (m, 2H), 0.70 - 0.54 (m, 2H). [000265] (2R)-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4-difluorocy clohexyl)amino]- 2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]-2-(hydroxymeth yl)azetidine-1-carboxamide (Isomer 1) (0.03 g, 51.32 umol, 1 eq) in DCM (2 mL) was added with DMP (43.53 mg, 102.64 umol, 31.78 uL, 2 eq), and the solution was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with Na ₂ S ₂ O ₃ (aq, 10 %) and NaHCO ₃ (aq, sat) and extracted with EA (5 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [water( NH ₄ HCO ₃ )-ACN];B%: 30%-60%,8min) to give (2R)-N-(4-cyclopropyl-2-fluoro- phenyl)-N-[2-[(4,4-difluorocyclohexyl)amino]-2-oxo-1-[4-(tri fluoromethyl)-3-pyridyl]ethyl]- 2-formyl-azetidine-1-carboxamide (Isomer 1) (9.38 mg, 16.10 umol, 31.37% yield, 100% purity) was obtained as a white solid. MS (ESI) m/z 583.1 [M+H] ⁺ . [000266] ¹ H NMR (400 MHz, CDCl ₃ -d) δ = 9.61 (s, 1H), 8.68 (d, J = 5.1 Hz, 2H), 7.52 (d, J = 5.0 Hz, 1H), 6.85 - 6.49 (m, 3H), 6.18 (br s, 1H), 4.58 - 4.34 (m, 1H), 4.08 - 3.85 (m, 1H), 3.50 (br s, 1H), 3.08 (br d, J = 2.9 Hz, 1H), 2.39 - 2.22 (m, 1H), 2.19 - 1.74 (m, 9H), 1.66 (br d, J = 11.7 Hz, 1H), 1.10 - 0.99 (m, 2H), 0.75 - 0.62 (m, 2H). Example 15: (2R)-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]-2- (hydroxymethyl)pyrrolidine-1-carboxamide (Compound 62)

Step 1: benzyl 2-(N-chlorocarbonyl-4-cyclopropyl-2-fluoro-anilino)-2-[4-(tr ifluoromethyl)-3- pyridyl]acetate [000267] A solution of benzyl 2-(4-cyclopropyl-2-fluoro-anilino)-2-[4-(trifluoromethyl)-3- pyridyl]acetate (0.35 g, 787.54 umol, 1 eq) and DIEA (610.69 mg, 4.73 mmol, 823.03 uL, 6 eq) in DCE (7 mL) was cooled to 0 °C, and then triphosgene (934.81 mg, 3.15 mmol, 4 eq) in DCE (2 mL) was added drop-wise at 0 °C. The resulting solution was stirred at 70 °C for 24 h under N ₂ atmosphere. Upon completion, a solution of benzyl 2-(N-chlorocarbonyl-4- cyclopropyl-2-fluoro-anilino)-2-[4-(trifluoromethyl)-3-pyrid yl]acetate (0.4 g, crude) in DCE (7 mL) was obtained as a yellow liquid and was used to the next step directly. Step 2: methyl (2R)-1-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3-pyridyl] ethyl]-(4- cyclopropyl-2-fluoro-phenyl)carbamoyl]pyrrolidine-2-carboxyl ate [000268] A solution of benzyl 2-(N-chlorocarbonyl-4-cyclopropyl-2-fluoro-anilino)-2-[4- (trifluoromethyl)-3-pyridyl]acetate (0.4 g, 789.15 umol, 1 eq) in DCE (5 mL) was cooled to 0 °C, and then methyl (2R)-pyrrolidine-2-carboxylate (653.49 mg, 3.95 mmol, 5 eq, HCl) and DIEA (611.94 mg, 4.73 mmol, 824.71 uL, 6 eq) in DCE (5 mL) was added at 0 °C, the solution was stirred at 25 °C for 13 h under N ₂ atmosphere. Upon completion, the reaction mixture was diluted with sat. NaHCO ₃ (100 mL) and extracted with DCM (50 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 20/1 to 2/1) to give methyl (2R)-1-[[2-benzyloxy-2-oxo-1-[4- (trifluoromethyl)-3-pyridyl]ethyl]-(4-cyclopropyl-2-fluoro-p henyl)carbamoyl]pyrrolidine-2- carboxylate (0.15 g, 225.16 umol, 28.53% yield, 90% purity) as a yellow oil. MS (ESI) m/z 600.2 [M+H] ⁺ . Step 3: 2-(4-cyclopropyl-2-fluoro-N-[(2R)-2-methoxycarbonylpyrrolidi ne-1- carbonyl]anilino)-2-[4-(trifluoromethyl)-3-pyridyl]acetic acid [000269] To a solution of methyl (2R)-1-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]-(4-cyclopropyl-2-fluoro-phenyl)carbamoyl]pyrr olidine-2-carboxylate (0.15 g, 250.18 umol, 1 eq) in EA (3 mL) was added Pd/C (250.18 umol, 10% purity, 1 eq), the solution was stirred at 25 °C for 2 h under H ₂ (505.36 ug, 250.18 umol, 1 eq) at 15 Psi. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give 2-(4-cyclopropyl-2-fluoro-N-[(2R)-2-methoxycarbonylpyrrolidi ne-1-carbonyl]anilino)-2-[4- (trifluoromethyl)-3-pyridyl]acetic acid (0.13 g, crude) as a yellow oil. Step 4: methyl (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4-difluorocyc lohexyl)amino]- 2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]carbamoyl]pyrro lidine-2-carboxylate [000270] To a solution of 2-(4-cyclopropyl-2-fluoro-N-[(2R)-2- methoxycarbonylpyrrolidine-1-carbonyl]anilino)-2-[4-(trifluo romethyl)-3-pyridyl]acetic acid (0.12 g, 235.55 umol, 1 eq) in ACN (3 mL) was added 4,4-difluorocyclohexanamine (63.67 mg, 471.10 umol, 2 eq), 1-methylimidazole (38.68 mg, 471.10 umol, 37.55 uL, 2 eq) and [chloro(dimethylamino)methylene]-dimethyl-ammonium;hexafluor ophosphate (132.18 mg, 471.10 umol, 2 eq). The resulting solution was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with DCM (20 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , Petroleum ether/Ethyl acetate = 1/1) to give methyl (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]carbamoyl]pyrrolidine-2-carboxylate (0.12 g, 172.36 umol, 73.17% yield, 90% purity) as a yellow oil. Step 5: (2R)-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4-difluorocy clohexyl)amino]-2- oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]-2-(hydroxymethyl )pyrrolidine-1-carboxamide [000271] A solution of methyl (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]carbamoyl]pyrrolidine-2-carboxylate (0.11 g, 175.55 umol, 1 eq) in EtOH (3 mL) was added CaCl ₂ (19.48 mg, 175.55 umol, 1 eq) was cooled to 0 °C, and NaBH ₄ (33.21 mg, 877.77 umol, 5 eq) was added. The resulting solution was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with sat. NH ₄ Cl (20 mL) and extracted with EA (10 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150*30mm*5um;mobile phase: [water(FA)-ACN];B%: 30%- 70%,8min) to give (2R)-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]-2- (hydroxymethyl)pyrrolidine-1-carboxamide (0.05 g, 82.70 umol, 47.11% yield, 99% purity) as a white solid. MS (ESI) m/z 599.0 [M+H] ⁺ . [000272] ¹ H NMR (400 MHz, CDCl ₃ -d) δ = 9.07 - 8.86 (m, 1H), 8.84 - 8.60 (m, 1H), 7.59 - 7.45 (m, 1H), 7.15 - 6.85 (m, 1H), 6.81 - 6.70 (m, 2H), 6.68 (br d, J = 12.2 Hz, 1H), 6.18 - 5.80 (m, 1H), 4.22 - 4.02 (m, 1H), 3.99 - 3.82 (m, 1H), 3.76 (br t, J = 10.9 Hz, 1H), 3.56 (dt, J = 5.9, 10.9 Hz, 2H), 3.08 (dt, J = 3.2, 7.1 Hz, 1H), 2.59 - 2.24 (m, 1H), 2.14 - 2.02 (m, 2H), 2.00 - 1.73 (m, 6H), 1.72 - 1.63 (m, 2H), 1.56 - 1.40 (m, 3H), 1.12 - 0.90 (m, 2H), 0.76 - 0.54 (m, 2H). Example 16: N-(4-tert-butylphenyl)-N-[2-[(4,4-difluorocyclohexyl)amino]- 2-oxo-1-[4- (trifluoromethyl)-3-pyridyl]ethyl]-3,3-dimethyl-2-oxo-butana mide (Compound 67)

Step 1: N-(4-tert-butylphenyl)-N-[2-[(4,4-difluorocyclohexyl)amino]- 2-oxo-1-[4- (trifluoromethyl)-3-pyridyl]ethyl]-3,3-dimethyl-2-oxo-butana mide [000273] A solution of 4-tert-butylaniline (0.3 g, 2.01 mmol, 317.46 uL, 1 eq) and 4- (trifluoromethyl)pyridine-3-carbaldehyde (352.02 mg, 2.01 mmol, 1 eq) in t-BuOH (5 mL) was stirred at 25 °C for 1 h, and then 1,1-difluoro-4-isocyano-cyclohexane (291.79 mg, 2.01 mmol, 1 eq), 3,3-dimethyl-2-oxo-butanoic acid (261.62 mg, 2.01 mmol, 1 eq) and ZnCl ₂ (2 M, 5.03 mL, 5 eq) was added. The mixture was then stirred at 25 °C for 15 h. Upon completion, the mixture was concentrated under reduced pressure and was purified by prep- HPLC (column: Phenomenex Luna C1875*30 mm*3 um; mobile phase: [water (FA)-ACN]; B%: 60%-100%, 8 min) to give the product N-(4-tert-butylphenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]-3,3-dimethyl-2- oxo-butanamide (0.12 g, 205.63 umol, 31.09% yield) as white solid. MS (ESI) m/z 582.2 [M+H] ⁺ Step 2: N-(4-tert-butylphenyl)-N-[2-[(4,4-difluorocyclohexyl)amino]- 2-oxo-1-[4- (trifluoromethyl)-3-pyridyl]ethyl]-3,3-dimethyl-2-oxo-butana mide [000274] The N-(4-tert-butylphenyl)-N-[2-[(4,4-difluorocyclohexyl)amino]- 2-oxo-1-[4- (trifluoromethyl)-3-pyridyl]ethyl]-3,3-dimethyl-2-oxo-butana mide was separated by SFC (column: REGIS(S,S)WHELK-O1(250 mm*25 mm,10um); mobile phase: [Neu-IPA]; B%: 10%-10%, 7 min) to give the product N-(4-tert-butylphenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyr idyl]ethyl]-3,3-dimethyl-2- oxo-butanamide (Isomer 1) (71 mg, 122.07 umol, 28.40% yield, 100% purity) as white solid. MS (ESI) m/z 582.2 [M+H] ⁺ [000275] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.60 (d, J = 5.1 Hz, 1H), 8.35 (s, 1H), 7.70 (d, J = 5.1 Hz, 1H), 7.25 (br s, 4H), 6.50 (s, 1H), 3.98 - 3.78 (m, 1H), 2.10 - 1.97 (m, 2H), 1.96 - 1.79 (m, 4H), 1.63 - 1.53 (m, 1H), 1.53 - 1.43 (m, 1H), 1.20 (s, 9H), 0.99 (s, 9H) [000276] N-(4-Tert-butylphenyl)-N-[2-[(4,4-difluorocyclohexyl)amino]- 2-oxo-1-[4- (trifluoromethyl)-3-pyridyl]ethyl]-3,3-dimethyl-2-oxo-butana mide (Isomer 2) (75 mg, 128.95 umol, 30.00% yield, 100% purity) was obtained as a white solid. MS (ESI) m/z 582.2 [M+H] ⁺ [000277] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.60 (d, J = 5.0 Hz, 1H), 8.35 (s, 1H), 7.70 (d, J = 5.1 Hz, 1H), 7.24 (br s, 4H), 6.50 (s, 1H), 3.89 (br s, 1H), 2.08 - 1.97 (m, 2H), 1.94 - 1.79 (m, 4H), 1.60 - 1.51 (m, 1H), 1.51 - 1.41 (m, 1H), 1.20 (s, 9H), 0.99 (s, 9H). Example 17: 2-[4-tert-butyl-N-[(1-cyanocyclobutyl)carbamoyl]anilino]-N-( 4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide (Compound 58) Step 1: 2-[4-tert-butyl-N-[(1-cyanocyclobutyl)carbamoyl]anilino]-N-( 4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide [000278] A solution of triphosgene (318.34 mg, 1.07 mmol, 1.5 eq) in DCM (5 mL) was cooled to 0 °C, and then 1-aminocyclobutanecarbonitrile (343.75 mg, 2.59 mmol, 3.63 eq, HCl) and DIEA (554.57 mg, 4.29 mmol, 747.40 uL, 6 eq) in DCM (5 mL) was added drop- wise, the solution was stirred at 0 °C for 1 h. Then 2-(4-tert-butylanilino)-N-(4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide (0.3 g, 715.17 umol, 1 eq) and DIEA (277.28 mg, 2.15 mmol, 373.70 uL, 3 eq) in DCM (5 mL) were added, and the resulting solution was stirred at 20 °C for 13 h under N ₂ . Upon completion, the reaction mixture was diluted with NaHCO ₃ (20 mL) and extracted with DCM (10 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The curde was purified by prep-TLC (SiO ₂ , Petroleum ether:Ethyl acetate = 1:1) to give 2-[4-tert-butyl-N-[(1-cyanocyclobutyl)carbamoyl]anilino]-N-( 4,4-difluorocyclohexyl)-2- (5-fluoro-3-pyridyl)acetamide (0.04 g, 59.08 umol, 8.26% yield, 80% purity) as a yellow oil. Step 2: 2-[4-tert-butyl-N-[(1-cyanocyclobutyl)carbamoyl]anilino]-N-( 4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide [000279] 2-[4-tert-butyl-N-[(1-cyanocyclobutyl)carbamoyl]anilino]-N-( 4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide (0.06 g, 110.78 umol, 1 eq) was separated by SFC (column: DAICEL CHIRALCEL OD(250mm*30mm,10um);mobile phase: [Neu-ETOH];B%: 20%-20%,9min) to give 2-[4-tert-butyl-N-[(1- cyanocyclobutyl)carbamoyl]anilino]-N-(4,4-difluorocyclohexyl )-2-(5-fluoro-3- pyridyl)acetamide (Isomer 1) (0.02 g, 35.27 umol, 31.83% yield, 95.5% purity) as a white solid. MS (ESI) m/z 541.3 [M+H] ⁺ . [000280] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.27 (d, J = 2.7 Hz, 1H), 8.20 (s, 1H), 7.37 - 7.27 (m, 3H), 7.14 (d, J = 8.6 Hz, 2H), 5.97 (s, 1H), 3.92 - 3.77 (m, 1H), 2.67 - 2.49 (m, 2H), 2.39 - 2.20 (m, 2H), 2.12 - 1.78 (m, 8H), 1.60 (br dd, J = 3.9, 10.6 Hz, 1H), 1.52 - 1.39 (m, 1H), 1.26 (s, 9H). [000281] 2-[4-Tert-butyl-N-[(1-cyanocyclobutyl)carbamoyl]anilino]-N-( 4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide (Isomer 2) (0.02 g, 33.35 umol, 30.10% yield, 90.3% purity) was obtained as a white solid. MS (ESI) m/z 541.3 [M+H] ⁺ . [000282] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.27 (d, J = 2.7 Hz, 1H), 8.19 (s, 1H), 7.32 (d, J = 8.7 Hz, 3H), 7.14 (d, J = 8.3 Hz, 2H), 5.97 (s, 1H), 3.84 (br t, J = 10.6 Hz, 1H), 2.66 - 2.52 (m, 2H), 2.38 - 2.22 (m, 2H), 2.13 - 1.77 (m, 8H), 1.59 (br dd, J = 3.1, 11.1 Hz, 1H), 1.53 - 1.39 (m, 1H), 1.26 (s, 9H). Example 18: 2-[4-tert-butyl-N-[(1-cyanocyclopentyl)carbamoyl]anilino]-N- (4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide (Compound 64) [000283] A solution of triphosgene (318.34 mg, 1.07 mmol, 1.50 eq) in DCM (3 mL) was cooled to 0 °C, and then 1-aminocyclopentanecarbonitrile (524.28 mg, 3.58 mmol, 5 eq, HCl) and DIEA (554.57 mg, 4.29 mmol, 747.40 uL, 6 eq) in DCM (3 mL) was added drop-wise, the solution was stirred at 0 °C for 1 h. Then 2-(4-tert-butylanilino)-N-(4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide (0.3 g, 715.17 umol, 1 eq) and DIEA (277.28 mg, 2.15 mmol, 373.70 uL, 3 eq) in DCM (3 mL) was added, the solution was stirred at 20 °C for 11 h under N ₂ . The resulting solution was stirred at 35 °C for 60 h under N ₂ . Upon completion, the reaction mixture was diluted with NaHCO ₃ (20 mL) and extracted with DCM (10 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by SFC (column: DAICEL CHIRALCEL OD(250mm*30mm,10um);mobile phase: [Neu- MeOH];B%: 20%-20%,12min) to give 2-[4-tert-butyl-N-[(1- cyanocyclopentyl)carbamoyl]anilino]-N-(4,4-difluorocyclohexy l)-2-(5-fluoro-3- pyridyl)acetamide (0.045 g, 62.36 umol, 8.72% yield, 77% purity) as a white solid.MS (ESI) m/z 555.3 [M+H] ⁺ . [000284] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.40 (d, J = 2.6 Hz, 1H), 8.22 (s, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 8.5 Hz, 3H), 7.08 (d, J = 8.4 Hz, 2H), 6.27 (s, 1H), 5.93 (s, 1H), 3.82 - 3.68 (m, 1H), 2.04 (br s, 8H), 1.64 (br d, J = 5.3 Hz, 4H), 1.58 - 1.47 (m, 2H), 1.42 - 1.32 (m, 2H), 1.21 (s, 9H). Example 19: Evaluation of antiviral activity of compounds against COVID-19 (nCoV- 2019, SARS-CoV2) Mpro in the enzymatic assay [000285] Compounds are assayed using standard methods to assess compound activity and IC50. As an exemplary for assessment of the SARS-COV2 Mpro, the C-His6-tagged Mpro (NC_045512) is cloned, expressed in E. coli and purified. The assay buffer contains 20 mM of Tris-HCl (pH 7.3), 100 mM of NaCl, 1 mM of EDTA, 5mM of TCEP and 0.1%BSA. The final concentrations of the Mpro protein and substrate are 25 nM and 25 μM, respectively, in the Mpro enzymatic assay. The Km of the Mpro substrate for the protease is 13.5 μM. [000286] The compounds are added to an assay plate. For 100% inhibition control (HPE, hundred percent effect), 1 μM GC376 is added. For no inhibition control (ZPE, zero percent effect), no compound is added. Each activity testing point has a relevant background control to normalize the fluorescence interference of compound. [000287] IC50 values of compounds are calculated with the GraphPad Prism software using the nonlinear regression model of log(inhibitor) vs. response -- Variable slope (four parameters). The inhibition activity is calculated using the formula below, IC50 values is calculated using the Inhibition% data. Inhibition% =[ (Sample- Average ZPE )/(Average HPE-Average ZPE)] * 100% ^{# #} HEP: Hundred percent effect controls. Containing substrate + enzyme + 1 μM GC376. ZPE: Zero percent effective controls. Containing enzyme + substrate, no compound. Sample: Compound activity testing wells. Containing compound + enzyme + substrate. BG: Compound background control wells. Containing compound + substrate, no enzyme. Example 20: Evaluation of antiviral activity of compounds against human coronavirus (HCov) 229E and OC43 in the cytopathic effect (CPE) assays [000288] Compounds are assayed using standard methods against multiple coronaviral strains, including HCoV 229E and OC43 strains. The antiviral activity of compounds is calculated based on the protection of the virus-induced CPE at each concentration normalized by the virus control. [000289] Reagents and instruments used in this assay include luminescent cell viability assay kit CellTiter Glo (Promega) and Microplate Reader Synergy2 (BioTek). Virus - HCoV 229E [000290] Cytopathic effect (CPE) is measured by CellTiter Glo following the manufacturer’s manual. The antiviral activity of compounds is calculated based on the protection of the virus-induced CPE at each concentration normalized by the virus control. Virus - HCov OC43 [000291] Reference compound used is remdesivir; detection reagent: CellTiter Glo.) The CPE are measured by CellTiter Glo following the manufacturer’s manual. The antiviral activity of compounds is calculated based on the protection of the virus-induced CPE at each concentration normalized by the virus control. [000292] The cytotoxicity of compounds is assessed under the same conditions, but without virus infection, in parallel. Cell viability is measured with CellTiter Glo. The antiviral activity and cytotoxicity of compounds are expressed as % Inhibition and % Viability, respectively, and calculated with formulas. [000293] Table 3 shows activity data. Table 3. Activity data for compounds. A > 30 μM, B > 10 μM and ≤30 μM, C ≥2 μM and ≤10 μM, D <2 μM. INCORPORATION BY REFERENCE [000294] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS [000295] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. [000296] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.