Certain chemical entities, compositions, and methods

Abstract

This disclosure provides compounds of formula (I), formula (Ia), and formula (Ib), pharmaceutical compositions comprising the foregoing, and methods of using the same, including uses in treating TYK2-mediated diseases, disorders, and / or conditions.

Description

[0001] Agent Ref.16525.0001-00304 CERTAIN CHEMICAL ENTITIES, COMPOSITIONS, AND METHODS RELATED APPLICATION [1] This application claims priority to Provisional Application No.63 / 626,712, filed on January 30, 2024, the content of which is incorporated by reference in its entirety. BACKGROUND OF THE DISCLOSURE [2] There are at least 400 enzymes identified as protein kinases. These enzymes catalyze the phosphorylation of target protein substrates. The phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate. The specific structure in the target substrate to which the phosphate is transferred is a tyrosine, serine, or threonine residue. Since these amino acid residues are the target structures for the phosphoryl transfer, these protein kinase enzymes are commonly referred to as tyrosine kinases or serine / threonine kinases. [3] The phosphorylation reactions, and counteracting phosphatase reactions, at the tyrosine, serine and threonine residues are involved in countless cellular processes that underlie responses to diverse intracellular signals (typically mediated through cellular receptors), regulation of cellular functions, and activation or deactivation of cellular processes. A cascade of protein kinases often participate in intracellular signal transduction and are necessary for the realization of these cellular processes. Because of their ubiquity in these processes, protein kinases can be found as an integral part of the plasma membrane or as cytoplasmic enzymes or localized in the nucleus, often as components of enzyme complexes. In many instances, these protein kinases are an essential element of the enzyme and structural protein complexes that determine where and when a cellular process occurs within a cell. [4] One example of such kinases is Tyrosine kinase 2 (TYK2), which together with JAK1, JAK2, and JAK3 belongs to the family of Janus kinases. Akin to other members of the JAK family, TYK2 is involved in the intracellular signaling of pro-inflammatory cytokines IL-12, IL- 23, and type I interferon (Leit et al., J. Med. Chem.2023, 66, 15, 10473–10496). These cytokines play critical roles in immune and inflammatory responses, and inhibition thereof has been shown to be useful for treating a variety of diseases with abnormal cellular response. Non- limiting examples of such disorders include autoimmune disorders (e.g., psoriasis, multiple sclerosis, type 1 diabetes), inflammatory disorders (e.g., Crohn’s disease, ulcerative colitis, inflammatory bowel disease), proliferative disorders (e.g., hematological cancer, leukemia), endocrine disorders (polycystic ovary syndrome, Crouzon’s syndrome), neurological disorders (e.g., Alzheimer’s disease), and disorders associated with transplantation (e.g., transplant Agent Ref.16525.0001-00304 rejection). Certain small molecule ligands of TYK2 have been disclosed previously (Raju et al., WO 2020 / 198379 A1; Raju et al., WO 2020 / 163778 A1; and Raju et al., WO 2021 / 092246 A1). [5] Because inhibition of JAK1, JAK2, and JAK3 has been linked to serious adverse effects, selevtive inhibition of TYK2 over the remaining Janus kinases by small molecule drugs is especially desirable (Pardanani et al., Leukemia 2013, 27, 1322−1327; Roda et al., Expert Rev. Gastroenterol. Hepatol.2020, 14, 789−796). At least for the foregoing reasons, there is an ongoing need for selective, efficient, and safe protein kinase inhibitors. SUMMARY OF THE DISCLOSURE [6] In one aspect, the present disclosure provides compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein Z1and Z2are independently selected from N and O, provided that when Z1is N then Z2is O, and when Z1is O then Z2is N; R1is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted sulfonyl, or optionally substituted aminosulfonyl; R2is hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted carbamimidoyl; or R1and R2together with the atoms to which they are attached form an optionally substituted heteroaryl ring; R3is optionally substituted heteroaryl, optionally substituted aryl, optionally substituted Agent Ref.16525.0001-00304 heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; R4is -C(O)N(R9)(R10); R5is hydrogen, optionally substituted lower alkyl, or optionally substituted cycloalkyl; R6and R7are independently hydrogen, halo, optionally substituted lower alkyl, or optionally substituted cycloalkyl; R8is hydrogen, optionally substituted lower alkyl, or optionally substituted cycloalkyl; R9and R10are independently hydrogen, optionally substituted lower alkyl, or optionally substituted cycloalkyl; L1is a covalent bond, -N(R5)-, -N(R5)C(R6)(R7)-, -O-, -C(O)-, -C(R6)(R7)-, or - C(R6)(R7)N(R5)-; and L2is a covalent bond or -N(R8)-. [7] In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or pharmaceutically acceptable salt of any of the compounds described herein. The pharmaceutical composition may be formulated in a form which is a tablet, capsule, powder, liquid, suspension, suppository, or aerosol. The pharmaceutical composition may be packaged with instructions for using the composition to treat a subject suffering from cancer. [8] In another aspect, the present disclosure provides a method of treating a TYK2-mediated disorder, disease, or condition, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutically acceptable salt or pharmaceutical composition of any one of the compounds described herein. In some embodiments, the disorder, disease, or condition is associated with type I interferon, IL-10, IL- 12, or IL-23 signaling. In some embodiments, the disorder is an autoimmune disorder. In some embodiments, the disorder is an inflammatory disorder. In some embodiments, the disorder is a proliferative disorder. In some embodiments, the disorder is an endocrine disorder. In some embodiments, the disorder is a neurological disorder. In some embodiments, the disorder is a disorder associated with transplantation. In some embodiments, the autoimmune disorder is type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, psoriatic arthritis, Crohn' s disease, alopecia, Sjogren’s syndrome, Bechet’s disease, ulcerative colitis, vitiligo, uveitis, or inflammatory bowel disease. In some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn' s disease, ulcerative colitis, or inflammatory bowel disease. In some embodiments, the proliferative disorder is Agent Ref.16525.0001-00304 hematological cancer or leukemia. In some embodiments, the proliferative disorder is associated with one or more activating mutations in TYK2. In some embodiments, the disorder is transplant rejection or graft versus host disease. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon' s syndrome, or type 1 diabetes. In some embodiments, the neurological disorder is Alzheimer's disease. INCORPORATION BY REFERENCE [9] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entireties to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE DISCLOSURE

[0010] As used herein, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0011] The following abbreviations and terms have the indicated meanings throughout: ACN Acetonitrile AIBN azobisisobutyronitrile Boc tert-butoxycarbonyl c- Cyclo Cbz Benzyloxycarbonyl Cmpd Compound DCE 1,2-dichloroethane DCM Dichloromethane DIEA N,N-diisopropylethylamine DMA Dimethylacetamide DMAP 4-dimethylaminopyridine DMEDA N,N’-dimethylethane-1,2-diamine DMF Dimethylformamide DMP Dess–Martin periodinane DMSO dimethyl sulfoxide equiv equivalent(s) Et Ethyl Agent Ref.16525.0001-00304 EtOAc or EA ethyl acetate EtOH Ethanol g Gram h Hour HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate HPLC high pressure liquid chromatography i- Iso kg Kilogram L or l Liter LANCE lanthanide chelate excite LC / MS LCMS, liquid chromatography-mass spectrometry LRMS low resolution mass spectrometry m / z mass-to-charge ratio Me Methyl MeOH Methanol mg Milligram min Minute mL Milliliter mmol Millimole MPa Megapascal n- Normal NBS N-bromosuccinimide NIS N-iodosuccinimide NMI 1-methyl-1H-imidazole NaOAc sodium acetate PE petroleum ether PMB p-methoxybenzyl Ph Phenyl Prep Preparative PyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate quant. Quantitative Agent Ref.16525.0001-00304 rt, r.t., or RT room temperature s- sec- (secondary) t- tert- (tertiary) TEA Triethylamine TFA trifluoroacetic acid TFAA trifluoroacetic anhydride TfOH triflic acid THF Tetrahydrofuran TR-FRET time-resolved fluorescence resonance energy transfer UV ultraviolet

[0012] As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence.

[0013] As used herein, a dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2is attached through the carbon atom.

[0014] As used herein, “optional” or “optionally” is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances wherein the event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” encompasses both “alkyl” and “substituted alkyl” as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible, and / or inherently unstable.

[0015] As used herein, “alkyl” refers to straight chain and branched chain having the indicated number of carbon atoms, usually from 1 to 20 carbon atoms, for example 1 to 8 carbon atoms, such as 1 to 6 carbon atoms. For example C1-C6alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms. When an alkyl residue having a specific number of carbons is named, all branched and straight chain versions having that number of carbons are intended to be encompassed; thus, for example, “butyl” is meant to include n-butyl, sec-butyl, isobutyl and t-butyl; “propyl” includes n-propyl and isopropyl. “Lower alkyl” refers to alkyl groups having one to six carbons. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3- hexyl, 3-methylpentyl, and the like. Alkylene is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment. Alkylene groups will usually have from 2 to 20 Agent Ref.16525.0001-00304 carbon atoms, for example 2 to 8 carbon atoms, such as from 2 to 6 carbon atoms. For example, C0alkylene indicates a covalent bond and C1alkylene is a methylene group.

[0016] As used herein, “alkenyl” refers to an unsaturated branched or straight-chain alkyl group having at least one carbon-carbon double bond derived by the removal of one molecule of hydrogen from adjacent carbon atoms of the parent alkyl. The group may be in either the cis or trans configuration about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en- 2-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but- 2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl; and the like. In certain embodiments, an alkenyl group has from 2 to 20 carbon atoms and in other embodiments, from 2 to 6 carbon atoms. “Lower alkenyl” refers to alkenyl groups having two to six carbons.

[0017] As used herein, “alkynyl” refers to an unsaturated branched or straight-chain alkyl group having at least one carbon-carbon triple bond derived by the removal of two molecules of hydrogen from adjacent carbon atoms of the parent alkyl. Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyls such as but- 1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and the like. In certain embodiments, an alkynyl group has from 2 to 20 carbon atoms and in other embodiments, from 3 to 6 carbon atoms. “Lower alkynyl” refers to alkynyl groups having two to six carbons.

[0018] As used herein, “cycloalkyl” refers to a non-aromatic carbocyclic ring, usually having from 3 to 7 ring carbon atoms. The ring may be saturated or have one or more carbon-carbon double or triple bonds. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl, as well as bridged and caged ring groups such as norbornane.

[0019] As used herein, “alkoxy” refers to an alkyl group of the indicated number of carbon atoms attached through an oxygen bridge such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, and the like. Alkoxy groups will usually have from 1 to 7 carbon atoms attached through the oxygen bridge. “Lower alkoxy” refers to alkoxy groups having one to six carbons.

[0020] As used herein, “acyl” refers to the groups H-C(O)-; (alkyl)-C(O)-; (cycloalkyl)-C(O)-; (aryl)-C(O)-; (heteroaryl)-C(O)-; and (heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure through the carbonyl functionality and wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are as described herein. Acyl groups have the indicated number Agent Ref.16525.0001-00304 of carbon atoms, with the carbon of the keto group being included in the numbered carbon atoms. For example a C2acyl group is an acetyl group having the formula CH3(C=O)-.

[0021] As used herein, “formyl” refers to the group -C(O)H.

[0022] As used herein, “alkoxycarbonyl” refers to a group of the formula (alkoxy)(C=O)- attached through the carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms. Thus a C1-C6alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker.

[0023] As used herein, “azido” refers to the group -N3.

[0024] As used herein, “amino” refers to the group -NH2.

[0025] As used herein, “mono- and di-(alkyl)amino” refers to secondary and tertiary alkyl amino groups, wherein the alkyl groups are as defined above and have the indicated number of carbon atoms. The point of attachment of the alkylamino group is on the nitrogen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino.

[0026] As used herein, “aminocarbonyl” refers to the group -CONRbRc, where Rbis H, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted alkoxy; and Rcis hydrogen or optionally substituted C1-C4 alkyl; or Rband Rctaken together with the nitrogen to which they are bound, form an optionally substituted 4- to 8-membered nitrogen-containing heterocycloalkyl which optionally includes 1 or 2 additional heteroatoms chosen from O, N, and S in the heterocycloalkyl ring; where each substituted group is independently substituted with one or more substituents independently C1-C4alkyl, aryl, heteroaryl, aryl-C1-C4alkyl-, heteroaryl-C1-C4alkyl-, C1-C4haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4alkyl-NH2, -N(C1-C4alkyl)(C1-C4alkyl), -NH(C1-C4alkyl), -N(C1-C4alkyl)(C1-C4alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO2H, -C(O)OC1-C4alkyl, -CON(C1-C4alkyl)(C1-C4alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4alkyl), -N(C1-C4alkyl)C(O)(phenyl), -C(O)C1-C4alkyl, -C(O)C1-C4alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), - SO2(C1-C4haloalkyl), -SO2NH2, -SO2NH(C1-C4alkyl), -SO2NH(phenyl), -NHSO2(C1-C4alkyl), -NHSO2(phenyl), or -NHSO2(C1-C4 haloalkyl).

[0027] As used herein, “aryl” refers to: 6-membered carbocyclic aromatic rings, for example, benzene; bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for Agent Ref.16525.0001-00304 example, naphthalene, indane, and tetralin; and tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.

[0028] For example, aryl includes 6-membered carbocyclic aromatic rings fused to a 4- to 8- membered non-aromatic ring containing 1 or more heteroatoms chosen from N, O, and S. For such fused, bicyclic ring systems wherein only one of the rings is a carbocyclic aromatic ring, the point of attachment may be at the carbocyclic aromatic ring or the non-aromatic ring. Aryl, however, does not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings is fused with an aromatic ring containing 1 or more heteroatoms chosen from N, O, and S, the resulting ring system is heteroaryl, not aryl, as defined herein.

[0029] As used herein, “aryloxy” refers to the group -O-aryl.

[0030] As used herein, “aralkyl” refers to the group -alkyl-aryl.

[0031] As used herein, “carbamimidoyl” refers to the group -C(=NH)-NH2.

[0032] As used herein, “substituted carbamimidoyl” refers to the group -C(=NRe)-NRfRgwhere Reis hydrogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl; and Rfand Rgare independently hydrogen optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl, provided that at least one of Re, Rf, and Rgis not hydrogen and wherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently -Ra, -ORb, optionally substituted amino (including -NRcCORb, -NRcCO2Ra, -NRcCONRbRc, -NRbC(NRc)NRbRc, - NRbC(NCN)NRbRc, and -NRcSO2Ra), halo, cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, and heteroaryl), optionally substituted acyl (such as -CORb), optionally substituted alkoxycarbonyl (such as -CO2Rb), aminocarbonyl (such as -CONRbRc), -OCORb, -OCO2Ra, -OCONRbRc, -OP(O)(ORb)ORc, sulfanyl (such as SRb), sulfinyl (such as -SORa), or sulfonyl (such as -SO2Raand -SO2NRbRc), where Rais optionally substituted C1-C6alkyl, optionally substituted aryl, or optionally substituted heteroaryl; Rbis H, optionally substituted C1-C6alkyl, optionally substituted aryl, or optionally substituted heteroaryl; and Agent Ref.16525.0001-00304 Rcis hydrogen or optionally substituted C1-C4 alkyl; or Rband Rc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4alkyl-, heteroaryl-C1-C4alkyl-, C1-C4haloalkyl, -OC1-C4alkyl, -OC1-C4alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4alkyl), -NH(C1-C4alkyl), -N(C1-C4alkyl)(C1-C4alkylphenyl), -NH(C1-C4alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO2H, -C(O)OC1-C4alkyl, -CON(C1-C4alkyl)(C1-C4alkyl), -CONH(C1-C4alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4alkyl, -C(O)C1-C4phenyl, -C(O)C1-C4haloalkyl, -OC(O)C1-C4alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4alkyl), -NHSO2(phenyl), or -NHSO2(C1-C4haloalkyl).

[0033] As used herein, “carboxy” refers to the group -C(O)OH.

[0034] As used herein, “cycloalkyloxy” refers to a cycloalkyl as defined above having one of the ring carbon atoms attached through an oxygen bridge. Examples of cycloalkyloxy include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy and cyclohexyloxy. “Substituted cycloalkyloxy” refers to a substituted cycloalkyl as defined above having one of the ring carbon atoms attached through an oxygen bridge, wherein the substituents are as defined for “substituted alkyl.”

[0035] As used herein, “halo” refers to fluoro, chloro, bromo, and iodo, and the term “halogen” includes fluorine, chlorine, bromine, and iodine.

[0036] As used herein, “haloalkyl” refers to alkyl as defined above having the specified number of carbon atoms, substituted with one or more halogen atoms, up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.

[0037] As used herein, “heteroaryl” refers to: 5- to 7-membered aromatic, monocyclic rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms chosen from N, O, and S, with the remaining ring atoms being carbon; bicyclic rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms chosen from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring; and Agent Ref.16525.0001-00304 tricyclic rings containing one or more, for example, from 1 to 5, or in certain embodiments, from 1 to 4, heteroatoms chosen from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring. In certain embodiments, a heteroaryl contrains one or more oxo groups attached to one or more ring caron atoms. Polycyclic heteroaryls include bicyclic heteroaryls and tricyclic heteroaryls. As used herein, the term “heteroaryl” refers to a group containing one or more points of attachment. For example, the term “heteroaryl” may refer to a group containing one point of attachment or two points of attachment (i.e., heteroarylene).

[0038] For example, heteroaryl includes a 5- to 7-membered aromatic ring fused to a 4- to 8- membered cycloalkyl or heterocycloalkyl ring. For such fused, bicyclic heteroaryl ring systems wherein only one of the rings contains one or more heteroatoms, the point of attachment may be at either ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In certain embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In certain embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiophenyl, furanyl, pyrrolyl, benzofuranyl, benzoimidazolyl, indolyl, pyridazinyl, triazolyl, quinolinyl, quinoxalinyl, quinazolinyl, 2-pyridonyl, pyrimidin-2(1H)-onyl, and 5,6,7,8-tetrahydroisoquinolinyl. Heteroaryl does not encompass or overlap with aryl, cycloalkyl, or heterocycloalkyl, as defined herein.

[0039] Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O-) substituents, such as pyridinyl N-oxides.

[0040] As used herein, “heterocycloalkyl” refers to a single, non-aromatic ring, usually with 3 to 8 ring atoms, containing at least 2 carbon atoms in addition to 1-3 heteroatoms independently chosen from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms. The ring may be saturated or have one or more carbon-carbon double bonds or carbon-carbon triple bonds. Suitable heterocycloalkyl groups include but are not limited to, for example, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, azetidinyl, diazepanyl, diazocanyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrazolidinyl, dihydrofuranyl, and tetrahydrofuranyl. Substituted heterocycloalkyl can also include ring systems substituted with one or more oxo (=O) or oxide (-O-) substituents, such as piperidinyl N- oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl. Agent Ref.16525.0001-00304

[0041] “Heterocycloalkyl” also includes bicyclic, bridged, and spirocyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently chosen from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; and the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteratoms independently chosen from oxygen, sulfur, and nitrogen and is not aromatic. For example, 8-azabicyclo[3.2.1]octanyl is a bridged heterocyclic ring system.

[0042] As used herein, “heterocycloalkyloxy” refers to a heterocycloalkyl as defined above having one of the ring carbon atoms attached through an oxygen bridge. For example, pyrrolidin- 3-yloxy is a heterocycloalkyloxy. “Substituted heterocycloalkyloxy” refers to a substituted heterocycloalkyl as defined above having one of the ring carbon atoms attached through an oxygen bridge, wherein the substituents are as defined for “substituted alkyl.”

[0043] As used herein, “sulfanyl” refers to the groups: -S-(optionally substituted (C1-C6)alkyl), - S-(optionally substituted cycloalkyl), -S-(optionally substituted aryl), -S-(optionally substituted heteroaryl), and -S-(optionally substituted heterocycloalkyl). Hence, sulfanyl includes the group C1-C6 alkylsulfanyl.

[0044] As used herein, “sulfinyl” refers to the groups: -S(O)-(optionally substituted (C1- C6)alkyl), -S(O)-(optionally substituted cycloalkyl), -S(O)-(optionally substituted aryl), -S(O)- optionally substituted heteroaryl), -S(O)-(optionally substituted heterocycloalkyl); and -S(O)- (optionally substituted amino).

[0045] As used herein, “sulfonyl” refers to the groups: -S(O2)-(optionally substituted (C1- C6)alkyl), -S(O2)-(optionally substituted cycloalkyl), -S(O2)-(optionally substituted aryl), -S(O2)- (optionally substituted heteroaryl), -S(O2)-(optionally substituted heterocycloalkyl), and -S(O2)- (optionally substituted amino).

[0046] As used herein, “aminosulfonyl” refers to the groups: -S(O2)NH2-, S(O2)NH(optionally substituted (C1-C6)alkyl), S(O2)N(optionally substituted (C1-C6)alkyl)2, -S(O2)NH-(optionally substituted cycloalkyl), -S(O2)N-(optionally substituted cycloalkyl)2,-S(O2)NH-(optionally substituted aryl), S(O2)N-(optionally substituted aryl)2, -S(O2)NH-(optionally substituted heteroaryl), -S(O2)N-(optionally substituted heteroaryl)2, -S(O2)N-(optionally substituted heterocycloalkyl)2, and -S(O2)NH-(optionally substituted heterocycloalkyl).As used herein, “substituted” refers to any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded. When a substituent is oxo (i.e. =O) then 2 hydrogens on the atom are replaced. Combinations of substituents and / or variables are permissible only if such combinations result in Agent Ref.16525.0001-00304 stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation as an agent having at least practical utility. Unless otherwise specified, substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion. For functional groups that are composed of a functional group for which optional substituents are provided herein, the definition of these optional substituents shall apply to such functional group as well. For instance, “alkoxy” is defined herein as “an alkyl group of the indicated number of carbon atoms attached through an oxygen bridge.” Thus, “substituted alkoxy” is “a substituted alkyl group of the indicated number of carbon atoms attached through an oxygen bridge,” wherein the optional substituents are as defined for “substituted alkyl.”

[0047] In some embodiments, substituents (such as in situations where a group is optionally substituted with one or more substituents) or “optional substituents” are independently selected from halogen, -R', -OR', =O, =NR', =N-OR', -NR'R", -SR', -SiR'R"R'", -OC(=O)R', -C(=O)R', - CO2R', -C(=O)NR'R", -OC(=O)NR'R", -NR"C(=O)R', -NR'-C(=O)NR"R'", -NR'-SO2NR"R'", - NR"CO2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -SO2R', - SO2NR'R", -NR"SO2R', -CN, -NO2, -N3, -CH(Ph)2, -(CH2)xOH (wherein x is an integer selected from 1 to 20), perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl. R', R", and R'" each independently refer to hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkenyl, optionally substituted cycloalkynyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted carbamimidoyl.

[0048] As used herein, the terms “substituted” alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, unless otherwise expressly defined, refer respectively to alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently -Ra, -ORb, optionally substituted amino (including -NRcCORb, -NRcCO2Ra, -NRcCONRbRc, - NRbC(NRc)NRbRc, -NRbC(NCN)NRbRc, and -NRcSO2Ra), halo, cyano, azido, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as -CORb), Agent Ref.16525.0001-00304 optionally substituted alkoxycarbonyl (such as -CO2Rb), aminocarbonyl (such as -CONRbRc), -OCORb, -OCO2Ra, -OCONRbRc, -OP(O)(ORb)ORc,sulfanyl (such as SRb), sulfinyl (such as -SORa),or sulfonyl (such as -SO2Raand -SO2NRbRc), where Rais optionally substituted C1-C6alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl; Rbis hydrogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and Rcis hydrogen or optionally substituted C1-C4 alkyl; or Rband Rc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4alkyl-, heteroaryl-C1-C4alkyl-, C1-C4haloalkyl, -OC1-C4alkyl, -OC1-C4alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), -CO2H, -C(O)OC1-C4 alkyl, -CON(C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4alkyl), -NHC(O)(phenyl), -N(C1-C4alkyl)C(O)(C1-C4alkyl), -N(C1-C4alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4alkyl, -SO2(C1-C4alkyl), -SO2(phenyl), -SO2(C1-C4haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl), or -NHSO2(C1-C4haloalkyl).

[0049] As used herein, “substituted acyl” refers to the groups (substituted alkyl)-C(O)-; (substituted cycloalkyl)-C(O)-; (substituted aryl)-C(O)-; (substituted heteroaryl)-C(O)-; and (substituted heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure through the carbonyl functionality and wherein substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, refer respectively to alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently -Ra, -ORb, optionally substituted amino (including -NRcCORb, -NRcCO2Ra, -NRcCONRbRc, -NRbC(NRc)NRbRc, -NRbC(NCN)NRbRc, and -NRcSO2Ra), halo, cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as -CORb), optionally substituted alkoxycarbonyl (such as -CO2Rb), aminocarbonyl (such Agent Ref.16525.0001-00304 as -CONRbRc), -OCORb, -OCO2Ra, -OCONRbRc, -OP(O)(ORb)ORc, sulfanyl (such as SRb), sulfinyl (such as -SORa), or sulfonyl (such as -SO2Raand -SO2NRbRc), where Rais optionally substituted C1-C6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl; Rbis H, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and Rcis hydrogen or optionally substituted C1-C4 alkyl; or Rband Rc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4alkyl-, heteroaryl-C1-C4alkyl-, C1-C4haloalkyl, -OC1-C4alkyl, -OC1-C4alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4alkyl), -NH(C1-C4alkyl), -N(C1-C4alkyl)(C1-C4alkylphenyl), -NH(C1-C4alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), -CO2H, -C(O)OC1-C4 alkyl, -CON(C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4alkyl, -SO2(C1-C4alkyl), -SO2(phenyl), -SO2(C1-C4haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl), or -NHSO2(C1-C4haloalkyl).

[0050] As used herein, “substituted alkoxy” refers to alkoxy wherein the alkyl constituent is substituted (i.e. -O-(substituted alkyl)) wherein “substituted alkyl” refers to alkyl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently chosen from -Ra, -ORb, optionally substituted amino (including -NRcCORb, -NRcCO2Ra, -NRcCONRbRc, -NRbC(NRc)NRbRc, -NRbC(NCN)NRbRc, and -NRcSO2Ra), halo, cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as -CORb), optionally substituted alkoxycarbonyl (such as -CO2Rb), aminocarbonyl (such as -CONRbRc), -OCORb, -OCO2Ra, -OCONRbRc, -OP(O)(ORb)ORc, sulfanyl (such as SRb), sulfinyl (such as -SORa), and sulfonyl (such as -SO2Raand -SO2NRbRc), where Rais optionally substituted C1-C6alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl; Rbis H, optionally substituted C1-C6alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and Agent Ref.16525.0001-00304 Rcis hydrogen or optionally substituted C1-C4 alkyl; or Rband Rc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4alkyl-, heteroaryl-C1-C4alkyl-, C1-C4haloalkyl, -OC1-C4alkyl, -OC1-C4alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4alkyl), -NH(C1-C4alkyl), -N(C1-C4alkyl)(C1-C4alkylphenyl), -NH(C1-C4alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), -CO2H, -C(O)OC1-C4alkyl, -CON(C1-C4alkyl)(C1-C4alkyl), -CONH(C1-C4alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4alkyl, -C(O)C1-C4alkylphenyl, -C(O)C1-C4haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4alkyl), -SO2NH(phenyl), -NHSO2(C1-C4alkyl), -NHSO2(phenyl), or-NHSO2(C1-C4 haloalkyl).

[0051] In some embodiments, a substituted alkoxy group is “polyalkoxy” or -O-(optionally substituted alkylene)-(optionally substituted alkoxy), and includes groups such as - OCH2CH2OCH3, and residues of glycol ethers such as polyethyleneglycol, and - O(CH2CH2O)xCH3, where x is an integer of 2-20, such as 2-10, and for example, 2-5. Another substituted alkoxy group is hydroxyalkoxy or -OCH2(CH2)yOH, where y is an integer of 1-10, such as 1-4.

[0052] As used herein, “substituted alkoxycarbonyl” refers to the group (substituted alkyl)-O- C(O)- wherein the group is attached to the parent structure through the carbonyl functionality and wherein substituted refers to alkyl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently -Ra, -ORb, optionally substituted amino (including -NRcCORb, -NRcCO2Ra, -NRcCONRbRc, -NRbC(NRc)NRbRc, - NRbC(NCN)NRbRc, and -NRcSO2Ra), halo, cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as -CORb), optionally substituted alkoxycarbonyl (such as -CO2Rb), aminocarbonyl (such as -CONRbRc), -OCORb, -OCO2Ra, -OCONRbRc, -OP(O)(ORb)ORc, sulfanyl (such as SRb), sulfinyl (such as -SORa), and sulfonyl (such as -SO2Raand -SO2NRbRc), where Rais optionally substituted C1-C6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl; Agent Ref.16525.0001-00304 Rbis H, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and Rcis hydrogen or optionally substituted C1-C4 alkyl; or Rband Rc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4alkyl-, heteroaryl-C1-C4alkyl-, C1-C4haloalkyl, -OC1-C4alkyl, -OC1-C4alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4alkyl), -NH(C1-C4alkyl), -N(C1-C4alkyl)(C1-C4alkylphenyl), -NH(C1-C4alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), -CO2H, -C(O)OC1-C4alkyl, -CON(C1-C4alkyl)(C1-C4alkyl), -CONH(C1-C4alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4alkyl, -C(O)C1-C4alkylphenyl, -C(O)C1-C4haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl), or -NHSO2(C1-C4 haloalkyl).

[0053] As used herein, “substituted amino” refers to the group -NHRdor -NRdRewherein Rdis hydroxyl, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted carbamimidoyl, aminocarbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkoxycarbonyl, sulfinyl and sulfonyl, and wherein Reis chosen from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl, and wherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently -Ra, -ORb, optionally substituted amino (including -NRcCORb, -NRcCO2Ra, -NRcCONRbRc, -NRbC(NRc)NRbRc, -NRbC(NCN)NRbRc, and -NRcSO2Ra), halo, cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as -CORb), optionally substituted alkoxycarbonyl (such as -CO2Rb), aminocarbonyl (such as -CONRbRc), -OCORb, -OCO2Ra, -OCONRbRc, -OP(O)(ORb)ORc, sulfanyl (such as SRb), sulfinyl (such as -SORa), or sulfonyl (such as -SO2Raand -SO2NRbRc), Agent Ref.16525.0001-00304 wherein Rais optionally substituted C1-C6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl; Rbis H, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and Rcis hydrogen or optionally substituted C1-C4 alkyl; or Rband Rc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and wherein each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently chosen from C1-C4alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4alkyl-OH, -OC1-C4haloalkyl, halo, -OH, -NH2, -C1-C4alkyl-NH2, -N(C1-C4alkyl)(C1-C4alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), -CO2H, -C(O)OC1-C4alkyl, -CON(C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4alkyl)C(O)(C1-C4alkyl), -N(C1-C4alkyl)C(O)(phenyl), -C(O)C1-C4alkyl, -C(O)C1-C4 alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), - SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), - NHSO2(C1-C4 alkyl), -NHSO2(phenyl), or -NHSO2(C1-C4 haloalkyl); and wherein optionally substituted acyl, optionally substituted alkoxycarbonyl, sulfinyl and sulfonyl are as defined herein.

[0054] The term “substituted amino” also refers to N-oxides of the groups -NHRd, and NRdRdeach as described above. N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid. The person skilled in the art is familiar with reaction conditions for carrying out the N-oxidation.

[0055] Combinations of chemical components (such as substituents, ring structures, or heteroatoms) as disclosed herein are those that result in the formation of stable or chemically feasible compounds. For abbreviation or according to common practice, certain hydrogen atoms attached to a certain atom (e.g., a carbon atom C or a nitrogen atom N) are not specifically spelled out in a chemical structure, formula, or notation; hydrogen atoms are deemed to be present to the extent the valences of the certain atom (e.g., C or N) are completed.

[0056] Compounds described herein include, but are not limited to, their optical isomers, racemates, and other mixtures thereof. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or Agent Ref.16525.0001-00304 chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column. In addition, compounds include Z- and E- forms (or cis- and trans- forms) of compounds with carbon-carbon double bonds. Where compounds described herein exist in various tautomeric forms, the term “compound” is intended to include all tautomeric forms of the compound.

[0057] Compounds of Formula I, Formula Ia, and Formula Ib also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. “Crystalline form,” “polymorph,” and “novel form” may be used interchangeably herein, and are meant to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to. Similarly, “pharmaceutically acceptable forms” of compounds of Formula I, Formula Ia, and Formula Ib also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the pharmaceutically acceptable salts, as well as mixtures thereof.

[0058] A “solvate” is formed by the interaction of a solvent and a compound. The term “compound” is intended to include solvates of compounds. Similarly, “pharmaceutically acceptable salts” includes solvates of pharmaceutically acceptable salts. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi- hydrates.

[0059] Compounds of Formula I, Formula Ia, and Formula Ib also include other pharmaceutically acceptable forms of the recited compounds, including chelates, non-covalent complexes, prodrugs, and mixtures thereof.

[0060] A “chelate” is formed by the coordination of a compound to a metal ion at two (or more) points. The term “compound” is intended to include chelates of compounds. Similarly, “pharmaceutically acceptable salts” includes chelates of pharmaceutically acceptable salts.

[0061] A “non-covalent complex” is formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding). Such non-covalent complexes are included Agent Ref.16525.0001-00304 in the term “compound”. Similarly, pharmaceutically acceptable salts include “non-covalent complexes” of pharmaceutically acceptable salts.

[0062] The term “hydrogen bond” refers to a form of association between an electronegative atom (also known as a hydrogen bond acceptor) and a hydrogen atom attached to a second, relatively electronegative atom (also known as a hydrogen bond donor). Suitable hydrogen bond donor and acceptors are well understood in medicinal chemistry.

[0063] “Hydrogen bond acceptor” refers to a group comprising an oxygen or nitrogen, such as an oxygen or nitrogen that is sp2–hybridized, an ether oxygen, or the oxygen of a sulfoxide or N-oxide.

[0064] The term “hydrogen bond donor” refers to an oxygen, nitrogen, or heteroaromatic carbon that bears a hydrogen.group containing a ring nitrogen or a heteroaryl group containing a ring nitrogen.

[0065] The compounds disclosed herein can be used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In one particular embodiment, the compound is deuterated at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the efficacy and increase the duration of action of drugs.

[0066] Deuterium substituted compounds can be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0067] As used herein, the term “deuterated substituted compound” refers to a compound having the same chemical structure as a reference compound but with one or more hydrogen atom(s) replaced by a deuterium atom (“D” or “2H”). It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending on the origin of chemical materials used in the synthesis. The concentration of naturally abundant stable hydrogen isotopes, notwithstanding this variation, is small and immaterial as compared to the degree of stable isotopic substitution of deuterated compounds described herein. Thus, unless otherwise stated, when a reference is made to a “deuterated substituted compound” of a compound of the disclosure, at least one hydrogen is replaced with deuterium at well above its natural isotopic abundance (which is typically about 0.015%). In some embodiments, the deuterated substituted Agent Ref.16525.0001-00304 compounds of the disclosure have an isotopic enrichment factor for each deuterium atom, of at least 3500 (52.5% deuterium incorporation at each designated deuterium), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), or at least 6600 (99% deuterium incorporation).

[0068] The term “isotopic enrichment factor,” as used herein, means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0069] “Pharmaceutically acceptable salts” include, but are not limited to salts with inorganic acids, such as hydrochlorate, phosphate, diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts; as well as salts with an organic acid, such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2- hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoate such as acetate, HOOC- (CH2)n-COOH where n is 0-4, and like salts. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0070] In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts.

[0071] “Prodrugs” described herein include any compound that becomes a compound of Formula I, Formula Ia, or Formula Ib when administered to a subject, e.g., upon metabolic processing of the prodrug. Similarly, “pharmaceutically acceptable salts” includes “prodrugs” of pharmaceutically acceptable salts. Examples of prodrugs include derivatives of functional groups, such as an amine group or a carboxylic acid group, in the compounds of Formula I, Formula Ia, and Formula Ib. Exemplary prodrugs of an amine group include, but are not limited to, amides, N-acyloxyalkoxycarbonyls, N-acyloxyalkylesters, ^-aminoketones, ^-aminoesters, imines (Schiff bases), N-Mannich bases, enamines, enaminones, and lactones (Simplício et al., Molecules.2008 Mar; 13(3): 519–547; Bundgaard H., Methods in Enzymology, Academic Press, 112, 1985, Pages 347-359, ISSN 0076-6879, ISBN 9780121820121). Exemplary prodrugs of a carboxylic acid carboxylic acid esters such as alkyl esters, hydroxyalkyl esters, arylalkyl esters, Agent Ref.16525.0001-00304 and aryloxyalkyl esters. Other exemplary prodrugs include lower alkyl esters such as ethyl ester, acyloxyalkyl esters such as pivaloyloxymethyl (POM), glycosides, and ascorbic acid derivatives.

[0072] Other exemplary prodrugs include amides of carboxylic acids. Exemplary amide prodrugs include metabolically labile amides that are formed, for example, with an amine and a carboxylic acid. Exemplary amines include NH2, primary, and secondary amines such as NHRx, and NRxRy, wherein Rxis hydrogen, (C1-C18)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1- C4)-alkyl-, (C6-C14)-aryl which is unsubstituted or substituted by a residue (C1-C2)-alkyl, (C1- C2)-alkoxy, fluoro, or chloro; heteroaryl-, (C6-C14)-aryl-(C1-C4)-alkyl- where aryl is unsubstituted or substituted by a residue (C1-C2)-alkyl, (C1-C2)-alkoxy, fluoro, or chloro; or heteroaryl-(C1-C4)-alkyl- and in which Ryhas the meanings indicated for Rxwith the exception of hydrogen or wherein Rxand Ry, together with the nitrogen to which they are bound, form an optionally substituted 4- to 7-membered heterocycloalkyl ring which optionally includes one or two additional heteroatoms chosen from nitrogen, oxygen, and sulfur. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series, in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

[0073] As used herein, the terms “group”, “radical” or “fragment” are synonymous and are intended to indicate functional groups or fragments of molecules attachable to a bond or other fragments of molecules.

[0074] As used herein, the term “leaving group” refers to the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under nucleophilic displacement conditions. Examples of leaving groups include, but are not limited to, dimethylhydroxylamino (e.g., Weinreb amide), halogen, alkane- or arylsulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.

[0075] As used herein, the term “protective group” or “protecting group” refers to a group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Certain processes of this disclosure rely upon the protective groups to block certain reactive sites present in the reactants. Examples of protecting groups can be found in Wuts et al., Green’s Protective Groups in Organic Synthesis, (J. Wiley, 4th ed.2006). Agent Ref.16525.0001-00304

[0076] As used herein, the term “deprotection” or “deprotecting” refers to a process by which a protective group is removed after a selective reaction is completed. Certain protective groups may be preferred over others due to their convenience or relative ease of removal. Without being limiting, deprotecting reagents for protected amino or anilino group include strong acid such as trifluoroacetic acid (TFA), concentrated HCl, H2SO4, or HBr, and the like.

[0077] As used herein, “modulation” refers to a change in activity as a direct or indirect response to the presence of a chemical entity as described herein, relative to the activity of in the absence of the chemical entity. The change may be an increase in activity or a decrease in activity, and may be due to the direct interaction of the compound with the a target or due to the interaction of the compound with one or more other factors that in turn affect the target's activity. For example, the presence of the chemical entity may, for example, increase or decrease the target activity by directly binding to the target, by causing (directly or indirectly) another factor to increase or decrease the target activity, or by (directly or indirectly) increasing or decreasing the amount of target present in the cell or organism.

[0078] As used herein, “active agent” is used to indicate a chemical entity which has biological activity. In certain embodiments, an “active agent” is a compound having pharmaceutical utility. For example an active agent may be an anti-cancer therapeutic.

[0079] As used herein, “significant” refers to any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student's T-test, where p < 0.05.

[0080] As used herein, a “pharmaceutically acceptable” component is one that is suitable for use with humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit / risk ratio.

[0081] As used herein, “therapeutically effective amount” of a chemical entity described herein refers to an amount effective, when administered to a human or non-human subject, to provide a therapeutic benefit such as amelioration of symptoms, slowing of disease progression, or prevention of disease.

[0082] “Treating” or “treatment” encompasses administration of at least one compound of Formula I, Formula Ia, Formula Ib, or a pharmaceutically acceptable salt of any of the foregoing, to a subject, particularly a human subject, in need of such an administration and includes (i) arresting the development of clinical symptoms of the disease, such as cancer, (ii) bringing about a regression in the clinical symptoms of the disease, such as cancer, and / or (iii) prophylactic treatment for preventing the onset of the disease, such as cancer. Agent Ref.16525.0001-00304

[0083] As used herein, “cancer” refers to all types of cancer or neoplasm or malignant tumors found in mammals, including carcinomas and sarcomas. Examples of cancer are cancer of the brain, breast, cervix, colon, head & neck, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus and Medulloblastoma.

[0084] As used herein, “subject” refers to an animal, e.g., a mammal, that has been or will be the object of treatment, observation or experiment. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the subject is a human.

[0085] The term “mammal” is intended to have its standard meaning, and encompasses humans, dogs, cats, sheep, and cows, for example.

[0086] As used herein, the term TYK2 is used to refer to the Tyrosine kinase 2, which is an enzyme that belongs to the Janus kinase family. The terms “TYK2” and “Tyrosine kinase 2” and the like are used interchangeably to refer to the gene or protein product of the gene. A. Compounds

[0087] In some embodiments, provided is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Z1and Z2are independently selected from N and O, provided that when Z1is N then Z2is O, and when Z1is O then Z2is N; R1is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted sulfonyl, or optionally substituted aminosulfonyl; R2is hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted Agent Ref.16525.0001-00304 aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted carbamimidoyl; or R1and R2together with the atoms to which they are attached form an optionally substituted heteroaryl ring; R3is optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; R4is -C(O)N(R9)(R10); R5is hydrogen, optionally substituted lower alkyl, or optionally substituted cycloalkyl; R6and R7are independently hydrogen, halo, optionally substituted lower alkyl, or optionally substituted cycloalkyl; R8is hydrogen, optionally substituted lower alkyl, or optionally substituted cycloalkyl; R9and R10are independently hydrogen, optionally substituted lower alkyl, or optionally substituted cycloalkyl; L1is a covalent bond, -N(R5)-, -N(R5)C(R6)(R7)-, -O-, -C(O)-, -C(R6)(R7)-, or - C(R6)(R7)N(R5)-; and L2is a covalent bond or -N(R8)-.

[0088] In some embodiments, provided is a compound of Formula Ia or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0089] In some embodiments, provided is a compound of Formula Ib or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0090] In some embodiments, R1is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally Agent Ref.16525.0001-00304 substituted aminocarbonyl, or optionally substituted acyl. In some embodiments, R1is optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, or optionally substituted acyl. In some embodiments, R1is optionally substituted lower alkyl or optionally substituted acyl. In some embodiments, R1is methyl, acetyl, or cyclopropyl. In some embodiments, R1is methyl (e.g., -CH3 or -CD3) or acetyl.

[0091] In some embodiments, R2is hydrogen, cyano, halo, hydroxy, carboxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, or optionally substituted aminocarbonyl. In some embodiments, R2is hydrogen, cyano, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl. In some embodiments, R2is hydrogen.

[0092] In some embodiments, R1and R2together with the atoms to which they are attached form an optionally substituted 5- to 6-membered heteroaryl ring. In some embodiments, R1and R2together with the atoms to which they are attached form a 5-membered heteroaryl ring. In some embodiments, R1and R2together with the atoms to which they are attached form a pyrrole ring.

[0093] In some embodiments, L1is a covalent bond, -N(R5)-, or -O-. In some embodiments, L1is -N(R5)-.

[0094] In some embodiments, R5is hydrogen, or lower alkyl. In some embodiments, R5is hydrogen or methyl. In some embodiments, R5is hydrogen.

[0095] In some embodiments, R3is optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted cycloalkyl. In some embodiments, R3is optionally substituted 6-membered aryl or optionally substituted 5- to 6- membered heteroaryl. In some embodiments, R3is optionally substituted 6-membered aryl. In some embodiments, R3is optionally substituted 5- to 6-membered heteroaryl. In some embodiments, R3is optionally substituted 6-membered heteroaryl.

[0096] In some embodiments, R3is optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted pyrazinyl. In some embodiments, R3is optionally substituted pyridinyl or optionally substituted pyrazinyl.

[0097] In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted with: optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted 8-azabicyclo[3.2.1]octanyl, optionally substituted piperidinyl, optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted pyridinyl, Agent Ref.16525.0001-00304 optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted oxadiazolyl, optionally substituted triazolyl, or optionally substituted isoxazolyl.

[0098] In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted with: optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, or optionally substituted isoxazolyl.

[0099] In some embodiments, R3is pyridonyl or pyrazinonyl, which are each independently optionally substituted with: optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, or optionally substituted isoxazolyl.

[0100] In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each , , , , Agent Ref.16525.0001-00304

[0101] In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted with . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, optionally substituted with . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted with . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are optionally substituted with . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, independently optionally substituted with . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . Agent Ref.16525.0001-00304 In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, independently optionally substituted with . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or independently optionally substituted with . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, independently optionally substituted Agent Ref.16525.0001-00304 . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or independently optionally substituted with . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . In Agent Ref.16525.0001-00304 some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, independently optionally substituted with . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted with . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or optionally Agent Ref.16525.0001-00304 substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, optionally substituted . In some embodiments, R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted . , , Agent Ref.16525.0001-00304 , , , , , , , , , , , Agent Ref.16525.0001-00304 or

[0103] In some embodiments, R3. In some embodiments, R3is R3 . In some embodiments, R3is R3 embodiments, R3. In some . In some some In Agent Ref.16525.0001-00304 some embodiments, R3. In some embodiments, R3is In some embodiments, R3is . In some embodiments, R3. In some embodiments, R3is is Agent Ref.16525.0001-00304 is embodiments, R3. In some embodiments, R3 embodiments, R3. In some embodiments, R3 embodiments, R3. In some In some embodiments, R3. In some embodiments, R3is R3 Agent Ref.16525.0001-00304

[0104] In some embodiments, L2is a covalent bond.

[0105] In some embodiments, R9and R10are independently hydrogen or optionally substituted cycloalkyl. In some embodiments, R9and R10are independently hydrogen, optionally substituted cyclopropyl, or optionally substituted cyclobutyl. In some embodiments, R9and R10are independently hydrogen, cyclopropyl, or cyclobutyl, wherein cyclopropyl and cyclobutyl are each independently optionally substituted with halogen or optionally substituted alkoxy. In some embodiments, R9and R10are independently , .In some embodiments, R9 is hydrogen and R10 is In some embodiments, R9is hydrogen and R10. In some embodiments, R9is hydrogen and R10. In some embodiments, R9is hydrogen and R10. In some embodiments, R9is hydrogen and R10. In some embodiments, R9is hydrogen and . In some embodiments, R9is hydrogen and R10. In some embodiments, .

[0106] In another a compound or pharmaceutically acceptable salt chosen from the group consisting of: N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)- 7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; Agent Ref.16525.0001-00304 5-((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)- 7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-((3'-methyl-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)- 7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((3'-methoxy-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((5'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)- 7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((5'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)- 7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-((5'-methyl-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)- 7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((5'-methoxy-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((3-oxo-4-(pyridin-2-yl)-3,4- dihydropyrazin-2-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((4-(3-fluoropyridin-2-yl)-3-oxo-3,4-dihydropyrazin-2-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(pyrimidin-2-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(pyrimidin-4-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(pyrazin-2-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(oxazol-2-yl)-2-oxo-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(oxazol-5-yl)-2-oxo-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((1-(isoxazol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(1H-pyrazol-5-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(1H-pyrazol-4-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; Agent Ref.16525.0001-00304 7-acetamido-N-((1R,2R)-2-methoxycyclobutyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,3'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-8H- isoxazolo[4,3-b]pyrrolo[2,3-d]pyridine-3-carboxamide; N-((2R)-2-fluorocyclopropyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((2S)-2-fluorocyclopropyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((2R)-2-methoxycyclopropyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((2S)-2-methoxycyclopropyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,5-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(pyrimidin-2-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,5-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,3'-bipyridin]-3- yl)amino)isoxazolo[4,5-b]pyridine-3-carboxamide; 5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)- 7-(methylamino)isoxazolo[4,5-b]pyridine-3-carboxamide; 5-((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)- 7-(methylamino)isoxazolo[4,5-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-((3'-methyl-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)- 7-(methylamino)isoxazolo[4,5-b]pyridine-3-carboxamide; 5-((3'-methoxy-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,5-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((3-oxo-4-(pyridin-2-yl)-3,4- dihydropyrazin-2-yl)amino)isoxazolo[4,5-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(pyrazin-2-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,5-b]pyridine-3-carboxamide; 5-((5'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)- 7-(methylamino)isoxazolo[4,5-b]pyridine-3-carboxamide; Agent Ref.16525.0001-00304 N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(oxazol-2-yl)-2-oxo-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,5-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(oxazol-5-yl)-2-oxo-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,5-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(pyrimidin-5-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(pyridazin-3-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(1H-1,2,3-triazol-5-yl)- 1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((5'-amino-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)- 7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((3'-amino-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)- 7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((1-((3S,4R)-3-fluoropiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N- ((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((1-((3R,4R)-3-fluoropiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N- ((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((1-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)- N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((1-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)- N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-phenyl-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((6-cyclopropylpyridin-2-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7- (methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((6-(4-methylpiperazin-1- yl)pyridin-2-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((6-morpholinopyridin-2- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-(methyl(2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-7- (methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-((6-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3- yl)pyridin-2-yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; Agent Ref.16525.0001-00304 N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(1-methylpyrrolidin-3-yl)-2- oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(1-methylpiperidin-4-yl)-2- oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(1-methylazetidin-3-yl)-2- oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; (S)-2-amino-3-(4-(3-((3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)-7- (methylamino)isoxazolo[4,3-b]pyridin-5-yl)amino)-2-oxopyridin-1(2H)-yl)phenyl)propanoic acid hydrochloride; N-((trans)-2-(methoxy-d3)cyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((trans)-2-(methoxy-d3)cyclobutyl)-7-((methyl-d3)amino)-5-((2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-((methyl-d3)amino)-5-((2-oxo-2H-[1,2'-bipyridin]- 3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((trans)-2-(difluoromethoxy)cyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-(difluoromethoxy)cyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-((1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1,2- dihydropyridin-3-yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((6'-methoxy-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((2,6'-dioxo-1',6'-dihydro-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-((1-(6-methoxypyrimidin-4-yl)-2-oxo-1,2- dihydropyridin-3-yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-((1-(1-methyl-1H-1,2,4-triazol-3-yl)-2-oxo-1,2- dihydropyridin-3-yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(6-oxo-1,6- dihydropyrimidin-4-yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; Agent Ref.16525.0001-00304 N-((1R,2R)-2-methoxycyclobutyl)-5-((1-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-2- oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-((1'-methyl-2'-oxo-1',2'-dihydro-[2,4'-bipyridin]-6- yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((2,2'-dioxo-1',2'-dihydro-2H-[1,4'-bipyridin]-3-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-((1'-methyl-2,2'-dioxo-1',2'-dihydro-2H-[1,4'- bipyridin]-3-yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-((1-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2- dihydropyridin-3-yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((1-(1-isopropyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1R,2R)- 2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((1-(1-cyclopropyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N- ((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((1-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1R,2R)- 2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((6'-methoxy-2-oxo-2H-[1,3'-bipyridin]-3-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 7-(cyclopropylamino)-N-((1R,2R)-2-methoxycyclobutyl)-5-((2-oxo-2H-[1,2'-bipyridin]- 3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(3-methylureido)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; and pharmaceutically acceptable salts thereof.

[0107] In yet another aspect, the present disclosure provides a compound chosen from the compounds set forth in Table 1 below and pharmaceutically acceptable salts thereof. Table 1. Illustrative Compounds of the Present Disclosure Cmpd No. Chemical Name e e Agent Ref.16525.0001-00304 C05 5-((5'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide 'fl 2 2H 12'bi idi l i N 1R2R 2 e - e - e - - )- e )- 4- 5- - )- - - - e e N- N- Agent Ref.16525.0001-00304 5-((1-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3- C28 yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3- b]pyridine-3-carboxamide 1- 2- - 4- - 2'- '- o- e e - Agent Ref.16525.0001-00304 N-((1R,2R)-2-methoxycyclobutyl)-5-((1-(1-methyl-1H-1,2,4-triazol-3-yl)-2- C49 oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine- 3-carboxamide n- de e 2- - - 3- - e [1 e co mpounds set forth in Table 1 and pharmaceutically acceptable salts of any of the foregoing.

[0109] In some embodiments, the present disclosure provides a compound chosen from the compounds set forth in Table 1. B. Methods of Making

[0110] Compounds disclosed herein may be prepared according to standard chemical practices and as illustrated by the routes described below in Examples 1-10. Materials used herein are either commercially available or prepared by synthetic methods generally known in the art. These schemes as illustrated in Examples 1-10 are not limited to the compounds listed or by any particular substituents, which are employed for illustrative purposes. Although various steps are described and depicted in the schemes, the steps in some cases may be performed in a different order than the order shown in the schemes. Various modifications to these synthetic reaction schemes may be made and will be suggested to one skilled in the art having referred to the Agent Ref.16525.0001-00304 disclosure contained in this Application. Numbering does not necessarily correspond to that of claims or other tables. C. Pharmaceutical Compositions and Formulations

[0111] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999).

[0112] Provided herein are pharmaceutical compositions comprising a compound of Formula I, Formula Ia, or Formula Ib, and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). In certain embodiments, the compounds described are administered as pharmaceutical compositions in which compounds of Formula I, Formula Ia, or Formula Ib, are mixed with other active ingredients, as in combination therapy. Encompassed herein are all combinations of actives set forth in the combination therapies section below and throughout this disclosure. In specific embodiments, the pharmaceutical compositions include one or more compounds of Formula I, Formula Ia, and / or Formula Ib.

[0113] A pharmaceutical composition, as used herein, refers to a mixture of a compound of Formula I, Formula Ia, or Formula Ib with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds of Formula I, Formula Ia, or Formula Ib, provided herein are administered in a pharmaceutical composition to a mammal having a disease or condition to be treated. In specific embodiments, the mammal is a human. In certain embodiments, therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other Agent Ref.16525.0001-00304 factors. The compounds described herein are used singly or in combination with one or more therapeutic agents as components of mixtures.

[0114] In one embodiment, one or more compounds of Formula I, Formula Ia, or Formula Ib, is formulated in an aqueous solution. In specific embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank’s solution, Ringer’s solution, or physiological saline buffer. In other embodiments, one or more compound of Formula I, Formula Ia, or Formula Ib, is formulated for transmucosal administration. In specific embodiments, transmucosal formulations include penetrants that are appropriate to the barrier to be permeated. In still other embodiments wherein the compounds described herein are formulated for other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and / or excipients.

[0115] In another embodiment, compounds described herein are formulated for oral administration. Compounds described herein, including compounds of Formula I, Formula Ia, or Formula Ib, are formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients. In various embodiments, the compounds described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like.

[0116] In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0117] In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coating. In specific embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solutions, optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent Agent Ref.16525.0001-00304 mixtures. Dyestuffs and / or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and / or pigments are optionally utilized to characterize different combinations of active compound doses.

[0118] In certain embodiments, therapeutically effective amounts of at least one of the compounds described herein are formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, push-fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, soft capsules, contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

[0119] In other embodiments, therapeutically effective amounts of at least one of the compounds described herein are formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In still other embodiments, the compounds described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations. In still other embodiments, the pharmaceutical composition of a compound of Formula I, Formula Ia, and / or Formula Ib is formulated in a form suitable for parenteral injection as sterile suspension, solution or emulsion in oily or aqueous vehicles. Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and / or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In additional embodiments, suspensions of the active compounds are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active Agent Ref.16525.0001-00304 ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0120] In still other embodiments, the compounds of Formula I, Formula Ia, or Formula Ib are administered topically. The compounds described herein are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[0121] In yet other embodiments, the compounds of Formula I, Formula Ia, or Formula Ib are formulated for transdermal administration. In specific embodiments, transdermal formulations employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and / or dispersed in a polymer or an adhesive. In various embodiments, such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. In additional embodiments, the transdermal delivery of the compounds of Formula I, Formula Ia, or Formula Ib, is accomplished by means of iontophoretic patches and the like. In certain embodiments, transdermal patches provide controlled delivery of the compounds of Formula I, Formula Ia, or Formula Ib. In specific embodiments, the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to increase absorption. Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that assist passage through the skin. For example, in one embodiment, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

[0122] In other embodiments, the compounds of Formula I, Formula Ia, or Formula Ib are formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists or powders. Pharmaceutical compositions of Formula I, Formula Ia, or Formula Ib, are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In specific embodiments, the dosage unit of a pressurized aerosol is determined by providing a valve to deliver a metered amount. In certain embodiments, capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or Agent Ref.16525.0001-00304 insufflator are formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0123] In still other embodiments, the compounds of Formula I, Formula Ia, or Formula Ib, are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low- melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.

[0124] In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are optionally used as suitable. Pharmaceutical compositions comprising a compound of Formula I, Formula Ia, or Formula Ib, are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0125] Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent or excipient and at least one compound of Formula I, Formula Ia, or Formula Ib, described herein as an active ingredient. The active ingredient is in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0126] Methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable Agent Ref.16525.0001-00304 excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions and creams. The form of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.

[0127] In some embodiments, a pharmaceutical composition comprising at least one compound of Formula I, Formula Ia, or Formula Ib, illustratively takes the form of a liquid where the agents are present in solution, in suspension or both. Typically when the composition is administered as a solution or suspension a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.

[0128] In certain embodiments, useful aqueous suspension contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate and dextran.

[0129] Useful pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of a compound of Formula I, Formula Ia, or Formula Ib. The term “solubilizing agent” generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

[0130] Furthermore, useful pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases Agent Ref.16525.0001-00304 and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

[0131] Additionally, useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0132] Other useful pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[0133] Still other useful compositions include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.

[0134] Still other useful compositions include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0135] In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.

[0136] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, the compounds described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.

[0137] In certain embodiments, the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and / or other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to Agent Ref.16525.0001-00304 about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof. D. Routes of Administration

[0138] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0139] In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. In yet other embodiments, the compound described herein is administered topically. E. Kits / Articles of Manufacture

[0140] For use in the therapeutic applications described herein, kits and articles of manufacture are also provided. In some embodiments, such kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from a variety of materials such as glass or plastic.

[0141] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products Include those found in, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials Agent Ref.16525.0001-00304 include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. For example, the container(s) includes one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein.

[0142] For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non- limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and / or tube labels listing contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In addition, a label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates directions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical compositions is presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack for example contains metal or plastic foil, such as a blister pack. Or, the pack or dispenser device is accompanied by instructions for administration. Or, the pack or dispenser is accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, Ccompositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Agent Ref.16525.0001-00304 F. Methods of Use

[0143] The chemical entities described herein are useful in the treatment, or in the preparation of a medicament for the treatment of various disorders. For example, compounds of Formula I, Formula Ia, and Formula Ib are useful as inhibitors of protein kinases. In some embodiments, the chemical entities described herein inhibit activity of one or more protein kinases. In some embodiments, the compounds of Formula I, Formula Ia, and Formula Ib are inhibitors of TYK2 and of mutants thereof. In some embodiments, the compounds of Formula I, Formula Ia, and Formula Ib are inhibitors of TYK2.

[0144] Without wishing to be bound by any particular theory, the compounds of Formula I, Formula Ia, and Formula Ib are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation of one or more kinases, such as TYK2, is implicated in the disease, condition, or disorder. TYK2 has been implicated in a wide range of diseases (Masse et al., WO 2019 / 023468 A1; Masse et al., WO 2020 / 081508 A1; and Masse et al., WO 2020 / 154474 A1). When activation of TYK2 is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as “TYK2- mediated disease” or disease symptom. Accordingly, in another aspect, the present disclosure provides a method for treating or lessening the severity of a disease, condition, or disorder where activation of TYK2 and / or other kinases is implicated in the disease state.

[0145] TYK2 is a tyrosine kinase and a member of the Janus kinase (JAKs) family. In mammals, there are four types of JAK proteins (i.e., TYK2, JAKl, JAK2, and JAK3), all of which are integral to cytokine signaling. Activation of TYK 2 occurs upon cytokine binding through association of cytoplasmic domains of type-I cytokine receptors, type-II cytokine receptors, type- I interferon receptors, and type-III interferon receptors. Among the cytokines that effect activation of TYK2 are interferons such as IFN-^, IFN-^, IFN-^, IFN-^, IFN-^, IFN-^, IFN-^, and IFN-^, interleukins such as IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL- 31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF (Bacon et al., J. Exp. Med. (1995) 181, 399; Finbloom et al., J. Immunol. (1995) 155, 1079; Parham et al., J. Immunol. (2002) 168, 5699; Velasquez et al., Cell (1992) 70, 313; Stahl et al., Science (1994) 263, 92; and Welham et al., J. Biol. Chem. (1995) 270, 12286). Once activated, TYK2 proceeds to phosphorylate other signaling proteins such as STATl, STAT2, STAT4, and STAT6.

[0146] TYK2 activity has been associated directly or indirectly with various diseases, including but not limited to inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis Agent Ref.16525.0001-00304 (Duerr et al., Science (2006) 314: 1461-1463); psoriasis (Strange et al., Nat. Genet. (2010) 42:985-992; Cho et al., N. Engl. J. Med (2011) 365: 1612-1623; Ishizaki et al., International Immunology (2014), 26(5): 257–267); ankylosing spondylitis (Cortes et al., Nat. Genet. (2013) 45(7):730-738); Behçet's Disease (Remmers et al., Nat. Genet. (2010) 42:698-702); asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis (Zhang et al., The FASEB Journal (2012) 26: 1-11); rheumatoid arthritis (Ishizaki et al., Intl. Immunol. (2011) 23(9):575-582); multiple sclerosis (Oyamada et al., J. Immunol. (2009) 183 :7539-7546; Ban et al., Eur J. Hum. Genet. (2009) 17: 1309-1313); systemic lupus erythematosus (Sigurdsson et al., Am. J. Hum. Genet. (2005) 76:528-537; Graham et al., PLoS Genetics (2011) 7(10):e1002341); tumors (Simma et al., Cancer Res. (2009) 69:203-211; Fontan et al., Cancer Disc. (2013) 3:494- 496); lymphoblastic leukemia (Sanda et al., Cancer Disc. (2013) 3(5):564-577); Alzheimer’s disease (Wan et al. J. Neurosci. (2010) 30(20):6873-6881); and alopecia areata (Xing et al., Nat. Med. (2014) 20: 1043-1049; Harel et al., Sci. Adv. (2015) 1(9):el500973).

[0147] The inhibition of kinases may be assayed in vitro, in vivo or in a cell line. Specifically, activity of one or more of the compounds of the instant disclosure as an inhibitor of TYK2 or mutant thereof may be determined through assays such as in vitro assays or in vivo assays. In vitro assays include assays that determine inhibition of either the phosphorylation activity or ATPase activity of activated kinase. Alternate in vitro assays quantitate the ability of the inhibitor to bind to kinase. Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor, complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with kinase bound to known radioligands. At 1 µM concentration, one or more compounds of the present disclosure exhibits at least about 50%, 60%, 70, 80%, 90% or even higher inhibition of kinases including TYK2. In some embodiments, the compounds of the present disclosure selectively inhibit TYK2. In some embodiments, the compounds of the present disclosure selectively inhibit TYK2 with reduced or no inhibition of one or more of JAK1, JAK2, and JAK3. In some embodiments, the compounds of the present disclosure selectively inhibit TYK2 with reduced or no inhibition of JAK2. Non-limiting examples of in vitro and in vivo assays useful in assaying a TYK2 inhibitory activity include those described and disclosed in one or more of the references above, each of which is herein incorporated by reference in its entirety.

[0148] In some embodiments, the compounds described herein are inhibitors of TYK2. In some embodiments, the compounds described herein are inhibitors of TYK2 that are useful for treating one or more disorders associated with TYK2 activity or activity of mutants of TYK2. In some Agent Ref.16525.0001-00304 embodiments, the present disclosure provides a method for treating a TYK2-mediated disorder comprising a step of administering to a patient in need thereof one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the presen disclosure provides methods for treating or lessening the severity of one or more diseases in which TYK2, or a mutant thereof, is known to play a role. Such TYK2-mediated disorders include but are not limited to autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders and disorders associated with transplantation.

[0149] In some embodiments, the present disclosure provides a method for treating one or more disorders, wherein the disorders are selected from one or more of autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and disorders associated with transplantation, wherein said method comprises administering to a patient in need thereof one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof in an effective amount.

[0150] In some embodiments, the disorder is an autoimmune disorder. In some embodiments the disorder is selected from type I diabetes, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behcet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease. In some embodiments, the disorder is an inflammatory disorder. In some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, or inflammatory bowel disease. In some embodiments, the disorder is a proliferative disorder. In some embodiments, the proliferative disorder is a hematological cancer. In some embodiments the proliferative disorder is a leukemia. In some embodiments, the leukemia is a T-cell leukemia. In some embodiments, the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the proliferative disorder is polycythemia vera, myelofibrosis, essential or thrombocytosis.

[0151] In some embodiments, the disorder is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon' s syndrome, or type I diabetes. In some embodiments, the disorder is a neurological disorder. In some embodiments, the neurological disorder is Alzheimer's disease. In some embodiments the proliferative disorder is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation in TYK2 is a mutation to the FERM domain, the JH2 domain, or the kinase domain. In some embodiments the activating mutation in TYK2 is selected from G36D, S47N, R425H, V73 ll, E957D, and Rl027H. In some embodiments, the disorder is associated with transplantation. In Agent Ref.16525.0001-00304 some embodiments, the disorder associated with transplantation is transplant rejection, or graft versus host disease.

[0152] In some embodiments, the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments, the disorder is associated with type I interferon signaling. In some embodiments, the disorder is associated with IL-10 signaling. In some embodiments, the disorder is associated with IL-12 signaling. In some embodiments, the disorder is associated with IL-23 signaling.

[0153] In some embodiments, the compounds of the present disclosure are useful in the treatment of inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, cutaneous lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0154] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof may be used for the treatment of diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrinassociated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g., idiopathic nephrotic syndrome or minal change nephropathy), chronic granulomatous disease, endometriosis, leptospiriosis renal disease, glaucoma, retinal disease, Agent Ref.16525.0001-00304 ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, musclewasting, catabolic disorders, obesity, fetal growth retardation, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget' s disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases, COPD (reduction of damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in conjunction with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, Type I diabetes, or Type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy,blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0155] In some embodiments, the inflammatory disease which can be treated according to the methods of the present disclosure is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Juvenile rheumatoid arthritis, Systemic jubenile idiopathic arthritis (SJIA), Cryopyrin Associated Periodic Syndrome (CAPS), and osteoarthritis.

[0156] In some embodiments, the inflammatory disease which can be treated according to the methods of the present disclosure is a Th1 or Th17 mediated disease. In some embodiments, the Th17 mediated disease is selected from cutaneous lupus erythematosus, Systemic lupus erythematosus, Multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0157] In some embodiments, the inflammatory disease which can be treated according to the methods of the present disclosure is selected from Sjogren' s syndrome, allergic disorders, osteoarthritis, conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis. Agent Ref.16525.0001-00304

[0158] The chemical entities described herein may be prepared in substantially pure form, typically by standard chromatographic methods, prior to formulation in a pharmaceutically acceptable form. The chemical entities described herein may be used in treating a variety of diseases, disorders, or conditions.

[0159] In certain embodiments, the compound of Formula I, Formula Ia, and Formula Ib is administered in combination with one or more additional therapeutic agents. This additional therapeutic agent, which may ordinarily be administered to treat or prevent a disease, disorder, or condition, may be administered in combination with the compounds of Formula I, Formula Ia, and Formula Ib. Non-limiting examples of such additional therapeutic agents include but are not limited to Aricept® and Excelon® for treatment of Alzheimer’s disease; Ritonavir for treatment of HIV and / or AIDS; L-DOPA / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine for treatment of Parkinson's disease; Avonex®, Rebif®, Copaxone®, mitoxantrone for treatment of multiple sclerosis; albuterol andSingulair® for treatment of asthma; yprexa, risperdal, seroquel, and haloperidol for treatment of schizophrenia; corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine for inflammatory diseases; cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine autoimmune disease; acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti- convulsants, ion channel blockers, and riluzole for treatment of Parkinson’s disease; beta- blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins for cardiovascular diseases; corticosteroids, cholestyramine, interferons, and anti-viral agents for treatment of liver diseases; and corticosteroids, and anti-leukemic agents for blood disorders.

[0160] In some embodiments, the chemical entities described herein may be administered in combination with one or more other therapeutic agents. In some embodiments, the chemical entities described herein may be used in conjunction with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.

[0161] In some embodiments, the chemical entities described herein may be administered in combination with one or more of, without limitation: treatments for Alzheimer's Disease such as Aricept® and Excelon®; treatments for HIV such as ritonavir; treatments for Parkinson's Disease such as LDOP A / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma such as albuterol and Singulair®; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF Agent Ref.16525.0001-00304 blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; agents that prolong or improve pharmacokinetics such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g., ketokenozole and ritonavir), and agents for treating immunodeficiency disorders such as gamma globulin.

[0162] In some embodiments, the chemical entities described herein may be administered in combination with one or more of a monoclonal antibody and an siRNA therapeutic.

[0163] In some embodiments, the additional agents may be administered separately from a provided combination therapy, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with one or more compounds of the present disclosure in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.

[0164] In some embodiments, the amount of additional therapeutic agent present in a compositions comprising one or more compounds of the present disclosure will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0165] In some embodiments, the present disclosure provides compositions comprising one or more compounds of Formula I, Formula Ia, and / or Formula Ib and one or more additional therapeutic agents. The therapeutic agent may be administered together with a compound of Formula I, Formula Ia, and / or Formula Ib or may be administered before or after administration of a compound of Formula I, Formula Ia, and / or Formula Ib. Suitable therapeutic agents are described in further detail below. In certain embodiments, a compound of Formula I, Formula Ia, and / or Formula Ib may be administered up to 5 min, 10 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, or 18 h before the therapeutic Agent Ref.16525.0001-00304 agent. In some embodiments, a compound of Formula I, Formula Ia, and / or Formula Ib may be administered up to 5 min, 10 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5, h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, or 18 h following the therapeutic agent.

[0166] In some embodiments, the present disclosure provides methods of treating an inflammatory disease, disorder or condition by administering to a patient in need thereof a compound of Formula I, Formula Ia, and / or Formula Ib and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biologic agents and include, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti-IL-1” agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), “anti-T-cell” agents such as abatacept (Orencia®), “anti-IL-6” agents such as tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HF A, Proventil® HF A), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo- Agent Ref.16525.0001-00304 Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such as omalizumab (Xolair®), nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron ®) in combination with lenalidomide (Revlimid ®), or any combination(s) thereof.

[0167] In some embodiments, the present disclosure provides methods of treating rheumatoid arthritis comprising administering to a patient in need thereof a compound of Formula I, Formula Ia, and / or Formula Ib and one or more additional therapeutic agents selected from non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti-IL-1” agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), antibodies such as rituximab (Rituxan®), “anti-T-cell” agents such as abatacept (Orencia®) and “anti-IL-6” agents such as tocilizumab (Actemra®).

[0168] In some embodiments, the present disclosure provides methods of treating osteoarthritis comprising administering to a patient in need thereof a compound of Formula I, Formula Ia, and / or Formula Ib and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac Agent Ref.16525.0001-00304 (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®) and monoclonal antibodies such as tanezumab.

[0169] In some embodiments, the present disclosure provides a method of treating cutaneous lupus erythematosus or systemic lupus erythematosus comprising administering to a patient in need thereof a compound of Formula I, Formula Ia, and / or Formula Ib and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

[0170] In some embodiments, the present disclosure provides a method of treating Crohn's disesase, ulcerative colitis, or inflammatory bowel disease comprising administering to a patient in need thereof a compound of Formula I, Formula Ia, and / or Formula Ib and one or more additional therapeutic agents selected from mesalamine (Asacol®) sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies, steroids, and antibiotics such as Flagyl or ciprofloxacin.

[0171] In some embodiments, the present disclosure provides a method of treating asthma comprising administering to a patient in need thereof a compound of Formula I, Formula Ia, and / or Formula Ib and one or more additional therapeutic agents selected from Singulair®, beta- 2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, and IgE antibodies such as omalizumab (Xolair®).

[0172] In some embodiments, the present disclosure provides a method of treating COPD comprising administering to a patient in need thereof a compound of Formula I, Formula Ia, Agent Ref.16525.0001-00304 and / or Formula Ib and one or more additional therapeutic agents selected from beta-2 agonists such as albuterol (Ventolin® HF A, Proventil® HF A), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®.

[0173] In some embodiments, the present disclosure provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a compound of Formula I, Formula Ia, and / or Formula Ib and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PBK inhibitor, a SYK inhibitor, and combinations thereof.

[0174] In some embodiments, the present disclosure provides methods of treating a solid tumor comprising administering to a patient in need thereof a compound of Formula I, Formula Ia, and / or Formula Ib and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PBK inhibitor, a SYK inhibitor, and combinations thereof.

[0175] In some embodiments, the present disclosure provides methods of treating a hematological malignancy comprising administering to a patient in need thereof a compound of Formula I, Formula Ia, and / or Formula Ib and a Hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological malignancy is DLBCL (Ramirez et al., Leuk. Res.2012, 36(10), 1267-1273).

[0176] In some embodiments, the present disclosure provides methods of treating diffuse large B-cell lymphoma (DLBCL) comprising administering to a patient in need thereof a compound of Formula I, Formula Ia, and / or Formula Ib and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof. Agent Ref.16525.0001-00304

[0177] In some embodiments, the present disclosure provides methods of treating multiple myeloma comprising administering to a patient in need thereof a compound of Formula I, Formula Ia, and / or Formula Ib and one or more additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PBK inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).

[0178] In some embodiments, the present disclosure provides methods of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of Formula I, Formula Ia, and / or Formula Ib and a BTK inhibitor, wherein the disease is selected from inflammatory bowel disease, arthritis, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still' s disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto' s thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjogren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain- Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus- myoclonus syndrome, ankylosing spondylosis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, membranous glomerulonephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, a hyperproliferative disease, rejection of transplanted organs or tissues, Acquired Immunodeficiency Syndrome, type 1 diabetes, graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, Agent Ref.16525.0001-00304 peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferative disorder, e.g., diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, Bcell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), nonHodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, or lymphomatoid granulomatosis, breast cancer, prostate cancer, or cancer of the mast cells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, diseases of the bone and joints including, without limitation, rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastasis, a thromboembolic disorder, (e.g., myocardial infarct, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, deep venous thrombosis), inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, permcus anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture' s syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto' s thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet' s disease, Agent Ref.16525.0001-00304 scleraderma, mycosis fungoides, acute inflammatory responses (such as acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0179] In some embodiments, the present disclosure provides methods of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of Formula I, Formula Ia, and / or Formula Ib and a PBK inhibitor, wherein the disease is selected from a cancer, a neurodegenative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin- induced platelet aggregation, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, and a CNS disorder.

[0180] In some embodiments, the present disclosure provides methods of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of Formula I, Formula Ia, and / or Formula Ib and a PBK inhibitor, wherein the disease is selected from benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma or a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, lymphomas, (including, for example, non-Hodgkin's Lymphoma (NHL) and Hodgkin's lymphoma (also termed Hodgkin's or Hodgkin's disease)), a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or a leukemia, diseases include Cowden syndrome, Lhermitte-Dudos disease and Bannayan-Zonana syndrome, or diseases in which the PBK / PKB pathway is aberrantly activated, asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection, acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other Agent Ref.16525.0001-00304 drug therapy, in particular other inhaled drug therapy, bronchitis of whatever type or genesis including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis, pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis, Loffler's syndrome, eosinophilic, pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophilrelated disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia grav1s, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g., including idiopathic nephrotic syndrome or minal change nephropathy, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia.

[0181] When a chemical entity described herein is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual subject, as well as the severity of the subject’s symptoms.

[0182] In some embodiments, a suitable amount of at least one chemical entity of the present disclosure is administered to a patient in need thereof for treating one or more of the various Agent Ref.16525.0001-00304 diseases and disorders described herein. Administration typically occurs in an amount of between about 0.01 mg / kg of body weight to about 100 mg / kg of body weight per day (administered in single or divided doses), such as at least about 0.1 mg / kg of body weight per day. A particular therapeutic dosage can include, e.g., from about 0.01 mg to about 1000 mg of the chemical entity, such as including, e.g., from about 1 mg to about 1000 mg. The quantity of the at least one chemical entity in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, such as from about 1 mg to 300 mg, for example 10 mg to 200 mg, according to the particular application. The amount administered will vary depending on the particular IC50 value of the at least one chemical entity used and the judgment of the attending clinician taking into consideration factors such as health, weight, and age. In combinational applications in which the at least one chemical entity described herein is not the sole active ingredient, it may be possible to administer lesser amounts of the at least one chemical entity and still have therapeutic or prophylactic effect.

[0183] In some embodiments, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

[0184] The actual dosage employed may be varied depending upon the requirements of the subject and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the at least one chemical entity. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

[0185] The amount and frequency of administration of the at least one chemical entities described herein, and if applicable other additional therapeutic agents, will be regulated according to the judgment of the attending clinician (physician) considering such factors as age, condition and size of the subject as well as severity of the disease being treated.

[0186] Also, in general, the at least one chemical entities described herein need not be administered in the same pharmaceutical composition as other additional therapeutic agent, and may, because of different physical and chemical characteristics, be administered by a different route. For example, the chemical entities / compositions may be administered orally to generate and maintain good blood levels thereof, while the additional therapeutic agent may be administered intravenously. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the Agent Ref.16525.0001-00304 knowledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

[0187] The particular choice of chemical entity (and where appropriate, additional therapeutic agent) will depend upon the diagnosis of the attending physicians and their judgment of the condition of the subject and the appropriate treatment protocol.

[0188] The chemical entities described herein (and where appropriate additional therapeutic agent) may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the proliferative disease, the condition of the subject, and the actual choice of chemotherapeutic agent and / or radiation to be administered in conjunction (i.e., within a single treatment protocol) with the chemical entity / composition.

[0189] In combinational applications and uses, the chemical entity / composition and the additional therapeutic agent need not be administered simultaneously or essentially simultaneously, and the initial order of administration of the chemical entity / composition, and the additional therapeutic agent, may not be important. Thus, the at least one chemical entity described herein may be administered first followed by the administration of the additional agentagent; or the additional therapeutic agent may be administered first followed by the administration of the at least one chemical entity described herein. This alternate administration may be repeated during a single treatment protocol. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the subject. For example, the additional therapeutic agent may be administered first, and then the treatment continued with the administration of the at least one chemical entity described herein followed, where determined advantageous, by the administration of the additional therapeutic agent, and so on until the treatment protocol is complete.

[0190] Thus, in accordance with experience and knowledge, the practicing physician can modify each protocol for the administration of a chemical entity / composition for treatment according to the individual subject 's needs, as the treatment proceeds.

[0191] The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the subject as well as more definite signs such as relief of disease-related symptoms. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment. Agent Ref.16525.0001-00304 EXAMPLES

[0192] The following examples serve to more fully describe the manner of using the subject matter of the present disclosure. These examples are presented for illustrative purposes and should not serve to limit the true scope of the present disclosure.

[0193] In carrying out the procedures of the methods described herein, it is of course to be understood that reference to particular buffers, media, reagents, cells, culture conditions and the like are not intended to be limiting, but are to be read so as to include all related materials that one of ordinary skill in the art would recognize as being of interest or value in the particular context in which that discussion is presented. For example, it is often possible to substitute one buffer system or culture medium for another and still achieve similar, if not identical, results. Those of skill in the art will have sufficient knowledge of such systems and methodologies so as to be able, without undue experimentation, to make such substitutions as will optimally serve their purposes in using the methods and procedures disclosed herein. Example 1: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo- 2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,5-b]pyridine-3-carboxamide

[0194] To a mmol, 2.3 equiv) in DMSO (100 mL) was added dimethyl malonate (23.2 g, 145.1 mmol, 2.3 equiv). The mixture was stirred at rt for 0.5 h.2-Chloro-3-nitropyridine (10.0 g, 63.1 mmol, 1.0 equiv) was added. The mixture was stirred at 100 °C for 1 h and cooled to rt. Saturated NH4Cl solution (200 mL) was added. The mixture was extracted with EA (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to afford diethyl 2-(3-nitropyridin-2-yl)malonate (16.4 g, 92%) as a yellow oil. Agent Ref.16525.0001-00304

[0195] To a solution of g, 40.4 mmol, 1.0 equiv) in DMSO (100 mL) were H2O (727 mg, 40.4 mmol, 1.0 equiv). The mixture was stirred at 120 °C for 16 h and cooled to rt. The reaction mixture was poured into brine (200 mL) and extract with EA (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford ethyl 2-(3-nitropyridin-2-yl)acetate (7.6 g, 89%) as a red oil, which was used in the next step without further purification.

[0196] A solution of mmol, 1.0 equiv) in EtOH (50 mL) was 2-(3-nitropyridin-2- yl)acetate (7.6 g, 36.2 mmol, 1.0 equiv) and isopentyl nitrite (433 mg, 36.2 mmol, 1.0 equiv). The mixture was stirred at rt for 16 h. The reaction mixture was concentrated and EA (100 mL) was added. The organic layer was washed with saturated NaHCO3solution (30 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated to afford ethyl (Z)-2-(hydroxyimino)-2-(3- nitropyridin-2-yl)acetate (8.1 g, crude) as a yellow solid, which was used in the next step without further purification.

[0197] To a solution of 2-yl)acetate (7.6 g, 31.7 mmol, 1.0 equiv) in DMF (50 mL) was added NaH (60%, dispersion in paraffin, 1.3 g, 31.7 mmol, 1.0 equiv). The mixture was stirred at 80 °C for 20 min. The reaction mixture was cooled to rt. Water (150 mL) was added and extracted with EA (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to afford ethyl isoxazolo[4,5-b]pyridine-3- carboxylate (4.6 g, 76%) as a yellow solid. Agent Ref.16525.0001-00304

[0198] To a solution of (4.6 g, 23.9 mmol, 1.0 equiv) in DCM (50 mL) 2.0 equiv) and TFAA (15.1 g, 71.8 mmol, 3.0 equiv). The mixture was stirred at rt for 16 h. The reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to afford 3-(ethoxycarbonyl)isoxazolo[4,5- b]pyridine 4-oxide (4.1 g, 82%) as a yellow solid.

[0199] To a solution (4.1 g, 19.7 mmol, 1.0 equiv) in DCE (30 was g, . The mixture was stirred at rt for 16 h. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (DCM / MeOH = 30 / 1, v / v) to afford ethyl 5- chloroisoxazolo[4,5-b]pyridine-3-carboxylate (2.7 g, 61%) as a yellow solid.

[0200] To a solution (2.7 g, 10.3 mmol, 1.0 equiv) in DCM (30 mL) were added carbamide peroxide (1.9 g, 20.6 mmol, 2.0 equiv) and TFAA (6.48 g, 30.8 mmol, 3.0 equiv). The mixture was stirred at rt for 16 h. The reaction mixture was concentrated, and the resulting residue was purified silica gel column chromatography chromatography (DCM / MeOH = 20 / 1, v / v) to afford 5-chloro-3- (ethoxycarbonyl)isoxazolo[4,5-b]pyridine 4-oxide (1.9 g, 76%) as a yellow solid.

[0201] A solution of 5- 4-oxide (710 mg, 2.9 mmol, 1.0 eq.) in POCl3(10 mL) was stirred at 110 °C for 1 h. The mixture was concentrated and the resulting residue was purified by silica gel column chromatography (DCM / MeOH = Agent Ref.16525.0001-00304 20 / 1, v / v) to afford ethyl 5,7-dichloroisoxazolo[4,5-b]pyridine-3-carboxylate (460 mg, 60%) as a white solid.

[0202] To a solution (460 mg, 1.76 mmol, 1.0 equiv) in -N-methyl- methanamine (532 mg, 3.52 mmol, 2.0 equiv) and DIEA (681 mg, 5.28 mmol, 3.0 equiv). The mixture was stirred at 80 °C for 16 h. Water (100 mL) was added, and the mixture was extracted with EA (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to afford ethyl 5-chloro-7-((4-methoxybenzyl)(methyl)amino)isoxazolo[4,5-b]pyridine-3-carboxylate (530 mg, 80%) as a yellow oil.

[0203] To a [4,5- b]pyridine-3-carboxylate (200 mg, 0.53 mmol, 1.0 equiv) in dioxane (5 mL) were added 3- amino-2H-[1,2'-bipyridin]-2-one (120 mg, 0.64 mmol, 1.2 equiv), APhos Pd G2 (30 mg, 0.05 mmol, 0.1 equiv) and Cs2CO3(346 mg, 1.06 mmol, 2.0 equiv). The mixture was stirred at 110 °C for 3 h under N2. The mixture was concentrated and the resulting residue was purified by silica gel column chromatography (PE / EA = 2 / 1, v / v) to afford ethyl 7-((4- methoxybenzyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,5- b]pyridine-3-carboxylate (120 mg, 43%) as a yellow solid.

[0204] To a [1,2'- bipyridin]-3-yl)amino)isoxazolo[4,5-b]pyridine-3-carboxylate (120 mg, 0.23 mmol, 1.0 equiv) in THF (2 mL) was added LiOH^H2O (14 mg, 0.35 mmol, 1.5 equiv). The mixture was stirred at 0 °C for 1 h. The mixture was acidified to pH 6 with a 1 N aqueous HCl solution and extracted Agent Ref.16525.0001-00304 with DCM (5 mL× 3). The mixture was dried over MgSO4, filtered, and concentrated to afford 7-((4-methoxybenzyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,5- b]pyridine-3-carboxylic acid (110 mg, crude) as a yellow solid, which was used in the next step without further purification.

[0205] To -3- yl)amino) were added (1R,2R)-2-methoxycyclobutan-1-amine hydrochloride (16 mg, 0.13 mmol, 1.1 equiv), 1- methylimidazole (21 mg, 0.24 mmol, 2.0 equiv) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (37 mg, 0.13 mmol, 1.1 equiv). The mixture was stirred at rt for 2 h. The mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to afford 7-((4-methoxybenzyl)(methyl)amino)-N- ((1R,2R)-2-methoxycyclobutyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,5- b]pyridine-3-carboxamide (20 mg, 29%) as a yellow solid.

[0206] To methoxycyclobutyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,5-b]pyridine-3- carboxamide (20 mg, 0.03 mmol, 1.0 equiv) in DCM (3 mL) was added TfOH (1 mL). The mixture was stirred at 0 °C for 1 h. The resulting mixture was washed with saturated NaHCO3solution, brine and dried over MgSO4. After filtration and concentration, the resulting residue was purified by Pre-HPLC to afford N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2- oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,5-b]pyridine-3-carboxamide (2 mg, 13%) as a white solid. LRMS (M+H+) m / z calculated 462.2, found 462.1.1H NMR (DMSO-d6400 MHz) δ 9.10 (d, J = 8.8 Hz, 1H), 8.72 (s, 1H), 8.64-8.65 (m, 1H), 8.55 (dd, J = 7.6, 1.6 Hz, 1H), 8.02- 8.06 (m, 1H), 7.83-7.86 (m, 1 H), 7.52-7.54 (m, 1H), 7.47 (dd, J = 7.2, 2.0 Hz, 1H), 7.41 (q, J = 4.4 Hz, 1H), 6.71 (s, 1H), 6.39 (t, J = 7.2 Hz, 1H), 4.033-4.41 (m, 1H), 3.84-3.89 (m, 1H), 3.25 (s, 3H), 2.86 (d, J = 4.8 Hz, 3H), 2.08-2.16 (m, 2H), 1.55-1.60 (m, 2 H). Agent Ref.16525.0001-00304 Example 2: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo- 2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0207] To a 1.0 equiv) in dioxane (500 were g, mmol, 1.2 equiv) and Pd(PPh3)Cl2(8.5 g, 12.1 mmol, 0.1 equiv). The mixture was stirred at 100 °C overnight under N2 atmosphere and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to afford 6-chloro-2-(1-ethoxyvinyl)-3-nitropyridin-4-amine (12 g, 56%) as a yellow solid.

[0208] To a solution of amine (22.0 g, 90.5 mmol, 1.0 equiv) in THF (100 mL) was added HCl (2 N, 25 mL). The mixture was stirred at 25 °C overnight. The mixture was diluted with EA (500 mL) and washed with saturated NaHCO3 solution (100 mL × 2), dried and concentrated to afford 1-(4-amino-6-chloro-3-nitropyridin-2- yl)ethanone (19.0 g, 97%) as a yellow solid, which was used in the next step without further purification.

[0209] To a solution of (16.0 g, 74.4 mmol, 1.0 equiv) in MeOH / EA (300 mL, v / v = 1:1) was added SnCl2 (56.4 g, 297.6 mmol, 4.0 equiv). The mixture was stirred at rt overnight. The reaction mixture was concentrated, diluted with DCM (300 mL). The organic layer was washed with saturated NaHCO3 solution (200 mL × 2), Agent Ref.16525.0001-00304 dried, filtered and concentrated to afford 5-chloro-3-methylisoxazolo[4,3-b]pyridin-7-amine (12.0 g, 88%), which was used in the next step without further purification.

[0210] To a solution of 5- amine (2.1 g, 11.5 mmol, 1.0 equiv) and (Boc) 2O mL) was added DMAP (146 mg, 1.19 mmol, 0.1 equiv). The mixture was stirred at rt for 2 h and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 6 / 1, v / v) to afford tert-butyl (tert-butoxycarbonyl)(5-chloro-3-methylisoxazolo[4,3-b]pyridin-7-yl)carbamate (3.2 g, 73%) as a yellow oil.

[0211] To a solution of [4,3- b]pyridin-7-yl)carbamate (3.2 g, 8.35 mmol, 1.0 equiv) in DCE (30 mL) were added NBS (1.8 g, 10.0 mmol, 1.1 equiv) and AIBN (410 mg, 2.49 mmol, 0.3 equiv). The mixture was stirred at 85 °C overnight and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to afford tert-butyl (3-(bromomethyl)-5-chloroisoxazolo[4,3- b]pyridin-7-yl)(tert-butoxycarbonyl)carbamate (2.5 g, 66%) as a yellow solid.

[0212] To a pyridin-7-yl)(tert- butoxycarbonyl)carbamate (2.5 g, 5.42 mmol, 1.0 equiv) in DMF (50 mL) were added 4- nitrobenzoic acid (1.1 g, 6.85 mmol, 1.2 equiv) and K2CO3(2.2 g, 16.2 mmol, 3.0 equiv) at 0 °C. The mixture was stirred at the rt for 2 h, saturated NH4Cl solution (60 mL) was added, and the mixture was extracted with EA (100 mL× 2). The combined organic layers were washed with brine, dried, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to afford (7-(bis(tert-butoxycarbonyl)amino)-5- chloroisoxazolo[4,3-b]pyridin-3-yl)methyl 4-nitrobenzoate (2.8 g, 95%) as a yellow oil. Agent Ref.16525.0001-00304

[0213] To a solution [4,3-b]pyridin-3- yl)methyl 4- was added LiOH^H2O (920 mg, 21.9 mmol, 1.5 equiv) in H2O (30 mL). The mixture was stirred at rt for 2 h, diluted with EA (300 mL). The organic layer was washed with saturated NaHCO3 solution (100 mL× 2), dried, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to afford tert-butyl (tert-butoxycarbonyl)(5-chloro-3- (hydroxymethyl)isoxazolo[4,3-b]pyridin-7-yl)carbamate (5.1 g, 88%) as a yellow solid.

[0214] To a solution of (hydroxymethyl)isoxazolo[4,3-b]pyridin-7-yl)carbamate (5.1 g, 12.78 mmol, 1.0 equiv) in DCM (100 mL) was added Dess-Martin periodinane (6.5 g, 15.34 mmol, 1.2 equiv). The mixture was stirred at rt overnight, and diluted with DCM (200 mL). The organic layer was washed with saturated NaHCO3solution (100 mL× 2), dried, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 10 / 1, v / v) to afford tert-butyl (tert- butoxycarbonyl)(5-chloro-3-formylisoxazolo[4,3-b]pyridin-7-yl)carbamate (3.2 g, 63%) as a yellow solid.

[0215] To a solution [4,3- b]pyridin-7-yl)carbamate (3.2 g, 8.06 mmol, 1.0 equiv) in ACN (30 mL) were added NIS (4.5 g, 20.1 mmol, 2.5 equiv), K2CO3(2.8 g, 20.1 mmol, 2.5 equiv) and MeOH (515.8 mg, 16.1 mmol, 2.0 equiv). The mixture was stirred at rt overnight, diluted with DCM (120 mL), washed with saturated NaHCO3solution (50 mL× 2), dried, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to afford methyl 7- (bis(tert-butoxycarbonyl)amino)-5-chloroisoxazolo[4,3-b]pyridine-3-carboxylate (2.2 g, 81%) as a yellow oil. Agent Ref.16525.0001-00304

[0216] To a solution of 5-chloroisoxazolo[4,3- b]pyridine-3-carboxylate mL) was added TFA (0.07 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, diluted with DCM (20 mL), washed with saturated NaHCO3 solution (50 mL× 2), dried, filtered and concentrated to afford methyl 7-((tert- butoxycarbonyl)amino)-5-chloroisoxazolo[4,3-b]pyridine-3-carboxylate (60 mg, 85%) as a yellow oil.

[0217] To a solution [4,3- b]pyridine-3- mg, were added CH3I (38 mg, 0.27 mmol, 1.5 equiv) and Cs2CO3 (117.0 mg, 0.36 mmol, 2.0 equiv). The mixture was stirred at rt for 3 h, diluted with EA (30 mL). The organic layer was washed with saturated NH4Cl solution, dried, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to afford methyl 7-((tert- butoxycarbonyl)(methyl)amino)-5-chloroisoxazolo[4,3-b]pyridine-3-carboxylate (38 mg, 62%) as a yellow oil.

[0218] To a [4,3- b]pyridine-3-carboxylate (38 mg, 0.11 mmol, 1.0 equiv) in dioxane (10 mL) were added 3- amino-2H-[1,2'-bipyridin]-2-one (24.3 mg, 0.13 mmol, 1.2 equiv), BrettPhos (16.1 mg, 0.03 mmol, 0.3 equiv), BrettPhos Pd G3 (27.2 mg, 0.03 mmol, 0.3 equiv) and Cs2CO3 (71.5 mg, 0.22 mmol, 2.0 equiv). The mixture was stirred at 70 °C for 2 h under N2 atmosphere and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 1 / 3, v / v) to afford methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]- 3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (39 mg, 72%) as a yellow solid. Agent Ref.16525.0001-00304

[0219] To a 2H-[1,2'- bipyridin]-3- 1.0 equiv) in THF (5 mL) was added LiOH^H2O (7.6 mg, 0.18 mmol, 3.0 equiv) in H2O (30 mL). The mixture was stirred at 25 °C for 3 h. The mixture was concentrated to afford 7-((tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylic acid (30 mg, crude) which was used in the next step without further purification.

[0220] To bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (30 mg, 0.06 mmol, 1.0 equiv) in DMF (5 mL) were added (1R,2R)-2-methoxycyclobutan-1-amine hydrochloride (8.1 mg, 0.06 mmol, 1.0 equiv), HATU (26.6 mg, 0.07 mmol, 1.2 equiv) and TEA (18.2 mg, 0.18 mmol, 3.0 equiv). The mixture was stirred at rt for 2 h and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to afford tert-butyl (3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridin-7-yl)(methyl)carbamate (30 mg, 90%) as a white solid.

[0221] ((2-oxo-2H- [1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (43 mg, 0.08 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL) at 0 °C. The mixture was stirred at rt for 2 h, diluted with DCM (20 mL). The organic layer was washed with saturated NaHCO3 solution, dried, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1, v / v) to afford N-((1R,2R)-2-methoxycyclobutyl)-7- (methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3- Agent Ref.16525.0001-00304 carboxamide (27 mg, 75%) as a white solid. LRMS (M+H+) m / z calculated 462.2, found 462.2.1H NMR (DMSO-d6, 400 MHz) δ 9.02 (s, 1H), 8.64-8.60 (m, 2H), 8.54 (d, J = 4.4 Hz, 1H), 8.06-8.03 (m, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.59-7.52 (m, 3H), 6.45-6.41 (m, 2H), 4.34-4.30 (m, 1H), 3.87-3.82 (m, 1H), 3.18 (s, 3H), 2.87-2.85 (d, J = 4.4 Hz, 3H), 2.19-2.08 (m, 2H), 1.59-1.45 (m, 2H). Example 3: Preparation of 5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)- 2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0222] To a DMA (30 mL) were added 3-aminopyridin-2(1H)-one (2.3 g, 20.9 mmol, 1.2 equiv) and K3PO4(7.4 g, 34.9 mmol, 2.0 equiv). The mixture was stirred at 100 °C overnight, diluted with DCM (50 mL). The organic layer was washed with saturated NH4Cl solution, dried, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to afford 3-amino-3'-fluoro-2H-[1,2'-bipyridin]-2-one (1.7 g, 48%) as a yellow solid.

[0223] To a [4,3- b]pyridine-3-carboxylate (80 mg, 0.23 mmol, 1.0 equiv) in toluene (10 mL) were added 3- amino-3'-fluoro-2H-[1,2'-bipyridin]-2-one (51.3 mg, 0.25 mmol, 1.1 equiv), BrettPhos (37.5 mg, 0.07 mmol, 0.3 equiv), BrettPhos Pd G3 (63.4 mg, 0.07 mmol, 0.3 equiv) and Cs2CO3 (149.5 mg, 0.46 mmol, 2.0 equiv). The mixture was stirred at 100 °C for 8 h under N2atmosphere and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = Agent Ref.16525.0001-00304 1 / 3, v / v) to afford methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((3'-fluoro-2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (50 mg, 42%) as a yellow solid.

[0224] To a fluoro-2-oxo-2H- [1,2'-bipyridin]- mmol, 1.0 equiv) in THF (5 mL) was added LiOH^H2O (12.6 mg, 0.3 mmol, 3.0 equiv) in H2O (1 mL). The mixture was stirred at 25 °C for 3 h. The mixture was concentrated to afford 7-((tert- butoxycarbonyl)(methyl)amino)-5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (50 mg, crude), which was used in the next step without further purification.

[0225] To 2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (50 mg, 0.1 mmol, 1.0 equiv) in DMF (5 mL) were added (1R,2R)-2-methoxycyclobutan-1-amine hydrochloride (16.3 mg, 0.12 mmol, 1.2 equiv), HATU (45.6 mg, 0.12 mmol, 1.2 equiv) and TEA (30.3 mg, 0.3 mmol, 3.0 equiv). The mixture was stirred at rt for 2 h and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to afford tert-butyl (5- ((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (50 mg, 86%) as a yellow solid.

[0226] -3- (((1R,2R)-2-methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (50 mg, 0.09 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL) at 0 °C. The mixture was stirred at rt for 2 h, diluted with DCM (20 mL), washed with saturated NaHCO3solution, dried, Agent Ref.16525.0001-00304 filtered and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1, v / v) to afford 5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3- carboxamide (33.6 mg, 78%) as a yellow solid. LRMS (M+H+) m / z calculated 480.2, found 480.1.1H NMR (DMSO-d6, 400 MHz) δ 9.02 (s, 1H), 8.67 (dd, J = 7.2, 2.4 Hz, 2H), 8.53-8.50 (m, 2H), 8.08-8.03 (m, 1H), 7.77-7.70 (m, 1H), 7.59-7.57 (m, 1H), 7.44 (dd, J = 6.8, 1.6 Hz, 1H), 6.45 (t, J = 7.2 Hz, 1H), 6.41 (s, 1H), 4.34-4.30 (m, 1H), 3.86-3.82 (m, 1H), 3.23 (s, 3H), 2.86- 2.84 (d, J = 4.4 Hz, 3H), 2.17-2.10 (m, 2H), 1.59-1.51 (m, 2H). Example 4: Preparation of 5-((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)- 2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0227] To a DMA (30 mL) were added 3-aminopyridin-2(1H)-one (1.4 g, 13.0 mmol, 1.2 equiv) and K3PO4 (4.6 g, 21.8 mmol, 2.0 equiv). The mixture was stirred at 100 °C overnight, diluted with DCM (50 mL). The organic layer was washed with saturated NH4Cl solution, dried, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to afford 3-amino-2-oxo-2H-[1,2'-bipyridine]-3'-carbonitrile (700 mg, 30%) as a yellow solid.

[0228] To a [4,3- b]pyridine-3-carboxylate (80 mg, 0.23 mmol, 1.0 equiv) in toluene (10 mL) were added 3- amino-2-oxo-2H-[1,2'-bipyridine]-3'-carbonitrile (53 mg, 0.25 mmol, 1.1 equiv), BrettPhos (37.5 Agent Ref.16525.0001-00304 mg, 0.07 mmol, 0.3 equiv), BrettPhos Pd G3 (63.4 mg, 0.07 mmol, 0.3 equiv) and Cs2CO3 (149.5 mg, 0.46 mmol, 2.0 equiv). The mixture was stirred at 100 °C for 8 h under N2atmosphere and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 1 / 3, v / v) to afford methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((3'-cyano-2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (80 mg, 67%) as a yellow solid.

[0229] To a 2-oxo-2H- [1,2'- - mmol, 1.0 equiv) in THF (5 mL) was added LiOH^H2O (18.9 mg, 0.45 mmol, 3.0 equiv) in H2O (1 mL). The mixture was stirred at 25 °C for 3 h. The mixture was concentrated to afford 7-((tert- butoxycarbonyl)(methyl)amino)-5-((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (75 mg, crude), which was used in the next step without further purification.

[0230] 2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (75 mg, 0.15 mmol, 1.0 equiv) in DMF (5 mL) were added (1R,2R)-2-methoxycyclobutan-1-amine hydrochloride (24.5 mg, 0.18 mmol, 1.2 equiv), PyBOP (93.6 mg, 0.18 mmol, 1.2 equiv) and TEA (45.4 mg, 0.45 mmol, 3.0 equiv). The mixture was stirred at rt for 2 h and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to afford tert-butyl (5- ((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (75 mg, 85%) as a yellow solid. Agent Ref.16525.0001-00304

[0231] To a solution of tert-butyl (5-((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3- (((1R,2R)-2-methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (75 mg, 0.12 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL) at 0 °C. The mixture was stirred at rt for 2 h, diluted with DCM (20 mL), washed with saturated NaHCO3solution, dried, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1, v / v) to afford 5-((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3- carboxamide (28.3 mg, 49%) as a yellow solid. LRMS (M+H+) m / z calculated 487.2, found 487.1.1H NMR (DMSO-d6, 400 MHz) δ 9.05 (s, 1H), 8.95 (dd, J = 4.8, 1.6 Hz, 2H), 8.73 (dd, J = 7.2, Hz, 1H), 8.65 (dd, J = 8.0, 1.6 Hz, 1H), 8.54 (d, J = 8.8 Hz, 1H), 7.83 (dd, J = 7.6, 4.8 Hz, , 7.60-7.59 (m, 1H), 7.48 (dd, J = 7.2, 2.0 Hz, 1H), 6.50 (t, J = 7.2, 1H), 6.46 (s, 1H), 4.34-4.31 (m, 1H), 3.88-3.86 (m, 1H), 3.23 (s, 3H), 2.86 (d, J = 4.8 Hz, 3H), 2.17-2.10 (m, 2H), 1.25-1.21 (m, 2H). Example 5: Preparation of 5-((5'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)- 2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0232] To a solution in DMA (30 mL) was added 3-aminopyridin-2(1H)-one (721 mg, 6.6 mmol, 1.2 equiv) and K3PO4 (2.3 g, 11.0 mmol, 2.0 equiv). The mixture was stirred at 100 °C overnight, diluted with DCM (50 mL). The organic layer was washed with saturated NH4Cl solution, dried, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to afford 3-amino-2-oxo-2H-[1,2'-bipyridine]-5'-carbonitrile (1.1 g, 94%) as a yellow solid. Agent Ref.16525.0001-00304

[0233] To a [4,3- b]pyridine- added 3- amino-2-oxo-2H-[1,2'-bipyridine]-5'-carbonitrile (50 mg, 0.23 mmol, 1.1 equiv), BrettPhos (37 mg, 0.07 mmol, 0.3 equiv), BrettPhos Pd G3 (63.4 mg, 0.07 mmol, 0.3 equiv) and Cs2CO3 (150 mg, 0.46 mmol, 2.0 equiv). The mixture was stirred at 100 °C for 6 h under N2atmosphere and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to afford methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((5'-cyano-2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (80 mg, 67%) as a yellow solid.

[0234] To a 2-oxo-2H- [1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (80 mg, 0.15 mmol, 1.0 equiv) in THF (5 mL) was added LiOH^H2O (18.9 mg, 0.45 mmol, 3.0 equiv) in H2O (1 mL). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated to afford 7-((tert- butoxycarbonyl)(methyl)amino)-5-((5'-cyano-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (80 mg, crude), which was used in the next step without further purification.

[0235] 2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (80 mg, 0.15 mmol, 1.0 equiv) in DMF (5 mL) were added (1R,2R)-2-methoxycyclobutan-1-amine hydrochloride (20.4 mg, 0.15 mmol, 1.0 equiv), PyBOP (93.6 mg, 0.18 mmol, 1.2 equiv) and TEA (45.5 mg, 0.45 mmol, 3.0 equiv). The mixture was stirred at rt for 2 h and concentrated. The resulting residue was Agent Ref.16525.0001-00304 purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to afford tert-butyl (5- ((5'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (50 mg, 43%) as a yellow solid.

[0236] -3- (( - (50 mg, 0.085 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL) at 0 °C. The mixture was stirred at rt for 2 h, diluted with DCM (20 mL). The organic layer was washed with saturated NaHCO3 solution, dried, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1, v / v) to afford 5-((5'-cyano-2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3- b]pyridine-3-carboxamide (9 mg, 22%) as a yellow solid. LRMS (M+H+) m / z calculated 487.2, found 487.0.1H NMR (DMSO-d6, 400 MHz) δ 9.14 (s, 1H), 9.05 (s, 1H), 8.64 (d, J = 7.2 Hz, 1H), 8.57-8.51 (m, 2H), 8.17 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 6.8 Hz, 1H), 7.60 (d, J = 4.4 Hz, 1H), 6.49 (t, J = 7.2 Hz, 1H), 6.44 (s, 1H), 4.34-4.39 (m, 1H), 3.87-3.82 (m, 1H), 3.23 (s, 3H), 2.86 (d, J = 4.4 Hz, 3H), 2.17-2.10 (m, 2H), 1.61-1.50 (m, 2H). Example 6: Preparation of 5-((5'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)- 2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0237] To a in dioxane (30 mL) was added 3-aminopyridin-2(1H)-one (750 mg, 6.8 mmol, 1.2 equiv), K2CO3(1.9 g, 14.2 Agent Ref.16525.0001-00304 mmol, 2.5 equiv), DMEDA (13 mg, 1.42 mmol, 0.25 equiv) and CuI (162 mg, 0.85 mmol, 0.15 equiv). The mixture was stirred at 115 °C overnight. The reaction mixture was filtered and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 30 / 1, v / v) to afford 3-amino-5'-fluoro-2H-[1,2'-bipyridin]-2-one (300 mg, 26%) as a brown solid.

[0238] To a [4,3- b]pyridine-3- mg, were added 3- amino-5'-fluoro-2H-[1,2'-bipyridin]-2-one (47 mg, 0.23 mmol, 1.1 equiv), BrettPhos (37 mg, 0.07 mmol, 0.3 equiv), BrettPhos Pd G3 (63.4 mg, 0.07 mmol, 0.3 equiv) and Cs2CO3(150 mg, 0.46 mmol, 2.0 equiv). The mixture was stirred at 100 °C for 6 h under N2 atmosphere and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to afford methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((5'-fluoro-2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (75 mg, 64%) as a yellow oil.

[0239] 2-oxo-2H- [1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (75 mg, 0.15 mmol, 1.0 equiv) in THF (5 mL) was added LiOH^H2O (18.9 mg, 0.45 mmol, 3.0 equiv) in H2O (1 mL). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated to afford 7-((tert- butoxycarbonyl)(methyl)amino)-5-((5'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (80 mg, crude), which was used in the next step without further purification. Agent Ref.16525.0001-00304

[0240] To a solution of 7-((tert-butoxycarbonyl)(methyl)amino)-5-((5'-cyano-2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (75 mg, 0.15 mmol, 1.0 equiv) in DMF (5 mL) were added (1R,2R)-2-methoxycyclobutan-1-amine hydrochloride (20.4 mg, 0.15 mmol, 1.0 equiv), PyBOP (93.6 mg, 0.18 mmol, 1.2 equiv) and TEA (45.5 mg, 0.45 mmol, 3.0 equiv). The mixture was stirred at rt for 2 h and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to afford tert-butyl (5- ((5'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (50 mg, 58%) as a yellow solid.

[0241] -3- (( - (50 mg, 0.085 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL) at 0 °C. The mixture was stirred at rt for 2 h, diluted with DCM (20 mL). The organic layer was washed with saturated NaHCO3solution, dried, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1, v / v) to afford 5-((5'-fluoro-2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3- b]pyridine-3-carboxamide (9 mg, 22%) as a yellow solid. LRMS (M+H+) m / z calculated 480.2, found 480.1.1H NMR (DMSO-d6, 400 MHz) δ 9.01 (s, 1H), 8.65 (s, 1H), 8.63 (d, J = 7.6 Hz, 1H), 8.52 (d, J = 8.4 Hz, 1H), 8.01-7.93 (m, 2H), 7.59-7.54 (m, 2H), 6.45-6.42 (m, 2H), 4.35- 4.31 (m, 1H), 3.86-3.84 (m, 1H), 3.23 (s, 3H), 2.86 (d, J = 3.2 Hz, 3H), 2.18-2.10 (m, 2H), 1.59- 1.50 (m, 2H). Example 7: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-5-((3'-methyl-2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide Agent Ref.16525.0001-00304

[0242] To a solution of 2- 1.0 equiv) in dioxane (30 mL) were added 3- - equiv), DMF (0.1mL) and K2CO3(3.2 g, 23.4 mmol, 2.0 equiv). The mixture was stirred at 100 °C overnight and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to afford 3-amino-3'-methyl-2H-[1,2'-bipyridin]-2-one (150 mg, 6%) as a yellow solid.

[0243] To a [4,3- b]pyridine-3-carboxylate (80 mg, 0.23 mmol, 1.0 equiv) in toluene (10 mL) were added 3- amino-3'-methyl-2H-[1,2'-bipyridin]-2-one (50.2 mg, 0.25 mmol, 1.1 equiv), BrettPhos (37.5 mg, 0.07 mmol, 0.3 equiv), BrettPhos Pd G3 (63.4 mg, 0.07 mmol, 0.3 equiv) and Cs2CO3 (149.5 mg, 0.46 mmol, 2.0 equiv). The mixture was stirred at 100 °C for 8 h under N2atmosphere and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 1 / 3, v / v) to afford methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5- ((3'-methyl-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (70 mg, 60%) as a yellow solid.

[0244] To a methyl-2-oxo-2H- [1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (70 mg, 0.14 mmol, 1.0 equiv) in THF (5 mL) was added LiOH^H2O (17.6 mg, 0.42 mmol, 3.0 equiv) in H2O (1 mL). The mixture was stirred at 25 °C for 3 h. The mixture was concentrated to afford 7-((tert- butoxycarbonyl)(methyl)amino)-5-((3'-methyl-2-oxo-2H-[1,2'-bipyridin]-3- Agent Ref.16525.0001-00304 yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (68 mg, crude), which was used in the next step without further purification.

[0245] 2H-[1,2'- - 1.0 equiv) in DMF (5 mL) were added (1R,2R)-2-methoxycyclobutan-1-amine hydrochloride (23.1 mg, 0.17 mmol, 1.2 equiv), PyBOP (88.4 mg, 0.17 mmol, 1.2 equiv) and TEA (42.4 mg, 0.42 mmol, 3.0 equiv). The mixture was stirred at rt for 2 h and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to afford tert-butyl (3- (((1R,2R)-2-methoxycyclobutyl)carbamoyl)-5-((3'-methyl-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (50 mg, 62%) as a yellow solid.

[0246] ((3'-methyl- 2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (50 mg, 0.09 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL) at 0 °C. The mixture was stirred at rt for 2 h, diluted with DCM (20 mL), washed with saturated NaHCO3 solution, dried, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1, v / v) to afford N-((1R,2R)-2-methoxycyclobutyl)-5-((3'-methyl-2-oxo-2H- [1,2'-bipyridin]-3-yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide (16.1 mg, 38%) as a yellow solid. LRMS (M+H+) m / z calculated 476.2, found 476.1.1H NMR (DMSO-d6, 400 MHz) δ 8.97 (s, 1H), 8.67 (d, J = 7.2 Hz, 2H), 8.52 (d, J = 8.4 Hz, 1H), 8.46 (d, J = 4.0 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.60-7.56 (m, 1H), 7.53-7.50 (m, 1H), 7.30-7.28 (m, 1H), 6.43- 6.41 (m, 2H), 4.34-4.31 (m, 1H), 3.88-3.85 (m, 1H), 3.23 (s, 3H), 2.86 (d, J = 4.8 Hz, 3H), 2.18- 2.10 (m, 2H), 2.14 (s, 3H), 1.57-1.54 (m, 2H). Agent Ref.16525.0001-00304 Example 8: Preparation of 5-((3'-methoxy-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N- ((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0247] To a solution of (500 mg, 2.4 mmol, 1.0 equiv) in MeOH (30 was g, 10.0 equiv). The mixture was stirred at 70 °C overnight and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to afford 3-amino-3'-methoxy-2H- [1,2'-bipyridin]-2-one (300 mg, 57%) as a white solid.

[0248] To a [4,3- b]pyridine-3-carboxylate (80 mg, 0.23 mmol, 1.0 equiv) in toluene (10 mL) were added 3- amino-3'-methoxy-2H-[1,2'-bipyridin]-2-one (54.2 mg, 0.25 mmol, 1.1 equiv), BrettPhos (37.5 mg, 0.07 mmol, 0.3 equiv), BrettPhos Pd G3 (63.4 mg, 0.07 mmol, 0.3 equiv) and Cs2CO3 (149.5 mg, 0.46 mmol, 2.0 equiv). The mixture was stirred at 100 °C for 8 h under N2atmosphere and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 1 / 3, v / v) to afford methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((3'-methoxy-2-oxo-2H- [1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (85 mg, 65%) as a yellow solid. Agent Ref.16525.0001-00304

[0249] To a solution of methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((3'-methoxy-2-oxo- 2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (85 mg, 0.16 mmol, 1.0 equiv) in THF (5 mL) was added LiOH^H2O (20.1 mg, 0.48 mmol, 3.0 equiv) in H2O (1 mL). The mixture was stirred at 25 °C for 3 h. The mixture was concentrated to afford 7-((tert- butoxycarbonyl)(methyl)amino)-5-((3'-methoxy-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (75 mg, crude), which was used in the next step without further purification.

[0250] 2H-[1,2'- - mg, 1.0 equiv) in DMF (5 mL) were added (1R,2R)-2-methoxycyclobutan-1-amine hydrochloride (24.5 mg, 0.18 mmol, 1.2 equiv), PyBOP (93.6 mg, 0.18 mmol, 1.2 equiv) and TEA (45.4 mg, 0.45 mmol, 3.0 equiv). The mixture was stirred at rt for 2 h and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to afford tert-butyl (5- ((3'-methoxy-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (70 mg, 79%) as a yellow solid.

[0251] -3- (((1R,2R)-2-methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (70 mg, 0.12 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL) at 0 °C. The mixture was stirred at rt for 2 h, diluted with DCM (20 mL). The organic layer was washed with saturated NaHCO3solution, dried, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1, v / v) to afford 5-((3'-methoxy-2-oxo-2H- [1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3- b]pyridine-3-carboxamide (33.3 mg, 56%) as a yellow solid. LRMS (M+H+) m / z calculated 492.2, found 492.1.1H NMR (DMSO-d6, 400 MHz) δ 8.95 (s, 1H), 8.60 (d, J = 7.2 Hz, 1H), Agent Ref.16525.0001-00304 8.52 (d, J = 8.8 Hz, 1H), 8.18 (d, J = 4.8 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.60-7.56 (m, 2H), 7.26 (d, J = 7.2 Hz, 1H), 6.39-6.34 (m, 2H), 4.35-4.31 (m, 1H), 3.88-3.85 (m, 1H), 3.82 (s, 3H), 3.23 (s, 3H), 2.85 (d, J = 4.4 Hz, 3H), 2.18-2.10 (m, 2H), 1.59-1.51 (m, 2H). Example 9: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-5-((5'-methyl-2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0252] To a solution equiv) in DCM (600 mL) were added g, g, 454.6 mmol, 2.0 equiv). The mixture was stirred at 25 °C overnight. The reaction mixture was washed with saturated NH4Cl solution, dried, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to afford benzyl (2-oxo-1,2- dihydropyridin-3-yl)carbamate (30.0 g, 55%) as a white solid.

[0253] To a solution of (2.0 g, 11.6 mmol, 1.0 equiv) in dioxane (70 mL) were added 2-bromo-5-methylpyridine (1.5 g, 13.9 mmol, 1.2 equiv), K2CO3 (4.0 g, 29.1 mmol, 2.5 equiv) and DMF (1 mL). The mixture was stirred at 110 °C overnight and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to afford benzyl (5'-methyl-2-oxo-2H-[1,2'-bipyridin]-3- yl)carbamate (1.5 g, 38%) as a yellow solid. Agent Ref.16525.0001-00304

[0254] To a solution of benzyl (5'-methyl-2-oxo-2H-[1,2'-bipyridin]-3-yl)carbamate (1.5 g, 4.5 mmol, 1.0 equiv) in MeOH (20 mL) was added 10% Pd / C (300 mg). The mixture was stirred at 25 °C under H2 (1.1 MPa) overnight. The reaction mixture was filtrated and concentrated to afford 3-amino-5'-methyl-2H-[1,2'-bipyridin]-2-one (850 mg, 94%) as an off-white solid.

[0255] To a [4,3- b]pyridine-3- mg, were added 3- amino-2-oxo-2H-[1,2'-bipyridine]-5'-carbonitrile (64 mg, 0.32 mmol, 1.1 equiv), BrettPhos (48.2 mg, 0.09 mmol, 0.3 equiv), BrettPhos Pd G3 (81.5 mg, 0.09 mmol, 0.3 equiv) and Cs2CO3 (189 mg, 0.58 mmol, 2.0 equiv). The mixture was stirred at 100 °C for 6 h under N2atmosphere and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to afford methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((5'-methyl-2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (70 mg, 48%) as a yellow solid.

[0256] To a 2-oxo-2H- [1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (70 mg, 0.14 mmol, 1.0 equiv) in THF (5 mL) was added LiOH^H2O (9 mg, 0.21 mmol, 1.5 equiv) in H2O (1 mL). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated to afford 7-((tert- butoxycarbonyl)(methyl)amino)-5-((5'-methyl-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (70 mg, crude), which was used in the next step without further purification.

[0257] 2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (70 mg, 0.14 mmol, 1.0 equiv) Agent Ref.16525.0001-00304 in DMF (5 mL) were added (1R,2R)-2-methoxycyclobutan-1-amine hydrochloride (19 mg, 0.14 mmol, 1.0 equiv), PyBOP (87 mg, 0.17 mmol, 1.2 equiv) and TEA (42 mg, 0.42 mmol, 3.0 equiv). The mixture was stirred at rt for 2 h and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to afford tert-butyl (3- (((1R,2R)-2-methoxycyclobutyl)carbamoyl)-5-((5'-methyl-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (55 mg, 69%) as a yellow solid.

[0258] (5'-methyl- 2-oxo- - (55 mg, 0.087 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL) at 0 °C. The mixture was stirred at rt for 2 h, diluted with DCM (20 mL), washed with saturated NaHCO3solution, dried, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to afford N-((1R,2R)-2-methoxycyclobutyl)-5-((5'-methyl-2-oxo-2H- [1,2'-bipyridin]-3-yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide (22 mg, 22%) as a yellow solid. LRMS (M+H+) m / z calculated 476.2, found 476.1.1H NMR (DMSO-d6, 400 MHz) δ 9.00 (s, 1H), 8.61 (d, J = 6.8 Hz, 1H), 8.52 (d, J = 8.8 Hz, 1H), 8.46 (s, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.58-7.54 (m, 2H), 6.44-6.40 (m, 2H), 6.44 (s, 1H), 4.36-4.31 (m, 1H), 3.86-3.83 (m, 1H), 3.23 (s, 3H), 2.86 (d, J = 4.8 Hz, 3H), 2.39 (s, 3H), 2.18- 2.10 (m, 2H), 1.57-1.53 (m, 2H). Example 10: Preparation of 5-((5'-methoxy-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N- ((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide Agent Ref.16525.0001-00304

[0259] To a solution of 2-bromo-5-methoxypyridine (2.0 g, 10.6 mmol, 1.0 equiv) in dioxane (100 mL) were added 3-aminopyridin-2(1H)-one (721 mg, 6.6 mmol, 1.2 equiv), K2CO3(3.7 g, 26.5 mmol, 2.0 equiv), CuI (604 mg, 2.2 mmol, 0.2 equiv) and DMF (5 mL). The mixture was stirred at 110 °C overnight. The reaction mixture was filtered and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to afford 3-amino- 5'-methoxy-2H-[1,2'-bipyridin]-2-one (900 mg, 39%) as an off-white solid.

[0260] To [4,3- b]pyridine-3-carboxylate (100 mg, 0.29 mmol, 1.0 equiv) in toluene (10 mL) were added 3- amino-5'-methoxy-2H-[1,2'-bipyridin]-2-one (69 mg, 0.32 mmol, 1.1 equiv), BrettPhos (48.2 mg, 0.09 mmol, 0.3 equiv), BrettPhos Pd G3 (81.5 mg, 0.09 mmol, 0.3 equiv) and Cs2CO3 (189 mg, 0.58 mmol, 2.0 equiv). The mixture was stirred at 100 °C for 6 h under N2atmosphere and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to afford methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((5'-methoxy-2-oxo-2H- [1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (130 mg, 86%) as a yellow solid.

[0261] To 2-oxo- 2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (130 mg, 0.25 mmol, 1.0 equiv) in THF (5 mL) was added LiOH^H2O (31.4 mg, 0.75 mmol, 1.5 equiv) in H2O (1 mL). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated to afford 7-((tert- butoxycarbonyl)(methyl)amino)-5-((5'-methoxy-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (130 mg, crude) which was used in the next step without further purification. Agent Ref.16525.0001-00304

[0262] 2H-[1,2'- 1.0 equiv) in DMF (5 mL) were added (1R,2R)-2-methoxycyclobutan-1-amine hydrochloride (36.7 mg, 0.27 mmol, 1.0 equiv), PyBOP (168.5 mg, 0.32 mmol, 1.2 equiv) and TEA (81.9 mg, 0.81 mmol, 3.0 equiv). The mixture was stirred at rt for 2 h and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 30 / 1, v / v) to afford tert-butyl (5-((5'-methoxy-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (80 mg, 50%) as a yellow solid.

[0002] Agent Ref.16525.0001-00304 To a solution of tert-butyl (5-((5'-methoxy-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3-(((1R,2R)- 2-methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (80 mg, 0.13 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL) at 0 °C. The mixture was stirred at rt for 2 h, diluted with DCM (20 mL), washed with saturated NaHCO3solution, dried, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 30 / 1, v / v) to afford 5-((5'-methoxy-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)- 2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide (32 mg, 50%) as a yellow solid. LRMS (M+H+) m / z calculated 492.2, found 492.1.1H NMR (DMSO-d6, 400 MHz) δ 8.99 (s, 1H), 8.61 (d, J = 6.8 Hz, 1H), 8.52 (d, J = 8.4 Hz, 1H), 8.31 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.64-7.50 (m, 3H), 6.41-6.39 (m, 2H), 4.35-4.31 (m, 1H), 3.92 (s, 3H), 3.87-3.82 (m, 1H), 3.23 (s, 3H), 2.86 (d, J = 4.4 Hz, 3H), 2.18-2.10 (m, 2H), 1.59-1.50 (m, 2H). Example 11: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1- (oxazol-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0263] To (30 mL) were added 3-aminopyridin-2(1H)-one (671 mg, 6.1 mmol, 1.2 equiv), Na2CO3 (1.1 g, 10.2 mmol, 2.0 equiv), Pd2(dba)3(457 mg, 0.5 mmol, 0.1 equiv) and xantphos (289 mg, 0.5 mmol, 0.1 equiv). The mixture was stirred at 100 ℃ overnight. The reaction mixture was filtered and concentrated. The resulting residue was purified by column column chromatography on silica gel (PE / EA = 1 / 1, v / v) to afford 3-amino-1-(oxazol-2-yl)pyridin-2(1H)-one (90 mg, 10%) as a yellow solid. Agent Ref.16525.0001-00304

[0264] 3-Amino-1-(oxazol-2-yl)pyridin-2(1H)-one was converted to methyl 7-((tert- butoxycarbonyl)(methyl)amino)-5-((1-(oxazol-2-yl)-2-oxo-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (100 mg, 41%) as a yellow solid, as described for methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate.

[0265] 1,2- to 7-((tert- butoxycarbonyl)(methyl)amino)-5-((1-(oxazol-2-yl)-2-oxo-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (140 mg, crude), as described for 7-((tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylic acid.

[0266] 3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid was converted to tert-butyl (3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)-5-((1-(oxazol-2-yl)-2-oxo-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (110 mg, 67%) as a yellow solid, as described for tert-butyl (5-((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate.

[0267] oxo-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate was converted to N- ((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(oxazol-2-yl)-2-oxo-1,2-dihydropyridin- 3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide (75.3 mg, 83%) as a yellow solid, as Agent Ref.16525.0001-00304 described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]- 3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 452.2, found 452.1.1H NMR (DMSO-d6, 400 MHz) δ 9.05 (s, 1H), 8.67 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 8.52 (d, J = 4.8 Hz, 1H), 8.33 (d, J = 0.8 Hz, 1H), 7.62-7.60 (m, 1H),7.48-7.44 (m, 2H), 6.46- 6.41 (m, 2H), 4.33-4.29 (m, 1H), 3.85-3.83 (m, 1H), 3.22 (s, 3H), 2.86 (d, J = 4.8 Hz, 3H), 2.15- 2.08 (m, 2H), 1.55-1.51 (m, 2H). Example 12: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo- 1-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0268] To a solution of in DMSO (30 mL) were added 3-aminopyridin-2(1H)-one (2.3 g, 21.0 mmol, 1.2 equiv), K2CO3(4.8 g, 35.0 mmol, 2.0 equiv) and CuI (332 mg, 1.75 mmol, 0.1 equiv). The mixture was stirred at 150 ℃ overnight. diluted with DCM (20 mL), washed with saturated NH4Cl solution, dried, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (PE / EA = 1 / 1, v / v) to afford 3-amino-1-(pyrimidin-2-yl)pyridin-2(1H)-one (600 mg, 18%) as a yellow solid.

[0269] 3- ((tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-1-(pyrimidin-2-yl)-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (90 mg, 36%) as a yellow solid, as described Agent Ref.16525.0001-00304 for methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate.

[0270] -1,2- 7-((tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-1-(pyrimidin-2-yl)-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (90 mg, crude), as described for 7-((tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylic acid. dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid was converted to tert- butyl (3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)-5-((2-oxo-1-(pyrimidin-2-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (87 mg, 51%) as a yellow solid, as described for tert-butyl (5-((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3- (((1R,2R)-2-methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate. yl)- 1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate was converted to N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(pyrimidin-2-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide (42 mg, 59%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide.LRMS (M+H+) m / z calculated Agent Ref.16525.0001-00304 463.2, found 463.1.1H NMR (DMSO-d6, 400 MHz) δ 9.05 (d, J = 4.8 Hz, 2H), 8.99 (s, 1H), 8.67 (dd, J = 2.0 Hz, 7.6 Hz, 1H), 8.53 (d, J = 8.4 Hz, 1H), 7.72 (t, J = 4.8 Hz, 4.8 Hz, 1H), 7.59- 7.58 (m, 1H), 7.50-7.44 (m, 1H), 6.42-6.39 (m, 2H), 4.34-4.30 (m, 1H), 3.86-3.84 (m, 1H), 3.23 (s, 3H), 2.86 (d, J = 4.4 Hz, 3H), 2.17-2.09 (m, 2H), 1.58-1.51 (m, 2H). Example 13: Preparation of 5-((4-(3-fluoropyridin-2-yl)-3-oxo-3,4-dihydropyrazin-2- yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3- carboxamide

[0273] mL) were added 3-aminopyrazin-2(1H)-one (1.4 g, 13.0 mmol, 1.2 equiv) and K3PO4 (4.6 g, 21.8 mmol, 2.5 equiv). The mixture was stirred at 100 ℃ overnight, diluted with DCM (50 mL), washed with saturated NH4Cl solution, dried, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (DCM / MeOH = 30 / 1, v / v) to afford 3-amino-1- (3-fluoropyridin-2-yl)pyrazin-2(1H)-one (800 mg, 44%) as a white solid.

[0274] 7-((tert- butoxycarbonyl)(methyl)amino)-5-((4-(3-fluoropyridin-2-yl)-3-oxo-3,4-dihydropyrazin-2- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (50 mg, 22%) as a yellow solid, as described for methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate. Agent Ref.16525.0001-00304

[0275] 2-yl)-3-oxo-3,4- to 7- ((tertbutoxycarbonyl)(methyl)amino)-5-((4-(3-fluoropyridin-2-yl)-3-oxo-3,4-dihydropyrazin-2- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (50 mg, crude), as described for 7-((tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylic acid.

[0276] 7-( 3,4- dihydropyrazin-2-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid was converted to tert- butyl (5-((4-(3-fluoropyridin-2-yl)-3-oxo-3,4-dihydropyrazin-2-yl)amino)-3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (45 mg, 77%) as a yellow solid, as described for tert-butyl (5-((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3- (((1R,2R)-2-methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate.

[0277] -3- (((1R,2R)-2-methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate was converted to 5-((4-(3-fluoropyridin-2-yl)-3-oxo-3,4-dihydropyrazin-2-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide (10 mg, 27%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo- 2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 481.2, found 481.2.1H NMR (DMSO-d6, 400 MHz) δ 9.55 (s, 1H), 8.91 (d, J = 8.8 Hz, 1H), 8.54 (d, J = 4.4 Hz, 1H), 8.11 (t, J = 8.8 Hz, 1H), 7.99 (d, J = 4.4 Hz, 1H), 7.75-7.78 (m, 1H), 7.40 (d, J = 4.4 Hz, 1H), 7.23 (s, 1H), 7.20 (d, J = 4.4 Hz, 1H), 4.31-4.35 (m, 1H), 3.90- 3.94 (m, 1H), 3.22 (s, 3H), 2.94 (d, J = 3.6 Hz, 3H), 2.09-2.13 (m, 2H), 1.55-1.65 (m, 2H). Agent Ref.16525.0001-00304 Example 14: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((3-oxo- 4-(pyridin-2-yl)-3,4-dihydropyrazin-2-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0278] 2-Fluoropyridine pyrazin-2(1H)-one (100 mg, 10%) as a yellow solid, as 2-yl)pyrazin-2(1H)-one.

[0279] 3- butoxycarbonyl)(methyl)amino)-5-((3-oxo-4-(pyridin-2-yl)-3,4-dihydropyrazin-2- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (60 mg, 35%) as a yellow solid, as described for methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate.

[0280] -3,4- dihydropyrazin-2-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate was converted to 7-((tert- butoxycarbonyl)(methyl)amino)-5-((3-oxo-4-(pyridin-2-yl)-3,4-dihydropyrazin-2- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (60 mg, crude), as described for 7-((tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylic acid. Agent Ref.16525.0001-00304

[0281] 7- 2-yl) (3-(((1R,2R)- 2-methoxycyclobutyl)carbamoyl)-5-((3-oxo-4-(pyridin-2-yl)-3,4-dihydropyrazin-2- yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (55 mg, 75%) as a yellow solid, as described for tert-butyl (5-((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate.

[0282] 2-yl)-3,4- dihydropyrazin-2-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate was converted to N- ((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((3-oxo-4-(pyridin-2-yl)-3,4- dihydropyrazin-2-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide (22 mg, 49%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 462.2, found 462.2.1H NMR (DMSO-d6, 400 MHz) δ 9.50 (s, 1H), 8.91 (d, J = 8.4 Hz, 1H), 8.66 (d, J = 4.0 Hz, 1H), 8.08 (t, J = 7.6 Hz, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.55-7.60 (m, 2H), 7.28 (s, 1H), 7.16 (d, J = 4.8 Hz, 1H), 4.31-4.35 (m, 1H), 3.91-3.94 (m, 1H), 3.22 (s, 3H), 2.94 (d, J = 3.6 Hz, 3H), 2.09-2.13 (m, 2H), 1.53-1.67 (m, 2H). Example 15: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo- 1-(1H-pyrazol-4-yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3- carboxamide Agent Ref.16525.0001-00304

[0283] To a solution of 4- 1.0 equiv) in THF (100 mL) was added NaH (1.6 g, 40.8 was stirred at 0 ℃ for 0.5 h. Then SEMCl (7.4 g, 44.2 mmol, 1.2 equiv) was added. The mixture was stirred at 0 ℃ for 16 h. Water (200 mL) was added and the mixture was extracted with EA (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford 4-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole (10 g, crude) as a yellow solid which was used in the next step without further purification.

[0284] 4-Bromo-1- to 3-amino-1- (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridin-2(1H)-one (800 mg, 65%) as a yellow solid, as described for 3-amino-5'-fluoro-2H-[1,2'-bipyridin]-2-one.

[0285] -one was converted to methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((2-oxo-1-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylate (150 mg, 70%) as a yellow solid, as described for methyl 7-((tert- butoxycarbonyl)(methyl)amino)-5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate. Agent Ref.16525.0001-00304

[0286] Methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((2-oxo-1-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylate was converted to 7-((tert-butoxycarbonyl)(methyl)amino)-5-((2-oxo-1- (1-((2(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (150 mg, crude), as described for 7-((tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylic acid.

[0287] - - [4,3- b]pyridine-3-carboxylic acid was converted to tert-butyl (3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)-5-((2-oxo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4- yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (120 mg, 71%) as a yellow solid, as described for tert-butyl (5-((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)-3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7- yl)(methyl)carbamate. (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3- b]pyridin-7-yl)(methyl)carbamate was converted to N-((1R,2R)-2-methoxycyclobutyl)-7- (methylamino)-5-((2-oxo-1-(1H-pyrazol-4-yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxamide (32 mg, 44%) as a brown solid, as described for N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 451.2, found 451.2.1H NMR (DMSO- d6, 400 MHz) δ 13.1 (s, 1H), 9.03 (s, 1H), 8.56 (d, J = 7.6 Hz, 1H), 8.51 (d, J = 8.8 Hz, 1H), (s, 1H), 7.98 (s, 1H), 7.57 (d, J = 6.4 Hz, 2H), 6.42 (s, 1H), 6.39 (t, J = 7.2 Hz, 1H), 4.28- Agent Ref.16525.0001-00304 4.34 (m, 1H), 3.81-3.88 (m, 1H), 3.23 (s, 3H), 2.86 (d, J = 4.4 Hz, 3H), 2.08-2.18 (m, 2H), 1.49- 1.59 (m, 2H). Example 16: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo- 1-(1H-pyrazol-5-yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3- carboxamide

[0289] 3- to 3-amino-1- (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridin-2(1H)-one (150 mg, 45%) as a yellow solid, as described for 3-amino-5'-fluoro-2H-[1,2'-bipyridin]-2-one. -one was converted to methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((2-oxo-1-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylate (60 mg, 38%) as a yellow solid, as described for methyl 7-((tert- butoxycarbonyl)(methyl)amino)-5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate. Agent Ref.16525.0001-00304

[0291] Methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((2-oxo-1-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylate was converted to 7-((tert-butoxycarbonyl)(methyl)amino)-5-((2-oxo-1- (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (150 mg, crude), as described for 7-((tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylic acid.

[0292] - - [4,3- b]pyridine-3-carboxylic acid was converted to tert-butyl (3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)-5-((2-oxo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3- yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (150 mg, 85%) as a yellow solid, as described for tert-butyl (5-((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)-3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7- yl)(methyl)carbamate. (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3- b]pyridin-7-yl)(methyl)carbamate was converted to N-((1R,2R)-2-methoxycyclobutyl)-7- (methylamino)-5-((2-oxo-1-(1H-pyrazol-5-yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxamide (75 mg, 75%) as a yellow solid, as described for N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 451.2, found 451.1.1H NMR (DMSO- d6, 400 MHz) δ 13.05 (s, 1H), 9.03 (s, 1H), 8.58 (dd, J = 1.6 Hz, 5.6 Hz, 1H), 8.52 (d, J = 8.8 Hz, , 7.78 (s, 1H), 7.73 (dd, J = 1.6 Hz, 7.2 Hz, 1H), 7.57 (s, 1H), 6.79 (t, J = 2.0 Hz, 2.0 Hz, Agent Ref.16525.0001-00304 1H), 6.42-6.38 (m, 2H), 4.34-4.32 (m, 1H), 3.84-3.82 (m, 1H), 3.22 (s, 3H), 2.87 (d, J = 4.8 Hz, 3H), 2.17-2.09 (m, 2H), 1.58-1.49 (m, 2H). Example 17: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo- 1-(pyrimidin-5-yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0294] 5- 2(1H)-one (400 mg, 68%) as a white solid, as described for 3-amino-5'-fluoro-2H-[1,2'-bipyridin]-2-one.

[0295] 3- (tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-1-(pyrimidin-5-yl)-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (54 mg, 31%) as a yellow solid, as described for methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate.

[0296] 5-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate was converted to 7-((tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-1-(pyrimidin-5-yl)-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (55 mg, crude), as described for 7-((tert- Agent Ref.16525.0001-00304 butoxycarbonyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylic acid.

[0297] 7-( 2-yl) (3-(((1R,2R)- 2-methoxycyclobutyl)carbamoyl)-5-((2-oxo-1-(pyrimidin-5-yl)-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (43 mg, 69%) as a yellow solid, as described for tert-butyl (5-((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate.

[0298] 5-yl)- 1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate was converted to N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(pyrimidin-5-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide (23 mg, 63%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 463.2, found 463.2.1H NMR (DMSO-d6, 400 MHz) δ 9.35 (s, 1H), 9.15 (s, 2H), 9.11 (s, 1H), 8.74 (dd, J = 5.6, 7.6 Hz, 1H), 8.58 (d, J = 8.8 Hz, 1H), 7.66 (t, J = 4.8 Hz, 1H), 7.58 (dd, J = 1.6, 6.8 Hz, 1H), 6.53 (t, J = 7.2 Hz, 1H), 6.51 (s, 1H), 4.37-4.41 (m, 1H), 3.91-3.93 (m, 1H), 3.29 (s, 3H), 2.91 (d, J = 4.4 Hz, 3H), 2.17-2.24 (m, 2H), 1.57-1.66 (m, 2H). Example 18: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo- 1-(pyrazin-2-yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide Agent Ref.16525.0001-00304

[0299] 2- 2(1H)-one (500 mg, 85%) as a yellow solid, -3'-carbonitrile.

[0300] 3- ((tert- - oxo- - yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (60 mg, 35%) as a yellow solid, as described for methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate.

[0301] yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate was converted to 7-((tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-1-(pyrazin-2-yl)-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (63 mg, crude), as described for 7-((tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylic acid.

[0302] 7-( 3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid was converted to tert-butyl (3-(((1R,2R)- 2-methoxycyclobutyl)carbamoyl)-5-((2-oxo-1-(pyrazin-2-yl)-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (40 mg, 60%) as a yellow solid, as Agent Ref.16525.0001-00304 described for tert-butyl (5-((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate.

[0303] 2-yl)-1,2- to N- ((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(pyrazin-2-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide (19 mg, 58%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 463.2, found 463.2.1H NMR (DMSO-d6, 400 MHz) δ 9.20 (s, 1H), 9.08 (s, 1H), 9.11 (s, 1H), 8.77 (t, J = 2.4 Hz, 2H), 8.67 (dd, J = 2.0, 7.6 Hz, 1H), 8.53 (d, J = 8.8 Hz, 1H), 7.61-7.63 (m, 2H), 6.50 (t J = 7.2 Hz, 1H), 4.31-4.35 (m, 1H), 3.84-3.90 (m, 1H), 3.23 (s, 3H), 2.86 (d, J = 4.8 Hz, 3H), 2.10-2.17 (m, 2H), 1.51-1.59 (m, 2H). Example 19: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo- 1-(pyrimidin-4-yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0304] yl)pyridin- 2(1H)-one (32 mg, 1.2%) as a yellow solid, as described for 3-amino-5'-fluoro-2H-[1,2'- bipyridin]-2-one. Agent Ref.16525.0001-00304

[0305] 3- - - yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (70 mg, 47%) as a yellow solid, as described for methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate.

[0306] -1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate was converted to 7-((tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-1-(pyrimidin-4-yl)-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (70 mg, crude), as described for 7-((tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylic acid. dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid was converted to tert- butyl (3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)-5-((2-oxo-1-(pyrimidin-4-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (70 mg, 78%) as a yellow solid, as described for tert-butyl (5-((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3- (((1R,2R)-2-methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate. Agent Ref.16525.0001-00304

[0308] 4-yl)- 1,2- to N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(pyrimidin-4-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide (27 mg, 49%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 463.2, found 463.1.1H NMR (DMSO-d6, 400 MHz) δ 9.31 (d, J = 0.8 Hz, 1H), 9.09 (s, 1H), 9.04 (d, J = 5.6 Hz, 1H), 8.64 (d, J = 6.0 Hz, 1H), 8.54 (d, J = 8.8 Hz, 1H), 8.19 (dd, J = 1.2 Hz, 5.6 Hz, 1H), 7.80 (dd, J = 1.6 Hz, 7.2 Hz, 1H), 7.62-7.61 (m, 1H), 6.50 (t, J = 7.2 Hz, 7.2 Hz, 1H), 4.34-4.30 (m, 1H), 3.85-3.83 (m, 1H), 3.28 (s, 3H), 2.89 (d, J = 7.6 Hz, 3H), 2.16-2.09 (m, 2H), 1.56-1.52 (m, 2H). Example 20: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1- (oxazol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0309] 5- 2(1H)-one (40 mg, 4%) as a yellow solid, as described for 3-amino-5'-fluoro-2H-[1,2'-bipyridin]-2-one. Agent Ref.16525.0001-00304

[0310] 3- - - yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (80 mg, 73%) as a brown solid, as described for methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate.

[0311] dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate was converted to 7-((tert- butoxycarbonyl)(methyl)amino)-5-((1-(oxazol-5-yl)-2-oxo-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (80 mg, crude), as described for 7-((tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylic acid.

[0312] 3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid was converted to tert-butyl (3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)-5-((1-(oxazol-5-yl)-2-oxo-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (60 mg, 63%) as a yellow solid, as described for tert-butyl (5-((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate. Agent Ref.16525.0001-00304

[0313] -2-oxo-1,2- to N- ((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(oxazol-5-yl)-2-oxo-1,2-dihydropyridin- 3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide (21 mg, 43%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]- 3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 452.2, found 452.2.1H NMR (DMSO-d6, 400 MHz) δ 9.11 (s, 1H), 8.64 (dd, J = 1.2, 7.6 Hz, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 7.62 (t, J = 4.8 Hz, 1H), 7.57 (d, J = 2.8 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 6.49 (t, J = 7.2 Hz, 1H), 6.44 (s, 1H), 4.29-4.34 (m, 1H), 3.83-3.85 (m, 1H), 3.22 (s, 3H), 2.86 (d, J = 4.8 Hz, 3H), 2.09-2.16 (m, 2H), 1.52-1.56 (m, 2H). Example 21: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo- 1-(pyridazin-3-yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0314] To a solution of in dioxane (20 mL) were added 3-aminopyridin-2(1H)-one (166 mg, 1.51 mmol, 1.2 equiv), K2CO3(345 mg, 2.5 mmol, 2.0 equiv) and CuI (25 mg, 0.13 mmol, 0.1 equiv). The mixture was stirred at 110 ℃ overnight, and then concentrated. The resulting residue was purified by column chromatography on silica gel (PE / EA = 1 / 1, v / v) to afford 3-amino-1-(pyridazin-3-yl)pyridin-2(1H)-one (75 mg, 31%) as a yellow solid. Agent Ref.16525.0001-00304

[0315] - - yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (75 mg, 47%) as a yellow solid, as described for methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate.

[0316] -1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate was converted to 7-((tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-1-(pyridazin-3-yl)-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (75 mg, crude), as described for 7-((tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylic acid. dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid was converted to tert- butyl (3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)-5-((2-oxo-1-(pyridazin-3-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (70 mg, 78%) as a yellow solid, as described for tert-butyl (5-((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3- (((1R,2R)-2-methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate. Agent Ref.16525.0001-00304 yl)- to N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(pyridazin-3-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide (23 mg, 42%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 463.2, found 463.1.1H NMR (DMSO-d6, 400 MHz) δ 9.36 (t, J = 1.6 Hz, 3.6 Hz, 1H), 9.05 (s, 1H), 8.70 (t, J = 0.8 Hz, 6.4 Hz, 1H), 8.54 (d, J = 8.8 Hz, 1H), 8.21 (dd, J = 1.2 Hz, 7.6 Hz, 1H), 7.98 (dd, J = 4.8 Hz, 8.8 Hz, 1H), 7.68-7.66 (m, 1H), 7.61-7.60 (m, 2H), 6.50 (t, J = 7.2 Hz, 6.8 Hz, 1H), 6.43 (s, 1H), 4.34-4.30 (m, 1H), 3.86-3.85 (m, 1H), 3.23 (s, 3H), 2.86 (d, J = 4.8 Hz, 3H), 2.16-2.09 (m, 2H), 1.57-1.54 (m, 2H). Example 22: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo- 1-(1H-1,2,3-triazol-5-yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3- carboxamide

[0319] To a 1,2,3-triazole (1.5 g, 5.4 mmol, 1.0 equiv) in dioxane (20 mL) were added 3-aminopyridin-2(1H)-one (715 mg, 6.5 mmol, 1.2 equiv), Cs2CO3 (3.5 g, 10.8 mmol, 2.0 equiv), DMEDA (44 mg, 0.5 mmol, 0.1 equiv) and CuI (95 mg, 0.5 mmol, 0.1 equiv). The mixture was stirred at 110 ℃ overnight, and then Agent Ref.16525.0001-00304 concentrated. The resulting residue was purified by column chromatography on silica gel (PE / EA = 1 / 1, v / v) to afford 3-amino-1-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4- yl)pyridin-2(1H)-one (100 mg, 6%) as a yellow solid.

[0320] 2(1H)- one - (trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (110 mg, 56%) as a yellow solid, as described for methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate.

[0321] (trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate was converted to 7-((tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-1-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3- triazol-4-yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (110 mg, crude), as described for 7-((tert-butoxycarbonyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid. (trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid was converted to tert-butyl (3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)-5-((2-oxo-1-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3- Agent Ref.16525.0001-00304 triazol-4-yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (120 mg, 97%) as a yellow solid, as described for tert-butyl (5-((3'-cyano-2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)-3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7- yl)(methyl)carbamate.

[0323] - - yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate was converted to N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(1H-1,2,3-triazol-5-yl)-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide (31 mg, 38%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 452.2, found 452.1.1H NMR (DMSO-d6, 400 MHz) δ 15.27 (s, 1H), 9.11 (d, J = 9.2 Hz, 1H), 8.64 (d, J = 9.2 Hz, 1H), 8.54 (d, J = 9.2 Hz, 1H), 8.32 (s, 1H), 7.80 (d, J = 6.0 Hz, 1H), 7.62-7.61 (m, 1H), 6.51- 6.44 (m, 2H), 4.33-4.29 (m, 1H), 3.84-3.82 (m, 1H), 3.22 (s, 3H), 2.86 (d, J = 4.4 Hz, 3H), 2.17- 2.11 (m, 2H), 1.58-1.49 (m, 2H). Example 23: Preparation of 5-((5'-amino-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N- ((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0324] tert- amino-2-oxo- 2H-[1,2'-bipyridin]-5'-yl)carbamate (1 g, 92%) as a yellow solid, as described for 3-amino-5'- fluoro-2H-[1,2'-bipyridin]-2-one. Agent Ref.16525.0001-00304 7- - - bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (75 mg, 41%) as a yellow solid, as described for methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((3'-fluoro-2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate. -2- oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate was converted to 7- ((tert-butoxycarbonyl)(methyl)amino)-5-((5'-((tert-butoxycarbonyl)amino)-2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (75 mg, crude), as described for 7-((tert-butoxycarbonyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid. [1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid was converted to tert- butyl (5-((5'-((tert-butoxycarbonyl)amino)-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (75 mg, 85%) as a yellow solid, as described for tert-butyl (5-((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3- (((1R,2R)-2-methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate. Agent Ref.16525.0001-00304 yl)- to N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(pyridazin-3-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide (23 mg, 42%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 463.2, found 463.1.1H NMR (DMSO-d6, 400 MHz) δ 9.36 (t, J = 1.6 Hz, 3.6 Hz, 1H), 9.05 (s, 1H), 8.70 (t, J = 0.8 Hz, 6.4 Hz, 1H), 8.54 (d, J = 8.8 Hz, 1H), 8.21 (dd, J = 1.2 Hz, 7.6 Hz, 1H), 7.98 (dd, J = 4.8 Hz, 8.8 Hz, 1H), 7.68-7.66 (m, 1H), 7.61-7.60 (m, 2H), 6.50 (t, J = 7.2 Hz, 6.8 Hz, 1H), 6.43 (s, 1H), 4.34-4.30 (m, 1H), 3.86-3.85 (m, 1H), 3.23 (s, 3H), 2.86 (d, J = 4.8 Hz, 3H), 2.16-2.09 (m, 2H), 1.57-1.54 (m, 2H). Example 24: Preparation of 5-((3'-amino-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N- ((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0329] tert- amino-2-oxo- 2H-[1,2'-bipyridin]-3'-yl)carbamate (220 mg, 20%) as a yellow solid, as described for 3-amino- 5'-fluoro-2H-[1,2'-bipyridin]-2-one. Agent Ref.16525.0001-00304

[0330] to methyl 7-((tert- - - 2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (85 mg, 46%) as a yellow solid, as described for methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((3'-fluoro-2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate.

[0331] amino)-2- oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate was converted to 7- ((tert-butoxycarbonyl)(methyl)amino)-5-((3'-((tert-butoxycarbonyl)amino)-2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (75 mg, crude), as described for 7-((tert-butoxycarbonyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid.

[0332] 2H- [1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid was converted to tert- butyl (5-((3'-((tert-butoxycarbonyl)amino)-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (80 mg, 91%) as a yellow solid, as described for tert-butyl (5-((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3- (((1R,2R)-2-methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate. Agent Ref.16525.0001-00304 -3- (( was converted to 5-((3'-amino-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide (24 mg, 42%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo- 2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 477.2, found 477.1.1H NMR (DMSO-d6, 400 MHz) δ 8.95 (s, 1H), 8.61 (d, J = 7.2 Hz, 1H), 8.53 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.58-7.57 (m, 1H), 7.25 (s, 2H), 7.21 (d, J = 6.4 Hz, 1H), 6.40-6.36 (m, 2H), 5.26 (s, 2H), 4.35-4.31 (m, 1H), 3.86-3.82 (m, 1H), 3.23 (s, 3H), 2.86 (d, J = 4.4 Hz, 3H), 2.16-2.09 (m, 2H), 1.60-1.50 (m, 2H). Example 25: Preparation of 5-((1-((3S,4R)-3-fluoropiperidin-4-yl)-2-oxo-1,2- dihydropyridin-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7- (methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0334] in DMF (30 mL) was added tert-butyl (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylate (2.2 g, 10.0 mmol, 1.0 equiv). The mixture was stirred at 0oC for 0.5 h, and then stirred at rt for 15 min. EDCI (2.5 g, 13.0 mmol, 1.3 equiv) and DMAP (300 mg, 2.5 mmol, 0.25 equiv) were added. The mixture was stirred at rt for 16 h. Saturated NH4Cl solution (100 mL) was added. The mixture was extracted with EA (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column Agent Ref.16525.0001-00304 chromatography on silica gel (PE / EA = 3 / 1, v / v) to afford methyl 1-((3S,4R)-1-(tert- butoxycarbonyl)-3-fluoropiperidin-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (2.4 g, 69%) as a yellow solid.

[0335] To a 4-yl)-2- oxo-1,2- (10 / 10 mL) were added LiOH.H2O (332 mg, 7.9 mmol, 2.0 equiv) in H2O (10 mL). The mixture was stirred at rt for 16 h. The mixture was acidified to pH 6 with aqueous HCl (1 N) and extracted with EA (10 mL× 3). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford 1-((3S,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-2-oxo-1,2-dihydropyridine-3- carboxylic acid (900 mg, crude) as a yellow solid, which was used in the next step without further purification.

[0336] To a -2-oxo-1,2- dihydropyridine-3-carboxylic acid (100 mg, 0.59 mmol, 1.0 equiv) in DMF (5 mL) were added TEA (129 mg, 1.2 mmol, 2.0 equiv) and DPPA (243 mg, 0.89 mmol, 1.5 equiv). The mixture was stirred at 80oC for 16 h. Water (10 mL) was added. The mixture was extracted with EA (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel on silica gel column (PE / EA = 1 / 1, v / v) to afford tert-butyl (3S,4R)-4-(3-amino-2-oxopyridin-1(2H)-yl)-3- fluoropiperidine-1-carboxylate (30 mg, 16%) as a yellow solid.

[0337] was converted to methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((1-((3S,4R)-1-(tert- butoxycarbonyl)-3-fluoropiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylate (35 mg, 90%) as a yellow solid, as described for methyl 7-((tert- Agent Ref.16525.0001-00304 butoxycarbonyl)(methyl)amino)-5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate. - 3- - carboxylate was converted to 7-((tert-butoxycarbonyl)(methyl)amino)-5-((1-((3S,4R)-1-(tert- butoxycarbonyl)-3-fluoropiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylic acid (30 mg, crude), as described for 7-((tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylic acid. fluoropiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3- carboxylic acid was converted to tert-butyl (3S,4R)-4-(3-((7-((tert- butoxycarbonyl)(methyl)amino)-3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)isoxazolo[4,3- b]pyridin-5-yl)amino)-2-oxopyridin-1(2H)-yl)-3-fluoropiperidine-1-carboxylate (30 mg, 88%) as a yellow solid, as described for tert-butyl (3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)-5-((2- oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate. methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-5-yl)amino)-2-oxopyridin-1(2H)-yl)-3- fluoropiperidine-1-carboxylate was converted to 5-((1-((3S,4R)-3-fluoropiperidin-4-yl)-2-oxo- 1,2-dihydropyridin-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7- (methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide (13 mg, 67%) as a yellow solid, as Agent Ref.16525.0001-00304 described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]- 3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 486.2, found 486.1.1H NMR (DMSO-d6, 400 MHz) δ 8.91 (s, 1H), 8.54 (dd, J = 7.2, 1.2 Hz, 1H), 8.48 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 4.8 Hz, 1H), 7.34 (d, J = 7.2 Hz, 1H), 6.39 (s, 1H), 6.34 (t, J = 7.2 Hz, 1H), 5.14-5.01 (m, 1H), 5.03 (d, J = 13.6 Hz, 1H), 4.24-4.32 (m, 1H), 3.80-3.82 (m, 1H), 3.11-3.31 (m, 5H), 2.67-2.87 (m, 5 H), 2.09-2.16 (m, 3H), 1.50-1.56 (m, 3H). Example 26: Preparation of 5-((1-((3R,4R)-3-fluoropiperidin-4-yl)-2-oxo-1,2- dihydropyridin-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7- (methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0341] tert-Butyl to methyl 1- ((3R,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-2-oxo-1,2-dihydropyridine-3- carboxylate (3 g, 46%) as yellow solid, as described for methyl 1-((3S,4R)-1-(tert- butoxycarbonyl)-3-fluoropiperidin-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate.

[0342] dihydropyridine-3-carboxylate was converted to 1-((3R,4R)-1-(tert-butoxycarbonyl)-3- fluoropiperidin-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (270 mg, 80%) as a white solid, as described for 1-((3S,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid. Agent Ref.16525.0001-00304

[0343] 1-((3R,4R)-1-(tert-Butoxycarbonyl)-3-fluoropiperidin-4-yl)-2-oxo-1,2-dihydropyridine- 3-carboxylic acid was converted to tert-butyl (3R,4R)-4-(3-amino-2-oxopyridin-1(2H)-yl)-3- fluoropiperidine-1-carboxylate (160 mg, 65%) as a white solid, as described for tert-butyl (3S,4R)-4-(3-amino-2-oxopyridin-1(2H)-yl)-3-fluoropiperidine-1-carboxylate.

[0344] carboxylate was - - butoxycarbonyl)-3-fluoropiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylate (172 mg, 23%) as a yellow solid, as described for methyl 7-((tert- butoxycarbonyl)(methyl)amino)-5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate. - 3-fluoropiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3- carboxylate was convered to 7-((tert-butoxycarbonyl)(methyl)amino)-5-((1-((3R,4R)-1-(tert- butoxycarbonyl)-3-fluoropiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylic acid (39 mg, 100%), as described for 7-((tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylic acid. fluoropiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3- carboxylic acid was converted to tert-butyl (3R,4R)-4-(3-((7-((tert- Agent Ref.16525.0001-00304 butoxycarbonyl)(methyl)amino)-3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)isoxazolo[4,3- b]pyridin-5-yl)amino)-2-oxopyridin-1(2H)-yl)-3-fluoropiperidine-1-carboxylate (14 mg, 29%) as a yellow solid, as described for tert-butyl (3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)-5-((2- oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate.

[0347] - -yl)-3- fluoropiperidine-1-carboxylate was converted to 5-((1-((3R,4R)-3-fluoropiperidin-4-yl)-2-oxo- 1,2-dihydropyridin-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7- (methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide (5 mg, 48%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]- 3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 486.1, found 486.1.1H NMR (DMSO-d6, 400 MHz) δ 8.90 (s, 1H), 8.49 (t, J = 7.2 Hz, 2H), 7.58-7.50 (m, 2H), 6.38-6.33 (m, 2H), 5.05-4.80 (m, 2H), 4.33-4.30 (m, 1H), 3.82-3.81 (m, 1H), 3.25 (s, 3H), 2.98-2.94 (m, 1H), 2.86 (d, J = 4.8 Hz, 3H), 2.60-2.57 (m, 2H), 2.32-2.31 (m, 1H) , 2.18- 2.07 (m, 2H) , 1.98-1.89 (m, 2H), 1.58-1.44 (m, 3H) Example 27: Preparation of 5-((1-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-oxo-1,2- dihydropyridin-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7- (methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0348] To 4-yl)-2- oxo-1,2-dihydropyridine-3-carboxylate (1.0 g, 2.8 mmol, 1.0 equiv) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred at rt for 1 h, and then concentrated to afford methyl 1- Agent Ref.16525.0001-00304 ((3S,4R)-3-fluoropiperidin-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate TFA salt (900 mg, crude) as a yellow oil, which was used in the next step without further purification.

[0349] To a 3- carboxylate HCHO (5 mL) and STAB (1.6 g, 7.7 mmol, 3.0 equiv). The mixture was stirred at 30oC for 12 h and concentrated. The resulting residue was purified by column chromatography on silica gel (DCM / MeOH =20 / 1, v / v) to afford methyl 1-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-oxo- 1,2-dihydropyridine-3-carboxylate (610 mg, 89%) as a yellow oil.

[0350] Methyl 3- carboxylate was converted to 1-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid (450 mg, 78%) as a yellow solid, as described for 1-((3S,4R)- 1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid.

[0351] To a 3-carboxylic acid (400 mg, 1.57 mmol, 1.0 equiv) in t-BuOH (10 mL) were added TEA (239 mg, 2.36 mmol, 1.5 equiv) and DPPA (650 mg, 2.36 mmol, 1.5 equiv). The mixture was stirred at 80oC for 16 h and concentrated. The resulting residue was purified by column chromatography on silica gel (DCM / MeOH = 20 / 1, v / v) to afford tert-butyl (1-((3S,4R)-3-fluoro-1-methylpiperidin- 4-yl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate (175 mg, 33%) as a yellow oil.

[0352] To a 4-yl)-2-oxo-1,2- dihydropyridin-3-yl)carbamate (175 mg, 0.54 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at rt for 1 h, diluted with DCM (20 mL), washed with saturated NaHCO3 solution, dried, filtered and concentrated. The resulting residue was purified by column Agent Ref.16525.0001-00304 column chromatography on silica gel (DCM / MeOH = 20 / 1, v / v) to afford 3-amino-1-((3S,4R)- 3-fluoro-1-methylpiperidin-4-yl)pyridin-2(1H)-one (60 mg, 50%) as a yellow solid.

[0353] 3- converted to methyl - - 4- yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (70 mg, 49%) as a yellow solid, as described for methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((3'-fluoro- 2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate.

[0354] methylpiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3- carboxylate was converted to7-((tert-butoxycarbonyl)(methyl)amino)-5-((1-((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3- carboxylic acid (70 mg, crude), as described for 7-((tert-butoxycarbonyl)(methyl)amino)-5-((2- oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid. fluoropiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3- carboxylic acid was converted to tert-butyl (5-((1-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2- oxo-1,2-dihydropyridin-3-yl)amino)-3-(((1R,2R)methoxycyclobutyl)carbamoyl)isoxazolo[4,3- b]pyridin-7-yl)(methyl)carbamate (45 mg, 58%) as a yellow solid, as described for tert-butyl (3- (((1R,2R)-2-methoxycyclobutyl)carbamoyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate. Agent Ref.16525.0001-00304 - yl)(methyl)carbamate was converted to 5-((1-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-oxo- 1,2-dihydropyridin-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7- (methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide (23 mg, 62%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]- 3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 500.2, found 500.1.1H NMR (DMSO-d6, 400 MHz) δ 8.92 (s, 1H), 8.54 (d, J = 7.2 Hz, 1H), 8.48 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 4.8 Hz, 1H), 7.37 (d, J = 6.8 Hz, 1H), 6.40 (s, 1H), 6.32 (t, J = 7.2 Hz, 1H), 4.79-5.00 (m, 2H), 4.28-4.33 (m, 1H), 3.78-3.84 (m, 1H), 3.21 (s, 3H), 3.11-3.18 (m, 1H), 2.98 (d, J = 10.8 Hz, 1H), 2.86 (d, J = 4.8 Hz, 3H), 2.33-2.47 (m, 2H), 2.24 (s, 4H), 2.09-2.16 (m, 2H), 1.70-1.72 (m, 1H), 1.47-1.58 (m, 2H). Example 28: Preparation of 5-((1-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-oxo-1,2- dihydropyridin-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7- (methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide .

[0357] Methyl oxo-1,2- dihydropyridine-3-carboxylate was converted to methyl 1-((3R,4R)-3-fluoropiperidin-4-yl)-2- oxo-1,2-dihydropyridine-3-carboxylate, as described for 3-amino-1-((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)pyridin-2(1H)-one. Agent Ref.16525.0001-00304

[0358] Methyl 3-carboxylate was converted to 3- carboxylate (1.5 g, 66%) as a white solid, as described for methyl 1-((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate.

[0359] 3- carboxylate was - - oxo-1,2- dihydropyridine-3-carboxylic acid (1.1 g, 77%) as a yellow solid, as described for 1-((3S,4R)-1- (tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid.

[0360] A 3- carboxylic acid (300 mg, 1.18 mmol, 1.0 equiv), DPPA (487 mg, 1.77 mmol, 1.5 equiv), TEA (239 mg, 2.36 mmol, 2.0 equiv) and BnOH (255 mg, 2.36 mmol, 2.0 equiv) in dioxane (20 mL) was stirred at 100oC for 48 h. Water (100 mL) was added and the mixture was extracted with EA (30 mL × 3). The combined organic layers were dried and concentrated. The resulting residue was purified by column chromatography on silica gel (PE / EA = 3 / 1, v / v) to afford benzyl (1-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate (100 mg, 24%) as a yellow solid.

[0361] To a 1,2- dihydropyridin-3-yl)carbamate (140 mg, 0.39 mmol, 1.0 equiv) in MeOH (4 mL) was added Pd / C(50 mg). The mixture was stirred at 25 ℃ for 16 h under H2. The mixture was filtered and concentrated in vacuo. The resulting residue was directly used for next step without further purification (70 mg, 80%) as a yellow solid. Agent Ref.16525.0001-00304 to - - yl)amino)-3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7- yl)(methyl)carbamate (86 mg, 54%) as a yellow oil, as described for methyl 7-((tert- butoxycarbonyl)(methyl)amino)-5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate. 3- yl)amino)-3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7- yl)(methyl)carbamate was converted to 5-((1-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-oxo- 1,2-dihydropyridin-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7- (methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide (34 mg, 49%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]- 3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 500.2, found 500.1.1H NMR (DMSO-d6, 400 MHz) δ 8.92 (s, 1H), 8.52-8.47 (m, 2H), 7.58-7.54 (m, 2H), 6.39 (s, 1H), 6.34 (t, J = 7.2 Hz, 1H), 5.22-4.84 (m, 2H), 4.35-4.27 (m, 1H), 3.84-3.79 (m, 1H), 3.30-3.26 (m, 1H), 3.21 (s, 3H), 2.85 (d, J = 4.0 Hz, 3H), 2.80-2.75 (m, 1H), 2.29 (s, 3H), 2.21-1.98 (m, 5H), 1.85 (s, 1H), 1.61-1.45 (m, 2H). Agent Ref.16525.0001-00304 Example 29: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo- 1-phenyl-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0364] To a solution in dioxane (20 mL) were added 3-nitropyridin-2(1H)-one (2.0 g, 14.2 mmol, 1.0 equiv), Cu(OAc)2(3.9 g, 21.4 mmol, 1.5 equiv) and pyridine (8 mL). The mixture was stirred at 100oC for 16 h and concentrated. The resulting residue was purified by column chromatography on silica gel (PE / EA = 2 / 1, v / v) to afford 3-nitro-1-phenylpyridin-2(1H)-one (550 mg, 18%) as a yellow solid.

[0365] To a solution mmol, 1.0 equiv) in MeOH (5 mL) was added Pd / C (50 mg). The mixture was stirred at rt for 4 h under H2 (1 atm). The mixture was filtered and concentrated to afford 3-amino-1-phenylpyridin-2(1H)-one (180 mg, crude) as a brown solid, which was used in the next step without further purification.

[0366] equiv) in toluene (5 mL) were added tert-butyl (5-chloro-3-(((1R,2R)-2- Agent Ref.16525.0001-00304 methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (140 mg, 0.34 mmol, 1.0 equiv), BrettPhos (36 mg, 0.068 mmol, 0.2 equiv), BrettPhos Pd G3 (61 mg, 0.068 mmol, 0.2 equiv) and Cs2CO3 (221 mg, 0.68 mmol, 2.0 equiv). The mixture was stirred at 100 ℃ for 16 h under N2atmosphere and concentrated. The resulting residue was purified by column chromatography on silica gel (PE / EA = 1 / 1, v / v) to afford tert-butyl (3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)-5-((2-oxo-1-phenyl-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (100 mg, 53%) as a yellow solid.

[0367] was to N- ((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-phenyl-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide (46 mg, 57%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 461.2, found 461.1.1H NMR (DMSO-d6, 400 MHz) δ 8.98 (s, 1H), 8.62 (d, J = 8 Hz, 1H), 8.52 (d, J = 8.4 Hz, 1H), 7.54-7.60 (m, 3H), 7.48-7.50 (m, 3H), 7.35 (d, J = 6.4 Hz, 1H), 6.41 (s, 1H), 6.38 (d, J = 7.2 Hz, 1H), 4.31-4.35 (m, 1H), 3.84-3.86 (m, 1H), 3.23 (s, 3H), 2.86 (d, J = 4.4 Hz, 3H), 2.10-2.18 (m, 2H), 1.53-1.57 (m, 2H). Example 30: Preparation of 5-((6-cyclopropylpyridin-2-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide Agent Ref.16525.0001-00304

[0368] 6- 2- yl)amino)- - yl)(methyl)carbamate (60 mg, 48%) as a yellow oil, as described for tert-butyl (3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)-5-((2-oxo-1-phenyl-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate.

[0369] methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate was converted to 5-((6-cyclopropylpyridin-2-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7- (methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide (11 mg, 25%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]- 3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 409.2, found 409.1.1H NMR (DMSO-d6, 400 MHz) δ 9.78 (s, 1H), 8.54 (d, J = 9.2 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 4.4 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.39 (s, 1H), 4.32-4.28 (m, 1H), 3.83-3.78 (m, 1H), 3.21 (s, 3H), 2.87 (d, J = 4.4 Hz, 3H), 2.18-2.03 (m, 3H), 1.58-1.47 (m, 2H), 0.95 (d, J = 8.0 Hz, 4H). Example 31: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((6-(4- methylpiperazin-1-yl)pyridin-2-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide Agent Ref.16525.0001-00304

[0370] To a equiv) in 2,4- dimethylphenol (1 1.1 equiv). The mixture was stirred at 140 ℃ for 16 h. The reaction was diluted with water and extracted with EA (15 mL × 3). The combined organic layers were concentrated and purified by column chromatography on silica gel (DCM / MeOH = 10 / 1, v / v) to afford 6-(4-methylpiperazin-1- yl)pyridin-2-amine (80 mg, 36%) as a yellow solid. -2- methoxycyclobutyl)carbamoyl)-5-((6-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)isoxazolo[4,3- b]pyridin-7-yl)(methyl)carbamate (60 mg, 36%) as a yellow oil, as described for tert-butyl (3- (((1R,2R)-2-methoxycyclobutyl)carbamoyl)-5-((2-oxo-1-phenyl-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate. 1- yl)pyridin-2-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate was converted to N- ((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((6-(4-methylpiperazin-1-yl)pyridin-2- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide (39 mg, 83%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 467.2, found 467.1.1H NMR (DMSO-d6, 400 MHz) δ 9.59 (s, 1H), 8.58 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 4.8 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 6.47 (d, J = 8.4 Hz, 1H), 6.35 (s, 1H), Agent Ref.16525.0001-00304 4.33-4.29 (m, 1H), 3.83-3.77 (m, 1H), 3.51 (s, 4H), 3.21 (s, 3H), 2.86 (d, J = 4.4 Hz, 3H), 2.41 (s, 4H), 2.23 (s, 3H), 2.19-2.08 (m, 2H), 1.59-1.48 (m, 2H). Example 32: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((6- morpholinopyridin-2-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0373] 6- yl)amino)-3- (((1R,2R)-2-methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (120 mg, 34%) as a yellow solid, as described for tert-butyl (3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)-5-((2-oxo-1-phenyl-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate.

[0374] methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (115 mg, 0.24 mmol, 1.0 equiv) was dissolved in morpholine (3 mL). The mixture was stirred at 65 ℃ for 16 h and concentrated. The resulting residue was purified by column column chromatography on silica gel (PE / EA = 1 / 1, v / v) to afford tert-butyl (3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)- 5-((6-morpholinopyridin-2-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (130 mg, 99%) as a yellow oil. Agent Ref.16525.0001-00304 2- yl) methoxycyclobutyl)-7-(methylamino)-5-((6-morpholinopyridin-2-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxamide (53 mg, 51%) as a yellow solid, as described for N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 454.2, found 454.1.1HNMR (DMSO- d6, 400 MHz) δ 9.62 (s, 1H), 8.58 (d, J = 9.2 Hz, 1H), 7.67 (d, J = 4.4 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 6.34 (s, 1H), 4.33-4.28 (m, 1H), 3.83- 3.77 (m, 1H), 3.71 (d, J = 4.4 Hz, 4H), 3.48 (d, J = 4.4 Hz, 4H), 3.21 (s, 3H), 2.86 (d, J = 4.4 Hz, 3H), 2.19-2.08 (m, 2H), 1.59-1.48 (m, 2H). Example 33: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-5-(methyl(2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide Boc H2N HCl Boc N

[0376] To a butoxycarbonyl)(methyl)amino)-5-chloroisoxazolo[4,3-b]pyridine-3-carboxylate (2.0 g, 5.8 mmol, 1.0 equiv) in ACN (50 mL) was added TMSOK (880 mg, 6.9 mmol, 1.2 equiv). The reaction mixture was stirred at 0oC for 1 h, and then N-methylimidazole (NMI) (2.0 g, 8.7 mmol, 1.5 equiv), N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (310 mg, 8.7 mmol, 1.5 equiv) and (1R,2R)-2-methoxycyclobutan-1-amine hydrochloride (938 Agent Ref.16525.0001-00304 mg, 6.9 mmol, 1.2 equiv) were added. The mixture was stirred at rt for 2 h and concentrated. The resulting residue was purified by column chromatography on silica gel (PE / EA = 3 / 1, v / v) to afford tert-butyl (5-chloro-3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)isoxazolo[4,3- b]pyridin-7-yl)(methyl)carbamate (1.4 g, 58%) as a yellow solid.

[0377] mg, 0.41 mmol, 1.0 equiv) in dioxane (10 mL) were added 3-amino-2H-[1,2'-bipyridin]-2-one (92 mg, 0.49 mmol, 1.2 equiv), BrettPhos (64 mg, 0.12 mmol, 0.3 equiv), BrettPhos Pd G3 (108 mg, 0.12 mmol, 0.3 equiv) and Cs2CO3 (266 mg, 0.82 mmol, 2.0 equiv). The mixture was stirred at 70oC overnight under N2atmosphere and concentrated. The resulting residue was purified by column column chromatography on silica gel (PE / EA = 1 / 3, v / v) to afford tert-butyl (3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridin-7-yl)(methyl)carbamate (92 mg, 40%) as a yellow solid. 2H- [1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (92 mg, 0.16 mmol, 1.0 equiv) in DMF (5 mL) were added CH3I (24 mg, 0.19 mmol, 1.2 equiv) and K2CO3(44 mg, 0.32 mmol, 2.0 equiv). The mixture was stirred at 25oC for 48 h and concentrated. The resulting residue was purified by column chromatography on silica gel (PE / EA = 1 / 1, v / v) to afford tert- butyl (3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)-5-(methyl(2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (70 mg, 76%) as a yellow solid. Agent Ref.16525.0001-00304 N- ((1R,2R)-2-methoxycyclobutyl)-5-(methyl(2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-7- (methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide (35 mg, 61%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]- 3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 476.2, found 476.1.1H NMR (DMSO-d6, 400 MHz) δ8.59-8.62 (m, 2H), 7.99-8.01 (m, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 6.8 Hz, 1H) , 7.63-7.64 (m, 1H), 7.51 (t, J = 5.6 Hz, 6.4 Hz, 1H), 6.51 (t, J = 6.8 Hz, 6.8 Hz, 1H), 5.6 (s, 1H), 4.24-4.20 (m, 1H), 3.63-3.62 (m, 1H), 3.85 (s, 3H), 3.16 (s, 3H), 2.81-2.80 (d, J = 3.2 Hz, 3H), 2.08-1.98 (m, 2H), 1.51-1.23 (m, 2H). Example 34: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-5-((6-(8-methyl-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridin2yl)amino)7(methylamino)isoxazolo[4,3-b]pyridine-3- carboxamide

[0380] To a equiv) in ACN (10 mL) were added 8-methyl-3,8-diazabicyclo[3.2.1]octane (250 mg, 1.26 mmol, 1.0 equiv) and DIEA (813 mg, 6.30 mmol, 5.0 equiv). The mixture was stirred at 100 ℃ for 16 h and concentrated. The resulting residue was purified by prep-HPLC to afford 8-methyl-3-(6-nitropyridin-2-yl)-3,8- diazabicyclo[3.2.1]octane (130 mg, 41%) as a yellow oil. Agent Ref.16525.0001-00304

[0381] To a octane (130 mg, 0.52 mmol, 1.0 . was stirred at 25 ℃ for 16 h under H2atmosphere. The reaction mixture was filtered and the filtrate was concentrated to afford 6-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-2-amine (110 mg, 97%) as a yellow solid. tert- butyl (3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)-5-((6-(8-methyl-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)amino)isoxazolo[4,3-b]pyridin-7- yl)(methyl)carbamate (60 mg, 21%) as a yellow oil, as described for tert-butyl (3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)-5-((2-oxo-1-phenyl-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate. diazabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)amino)isoxazolo[4,3-b]pyridin-7- yl)(methyl)carbamate was converted to N-((1R,2R)-2-methoxycyclobutyl)-5-((6-(8-methyl-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3- carboxamide (31 mg, 66%) as a yellow solid, as described for N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 493.3, found 493.1.1H NMR (DMSO- d6, 400 MHz) δ 9.54 (s, 1H), 8.58 (d, J = 9.2 Hz, 1H), 7.67-7.64 (m, 1H), 7.47 (t, J = 8.4 Hz, Agent Ref.16525.0001-00304 1H), 7.34 (d, J = 6.8 Hz, 1H), 6.41 (s, 1H), 6.33 (d, J = 8.4 Hz, 1H) 4.33-4.28 (m, 1H), 3.83-3.77 (m, 3H), 3.21 (s, 5H), 2.94 (d, J = 10.4 Hz, 2H), 2.85 (d, J = 4.8 Hz, 3H), 2.24 (s, 3H), 2.18-2.07 (m, 2H), 1.96-1.93 (m, 2H), 1.61-1.45 (m, 4H). Example 35: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(1- methylpyrrolidin-3-yl)-2oxo1,2dihydropyridin3yl)amino)isoxazolo[4,3-b]pyridine-3- carboxamide

[0384] To a solution equiv) in DMF (30 mL) were added tert-butyl 3-bromopyrrolidine-1-carboxylate (5.1 g, 20.4 mmol, 1.5 equiv) and K2CO3 (3.7 g, 27.1 mmol, 2.0 equiv). The mixture was stirred at 100 ℃ for 2 h. The reaction mixture was diluted with water and extracted with EA (20 mL× 3). The combined organic layers were concentrated. The resulting residue was purified by column chromatography on silica gel (PE / EA = 1 / 1, v / v) to afford tert-butyl 3-(3-nitro-2-oxopyridin-1(2H)-yl)pyrrolidine-1- carboxylate (770 mg, 18%) as a yellow oil.

[0385] tert-Butyl 3- was converted to afford 3-nitro-1-(pyrrolidin-3-yl)pyridin-2(1H)-one (800 mg, crude) as a yellow oil, as described for 3-amino-1-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)pyridin-2(1H)-one. Agent Ref.16525.0001-00304

[0386] 3-Nitro-1-(pyrrolidin-3-yl)pyridin-2(1H)-one was converted to 1-(1-methylpyrrolidin-3- yl)-3-nitropyridin-2(1H)-one (730 mg, 86%) as a yellow oil, as described for methyl 1-((3S,4R)- 3-fluoro-1-methylpiperidin-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate.

[0387] 1-(1- to 3-amino-1-(1- methylpyrrolidin-3-yl) - as described for 6-(8- methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-2-amine.

[0388] (3- (((1R,2R)-2-methoxycyclobutyl)carbamoyl)-5-((1-(1-methylpyrrolidin-3-yl)-2-oxo-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (31 mg, 15%) as a yellow oil, as described for tert-butyl (3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)-5-((2-oxo- 1-phenyl-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate. 3- yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate was converted to N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(1-methylpyrrolidin-3- yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide (15 mg, 64%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2- oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 468.2, found 468.1.1H NMR (DMSO-d6, 400 MHz) δ 8.91 (s, 1H), 8.51-8.48 (m, 2H), 7.61-7.57 (m, 2H), 6.40 (s, 1H), 6.35 (t, J = 7.2 Hz, 1H) 5.49-5.46 (m, 1H), 4.33-4.29 (m, Agent Ref.16525.0001-00304 1H), 3.83-3.78 (m, 1H), 3.21 (s, 3H), 3.04-2.99 (m, 1H), 2.85 (d, J = 4.8 Hz, 3H), 2.59-2.55 (m, 2H), 2.45-2.42 (m, 1H), 2.31 (s, 3H), 2.26-2.08 (m, 3H), 1.78-1.73 (m, 1H), 1.58-1.46 (m, 2H). Example 36: Preparation of 7-amino-N-((1R,2R)-2-methoxycyclobutyl)-5-((1-(1- methylpiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3- carboxamide

[0390] To a -1,2,3,6- tetrahydropyridine (2 g, 8.9 mmol, 1.0 equiv) in ACN / EtOH (15 mL / 3 mL) were added 3- nitropyridin-2(1H)-one (1.4 g, 8.9 mmol, 1.0 equiv), Cu(OAc)2(1.6 g, 17.8 mmol, 2.0 equiv) and TEA (1.8 g, 17.8 mmol, 2.0 equiv). The mixture was stirred at 80oC for 2 h and concentrated. The resulting residue was purified by column chromatography on silica gel (DCM / MeOH = 30 / 1, v / v) to afford 1'-methyl-3-nitro-1',2',3',6'-tetrahydro-2H-[1,4'-bipyridin]-2-one (300 mg, crude) as a yellow solid, which was used in the next step without further purification.

[0391] To a -2-one (300 mg, 1.3 mmol, 1.0 equiv) in MeOH (10 mL) was added Pd / C (90 mg). The mixture was stirred at rt for 12 h under H2(1 atm). The mixture was filtered and the filtrate was concentrated to afford 3-amino-1-(1-methylpiperidin-4-yl)pyridin-2(1H)-one (150 mg, crude) as a yellow solid, which was used in the next step without further purification. Agent Ref.16525.0001-00304

[0392] (3- (( - - - dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (70 mg, 36%) as a yellow solid, as described for tert-butyl (3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)-5-((2- oxo-1-phenyl-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate. 4-yl)- 2-oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate was converted to 7-amino-N-((1R,2R)-2-methoxycyclobutyl)-5-((1-(1-methylpiperidin-4-yl)-2-oxo- 1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide (39 mg, 68%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo- 2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 482.2, found 482.1.1H NMR (DMSO-d6, 400 MHz) δ 8.90 (s, 1H), 8.46-8.51 (m, 2H), 7.57 (d, J = 4.8 Hz, 1H), 7.43 (t, J = 5.6 Hz, 1H), 6.39 (s, 1H), 6.31 (t, J = 6.8 Hz, 1H), 4.75-4.76 (m, 1H), 4.31 (t, J = 8.4 Hz, 1H), 3.80-3.82 (m, 1H), 3.32(s, 3H), 2.93-2.95 (m, 2H), 2.86 (d, J = 4.8 Hz, 3H), 2.24 (s, 3H), 2.08-2.18 (m, 4H), 1.90-1.96 (m, 2H), 1.74-1.44 (m, 2H),1.47-1.58 (m, 2H).

[0003] Agent Ref.16525.0001-00304 Example 37: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(1- methylazetidin-3-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3- carboxamide

[0394] tert- nitro-2- oxopyridin-1 - mg, as a as described for tert-butyl 3-(3-nitro-2-oxopyridin-1(2H)-yl)pyrrolidine-1-carboxylate.

[0395] tert-Butyl was converted to tert-butyl 3-(3-amino-2-oxopyridin-1(2H)-yl)azetidine-1-carboxylate (600 mg, 84%) as a brown oil, as described for 6-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-2-amine. to tert-butyl 3-(3-((7-((tert-butoxycarbonyl)(methyl)amino)-3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-5-yl)amino)-2-oxopyridin-1(2H)- yl)azetidine-1-carboxylate (300 mg, 57%) as a yellow solid, as described for tert-butyl (3- (((1R,2R)-2-methoxycyclobutyl)carbamoyl)-5-((2-oxo-1-phenyl-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate. Agent Ref.16525.0001-00304 yl)azetidine-1-carboxylate was converted to 5-((1-(azetidin-3-yl)-2-oxo-1,2-dihydropyridin-3- yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3- carboxamide (155 mg, 25%) as a brown solid, as described for N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxamide. - 2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide (70 mg, 0.16 mmol, 1.0 equiv) in MeOH (3 mL) were added CH2O (70 mg, 0.16 mmol, 1.0 equiv) and NaBH3CN (20 mg, 0.32 mmol, 2.0 equiv) at 0 ℃. The mixture was stirred at rt for 1 h and concentrated. The resulting residue was purified by column chromatography on silica gel (DCM / MeOH = 10 / 1, v / v) to afford N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(1- methylazetidin-3-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3- carboxamide (14 mg, 18%) as a yellow solid. LRMS (M+H+) m / z calculated 454.2, found 454.1.1H NMR (DMSO-d6, 400 MHz) δ 8.92 (s, 1H), 8.51 (t, J = 7.6 Hz, 2H), 7.55 (t, J = 8.0 Hz, 2H), 6.39 (s, 1H), 6.36 (t, J = 6.8 Hz, 1H), 5.07 (t, J = 6.8 Hz, 1H), 4.29-4.31 (m, 1H), 3.81-3.83 (m, 1H), 3.74-3.79 (m, 2H), 3.17-3.25(m, 5H), 2.85 (d, J = 4.8 Hz, 3H), 2.30 (d, J = 11.6 Hz, 3H), 2.09-2.17 (m, 2H),1.47-1.58 (m, 2H). Agent Ref.16525.0001-00304 Example 38: Preparation of (S)-2-amino-3-(4-(3-((3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)-7-(methylamino)isoxazolo[4,3-b]pyridin-5-yl)amino)-2- oxopyridin-1(2H)-yl)phenyl)propanoic acid hydrochloride

[0399] To a propanoic acid (5.0 g, 12.8 mmol, were mg, mmol, 1.2 equiv) and (Boc)2O (4.2 g, 19.2 mmol, 1.2 equiv). The mixture was stirred at 40oC overnight and concentrated. The resulting residue was purified by column chromatography on silica gel (PE / EA = 5 / 1, v / v) to afford tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4- iodophenyl)propanoate (4.1 g, 72%) as a white solid. O N

[0400] To a iodophenyl)propanoate (2.0 g, 4.5 mmol, 1.0 equiv) in dioxane (30 mL) were added 3- aminopyridin-2(1H)-one (495 mg, 4.5 mmol, 1.0 equiv), CuI (171 mg, 0.9 mmol, 0.2 equiv), K2CO3(1.6 g, 11.3 mmol, 2.5 equiv) and N,N'-Dimethylethylenediamine (DMEDA) (79 mg, 0.9 mmol, 0.2 equiv). The mixture was stirred at 100oC overnight under N2 atmosphere and concentrated. The resulting residue was purified by column chromatography on silica gel (PE / EA = 1 / 1, v / v) to afford tert-butyl (S)-3-(4-(3-amino-2-oxopyridin-1(2H)-yl)phenyl)-2-((tert- butoxycarbonyl)amino)propanoate (1.8 g, 93%) as a white solid. Agent Ref.16525.0001-00304 - butoxycarbonyl)(methyl)amino)-3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)isoxazolo[4,3- b]pyridin-5-yl)amino)-2-oxopyridin-1(2H)-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (80 mg, 27%) as a yellow solid, as described for tert-butyl (3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)-5-((2-oxo-1-phenyl-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate. methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-5-yl)amino)-2-oxopyridin-1(2H)- yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate was converted to (S)-2-amino-3-(4-(3-((3- (((1R,2R)-2-methoxycyclobutyl)carbamoyl)-7-(methylamino)isoxazolo[4,3-b]pyridin-5- yl)amino)-2-oxopyridin-1(2H)-yl)phenyl)propanoic acid hydrochloride (25 mg, 43%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo- 2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 584.2, found 548.1.1H NMR (D2O, 400 MHz) δ 7.76 (d, J = 6.8 Hz, 1H), 7.60 (d, J = 6.4 Hz, 1H), 7.38-7.31 (m, 4H), 6.57 (t, J = 7.2 Hz, 7.2 Hz, 1H), 5.6 (s, 1H), 4.20-4.18 (m, 1H), 4.12 (t, J = 6.8 Hz, 6.4 Hz, 1H), 3.29-3.28 (m, 1H), 3.25 (s, 3H), 3.18-3.12 (m, 1H), 2.92 (d, J = 13.2 Hz, 3H), 2.05-2.03 (m, 2H), 1.49-1.45 (m, 2H). Agent Ref.16525.0001-00304 Example 39: Preparation of N-((1R,2R)-2-(methoxy-d3)cyclobutyl)-7-(methylamino)-5-((2- oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0403] To a 1.0 equiv) in THF (10 were mg, 4.5 mmol, 1.2 equiv). The mixture was stirred at rt for 6 h and concentrated. The resulting residue was purified by column chromatography on silica gel (PE / EA = 5 / 1, v / v) to afford (1R,2R)-N,N- dibenzyl-2-(methoxy-d3)cyclobutan-1-amine (960 mg, 90%) as a white solid.

[0404] To a solution 1-amine (960 mg, 3.4 mmol, 1.0 equiv) in MeOH (10 mL) was added Pd / C (300 mg). The mixture was stirred at rt for 16 h under H2(60 Psi). After filtration, 1M HCl / dioxane (1 mL) was added. The mixture was stirred at rt for 1 h and concentrated to afford (1R,2R)-2-(methoxy-d3)cyclobutan-1-amine HCl salt (380 mg, 81%) as a white solid. -3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (100 mg, 0.21 mmol, 1.0 equiv) in DMF (2 mL) were added (1R,2R)-2-(methoxy-d3)cyclobutan-1-amine HCl salt (30 mg, 0.21 mmol, 1.0 equiv), HATU (96 mg, 0.25 mmol, 1.2 equiv) and TEA (64 mg, 0.63 mmol, 3.0 equiv). The mixture was stirred at rt for 2 h. The mixture was concentrated and the resulting residue was purified by column chromatography on silica gel (DCM / MeOH = 20 / 1, v / v) to afford tert-butyl Agent Ref.16525.0001-00304 (3-(((1R,2R)-2-(methoxy-d3)cyclobutyl)carbamoyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (75 mg, 64%) as a yellow solid.

[0406] - to N- ((1R,2R)-2-(methoxy-d3)cyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide (46 mg, 77%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 465.2, found 465.1.1H NMR (DMSO-d6400 MHz) δ 9.03 (s, 1H), 8.64 (t, J = 4.8 Hz, 2H), 8.53 (d, J = 8.8 Hz, 8.03-8.07 (m, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.52-7.61 (m, 3H), 6.43-6.46 (m, 2H), 4.32 (t, J = 8.4 Hz, 1H), 3.84-3.86 (m, 1H), 2.86 (d, J = 4.8 Hz, 3H), 2.10-2.18 (m, 2H), 1.51-1.59 (m, 2H). Example 40: Preparation of N-((1R,2R)-2-(methoxy-d3)cyclobutyl)-7-((methyl-d3)amino)- 5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0407] bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (100 mg, 0.21 mmol, 1.0 equiv) in DMF (2 mL) were added (1R,2R)-2-(methoxy-d3)cyclobutan-1-amine HCl salt (30 mg, 0.21 mmol, 1.0 equiv), HATU (96 mg, 0.25 mmol, 1.2 equiv) and TEA (64 mg, 0.63 mmol, 3.0 equiv). The mixture was stirred at rt for 2 h and concentrated. The resulting residue was purified Agent Ref.16525.0001-00304 by column chromatography on silica gel (DCM / MeOH = 20 / 1, v / v) to afford tert-butyl (3- (((1R,2R)-2-(methoxy-d3)cyclobutyl)carbamoyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl-d3)carbamate (52 mg, 44%) as a yellow solid. - to N- ((1R,2R)-2-(methoxy-d3)cyclobutyl)-7-((methyl-d3)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide (46 mg, 77%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 468.2, found 468.1.1H NMR (DMSO-d6400 MHz) δ 9.02 (s, 1H), 8.64 (t, J = 4.8 Hz, 2H), 8.53 (d, J = 8.8 Hz, 8.03-8.07 (m, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.52-7.59 (m, 3H), 6.42-6.46 (m, 2H), 4.32 (t, J = 8.4 Hz, 1H), 3.84-3.86 (m, 1H), 2.10-2.18 (m, 2H), 1.53-1.57 (m, 2H). Example 41: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-7-((methyl-d3)amino)-5-((2- oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0409] To a solution mmol, 1.0 equiv) in ACN (100 mL) were added CD3I (10.5 g, 72.6 mmol, 3.0 equiv) and K2CO3(10.0 g, 72.6 mmol, 3.0 equiv). The mixture was stirred at 90oC for 16 h and concentrated. The resulting residue was purified by column chromatography on silica gel (PE / EA = 3 / 1, v / v) to afford 2,6-dichloro-N- (methyl-d3)-3-nitropyridin-4-amine (2.5 g, 46%) as a yellow solid. Agent Ref.16525.0001-00304

[0410] To a g, 11.2 mmol, 1.0 equiv) in equiv), Cu(OTf)2(105 mg, 1.12 mmol, 0.1 equiv), Cs2CO3(10.9 g, 33.6 mmol, 3.0 equiv) and dimethyl malonate (2.9 g, 22.4 mmol, 2.0 equiv). The mixture was stirred at 80 °C for 16 h and concentrated. The resulting residue was purified by column chromatography on silica gel (PE / EA = 1 / 1, v / v) to afford dimethyl 2-(6-chloro-4-((methyl-d3)amino)-3-nitropyridin-2- yl)malonate (2.1 g, 58%) as a yellow solid.

[0411] Dimethyl 2- (2.1 g, 6.6 mmol, 1.0 equiv) was dissolved in xylene (50 mL). The mixture was stirred at 200 °C for 48 h with Soxhlet extractor. The mixture was concentrated and the resulting residue was purified by column chromatography on silica gel (PE / EA = 3 / 1, v / v) to afford methyl 5-chloro-7-((methyl- d3)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (1.3 mg, 81%) as a yellow solid.

[0412] To a solution [4,3-b]pyridine-3- carboxylate (1.3 g, 5.3 mmol, 1.0 equiv) in DCM (100 mL) were added DMAP (61 mg, 0.5 mmol, 0.1 equiv) and (Boc)2O (2.3 g, 10.6 mmol, 2.0 equiv). The mixture was stirred at rt for 5 h and concentrated. The resulting residue was purified by column chromatography on silica gel (PE / EA = 5 / 1, v / v) to afford methyl 7-((tert-butoxycarbonyl)(methyl-d3)amino)-5- chloroisoxazolo[4,3-b]pyridine-3-carboxylate (1.4 g, 76%) as a yellow solid. Agent Ref.16525.0001-00304

[0413] pyridine-3- ((2-oxo-2H- [1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate (300 mg, 52%) as a yellow solid, as described for methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((3'-fluoro-2-oxo-2H- [1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate.

[0414] -3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate was converted to 7-((tert- butoxycarbonyl)(methyl-d3)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylic acid (300 mg, crude), as described for 7-((tert- butoxycarbonyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxylic acid. D3C D3C H2N HCl NBoc NBoc O

[0415] yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid was converted to tert-butyl (3-(((1R,2R)-2- methoxycyclobutyl)carbamoyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridin-7-yl)(methyl-d3)carbamate (65 mg, 19%) as a yellow solid, as described for tert-butyl (3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate. Agent Ref.16525.0001-00304

[0416] - 3-yl) -2- methoxycyclobutyl)-7-((methyl-d3)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide (28 mg, 50%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 465.2, found 465.1.1H NMR (DMSO-d6, 400 MHz) δ 9.02 (s, 1H), 8.65-8.54 (m, 2H), 8.54 (d, J = 9.2 Hz, 1H), 8.06-8.03 (m, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.59-7.52 (m, 3H), 6.45-6.42 (m, 2H), 4.34- 4.30 (m, 1H), 3.87-3.82 (m, 1H), 3.14 (s, 3H), 2.19-2.08 (m, 2H), 1.59-1.50 (m, 2H). Example 42: Preparation of N-((trans)-2-(difluoromethoxy)cyclobutyl)-7-(methylamino)-5- ((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0417] To a 3.8 mmol, 1.0 equiv) and CuI (215 mg, 1.13 mmol, 0.3 equiv) in ACN (20 mL) was added 2,2-difluoro-2- (fluorosulfonyl)acetic acid (3.3 g, 18.8 mmol, 5.0 equiv) at 60 ℃. The mixture was stirred at 60 ℃ for 1 h. The reaction mixture was diluted with saturated NaHCO3 solution and extracted with EA (15 mL × 3). The combined organic layers were concentrated. The residue was purified by column chromatography on silica gel (PE / EA = 10 / 1, v / v) to afford (trans)-N,N-dibenzyl-2- (difluoromethoxy)cyclobutan-1-amine (350 mg, 29%) as a yellow oil. Agent Ref.16525.0001-00304

[0418] To a 1-amine (350 mg, 1.10 mmol, 1.0 , 2 (100 mg) and AcOH (0.5 mL). The mixture was stirred at 50 °C under H2(0.5 MPa) for 16 h. The reaction mixture was filtered. To this filtrate was added HCl in dioxane (1N, 2 mL) at 0 °C and the mixture was stirred for 1 h and concentrated to afford (trans)-2-(difluoromethoxy)cyclobutan-1- amine hydrogen chloride (200 mg, 86%) as a white solid.

[0419] (53 mg, 0.25 mmol, 1.0 equiv) in DMF (4 mL) were added HATU (144 mg, 0.38 mmol, 1.5 equiv), 7-((tert-butoxycarbonyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylic acid (120 mg, 0.25 mmol, 1.0 equiv) and Et3N (76 mg, 0.75 mmol, 3.0 equiv). The mixture was stirred at rt for 1 h. The reaction mixture was diluted with water and extracted with EA (15 mL × 3). The combined organic layers were concentrated and purified by column chromatography on silica gel (PE / EA = 1 / 1, v / v) to afford tert-butyl (3-(((trans)-2-(difluoromethoxy)cyclobutyl)carbamoyl)-5-((2-oxo-2H-[1,2'-bipyridin]- 3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (100 mg, 67%) as a yellow solid.

[0420] bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate was converted to N- ((trans)-2-(difluoromethoxy)cyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide (40 mg, 48%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 498.2, found 498.1.1H NMR (DMSO-d6, 400 MHz) δ 9.00 (s, 1H), 8.71-8.60 (m, 3H), 8.07-8.03 (m, 1H), 7.85 Agent Ref.16525.0001-00304 (d, J = 8.0 Hz, 1H), 7.60-7.52 (m, 3H), 6.88-6.51 (m, 1H), 6.46-6.43 (m, 2H), 4.65-4.57 (m, 1H), 4.55-4.49 (m, 1H), 2.86 (d, J = 4.8 Hz, 3H), 2.26-2.16 (m, 2H), 1.85-1.75 (m, 1H), 1.71-1.61 (m, 1H). Example 43: Preparation of N-((1R,2R)-2-(difluoromethoxy)cyclobutyl)-7-(methylamino)- 5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0421] (1R,2R)-2- -N,N-dibenzyl-2- (difluoromethoxy)cyclobutan-1-amine (110 mg, 37%) as a yellow oil, as described for (trans)- N,N-dibenzyl-2-(difluoromethoxy)cyclobutan-1-amine.

[0422] (1R,2R)- converted to (1R,2R)-2-(difluoromethoxy)cyclobutan-1-amine hydrogen chloride (60 mg, 82%) as a white solid, as described for (trans)-2-(difluoromethoxy)cyclobutan-1-amine.

[0423] (((1R,2R)-2-(difluoromethoxy)cyclobutyl)carbamoyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (120 mg, 69%) as a yellow solid, as described for tert-butyl (3-(((trans)-2-(difluoromethoxy)cyclobutyl)carbamoyl)-5-((2-oxo-2H- [1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate. Agent Ref.16525.0001-00304 [1,2'- N- ((1R,2R)-2-(difluoromethoxy)cyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide (36 mg, 36%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 498.2, found 498.0.1H NMR (DMSO-d6, 400 MHz) δ 9.00 (s, 1H), 8.71-8.59 (m, 3H), 8.07-8.03 (m, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.60-7.52 (m, 3H), 6.88-6.51 (m, 1H), 6.46-6.43 (m, 2H), 4.65-4.57 (m, 1H), 4.55-4.49 (m, 1H), 2.86 (d, J = 4.8 Hz, 3H), 2.26-2.16 (m, 2H), 1.82-1.77 (m, 1H), 1.71-1.64 (m, 1H). Example 44: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo- 1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide

[0425] 2- methoxycyclobutyl)carbamoyl)-5-((2-methoxypyridin-3-yl)amino)isoxazolo[4,3-b]pyridin-7- yl)(methyl)carbamate (210 mg, 57%) as a yellow solid, as described for methyl 7-((tert- Agent Ref.16525.0001-00304 butoxycarbonyl)(methyl)amino)-5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxylate.

[0426] 0.4 mmol, 1.0 equiv) in ACN (20 mL) were added TMSCl (130 mg, 1.2 mmol, 3.0 equiv) and NaI (180 mg, 1.2 mmol, 3.0 equiv). The mixture was stirred at 80oC overnight and concentrated. The resulting residue was purified by column chromatography on silica gel (PE / EA = 1 / 3, v / v) to afford tert- butyl (3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)-5-((2-oxo-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (150 mg, 77%) as a yellow solid.

[0427] 3-yl)amino)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate was converted to N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxamide (100 mg, 84%) as a yellow solid, as described for N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3- b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 385.4, found 385.1.1H NMR (DMSO- d6, 400 MHz) δ 11.96 (s, 1H), 8.86 (s, 1H), 8.52-8.48 (m, 2H), 7.55-7.54 (m, 1H), 7.09 (d, J = 4.8 Hz, 1H), 6.39 (s, 1H), 6.23 (t, J = 6.8 Hz, 7.2 Hz, 1H), 4.33-4.29 (m, 1H), 3.82-3.80 (m, 1H), 3.21 (s, 3H), 2.85-2.84 (d, J = 4.8 Hz, 3H), 2.16-2.08 (m, 2H), 1.56-1.46 (m, 2H).

[0004] Agent Ref.16525.0001-00304 Example 45: Preparation of N-((1R,2R)-2-methoxycyclobutyl)-5-((1-(5-methyl-1,3,4- oxadiazol-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)isoxazolo[4,3- b]pyridine-3-carboxamide

[0428] 1,2- mg, 1.0 equiv) in DMF (4 mL) were added K2CO3 (54 mg, 0.39 mmol, 3.0 equiv) and 2-bromo-5- methyl-1,3,4-oxadiazole (42 mg, 0.26 mmol, 2.0 equiv). The mixture was stirred at 100 ℃ for 3 h. The reaction mixture was diluted with water and extracted with EA (15 mL × 3). The combined organic layers were concentrated. The residue was purified by column chromatography on silica gel (DCM / MeOH = 20 / 1, v / v) to afford N-((1R,2R)-2- methoxycyclobutyl)-5-((1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1,2-dihydropyridin-3- yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide (14 mg, 24%) as a yellow solid. LRMS (M+H+) m / z calculated 467.2, found 467.0.1H NMR (DMSO-d6, 400 MHz) δ 9.10 (s, 1H), 8.71-8.69 (m, 1H), 8.52 (d, J = 8.8 Hz, 1H), 8.65-8.63 (m, 1H), 7.48-7.46 (m, 1H), 6.50 (t, J = 7.2 Hz, 1H), 6.41 (s, 1H), 4.33-4.29 (m, 1H), 3.87-3.82 (m, 1H), 3.17 (s, 3H), 2.85 (d, J = 4.8 Hz, 3H), 2.54 (s, 3H), 2.17-2.07 (m, 2H), 1.60-1.47 (m, 2H).

[0005] Agent Ref.16525.0001-00304 Example 46: Preparation of 5-((6'-methoxy-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N- ((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide was to 5-((6'-methoxy-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7- (methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide (15 mg, 64%) as a yellow solid, as described for N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]- 3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide. LRMS (M+H+) m / z calculated 492.2, found 492.1.1H NMR (DMSO-d6, 400 MHz) δ 9.03 (s, 1H), 8.63-8.61 (m, 1H), 8.52 (d, J = 9.2 Hz, 1H), 7.94 (t, J = 7.6 Hz, 1H), 7.66-7.64 (m, 1H), 7.61-7.58 (m, 1H), 7.44 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.43 (t, J = 7.6 Hz, 2H), 4.35-4.31 (m, 1H), 3.89 (s, 3H), 3.86-3.82 (m, 1H), 3.23 (s, 3H), 2.86 (d, J = 4.8 Hz, 3H), 2.20-2.08 (m, 2H), 1.59-1.51 (m, 2H). Example 47: Preparation of 5-((2,6'-dioxo-1',6'-dihydro-2H-[1,2'-bipyridin]-3-yl)amino)-N- ((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide Agent Ref.16525.0001-00304

[0430] 2-Bromo-6- 2H-[1,2'-bipyridin]-2- one (120 mg, 61%) [1,2'-bipyridin]-2- one.

[0431] ((6'- oxo- - - - methoxycyclobutyl)carbamoyl)isoxazolo[4,3-b]pyridin-7-yl)(methyl)carbamate (120 mg, 55%) as a yellow solid, as described for methyl 7-((tert-butoxycarbonyl)(methyl)amino)-5-((3'-fluoro- 2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3...

Claims

Agent Ref.16525.0001-00304 What is claimed is:

1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein Z1and Z2are independently selected from N and O, provided that when Z1is N then Z2is O, and when Z1is O then Z2is N; R1is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted sulfonyl, or optionally substituted aminosulfonyl; R2is hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted carbamimidoyl; or R1and R2together with the atoms to which they are attached form an optionally substituted heteroaryl ring; R3is optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; R4is -C(O)N(R9)(R10); R5is hydrogen, optionally substituted lower alkyl, or optionally substituted cycloalkyl; R6and R7are independently hydrogen, halo, optionally substituted lower alkyl, or optionally substituted cycloalkyl; R8is hydrogen, optionally substituted lower alkyl, or optionally substituted cycloalkyl;Agent Ref.16525.0001-00304 R9and R10are independently hydrogen, optionally substituted lower alkyl, or optionally substituted cycloalkyl; L1is a covalent bond, -N(R5)-, -N(R5)C(R6)(R7)-, -O-, -C(O)-, -C(R6)(R7)-, or - C(R6)(R7)N(R5)-; and L2is a covalent bond or -N(R8)-.

2. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound or pharmaceutically acceptable salt is selected from a compound of Formula Ia:or a pharmaceutically acceptable salt thereof.

3. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound or pharmaceutically acceptable salt is selected from a compound of Formula Ib:or a pharmaceutically acceptable salt thereof.

4. The compound or pharmaceutically acceptable salt of anyone of claims 1-3, wherein R1is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aminocarbonyl, or optionally substituted acyl.

5. The compound or pharmaceutically acceptable salt of anyone of claims 1-3, wherein R1is optionally substituted lower alkyl, optionally substituted acyl, optionally substituted aminocarbonyl, or optionally substituted cycloalkyl.

6. The compound or pharmaceutically acceptable salt of anyone of claims 1-3, wherein R1is methyl, acetyl, or cyclopropyl.

7. The compound or pharmaceutically acceptable salt of anyone of claims 1-3, wherein R1is methyl or acetyl.

8. The compound or pharmaceutically acceptable salt of anyone of claims 1-7, wherein R2isAgent Ref.16525.0001-00304 hydrogen, cyano, halo, hydroxy, carboxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, or optionally substituted aminocarbonyl.

9. The compound or pharmaceutically acceptable salt of anyone of claims 1-7, wherein R2is hydrogen, cyano, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl.

10. The compound or pharmaceutically acceptable salt of anyone of claims 1-7, wherein R2is hydrogen.

11. The compound or pharmaceutically acceptable salt of anyone of claims 1-7, wherein R1and R2together with the atoms to which they are attached form an optionally substituted 5- to 6- membered heteroaryl ring.

12. The compound or pharmaceutically acceptable salt of anyone of claims 1-7, wherein R1and R2together with the atoms to which they are attached form a 5-membered heteroaryl ring.

13. The compound or pharmaceutically acceptable salt of anyone of claims 1-7, wherein R1and R2together with the atoms to which they are attached form a pyrrole ring.

14. The compound or pharmaceutically acceptable salt of anyone of claims 1-13, wherein L1is a covalent bond, -N(R5)-, or -O-.

15. The compound or pharmaceutically acceptable salt of anyone of claims 1-13, wherein L1is -N(R5)-.

16. The compound or pharmaceutically acceptable salt of anyone of claims 1-15, wherein R5is hydrogen, or lower alkyl.

17. The compound or pharmaceutically acceptable salt of anyone of claims 1-15, wherein R5is hydrogen.

18. The compound or pharmaceutically acceptable salt of anyone of claims 1-17, wherein R3is optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted cycloalkyl.

19. The compound or pharmaceutically acceptable salt of anyone of claims 1-17, wherein R3is optionally substituted 6-membered aryl or optionally substituted 5- to 6-membered heteroaryl.

20. The compound or pharmaceutically acceptable salt of anyone of claims 1-17, wherein R3is optionally substituted 5- to 6-membered heteroaryl.

21. The compound or pharmaceutically acceptable salt of anyone of claims 1-17, wherein R3is optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted pyrazinyl.Agent Ref.16525.0001-00304 22. The compound or pharmaceutically acceptable salt of anyone of claims 1-17, wherein R3is optionally substituted pyridinyl or optionally substituted pyrazinyl.

23. The compound or pharmaceutically acceptable salt of anyone of claims 1-17, wherein R3is phenyl, pyridinyl, pyridonyl, or pyrazinonyl, which are each independently optionally substituted with: optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, or optionally substituted isoxazolyl.

24. The compound or pharmaceutically acceptable salt of anyone of claims 1-17, wherein R3is pyridonyl or pyrazinonyl, which are each independently optionally substituted with: optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted 8-azabicyclo[3.2.1]octanyl, optionally substituted piperidinyl, optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted oxadiazolyl, optionally substituted triazolyl, or optionally substituted isoxazolyl.

25. The compound or pharmaceutically acceptable salt of anyone of claims 1-24, wherein L2is a covalent bond.

26. The compound or pharmaceutically acceptable salt of anyone of claims 1-25, wherein R9and R10are independently hydrogen or optionally substituted cycloalkyl.

27. The compound or pharmaceutically acceptable salt of anyone of claims 1-25, wherein R9and R10are independently hydrogen, optionally substituted cyclopropyl, or optionally substituted cyclobutyl.

28. The compound or pharmaceutically acceptable salt of anyone of claims 1-25, wherein R9and R10are independently hydrogen, cyclopropyl, or cyclobutyl, wherein cyclopropyl and cyclobutyl are each independently optionally substituted with halogen or optionally substituted alkoxy.

29. A compound chosen from the group consisting of: N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)- 7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)- 7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide;Agent Ref.16525.0001-00304 N-((1R,2R)-2-methoxycyclobutyl)-5-((3'-methyl-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)- 7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((3'-methoxy-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((5'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)- 7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((5'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)- 7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-((5'-methyl-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)- 7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((5'-methoxy-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((3-oxo-4-(pyridin-2-yl)-3,4- dihydropyrazin-2-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((4-(3-fluoropyridin-2-yl)-3-oxo-3,4-dihydropyrazin-2-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(pyrimidin-2-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(pyrimidin-4-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(pyrazin-2-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(oxazol-2-yl)-2-oxo-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(oxazol-5-yl)-2-oxo-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((1-(isoxazol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(1H-pyrazol-5-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(1H-pyrazol-4-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; 7-acetamido-N-((1R,2R)-2-methoxycyclobutyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide;Agent Ref.16525.0001-00304 N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,3'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-8H- isoxazolo[4,3-b]pyrrolo[2,3-d]pyridine-3-carboxamide; N-((2R)-2-fluorocyclopropyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((2S)-2-fluorocyclopropyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((2R)-2-methoxycyclopropyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((2S)-2-methoxycyclopropyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,5-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(pyrimidin-2-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,5-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,3'-bipyridin]-3- yl)amino)isoxazolo[4,5-b]pyridine-3-carboxamide; 5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)- 7-(methylamino)isoxazolo[4,5-b]pyridine-3-carboxamide; 5-((3'-cyano-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)- 7-(methylamino)isoxazolo[4,5-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-((3'-methyl-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)- 7-(methylamino)isoxazolo[4,5-b]pyridine-3-carboxamide; 5-((3'-methoxy-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,5-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((3-oxo-4-(pyridin-2-yl)-3,4- dihydropyrazin-2-yl)amino)isoxazolo[4,5-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(pyrazin-2-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,5-b]pyridine-3-carboxamide; 5-((5'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)- 7-(methylamino)isoxazolo[4,5-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(oxazol-2-yl)-2-oxo-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,5-b]pyridine-3-carboxamide;Agent Ref.16525.0001-00304 N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(oxazol-5-yl)-2-oxo-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,5-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(pyrimidin-5-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(pyridazin-3-yl)-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(1H-1,2,3-triazol-5-yl)- 1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((5'-amino-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)- 7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((3'-amino-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)- 7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((1-((3S,4R)-3-fluoropiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N- ((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((1-((3R,4R)-3-fluoropiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N- ((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((1-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)- N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((1-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)- N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-phenyl-1,2- dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((6-cyclopropylpyridin-2-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-7- (methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((6-(4-methylpiperazin-1- yl)pyridin-2-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((6-morpholinopyridin-2- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-(methyl(2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-7- (methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-((6-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3- yl)pyridin-2-yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(1-methylpyrrolidin-3-yl)-2- oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide;Agent Ref.16525.0001-00304 N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(1-methylpiperidin-4-yl)-2- oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(1-methylazetidin-3-yl)-2- oxo-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; (S)-2-amino-3-(4-(3-((3-(((1R,2R)-2-methoxycyclobutyl)carbamoyl)-7- (methylamino)isoxazolo[4,3-b]pyridin-5-yl)amino)-2-oxopyridin-1(2H)-yl)phenyl)propanoic acid hydrochloride; N-((trans)-2-(methoxy-d3)cyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((trans)-2-(methoxy-d3)cyclobutyl)-7-((methyl-d3)amino)-5-((2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-((methyl-d3)amino)-5-((2-oxo-2H-[1,2'-bipyridin]- 3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((trans)-2-(difluoromethoxy)cyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-(difluoromethoxy)cyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'- bipyridin]-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1,2-dihydropyridin-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-((1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1,2- dihydropyridin-3-yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((6'-methoxy-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((2,6'-dioxo-1',6'-dihydro-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-((1-(6-methoxypyrimidin-4-yl)-2-oxo-1,2- dihydropyridin-3-yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-((1-(1-methyl-1H-1,2,4-triazol-3-yl)-2-oxo-1,2- dihydropyridin-3-yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(6-oxo-1,6- dihydropyrimidin-4-yl)-1,2-dihydropyridin-3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-((1-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-2- oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide;Agent Ref.16525.0001-00304 N-((1R,2R)-2-methoxycyclobutyl)-5-((1'-methyl-2'-oxo-1',2'-dihydro-[2,4'-bipyridin]-6- yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((2,2'-dioxo-1',2'-dihydro-2H-[1,4'-bipyridin]-3-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-((1'-methyl-2,2'-dioxo-1',2'-dihydro-2H-[1,4'- bipyridin]-3-yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-5-((1-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2- dihydropyridin-3-yl)amino)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((1-(1-isopropyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1R,2R)- 2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((1-(1-cyclopropyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N- ((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((1-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1R,2R)- 2-methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 5-((6'-methoxy-2-oxo-2H-[1,3'-bipyridin]-3-yl)amino)-N-((1R,2R)-2- methoxycyclobutyl)-7-(methylamino)isoxazolo[4,3-b]pyridine-3-carboxamide; 7-(cyclopropylamino)-N-((1R,2R)-2-methoxycyclobutyl)-5-((2-oxo-2H-[1,2'-bipyridin]- 3-yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; N-((1R,2R)-2-methoxycyclobutyl)-7-(3-methylureido)-5-((2-oxo-2H-[1,2'-bipyridin]-3- yl)amino)isoxazolo[4,3-b]pyridine-3-carboxamide; and pharmaceutically acceptable salts thereof.

30. A compound chosen from the compounds of Table 1 and pharmaceutically acceptable salts thereof.

31. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound or pharmaceutically acceptable salt of any one of claims 1-30.

32. The pharmaceutical composition of claim 31, wherein the pharmaceutical composition is formulated in a form of tablets, capsules, powders, liquids, suspensions, suppositories, or aerosols.

33. A packaged pharmaceutical composition comprising a pharmaceutical composition of claim 31 or 32 and instructions for using the composition to treat a subject suffering from a TYK2-mediated disorder, disease, or condition.

34. A method of inhibiting TYK2 in a biological sample comprising contacting the sample with the compound or pharmaceutically acceptable salt of any one of claims 1-30, or the pharmaceutical composition of any one of claims 31-33.Agent Ref.16525.0001-00304 35. A method of inhibiting TYK2 in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1-30 or the pharmaceutical composition of any one of claims 31-33.

36. A method of treating a TYK2-mediated disorder, disease, or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1-30 or the pharmaceutical composition of any one of claims 31-33.

37. The method of any one of claims 34-36, wherein the disorder, disease, or condition is associated with type I interferon, IL-10, IL-12, or IL-23 signaling.

38. The method of any one of claims 34-37, wherein the disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.

39. The method of any one of claims 34-37, wherein the disorder is an autoimmune disorder.

40. The method of claim 38 or 39, wherein the autoimmune disorder is type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, psoriatic arthritis, Crohn' s disease, alopecia, Sjogren’s syndrome, Bechet’s disease, ulcerative colitis, vitiligo, uveitis, or inflammatory bowel disease.

41. The method of any one of claims 34-38, wherein the disorder is an inflammatory disorder.

42. The method of claim 38 or 41, wherein the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn' s disease, ulcerative colitis, or inflammatory bowel disease.

43. The method of any one of claims 34-38, wherein the disorder is a proliferative disorder.

44. The method of claims 38 or 43, wherein the proliferative disorder is hematological cancer or leukemia.

45. The method of any one of claims 38, 43, or 44, wherein the proliferative disorder is associated with one or more activating mutations in TYK2.

46. The method of any one of claims 34-38, wherein the disorder is associated with transplantation.

47. The method of claims 38 or 46, wherein the disorder is transplant rejection or graft versus host disease.

48. The method of any one of claims 34-38, wherein the disorder is an endocrine disorder.

49. The method of claims 38 or 48, wherein the endocrine disorder is polycystic ovary syndrome, Crouzon's syndrome, or type 1 diabetes.

50. The method of any one of claims 34-38, wherein the disorder is a neurological disorder.Agent Ref.16525.0001-00304 51. The method of any one of claims 38 or 50, wherein the neurological disorder is Alzheimer's disease.