Pyrrolidone derivatives as inhibitors of NF [kappa] B-inducing kinases

Abstract

The present disclosure relates to compounds of formula (I) that inhibit NIK and pharmaceutical compositions comprising such compounds and methods of use thereof. These compounds and pharmaceutical compositions are useful for the prevention or treatment of diseases such as inflammatory and autoimmune disorders. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 364,552, filed May 11, 2022, which is hereby incorporated by reference in its entirety. Technical Field

[0003] The present disclosure relates to the fields of chemistry and medicine. More specifically, the present disclosure relates to NF-κB-inducing kinase inhibitors and their use in medical treatment. Background Art

[0004] NF-κB-inducing kinase (NIK) is a serine / threonine kinase transcription factor that regulates the expression of various genes involved in immune response disorders. Due to this immune system regulatory role, NIK inhibition blocks several downstream pathways that produce inflammatory molecules. Clinical validation using biologics has confirmed the key role of several NIK-dependent pathways in autoimmune diseases. See, for example, SV Navarra et al., The Lancet, 2011; 377(9767):721-31. One way to mitigate or eliminate the adverse effects associated with NIK activity is to increase NIK inhibition.

[0005] Therefore, there is a need to develop effective NIK inhibitors that can be used to treat various diseases. Summary of the Invention

[0006] The present application discloses compounds of formula I:

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein A, B, W, R 1 and R 2 As defined herein.

[0009] The present application also discloses a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0010] The present application also discloses a method for treating a disease, disorder or medical condition mediated by NIK activity, the method comprising administering to a subject in need of such treatment an effective amount of (i) a compound of Formula I or a pharmaceutically acceptable carrier thereof, or (ii) a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In some embodiments, the disease, disorder or medical condition mediated by NIK activity is selected from the group consisting of: inflammatory disorders, autoimmune disorders, cancer, metabolic disorders and osteoporosis. In some embodiments, the disease, disorder or medical condition mediated by NIK activity is selected from systemic lupus erythematosus ("SLE"), rheumatoid arthritis ("RA"), Sjogren's syndrome (Sjogren's syndrome), lupus nephritis, inflammatory bowel disease (“IBD”), ANCA-associated vasculitis, myositis, IgG4-related disease, bullous pemphigoid, neuromyelitis optica spectrum disorder (“NMOSD”), atopic dermatitis (“AD”), hidradenitis suppurativa (“HS”), steatosis, nonalcoholic steatohepatitis (“NASH”), primary biliary cirrhosis, leukemia, lymphoma, pancreatic cancer, breast cancer, melanoma, obesity, diabetes, acute kidney injury, IgAN, autosomal dominant polycystic kidney disease (“ADCKD”), membranous nephropathy, osteoporosis, bone resorption (periodontitis), multiple sclerosis (“MS”), immune thrombocytopenic purpura, transplantation, myasthenia gravis, scleroderma, myositis, IgG4-related disease, and bullous pemphigoid.

[0011] Additional embodiments, features, and advantages of the disclosure will be apparent from the following detailed description and through practice of the disclosure. DETAILED DESCRIPTION

[0012] The discussion of documents, acts, materials, devices, articles and the like included in this specification is intended to provide context for the present disclosure. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any invention disclosed or claimed.

[0013] NF-κB-inducing kinase (referred to as NIK, also known as MAP3K14) is a regulator and driver of the non-classical NIK cascade and therefore represents an attractive target for therapeutic intervention. The embodiments described herein relate to compounds that inhibit NIK and pharmaceutical compositions comprising such compounds. The compounds described herein and their pharmaceutical compositions can be used to prevent or treat diseases such as inflammatory disorders and autoimmune disorders.

[0014] NIK-dependent transcriptional activation is a tightly controlled signal transduction pathway that involves sequential events including phosphorylation and protein degradation. In the NIK activation pathway, known as the non-classical pathway, activation is achieved by phosphorylation of the catalytic complex subunit IKKα, leading to partial proteolysis of the gene product p100, thereby releasing the DNA-binding protein p52, which then heterodimerizes with another DNA-binding protein, RelB, translocates to the nucleus, and mediates gene expression. The non-classical pathway is activated by ligands such as CD40 ligand, B-cell activating factor (BAFF), lymphotoxin beta receptor ligand, TNF-related weak inducer of apoptosis (TWEAK) cytokine, and receptor activator of nuclear factor kappa-B ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11). NIK has been shown to be required for these ligands to activate this pathway (S.-C. Sun, Nat Rev Immunol. 2017, 17(9), 545-558). Due to its role, NIK expression is tightly regulated. Under normal non-stimulated conditions, NIK protein levels are very low. This is due to its interaction with protein 3 (BIRC3, also known as CIAP2) containing baculovirus IAP repeats and a series of TNF receptor-associated factors (TRAF2 and TRAF3), which are ubiquitin ligases and lead to NIK degradation. It is believed that when the non-classical pathway is stimulated by ligands under pathological / abnormal conditions, the activated receptor now competes for TRAF, dissociates the TRAF-BIRC3-NIK complex, and thus increases the level of NIK (for a more detailed analysis of this background, see, for example, S.-C. Sun (as cited above) and Thu and Richmond, Cytokine Growth FR 2010, 21, 213-226). NIK plays a role in promoting immune response disorders, so an increase in NIK levels is undesirable, and a method of alleviating or eliminating the adverse effects associated with this increase is NIK inhibition.

[0015] BAFF / BAFF-R is a clinically validated therapeutic target, and its inhibition is considered to be beneficial for the treatment of systemic lupus erythematosus (SLE). Belimumab (anti-BAFF antibody) has been approved for the treatment of seropositive SLE patients (SV Navarra et al., The Lancet, 2011; 377 (9767): 721-31). The CD40L / CD40 pathway plays a key role in T-dependent B cell activation, dendritic cell maturation and tissue inflammation / immunity (R. Elgueta et al., Immunol. Rev. 2009; 229 (1): 152-72). Anti-CD40L antibodies have shown promising efficacy in Phase 2 clinical studies in patients with SLE (PI Sidiropoulos and DT Boumpas, Lupus 2004 May; 13 (5): 391-7). Mice lacking NIK (R. Shinkura et al., Nature Genetics 1999; 22(1): 74-7; HD Brightbill et al., J Immunol. 2015; 195(3): 953-64) or conditional knockout of NIK (HD Brightbill et al., J Immunol. 2015; 195(3): 953-64) or human patients carrying NIK gene mutations (KL Willmann et al., Nature Comm. 2014; 5: 5360) show defects in NIK non-canonical activation pathways such as BAFF and CD40L pathways, decreased B lymphocytes in peripheral blood and lymphoid organs, and lower T cell-dependent antibody responses supporting NIK as a therapeutic target for SLE.

[0016] NIK has been described as "important in the immune and bone-destructive components of inflammatory arthritis and represents a possible therapeutic target for these diseases." K. Aya et al. (J. Clin. Invest. 2005, 115, 1848-1854). Mice lacking functional NIK have no peripheral lymph nodes, have defective B cells and T cells, and have impaired receptor activators for NIK ligand-stimulated osteoclastogenesis. K. Aya et al. (J. Clin. Invest. 2005, 115, 1848-1854) used NIK- / - mice to study the role of NIK in a murine model of inflammatory arthritis. The serum transfer arthritis model is triggered by preformed antibodies and requires only intact neutrophils and complement systems in the recipient. Although NIK- / - mice have inflammation comparable to NIK+ / + controls, Ada et al. (as cited above) revealed a significant reduction in periarticular osteoclastogenesis and reduced bone erosion. In contrast, NIK- / - mice are completely resistant to antigen-induced arthritis (AIA), which requires complete antigen presentation and lymphocyte function, but does not require lymph nodes. In addition, the transfer of NIK+ / + splenocytes or T cells to Rag2- / - mice confers susceptibility to AIA, while the transfer of NIK- / - cells does not have this effect. NIK- / - mice are also resistant to hereditary, spontaneous forms of arthritis, which are produced in mice expressing both the KRN T cell receptor and H-2g7. Transgenic mice were used together with OC lineage expression of NIK lacking its TRAF3 binding domain (NT3) to demonstrate that constitutive activation of NIK drives enhanced osteoclastogenesis and bone resorption under basal conditions and in response to inflammatory stimuli. See Aya et al., as cited above. In addition, constitutive activation of NIK drives enhanced osteoclastogenesis and bone resorption under basal conditions and in response to inflammatory stimuli. (C. Yang et al., PLoS ONE 2010, 5(11):e15383, doi:10.1371 / journal.pone.0015383).

[0017] NIK is also a therapeutic target for other BAFF, CD40L or lymphotoxin beta receptor ligand-driven autoimmune disorders such as Sjögren's syndrome (J. Groom et al., J. Clin. Invest. 2002; 109(1):59-68) and proliferative lupus glomerulonephritis (DT Boumpas et al., Arthritis & Rheumatism 2003; 48(3):719-27).

[0018] definition

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Otherwise, certain terms used herein have the meanings described in this specification.

[0020] In order to help the reader of the application, description is divided into each paragraph or chapter, or relates to each embodiment of the application.These divisions should not be considered as the main content of paragraph or chapter or embodiment being separated from the main content of another paragraph or chapter or embodiment.On the contrary, it will be understood by those skilled in the art that this description has a wide range of applications, and contains all combinations of conceivable each chapter, paragraph and sentence. Discussion of any embodiment is only intended to be exemplary, and is not intended to show that the scope of the disclosure (including claims) is limited to these examples.

[0021] It must be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0022] As used herein, the terms "including," "containing," and "comprising" are used in their open, non-limiting sense.

[0023] In order to provide a more concise description, some quantitative expressions given herein are not modified by the term "about". It should be understood that, regardless of whether the term "about" is explicitly used, each quantity given herein is intended to refer to the actual given value, and it is also intended to refer to the approximate value of these given values ​​that can be reasonably inferred based on ordinary skills in the art, including equivalent values ​​and approximate values ​​of these given values ​​caused by experimental and / or measurement conditions.

[0024] With respect to the methods of the present disclosure, the term "administering" means a method of therapeutically or prophylactically preventing, treating, or ameliorating a syndrome, disorder, or disease as described herein by using a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof. Such methods include administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof at different times during the course of treatment, or administering simultaneously or sequentially as a combination therapy.

[0025] The term "subject" refers to a patient, which can be an animal, preferably a mammal, most preferably a human, who will be or has been treated by a method according to an embodiment of the present application. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs) (such as monkeys or apes), humans, etc., and more preferably include humans.

[0026] The term "therapeutically effective amount" or "effective amount" means that amount of an active compound or agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, including preventing, treating or ameliorating the symptoms of the syndrome, disorder or disease being treated.

[0027] As used herein, the term "treating" or "treatment" is defined as applying or administering a therapeutic agent, i.e., a compound of the present disclosure (alone or in combination with another agent), to a patient suffering from a disorder or disease as described herein, its symptoms, or the likelihood of developing such a disorder or disease, or applying or administering a therapeutic agent to a tissue or cell line isolated from a patient (e.g., for diagnosis or ex vivo application) with the purpose of curing, healing, alleviating, relieving, altering, remedying, improving, ameliorging, or affecting the disorder or disease, its symptoms, or the likelihood of developing the disorder or disease. Such treatments can be modified or improved based on knowledge gained from the field of pharmacogenomics.

[0028] As used herein, the term "prevent" or "preventing" means that a disease or disorder does not develop if it has not already occurred, or that the disorder or disease does not develop further if it has already occurred. The ability to prevent some or all symptoms associated with a disorder or disease is also contemplated.

[0029] The term "C (a-b) "" (wherein a and b are integers indicating the number of carbon atoms) refers to, for example, alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl, or to the alkyl portion of a group containing from a to b (inclusive) carbon atoms, wherein alkyl appears as a prefix root. For example, C (1-4) represents a group containing 1, 2, 3 or 4 carbon atoms.

[0030] The term "alkyl" is a straight or branched chain saturated hydrocarbon. For example, an alkyl group can have 1 to 12 carbon atoms (i.e., (C1-C 12) alkyl), 1 to 6 carbon atoms (i.e., (C1-C6) alkyl), 1 to 4 carbon atoms (i.e., (C1-C4) alkyl), or 1 to 3 carbon atoms (i.e., (C1-C3) alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), isopropyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-bu, n-butyl, -CH2CH2CH2CH3), 2-butyl (s-bu, s-butyl, -CH(CH3)CH2CH3), tert-butyl (t-bu, t-butyl, -CH(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH 3), 2-pentyl (-CH(CH3)CH2CH2CH3), neopentyl (-CH2C(CH3)3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), heptyl (-(CH2)6CH3), octyl (-(CH2)7CH3), 2,2,4-trimethylpentyl (-CH2C(CH3)2CH2CH(CH3)2), nonyl (-(CH2)8CH3), decyl (-(CH2)9CH3), undecyl (-(CH2) 10 CH3) and dodecyl (-(CH2) 11 In one embodiment, alkyl refers to C (1-6) In another embodiment, alkyl refers to C (1-4) In another embodiment, alkyl refers to C (1-3) alkyl.

[0031] The term "halo" or "halogen" refers to bromo (-Br), chloro (-Cl), fluoro (-F), or iodo (-I). In one embodiment, halo refers to fluoro.

[0032] The term "haloalkyl" refers to a straight or branched chain alkyl group having 1 to 12 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms in the chain, optionally with one or more H substituted with a halo. Examples of "haloalkyl" groups include trifluoromethyl (CF3), difluoromethyl (CF2H), monofluoromethyl (CH2F), pentafluoroethyl (CF2CF3), tetrafluoroethyl (CHFCF3), monofluoroethyl (CH2CH2F), trifluoroethyl (CH2CF3), tetrafluorotrifluoromethylethyl (CF(CF3)2), and groups that would be considered equivalent to any of the foregoing examples based on one of ordinary skill in the art and the teachings provided herein. In one embodiment, a haloalkyl group refers to a C (1-6)In another embodiment, haloalkyl refers to C (1-4) In another embodiment, alkyl refers to C (1-3) Halogenated alkyl.

[0033] The term "cycloalkyl" refers to a group having, for example, 3 to 10 carbon atoms (ie, C (3-10) cycloalkyl), 3 to 8 carbon atoms (i.e., C (3-8) cycloalkyl) or 3 to 6 carbon atoms (i.e., C (3-6) All saturated or partially unsaturated carbocyclic ring systems of a cycloalkyl group (cycloalkyl), wherein the cycloalkyl ring system has a single ring or multiple rings in a spirocyclic or bridged configuration. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Some cycloalkyl groups may exist as spirocycloalkyl groups, in which two cycloalkyl rings are fused through a single carbon atom; for example, but not limited to, spiropentyl is exemplified by For example, but not limited to, examples of spirohexyl groups include For example, but not limited to, examples of cycloheptyl groups include For example, but not limited to, examples of cyclooctyl groups include In one embodiment, cycloalkyl refers to a C (3-10) In another embodiment, cycloalkyl refers to C (3-8) In another embodiment, cycloalkyl refers to C (3-6) Cycloalkyl.

[0034] Unless otherwise specified, the term "aryl" refers to a polyunsaturated (typically aromatic) hydrocarbon group, which can be a single ring or multiple rings (up to three rings) fused together or covalently linked. The term aromatic is well known to those skilled in the art and refers to a cyclic conjugated system of 4n+2 electrons, i.e., having 6, 10, 14, etc. π-electrons (Hückel's rule). Examples of aryl groups include phenyl, naphthyl, anthracenyl. In one embodiment, aryl refers to C (6-10) In another embodiment, aryl refers to phenyl.

[0035] The term "heterocyclyl" or "heterocycloalkyl" refers to a single saturated or partially unsaturated ring having 3 to 12 ring members, 3 to 10 ring members, 3 to 8 ring members, or 3 to 6 ring members and containing carbon atoms and at least one atom other than carbon in the ring, wherein the atom is selected from N, O, and S. The terms "heterocyclyl" and "heterocycloalkyl" include cyclic esters (e.g., lactones) and cyclic amides (e.g., lactams). Exemplary heterocycles include, but are not limited to, oxetane, aziridine, azetidinyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, and thiomorpholinyl. Unless otherwise indicated, a heterocyclyl group is attached to its side group at any heteroatom or carbon atom that produces a stable structure. In one embodiment, heterocyclyl refers to a 3 to 10-membered heterocyclyl. In another embodiment, heterocyclyl refers to a 3 to 8-membered heterocyclyl. In another embodiment, heterocyclyl refers to a 3 to 6-membered heterocyclyl.

[0036] As used herein, the term "5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms" refers to a saturated or partially saturated bridged polycyclic, fused polycyclic or spiropolycyclic ring system having 5 to 12 ring members (or 7 to 12 ring members or 7 to 10 ring members) and containing carbon atoms and 1 to 7 heteroatoms, 1 to 5 heteroatoms, 1 to 4 heteroatoms or 1 to 3 heteroatoms, wherein these heteroatoms are independently selected from N, O and S. The ring system can include fully unsaturated aromatic rings; however, at least one other ring in the polycyclic ring system must be saturated or partially saturated. In some embodiments, the term refers to a fused bicyclic ring system. In some embodiments, the term refers to a fused bicyclic ring system in which one ring is an aromatic ring. The term includes cyclic esters (e.g., lactones) and cyclic amides (e.g., lactams). Non-limiting examples of 5- to 12-membered bicyclic or tricyclic ring systems containing one or more heteroatoms include 3-oxabicyclo[3.1.0]hexyl, indolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 4,5,6,7-tetrahydro-1H-indazolyl, 6,7-dihydro-5H-cyclopenta[c]pyridazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, 3-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazinyl, and 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-onyl. Unless otherwise indicated, a bicyclic or tricyclic ring system is attached to its side group at any heteroatom or carbon atom that results in a stable structure. In one embodiment, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms refers to a 5- to 12-membered bicyclic ring system containing one or more heteroatoms. In another embodiment, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms refers to a 7- to 12-membered bicyclic ring system containing one or more heteroatoms. In another embodiment, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms refers to a 7- to 10-membered bicyclic ring system containing one or more heteroatoms.

[0037] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic ring system having 5 to 12 ring members, 5 to 10 ring members or 5 to 6 ring members and containing carbon atoms and 1 to 5 heteroatoms, 1 to 3 heteroatoms or 1 to 2 heteroatoms, wherein these heteroatoms are independently selected from the group consisting of N, O and S. The term heteroaryl includes aromatic rings with 5 or 6 members, wherein the ring consists of carbon atoms and has at least one heteroatom member. Suitable heteroatoms include nitrogen, oxygen and sulfur. In some embodiments, in the case of 5-membered rings, the heteroaryl ring preferably contains one member in nitrogen, oxygen or sulfur, and in addition up to 3 additional nitrogens. In some embodiments, in the case of 6-membered rings, the heteroaryl ring contains 1 to 3 nitrogen atoms. For the case where the 6-membered ring has 3 nitrogens, at most 2 nitrogen atoms are adjacent. The example of heteroaryl group includes furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl, benzotriazolyl, quinolyl, isoquinolyl, quinazolinyl, pyrazolopyridinyl and pyrazolopyrimidinyl. Those skilled in the art will recognize that the heteroaryl groups listed are not exhaustive, and other substances within the scope of these qualified terms can also be selected. Unless otherwise indicated, heteroaryl is connected with its side group on any heteroatom or carbon atom causing stable structure. In one embodiment, heteroaryl refers to 5 to 10 yuan of heteroaryl. In another embodiment, heteroaryl refers to a 5- to 8-membered heteroaryl. In another embodiment, heteroaryl refers to a 5- to 6-membered heteroaryl. In another embodiment, heteroaryl refers to a 5-membered heteroaryl.

[0038] The term "substituted" means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents. If the term "substituted" is used to describe a structural system, it means that substitution occurs at any valence-allowed position on that system.

[0039] When the compounds disclosed herein have at least one stereocenter, they may exist as enantiomers or diastereomers, respectively. It should be understood that all such isomers and mixtures thereof are encompassed within the scope of the present disclosure.

[0040] "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of one another.

[0041] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A "racemic" mixture is a 1:1 mixture of a pair of enantiomers. A "non-racemic" mixture of enantiomers is one in which the enantiomers are mixed in a ratio other than 1:1.

[0042] If the method for preparing the compounds according to the present disclosure produces a mixture of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. These compounds can be prepared in racemic form, non-racemic mixtures, or single enantiomers can be prepared by enantiospecific synthesis or by splitting. For example, diastereomeric pairs can be formed by standard techniques, such as by forming salts with optically active acids (such as (-)-di-p-toluoyl-D-tartaric acid and / or (+)-di-p-toluoyl-L-tartaric acid), followed by fractional crystallization and regeneration of the free base, thereby splitting these compounds into their component enantiomers. The compounds can also be split by forming diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, these compounds can be split using chiral column bottles HPLC or SFC. In some cases, there may be rotational isomers of the compound, which can be separated by 1 H NMR observations, leading to 1 Complex multiplets and peak integration in HNMR spectra.

[0043] Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. Chiral centers of known absolute configuration are labeled by prefixes R and S specified using standard sequential rule procedures and, where necessary, by appropriate positional precedence (Pure & Appl. Chem. 45, 1976, 11–30). Certain enantiomers and diastereoisomer pairs appear together in the examples. These enantiomers / diastereomers can be specified and characterized as Enantiomer 1 or Enantiomer 2 (or, alternatively, Diastereomer 1 or Diastereomer 2) in the following synthetic methods. Presenting stereoisomers in this way conveys that the compounds are prepared or separated individually as pure single enantiomers or diastereomers at the determined stereocenters. However, unless otherwise indicated, when a pure single enantiomer (or diastereomer) is presented in the examples of the present disclosure together with the corresponding pure single enantiomer (or diastereomer), the order in which the chemical structures / IUPAC names are presented does not necessarily correspond to the order in which the example numbers are listed. For example, when the R and S enantiomers of a compound are presented side by side under the heading "Example X and Example Y," then Example X can be the R enantiomer or the S enantiomer and Example Y the opposite enantiomer, regardless of the order in which the IUPAC names or chemical structures of the compounds appear, unless otherwise indicated in the subsequent methods and characterizations.

[0044] In any process for preparing the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups in any of the molecules concerned. This can be achieved by conventional protecting groups, such as "Protective Groups in Organic Chemistry", edited by JFW McOmie, Plenum Press, 1973; and TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons, 1991. The protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0045] Furthermore, within the scope of the present disclosure, any element, particularly when referenced to a compound of the present disclosure or a pharmaceutically acceptable salt thereof, is intended to encompass all isotopes or isotopic mixtures (naturally occurring or synthetically produced) of that element in its natural abundance or in its isotopically enriched form. For example, reference to hydrogen or "H" includes within its scope 1 H. 2 H (i.e. deuterium or D) and 3 H (ie, tritium or T). In some embodiments, the compounds described herein include 2 H (i.e. deuterium) isotopes. For example, -C (1-6) Alkyl groups include not only -C 1 H3, and also includes C 1 HD2, C 1 H2D, CD3 and other isotopic forms; including not only C 1 H2C 1 H3, C 1 HDC 1 HD2, C 1 HDC 1 H2D、C 1 H2C 1 H3, CD2CD3, etc. Similarly, in the case of unspecified hydrogen atoms in the chemical structure, those hydrogen atoms may be 1 H. 2 H (i.e., deuterium or D) or 3 H (i.e., tritium or T). By way of example, the group Also covers Similarly, references to carbon and oxygen include within their scope 12 C. 13 C and 14 C and 15 O and16 O and 17 O and 18 O. The isotope may be radioactive or non-radioactive. The radiolabeled compounds of the present disclosure may include a radioisotope selected from the group consisting of: 3 H. 11 C. 18 F. 35 S. 122 I. 123 I. 125 I. 131 I. 75 Br, 76 Br, 77 Br and 82 In some embodiments, the radioisotope is selected from the group consisting of 3 H. 11 C and 18 F's group.

[0046] Reference herein to a compound is intended to include reference to any of: (a) the compound in the form actually recited, and (b) the compound in any form in which the compound is present in the medium in which the compound is present. For example, reference herein to a compound such as R-COOH encompasses reference to, for example, R-COOH (s) 、R-COOH (sol) and R-COO - (sol) In this example, R-COOH (s) refers to a solid compound, which may be in the form of, for example, a tablet or some other solid pharmaceutical composition or formulation; R-COOH (sol) refers to the undissociated form of the compound in the solvent; while R-COO - (sol) refers to the dissociated form of a compound in a solvent, such as the dissociated form of a compound in an aqueous environment, whether such dissociated form is derived from R-COOH, a salt thereof, or a compound that dissociates in the medium under consideration to produce R-COO -In another example, a statement such as "exposing an entity to a compound of formula R-COOH" means exposing the entity to one or more forms of the compound R-COOH present in the medium in which the exposure occurs. In yet another example, a statement such as "reacting an entity with a compound of formula R-COOH" means reacting (a) such entity (being one or more chemically related forms of such entity present in the medium in which the reaction occurs) with (b) one or more chemically related forms of the compound R-COOH present in the medium in which the reaction occurs. In this regard, if the entity is, for example, in an aqueous environment, it is understood that the compound R-COOH is in the same medium and thus the entity is being exposed to compounds such as R-COOH. (aq) and / or R-COO - (aq) , wherein the subscript "(aq)" represents "aqueous" according to its conventional meaning in chemistry and biochemistry. In these naming examples, a carboxylic acid functional group is selected; however, this selection is not intended to be limiting, but is merely illustrative. It should be understood that similar examples can be provided with other functional groups, including but not limited to hydroxyl groups, basic nitrogen members (such as those in amines), and any other groups that interact or transform in a medium containing the compound in a known manner. Such interactions and transformations include but are not limited to dissociation, association, tautomerism, solvolysis including hydrolysis, solvation including hydration, protonation, and deprotonation. No further examples are provided herein in this regard, as these interactions and transformations in a given medium are known to any person of ordinary skill in the art.

[0047] The term "pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or corresponding agency in a country outside the United States or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0048] "Pharmaceutical acceptable salt" is intended to mean a salt of a free acid or base of a compound disclosed herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. It should possess the desired pharmacological activity of the parent compound. Generally, see GS Paulekuhn et al., "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database", J. Med. Chem., 2007, 50: 6665–72, SM Berge et al., "Pharmaceutical Salts", JPharm Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with patient tissues without undue toxicity, irritation, or allergic response. The compounds of the present disclosure may possess sufficiently acidic groups, sufficiently basic groups, or both types of functional groups and accordingly react with a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts.

[0049] Compounds of the present disclosure

[0050] The present application discloses compounds of formula I:

[0051]

[0052] or a pharmaceutically acceptable salt thereof, wherein:

[0053] A is optionally replaced by one to three selected from -C (1-4) Alkyl and -C (1-4) a 5-membered heteroaryl group substituted with a haloalkyl group;

[0054] B is a furyl group, a piperidinyl group, or a group having the following structure:

[0055]

[0056] W is CH2, CHF or CF2;

[0057] V is N, CH or CR V ;

[0058] X is N, CH or CR X;

[0059] Y is N, CH or CR Y ;

[0060] Z is N, CH or CR Z ;

[0061] R V 、R X 、R Y and R Z are each independently halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl or -OC (1-4) alkyl;

[0062] R 1 is hydrogen, -C (1-4) Alkyl or -C (1-4) alkyl halide;

[0063] R 2 is -N(H)(5- to 10-membered heteroaryl), -C (6-10) Aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, wherein -N(H)(5- to 10-membered heteroaryl), -C (6-10) Aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group are each optionally substituted by one to five R 3 group substitution;

[0064] Each R 3 Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-10) Cycloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 )、-C(O)OH、-C(O)N(R N1 )(R N4 ),-C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (1-3) alkyl (phenyl), 3 to 8 membered heterocyclic group or 5 to 6 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6)Alkyl, -OC (1-6) Haloalkyl, -OC (3-10) Cycloalkyl, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (1-3) Alkyl (phenyl), 3 to 8 membered heterocyclic group and 5 to 6 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C (3-6) Cycloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C (1-4) Alkyl OC (1-4) Alkyl radical substitution;

[0065] R N1 is hydrogen or C (1-4) alkyl;

[0066] R N2 、R N3 and R N4 Each occurrence is independently hydrogen, -C (1-4) Alkyl, -C (3-6) Cycloalkyl, -C(O)C (1-4) Alkyl, -C (1-4) Alkyl (4 to 6 membered heterocyclyl), 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, wherein the 4 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to three selected from -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C(O)C (1-4) Alkyl radical substitution;

[0067] Provided that at least two of V, X, Y, and Z are CH; and

[0068] The prerequisite is that if R 2 is pyrimidinyl, the pyrimidinyl is replaced by a moiety selected from -OC (1-6) Alkyl and -C(O)N(R N1 )(R N4 ) and optionally further substituted by one to two R 3 Group substitution.

[0069] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0070] A is optionally replaced by one to three selected from -C (1-4) Alkyl and -C (1-4)a 5-membered heteroaryl group substituted with a haloalkyl group;

[0071] B is a furyl group, a piperidinyl group, or a group having the following structure:

[0072]

[0073] W is CH2 or CF2;

[0074] V is N, CH or CR V ;

[0075] X is N, CH or CR X ;

[0076] Y is N, CH or CR Y ;

[0077] Z is N, CH or CR Z ;

[0078] R V 、R X 、R Y and R Z are each independently halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl or -OC (1-4) alkyl;

[0079] R 1 is hydrogen, -C (1-4) Alkyl or -C (1-4) alkyl halide;

[0080] R 2 is -N(H)(5- to 10-membered heteroaryl), -C (6-10) Aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, wherein -N(H)(5- to 10-membered heteroaryl), -C (6-10) Aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group are each optionally substituted by one to five R 3 group substitution;

[0081] Each R 3 Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-10) Cycloalkyl, -C (1-3)Alkyl-N(R N1 )(R N3 )、-C(O)OH、-C(O)N(R N1 )(R N4 ),-C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (1-3) alkyl (phenyl), 3 to 8 membered heterocyclic group or 5 to 6 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-10) Cycloalkyl, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (1-3) Alkyl (phenyl), 3 to 8 membered heterocyclic group and 5 to 6 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C (3-6) Cycloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C (1-4) Alkyl OC (1-4) Alkyl radical substitution;

[0082] R N1 is hydrogen or C (1-4) alkyl;

[0083] R N2 is hydrogen, -C (1-4) Alkyl, -C (3-6) Cycloalkyl, -C(O)C (1-4) Alkyl, -C (1-4) Alkyl (4 to 6 membered heterocyclyl), 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, wherein the 4 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to three selected from -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C(O)C (1-4) Alkyl radical substitution;

[0084] R N3 is hydrogen, -C (3-6) Cycloalkyl or 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is optionally further substituted by one to three -C (1-4) Alkyl group substitution;

[0085] R N4 is hydrogen, -C (1-4)an alkyl group or a 4- to 6-membered heterocyclic group;

[0086] Provided that at least two of V, X, Y, and Z are CH; and

[0087] The prerequisite is that if R 2 is pyrimidinyl, the pyrimidinyl is replaced by a moiety selected from -OC (1-6) Alkyl and -C(O)N(R N1 )(R N4 ) and optionally further substituted by one to two R 3 Group substitution.

[0088] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0089] A is optionally replaced by one to three -C (1-4) a 5-membered heteroaryl substituted with an alkyl group;

[0090] B is a furyl group, a piperidinyl group, or a group having the following structure:

[0091]

[0092] W is CH2 or CF2;

[0093] V is N, CH or CR V ;

[0094] X is N, CH or CR X ;

[0095] Y is N, CH or CR Y ;

[0096] Z is N, CH or CR Z ;

[0097] R V is a halo group;

[0098] R X 、R Y and R Z are each independently halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl or -OC (1-4) alkyl;

[0099] R 1 is hydrogen, -C (1-4) Alkyl or -C (1-4) alkyl halide;

[0100] R 2 is -N(H)(5- to 10-membered heteroaryl), -C (6-10)Aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, wherein -N(H)(5- to 10-membered heteroaryl), -C (6-10) Aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group are each optionally substituted by one to five R 3 group substitution;

[0101] Each R 3 Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 )、-C(O)OH、-C(O)N(R N1 )(R N4 ),-C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (1-3) alkyl (phenyl), 3 to 8 membered heterocyclic group or 5 to 6 membered heteroaryl, wherein the 3 to 8 membered heterocyclic group and the 5 to 6 membered heteroaryl are optionally further substituted by one to five selected from halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C (3-6) Cycloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C (1-4) Alkyl OC (1-4) Alkyl radical substitution;

[0102] R N1 is hydrogen or C (1-4) alkyl;

[0103] R N2 is hydrogen, -C (1-4) Alkyl, -C (3-6) Cycloalkyl, -C(O)C (1-4) Alkyl, -C (1-4) Alkyl (4 to 6 membered heterocyclyl), 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, wherein the 4 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to three selected from -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C(O)C (1-4) Alkyl radical substitution;

[0104] R N3 is hydrogen, -C (3-6) Cycloalkyl or 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is optionally further substituted by one to three -C (1-4) Alkyl group substitution;

[0105] R N4 is hydrogen, -C (1-4) an alkyl group or a 4- to 6-membered heterocyclic group;

[0106] Provided that at least two of V, X, Y, and Z are CH; and

[0107] The prerequisite is that if R 2 is pyrimidinyl, the pyrimidinyl is replaced by a moiety selected from -OC (1-6) Alkyl and -C(O)N(R N1 )(R N4 ) and optionally further substituted by one to two R 3 Group substitution.

[0108] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0109] A is optionally replaced by a-C (1-4) a 5-membered heteroaryl substituted with an alkyl group;

[0110] B is:

[0111]

[0112] W is CH2 or CF2;

[0113] V is N, CH or CF;

[0114] X is N, CH or CR X ;

[0115] Y is N, CH or CR Y ;

[0116] Z is N, CH or CR Z ;

[0117] R X 、R Y and R Z are each independently fluorine, -CH3 or -OCH3;

[0118] R 1 is hydrogen or -CF3;

[0119] R 2is a 5- to 12-membered bicyclic or tricyclic ring system or a 5- to 10-membered heteroaryl group containing one or more heteroatoms, wherein each of the 5- to 12-membered bicyclic or tricyclic ring system or the 5- to 10-membered heteroaryl group containing one or more heteroatoms is optionally replaced by one to five R 3 group substitution;

[0120] Each R 3 Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 )、-C(O)OH、-C(O)N(R N1 )(R N4 ),-C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (1-3) alkyl (phenyl), 3 to 8 membered heterocyclic group or 5 to 6 membered heteroaryl, wherein the 3 to 8 membered heterocyclic group and the 5 to 6 membered heteroaryl are optionally further substituted by one to five selected from halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C (3-6) Cycloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C (1-4) Alkyl OC (1-4) Alkyl radical substitution;

[0121] R N1 It is hydrogen;

[0122] R N2 is hydrogen, -C (1-4) Alkyl, -C (3-6) Cycloalkyl, -C(O)C (1-4) Alkyl, -C (1-4) Alkyl (4 to 6 membered heterocyclyl), 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, wherein the 4 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to three selected from -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C(O)C (1-4) Alkyl radical substitution;

[0123] R N3 is hydrogen, -C(3-6) Cycloalkyl or 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is optionally further substituted by one to three -C (1-4) Alkyl group substitution;

[0124] R N4 is hydrogen, -C (1-4) an alkyl group or a 4- to 6-membered heterocyclic group;

[0125] Provided that at least two of V, X, Y, and Z are CH; and

[0126] The prerequisite is that if R 2 is pyrimidinyl, the pyrimidinyl is replaced by a moiety selected from -OC (1-6) Alkyl and -C(O)N(R N1 )(R N4 ) and optionally further substituted by one to two R 3 Group substitution.

[0127] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0128] A is optionally replaced by one to three selected from -C (1-4) Alkyl and -C (1-4) a 5-membered heteroaryl group substituted with a haloalkyl group;

[0129] B is a furyl group, a piperidinyl group, or a group having the following structure:

[0130]

[0131] W is CH2, CHF or CF2;

[0132] V is N, CH or CR V ;

[0133] X is N, CH or CR X ;

[0134] Y is N, CH or CR Y ;

[0135] Z is N, CH or CR Z ;

[0136] R V 、R X 、R Y and R Z are each independently halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl or -OC (1-4) alkyl;

[0137] R1 is hydrogen, -C (1-4) Alkyl or -C (1-4) alkyl halide;

[0138] R 2 is -N(H)(5- to 10-membered heteroaryl), -C (6-10) aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, wherein: the -N(H)(5- to 10-membered heteroaryl) is optionally replaced by one to five R 3a Group substituted, the -C (6-10) The aryl group is optionally substituted by one to five R 3b The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 3c and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 3d group substitution;

[0139] R 3a 、R 3b 、R 3c and R 3d Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-10) Cycloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 )、-C(O)OH、-C(O)N(R N1 )(R N4 ),-C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (1-3) alkyl (phenyl), 3 to 8 membered heterocyclic group or 5 to 6 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-10) Cycloalkyl, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (1-3) Alkyl (phenyl), 3 to 8 membered heterocyclic group and 5 to 6 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -C (1-4) Alkyl, -C (1-4)Haloalkyl, -C (3-6) Cycloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C (1-4) Alkyl OC (1-4) Alkyl radical substitution;

[0140] R N1 is hydrogen or C (1-4) alkyl;

[0141] R N2 、R N3 and R N4 Each occurrence is independently hydrogen, -C (1-4) Alkyl, -C (3-6) Cycloalkyl, -C(O)C (1-4) Alkyl, -C (1-4) Alkyl (4 to 6 membered heterocyclyl), 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, wherein the 4 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to three selected from -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C(O)C (1-4) Alkyl radical substitution;

[0142] Provided that at least two of V, X, Y, and Z are CH; and

[0143] The prerequisite is that if R 2 is pyrimidinyl, the pyrimidinyl is replaced by a moiety selected from -OC (1-6) Alkyl and -C(O)N(R N1 )(R N4 ) and optionally further substituted by one to two R 3d Group substitution.

[0144] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0145] A is optionally replaced by one to three selected from -C (1-4) Alkyl and -C (1-4) a 5-membered heteroaryl group substituted with a haloalkyl group;

[0146] B is a furyl group, a piperidinyl group, or a group having the following structure:

[0147]

[0148] W is CH2 or CF2;

[0149] V is N, CH or CR V ;

[0150] X is N, CH or CR X ;

[0151] Y is N, CH or CR Y ;

[0152] Z is N, CH or CR Z ;

[0153] R V 、R X 、R Y and R Z are each independently halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl or -OC (1-4) alkyl;

[0154] R 1 is hydrogen, -C (1-4) Alkyl or -C (1-4) alkyl halide;

[0155] R 2 is -N(H)(5- to 10-membered heteroaryl), -C (6-10) aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, wherein: the -N(H)(5- to 10-membered heteroaryl) is optionally replaced by one to five R 3a Group substituted, the -C (6-10) The aryl group is optionally substituted by one to five R 3b The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 3c and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 3d group substitution;

[0156] R 3a and R 3b Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 ) or -C(O)N(R N1 )(R N4 );

[0157] R3c and R 3d Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-10) Cycloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 )、-C(O)OH、-C(O)N(R N1 )(R N4 ),-C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (1-3) alkyl (phenyl), 3 to 8 membered heterocyclic group or 5 to 6 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-10) Cycloalkyl, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (1-3) Alkyl (phenyl), 3 to 8 membered heterocyclic group and 5 to 6 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C (3-6) Cycloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C (1-4) Alkyl OC (1-4) Alkyl radical substitution;

[0158] R N1 is hydrogen or C (1-4) alkyl;

[0159] R N2 、R N3 and R N4 Each occurrence is independently hydrogen, -C (1-4) Alkyl, -C (3-6) Cycloalkyl, -C(O)C (1-4) Alkyl, -C (1-4) Alkyl (4 to 6 membered heterocyclyl), 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, wherein the 4 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to three selected from -CN, -C (1-4)Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C(O)C (1-4) Alkyl radical substitution;

[0160] Provided that at least two of V, X, Y, and Z are CH; and

[0161] The prerequisite is that if R 2 is pyrimidinyl, the pyrimidinyl is replaced by a moiety selected from -OC (1-6) Alkyl and -C(O)N(R N1 )(R N4 ) and optionally further substituted by one to two R 3d Group substitution.

[0162] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0163] A is optionally replaced by one to three selected from -C (1-4) Alkyl and -C (1-4) a 5-membered heteroaryl group substituted with a haloalkyl group;

[0164] B is a furyl group, a piperidinyl group, or a group having the following structure:

[0165]

[0166] W is CH2 or CF2;

[0167] V is N, CH or CR V ;

[0168] X is N, CH or CR X ;

[0169] Y is N, CH or CR Y ;

[0170] Z is N, CH or CR Z ;

[0171] R V is a halo group;

[0172] R X 、R Y and R Z are each independently halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl or -OC (1-4) alkyl;

[0173] R 1 is hydrogen, -C(1-4) Alkyl or -C (1-4) alkyl halide;

[0174] R 2 is -N(H)(5- to 10-membered heteroaryl), -C (6-10) aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, wherein: the -N(H)(5- to 10-membered heteroaryl) is optionally replaced by one to five R 3a Group substituted, the -C (6-10) The aryl group is optionally substituted by one to five R 3b The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 3c and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 3d group substitution;

[0175] R 3a and R 3b Each occurrence is independently -N(R N1 )(R N2 ) or -C(O)N(R N1 )(R N4 );

[0176] Each R 3c Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 )、-C(O)OH、-C(O)N(R N1 )(R N4 ) or -C (1-3) Alkyl (phenyl);

[0177] Each R 3d Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-10) Cycloalkyl, -C (1-3) Alkyl-N(R N1 )(RN3 )、-C(O)N(R N1 )(R N4 ),-C (1-3) alkyl (3 to 8 membered heterocyclic group), 3 to 8 membered heterocyclic group or 5 to 6 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-10) Cycloalkyl, -C (1-3) Alkyl (3 to 8 membered heterocyclyl), 3 to 8 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C (3-6) Cycloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C (1-4) Alkyl OC (1-4) Alkyl radical substitution;

[0178] R N1 is hydrogen or C (1-4) alkyl;

[0179] R N2 is hydrogen, -C (1-4) Alkyl, -C (3-6) Cycloalkyl, -C(O)C (1-4) Alkyl, -C (1-4) Alkyl (4 to 6 membered heterocyclyl), 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, wherein the 4 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to three selected from -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C(O)C (1-4) Alkyl radical substitution;

[0180] R N3 is hydrogen, -C (3-6) Cycloalkyl or 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is optionally further substituted by one to three -C (1-4) Alkyl group substitution;

[0181] R N4 is hydrogen, -C (1-4) an alkyl group or a 4- to 6-membered heterocyclic group;

[0182] Provided that at least two of V, X, Y, and Z are CH; and

[0183] The prerequisite is that if R 2 is pyrimidinyl, the pyrimidinyl is replaced by a moiety selected from -OC (1-6) Alkyl and -C(O)N(R N1 )(R N4 ) and optionally further substituted by one to two R 3d Group substitution.

[0184] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0185] A is optionally replaced by one to three -C (1-4) a 5-membered heteroaryl substituted with an alkyl group;

[0186] B is a furyl group, a piperidinyl group, or a group having the following structure:

[0187]

[0188] W is CH2 or CF2;

[0189] V is N, CH or CR V ;

[0190] X is N, CH or CR X ;

[0191] Y is N, CH or CR Y ;

[0192] Z is N, CH or CR Z ;

[0193] R V is a halo group;

[0194] R X 、R Y and R Z are each independently halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl or -OC (1-4) alkyl;

[0195] R 1 is hydrogen, -C (1-4) Alkyl or -C (1-4) alkyl halide;

[0196] R 2 is -N(H)(5- to 10-membered heteroaryl), -C (6-10) aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, wherein: the -N(H)(5- to 10-membered heteroaryl) is optionally replaced by one -N(RN1 )(R N2 ) group, the -C (6-10) The aryl group is optionally replaced by a -C(O)N(R N1 )(R N4 ) group, the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally replaced by one to five R 3c and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 3d group substitution;

[0197] Each R 3c Each occurrence is independently -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -C(O)OH, -C(O)N(R N1 )(R N4 ) or -C (1-3) Alkyl (phenyl);

[0198] Each R 3d Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 )、-C(O)N(R N1 )(R N4 ),-C (1-3) alkyl (3 to 8 membered heterocyclyl), 3 to 8 membered heterocyclyl or 5 to 6 membered heteroaryl, wherein the 3 to 8 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C (3-6) Cycloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C (1-4) Alkyl OC (1-4) Alkyl radical substitution;

[0199] R N1 is hydrogen or C (1-4) alkyl;

[0200] R N2 is hydrogen, -C(1-4) Alkyl, -C (3-6) Cycloalkyl, -C(O)C (1-4) Alkyl, -C (1-4) Alkyl (4 to 6 membered heterocyclyl), 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, wherein the 4 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to three selected from -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C(O)C (1-4) Alkyl radical substitution;

[0201] R N3 is hydrogen, -C (3-6) Cycloalkyl or 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is optionally further substituted by one to three -C (1-4) Alkyl group substitution;

[0202] R N4 is hydrogen, -C (1-4) an alkyl group or a 4- to 6-membered heterocyclic group;

[0203] Provided that at least two of V, X, Y, and Z are CH; and

[0204] The prerequisite is that if R 2 is pyrimidinyl, the pyrimidinyl is replaced by a moiety selected from -OC (1-6) Alkyl and -C(O)N(R N1 )(R N4 ) and optionally further substituted by one to two R 3d Group substitution.

[0205] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0206] A is optionally replaced by a-C (1-4) a 5-membered heteroaryl substituted with an alkyl group;

[0207] B is:

[0208]

[0209] W is CH2 or CF2;

[0210] V is N, CH or CF;

[0211] X is N, CH or CR X ;

[0212] Y is N, CH or CR Y ;

[0213] Z is N, CH or CR Z ;

[0214] R X 、R Y and R Z are each independently fluorine, -CH3 or -OCH3;

[0215] R 1 is hydrogen or -CF3;

[0216] R 2 is -N(H)(5- to 10-membered heteroaryl), -C (6-10) aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, wherein: the -N(H)(5- to 10-membered heteroaryl) is optionally substituted with one -NH2 group, the -C (6-10) The aryl group is optionally substituted with one -C(O)NH2 group, and the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with one to five R 3c and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 3d group substitution;

[0217] Each R 3c Each occurrence is independently -NH2, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -C(O)OH, -C(O)NH2 or -C (1-3) Alkyl (phenyl);

[0218] Each R 3d Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 )、-C(O)N(R N1 )(R N4 ),-C (1-3) alkyl (3 to 8 membered heterocyclyl), 3 to 8 membered heterocyclyl or 5 to 6 membered heteroaryl, wherein the 3 to 8 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C(3-6) Cycloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C (1-4) Alkyl OC (1-4) Alkyl radical substitution;

[0219] R N1 It is hydrogen;

[0220] R N2 is hydrogen, -C (1-4) Alkyl, -C (3-6) Cycloalkyl, -C(O)C (1-4) Alkyl, -C (1-4) Alkyl (4 to 6 membered heterocyclyl), 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, wherein the 4 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to three selected from -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C(O)C (1-4) Alkyl radical substitution;

[0221] R N3 is hydrogen, -C (3-6) Cycloalkyl or 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is optionally further substituted by one to three -C (1-4) Alkyl group substitution;

[0222] R N4 is hydrogen, -C (1-4) an alkyl group or a 4- to 6-membered heterocyclic group;

[0223] Provided that at least two of V, X, Y, and Z are CH; and

[0224] The prerequisite is that if R 2 is pyrimidinyl, the pyrimidinyl is replaced by a moiety selected from -OC (1-6) Alkyl and -C(O)N(R N1 )(R N4 ) and optionally further substituted by one to two R 3d Group substitution.

[0225] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ia-1:

[0226]

[0227] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ia-2:

[0228]

[0229] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is optionally replaced by a -C (1-4) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is a 5-membered heteroaryl group optionally substituted with one methyl group. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is a 5-membered heteroaryl group optionally substituted with one methyl group.

[0230] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein A is oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, or triazolyl, each of which is optionally substituted with a -C (1-4) Alkyl group substitution. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl or triazolyl, each of which is optionally substituted with a methyl group. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl or triazolyl. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is isoxazolyl or pyrazolyl. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is isoxazolyl. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is pyrazolyl.

[0231] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is

[0232] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is

[0233] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is

[0234] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is

[0235] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ib-1:

[0236]

[0237] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ib-2:

[0238]

[0239] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein W is CH2, CHD, CD2, or CF2. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein W is CH2 or CF2. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein W is CH2. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein W is CF2.

[0240] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein B is

[0241] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein B is

[0242] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein V is N, CH, or CF. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein V is N. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein V is CH. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein V is CR V In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein V is CF.

[0243] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein X is N, CH, CF, or C-CH3. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein X is CH, CF, or C-CH3. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein X is CH, CF, or C-CH3. XIn some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein X is CH. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein X is CR X In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein X is CF. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein X is C-CH3.

[0244] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Y is N, CH, CF, C-CH3 or C-OCH3. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Y is CH, CF, C-CH3 or C-OCH3. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Y is CH or CR Y In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Y is CH. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Y is CR Y In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein Y is CF. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein Y is C-CH3. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein Y is C-OCH3.

[0245] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Z is N, CH, CF, or C-CH3. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Z is N or CH. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Z is N. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Z is CH. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Z is CR Z In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein Z is CF. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein Z is C-CH3.

[0246] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein V is CR V And R vIs halo, and wherein X, Y, and Z are CH. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein V is CH; X, Y, and Z are N or CH, and at least one of X, Y, and Z is N. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein V is CH, and X, Y, and Z are independently selected from N, CH, C-(halogen), C-(C 1-4 Alkyl) or C-(OC (1-4) alkyl).

[0247] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein V is N or CH; X is N or CH; Y is N or CH; and Z is N, CH, or CR Z In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein V is N or CH; X is N or CH; Y is N, CH or CR Y ; and Z is N or CH. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein V is N or CH; X is N or CH; Y is N or CH; and Z is N or CH; wherein no more than one of V, X, Y, and Z is N.

[0248] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R V 、R X 、R Y and R Z are each independently halo, -C (1-4) Alkyl or -OC (1-4) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R V 、R X 、R Y and R Z are each independently halo or -C (1-4) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R V 、R X 、R Y and R Z are each independently fluorine, -CH3 or -OCH3. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R V 、R X 、R Y and R Z It's fluorine.

[0249] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R V In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R V It's fluorine.

[0250] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R X Is halogenated or -C (1-4) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R X It is fluorine or -CH3.

[0251] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R Y Is a halo group, -C (1-4) Alkyl or -OC (1-4) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R Y It is fluorine, -CH3 or -OCH3.

[0252] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R Z Is halogenated or -C (1-4) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R Z It is fluorine or -CH3.

[0253] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein: V is N, CH, or CF; X is N, CH, CF, or C-CH3; Y is N, CH, CF, C-CH3, or C-OCH3; and Z is N, CH, CF, or C-CH3. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein: V is N, CH, or CF; X is CH, CF, or C-CH3; Y is CH, CF, C-CH3, or C-OCH3; and Z is N, CH, CF, or C-CH3.

[0254] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein B is

[0255] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein B is

[0256] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein B is

[0257] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein B is

[0258] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein B is

[0259] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ic-1:

[0260]

[0261] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ic-2:

[0262]

[0263] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ic-3:

[0264]

[0265] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 1 is hydrogen, -C (1-4) Alkyl or -C (1-4) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 1 is hydrogen or -C (1-4) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 1 Is hydrogen or -CF3. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 1 In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 1 Yes -CF3.

[0266] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of any one of Formulas Id-1 to Id-5:

[0267]

[0268]

[0269] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of any one of Formulas Ie-1 to Ie-6:

[0270]

[0271] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms or a 5- to 10-membered heteroaryl group, each of which is optionally substituted by one to five R 3 Group substitution.

[0272] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 3 Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-10) Cycloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 )、-C(O)OH、-C(O)N(R N1 )(R N4 ),-C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (1-3) alkyl (phenyl), 3 to 8 membered heterocyclic group or 5 to 6 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-10) Cycloalkyl, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (1-3) Alkyl (phenyl), 3 to 8 membered heterocyclic group and 5 to 6 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C (3-6) Cycloalkyl, -OC (1-4) Alkyl, -OC(1-4) Haloalkyl and -C (1-4) Alkyl OC (1-4) Alkyl groups are substituted.

[0273] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 3 Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 )、-C(O)OH、-C(O)N(R N1 )(R N4 ),-C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (1-3) alkyl (phenyl), 3 to 8 membered heterocyclic group or 5 to 6 membered heteroaryl, wherein the 3 to 8 membered heterocyclic group and the 5 to 6 membered heteroaryl are optionally further substituted by one to five selected from halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C (3-6) Cycloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C (1-4) Alkyl OC (1-4) Alkyl groups are substituted.

[0274] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 3 Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -C(O)N(R N1 )(R N4 ) or 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is optionally further substituted by one to five members selected from halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C (3-6) Cycloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C (1-4) Alkyl OC(1-4) Alkyl groups are substituted.

[0275] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 3 Each occurrence is independently -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -C(O)N(R N1 )(R N4 ) or 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is optionally further substituted by one to three selected from -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C (3-6) Cycloalkyl and -OC (1-4) Alkyl groups are substituted.

[0276] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 3 Each occurrence is independently -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -C(O)N(R N1 )(R N4 ) or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally further substituted by one to three -C (1-4) Alkyl group substituted.

[0277] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms or a 5- to 10-membered heteroaryl group, wherein the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally replaced by one to five R 3c and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 3d Group substitution.

[0278] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is optionally replaced by one to five R 3a In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is optionally replaced by one to five R 3aIn some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is optionally replaced by one to five R 3a -N(H)(thiazolopyrimidinyl) substituted with a group.

[0279] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 3a Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 ) or -C(O)N(R N1 )(R N4 In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 3a Each occurrence is independently -N(R N1 )(R N2 ) or -C(O)N(R N1 )(R N4 In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 3a Yes-N(R N1 )(R N2 In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 3a It is -NH2.

[0280] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 yes

[0281] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is optionally replaced by one to five R 3b -C substituted with a group (6-10) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is optionally replaced by one to three R 3b substituted phenyl groups.

[0282] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 3b Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 ) or -C(O)N(R N1 )(R N4 In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 3b Each occurrence is independently -N(R N1 )(R N2 ) or -C(O)N(R N1 )(R N4 In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 3b Yes-C(O)N(R N1 )(R N4 In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 3b It is -C(O)NH2.

[0283] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 yes

[0284] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is optionally replaced by one to five R 3c In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is optionally replaced by one to three R 3c In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is optionally replaced by one to three R 3c A 7- to 12-membered tricyclic ring system containing one or more heteroatoms which is substituted by a group.

[0285] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 Selected from the group consisting of:

[0286]

[0287] They are each optionally replaced by one to three R 3c Group substitution.

[0288] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 Selected from the group consisting of:

[0289]

[0290] They are each optionally replaced by one to three R 3c Group substitution.

[0291] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 yes:

[0292]

[0293] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 yes:

[0294]

[0295] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 3c Is halogen, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 )、-C(O)OH、-C(O)N(R N1 )(R N4 ) or -C (1-3) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 3c Yes-N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC(1-6) Alkyl, -C(O)OH, -C(O)N(R N1 )(R N4 ) or -C (1-3) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 3c It is -NH2, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -C(O)OH, -C(O)NH2 or -C (1-3) Alkyl (phenyl).

[0296] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 yes:

[0297]

[0298] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 yes:

[0299]

[0300] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is optionally replaced by one to five R 3d In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is a 5- to 6-membered monocyclic heteroaryl or a 9- to 10-membered bicyclic heteroaryl, each of which is optionally substituted by one to five R 3d Group substitution.

[0301] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is optionally replaced by one to three R 3d In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is optionally replaced by one to three R 3d In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is optionally replaced by one to three R 3d In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is optionally replaced by one to three R3d A 10-membered heteroaryl group substituted with a group.

[0302] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is pyrazolyl, imidazolyl, furanyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, indazolyl, benzimidazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolopyridazinyl, pyrrolotriazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, triazolopyridinyl, quinazolinyl, isoquinolinonyl, quinazolinonyl, pyridopyrimidinyl, pyridopyrimidonyl, pyrimidopyrimidinyl, benzoxazolyl, thiazolopyrimidinyl, furopyridinyl or thienopyrimidinyl, each of which is optionally substituted by one to three R 3d In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is thiazolyl, pyridyl, pyrimidinyl, indazolyl, pyrazolopyridinyl or imidazopyridinyl, each of which is optionally substituted by one to three R 3d Group substitution.

[0303] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 Selected from the group consisting of:

[0304]

[0305]

[0306] They are each optionally replaced by one to three R 3d Group substitution.

[0307] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 Selected from the group consisting of:

[0308]

[0309] They are each optionally replaced by one to three R 3d Group substitution.

[0310] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 Selected from the group consisting of:

[0311]

[0312] They are each optionally replaced by one to three R 3d Group substitution.

[0313] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 yes:

[0314]

[0315]

[0316] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 yes:

[0317]

[0318] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 3d Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-10) Cycloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 )、-C(O)N(R N1 )(R N4 ),-C (1-3) alkyl (3 to 8 membered heterocyclic group), 3 to 8 membered heterocyclic group or 5 to 6 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-10) Cycloalkyl, -C (1-3) Alkyl (3 to 8 membered heterocyclyl), 3 to 8 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C (3-6) Cycloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C (1-4) Alkyl OC (1-4) Alkyl groups are substituted.

[0319] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 3d Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 )、-C(O)N(R N1 )(R N4 ),-C (1-3) alkyl (3 to 8 membered heterocyclyl), 3 to 8 membered heterocyclyl or 5 to 6 membered heteroaryl, wherein the 3 to 8 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C (3-6) Cycloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C (1-4) Alkyl OC (1-4) Alkyl groups are substituted.

[0320] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 3d Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -C(O)N(R N1 )(R N4 ) or 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is optionally further substituted by one to five members selected from halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C (3-6) Cycloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C (1-4) Alkyl OC (1-4) Alkyl groups are substituted.

[0321] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 3d Each occurrence is independently -N(RN1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -C(O)N(R N1 )(R N4 ) or 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is optionally further substituted by one to three selected from -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C (3-6) Cycloalkyl and -OC (1-4) Alkyl groups are substituted.

[0322] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 3d Each occurrence is independently -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -C(O)N(R N1 )(R N4 ) or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally further substituted by one to three -C (1-4) Alkyl group substituted.

[0323] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 yes:

[0324]

[0325]

[0326]

[0327]

[0328]

[0329] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 yes:

[0330]

[0331]

[0332]

[0333] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 yes:

[0334]

[0335] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 yes:

[0336]

[0337]

[0338]

[0339] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 yes:

[0340]

[0341]

[0342] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 yes:

[0343]

[0344] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R N1 It's hydrogen.

[0345] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R N2 is hydrogen, -C (1-4) Alkyl, -C (3-6) Cycloalkyl, -C(O)C (1-4) Alkyl, -C (1-4) Alkyl (4 to 6 membered heterocyclyl), 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, wherein the 4 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to three selected from -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C(O)C (1-4) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R N2 is hydrogen, -C(1-4) Alkyl, -C (3-6) Cycloalkyl, 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, wherein the 4 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to three selected from -C (1-4) Alkyl and -C (1-4) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R N2 is hydrogen, 4 to 6 membered heterocyclyl or 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is optionally further substituted by one to three -C (1-4) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R N2 In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R N2 is a 4- to 6-membered heterocyclyl. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R N2 is optionally replaced by one to three -C (1-4) 5- to 6-membered heteroaryl substituted with an alkyl group.

[0346] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R N3 is hydrogen, -C (3-6) Cycloalkyl or 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is optionally further substituted by one to three -C (1-4) Alkyl group substituted.

[0347] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R N4 is hydrogen, -C (1-4) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R N4 It's hydrogen.

[0348] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein no more than one of V, X, Y, and Z is N. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein at least three of V, X, Y, and Z are CH.

[0349] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein if R 2 is a pyrimidinyl group, the pyrimidinyl group is replaced by a -C(O)N(R N1 )(R N4 ) group, and optionally further substituted with one to two R3d Group substitution.

[0350] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein if R 2 is a pyrimidinyl group, then R 2 Having a structure selected from the group consisting of:

[0351]

[0352] At least one of the R 3d The group is -C(O)N(R N1 )(R N4 ).

[0353] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein if R 2 is a pyrimidinyl group, then R 2 Having a structure selected from the group consisting of:

[0354]

[0355] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula If:

[0356]

[0357] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula If:

[0358]

[0359] in:

[0360] A is isoxazolyl;

[0361] Z is N or CH;

[0362] R 2 is optionally replaced by one to three R 3d a 5- to 10-membered heteroaryl group substituted with a group;

[0363] Each R 3d Each occurrence is independently -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -C(O)N(R N1 )(R N4) or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally further substituted by one to three -C (1-4) Alkyl group substitution;

[0364] R N1 It is hydrogen;

[0365] R N2 is hydrogen, 4 to 6 membered heterocyclyl or 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is optionally further substituted by one to three -C (1-4) Alkyl group substitution; and

[0366] R N4 It is hydrogen;

[0367] The prerequisite is that if R 2 is a pyrimidinyl group, the pyrimidinyl group is replaced by a -C(O)N(R N1 )(R N4 ) group and optionally further substituted with one to two R 3d Group substitution.

[0368] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, having a structure as shown in any one of Tables 1A to 1J.

[0369] Table 1A

[0370]

[0371]

[0372]

[0373] Table 1B

[0374]

[0375]

[0376]

[0377] Table 1C

[0378]

[0379]

[0380]

[0381] Table 1D

[0382]

[0383]

[0384]

[0385] Table 1E

[0386]

[0387]

[0388]

[0389] Table 1F

[0390]

[0391]

[0392]

[0393] Table 1G

[0394]

[0395]

[0396]

[0397] Table 1H

[0398]

[0399]

[0400]

[0401] Table II

[0402]

[0403]

[0404]

[0405] Table 1J

[0406]

[0407]

[0408]

[0409] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, having a structure as shown in any one of Tables 2A to 2J.

[0410] Table 2A

[0411]

[0412]

[0413]

[0414] Table 2B

[0415]

[0416]

[0417]

[0418] Table 2C

[0419]

[0420]

[0421]

[0422] Table 2D

[0423]

[0424]

[0425]

[0426] Table 2E

[0427]

[0428]

[0429]

[0430] Table 2F

[0431]

[0432]

[0433]

[0434] Table 2G

[0435]

[0436]

[0437]

[0438] Table 2H

[0439]

[0440]

[0441]

[0442] Table 2I

[0443]

[0444]

[0445]

[0446] Table 2J

[0447]

[0448]

[0449] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof selected from the group consisting of:

[0450]

[0451] In some embodiments, disclosed herein are compounds of Formula I having the following structure:

[0452]

[0453] or a pharmaceutically acceptable salt thereof.

[0454] In some embodiments, disclosed herein are compounds of Formula I having the following structure:

[0455]

[0456] or a pharmaceutically acceptable salt thereof.

[0457] In some embodiments, disclosed herein are compounds of Formula I having the following structure:

[0458]

[0459] or a pharmaceutically acceptable salt thereof.

[0460] In some embodiments, disclosed herein are compounds of Formula I having the following structure:

[0461]

[0462] or a pharmaceutically acceptable salt thereof.

[0463] In some embodiments, disclosed herein are compounds of Formula I having the following structure:

[0464]

[0465] or a pharmaceutically acceptable salt thereof.

[0466] In some embodiments, disclosed herein are compounds of Formula I having the following structure:

[0467]

[0468] or a pharmaceutically acceptable salt thereof.

[0469] In some embodiments, disclosed herein are compounds of Formula I having the following structure:

[0470]

[0471] or a pharmaceutically acceptable salt thereof.

[0472] In some embodiments, disclosed herein are compounds of Formula I having the following structure:

[0473]

[0474] or a pharmaceutically acceptable salt thereof.

[0475] In some embodiments, disclosed herein are compounds of Formula I having the following structure:

[0476]

[0477] or a pharmaceutically acceptable salt thereof.

[0478] In some embodiments, disclosed herein are compounds of Formula I having the following structure:

[0479]

[0480] or a pharmaceutically acceptable salt thereof.

[0481] In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0482] Therapeutic uses

[0483] The present disclosure also relates to a method for treating a disease, disorder or medical condition mediated by NIK activity, comprising administering to a subject in need of such treatment an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0484] The present disclosure also relates to a method for preventing a disease, disorder or medical condition mediated by NIK activity, comprising administering to a subject in need of such treatment an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0485] The present disclosure also relates to a method for ameliorating or improving the symptoms of a disease, disorder or medical condition mediated by NIK activity, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds described herein can be administered in combination with one or more additional therapeutic agents.

[0486] In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is selected from an inflammatory disorder and an autoimmune disorder.

[0487] In some embodiments, the disease, disorder, or medical condition is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, and lupus nephritis.

[0488] In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is selected from the group consisting of an inflammatory disorder, an autoimmune disorder, cancer, a metabolic disorder, and osteoporosis.

[0489] In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is an autoantibody-associated disease. In some embodiments, the autoantibody-associated disease is selected from the group consisting of anti-neutrophil cytoplasmic antibodies ("ANCA")-associated vasculitis, scleroderma, Sjögren's syndrome, myositis, IgG4-related disease, bullous pemphigoid, and neuromyelitis optica spectrum disorder ("NMOSD").

[0490] In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is an immune-mediated dermatitis indication. In some embodiments, the immune-mediated dermatitis indication is selected from the group consisting of atopic dermatitis and hidradenitis suppurativa.

[0491] In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is liver inflammation or liver damage. In some embodiments, liver inflammation or liver damage is selected from the group consisting of steatosis, nonalcoholic steatohepatitis ("NASH"), and primary biliary cirrhosis.

[0492] In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is cancer. In some embodiments, the cancer is selected from the group consisting of leukemia, lymphoma, pancreatic cancer, breast cancer, and melanoma.

[0493] In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is a metabolic disorder. In some embodiments, the metabolic disorder is selected from the group consisting of obesity and diabetes. In some embodiments, the diabetes is type 2 diabetes.

[0494] In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is a kidney disease. In some embodiments, the kidney disease is selected from the group consisting of acute kidney injury, Buerger's disease (IgA nephropathy (IgAN)), autosomal dominant polycystic kidney disease ("ADCKD"), and membranous nephropathy.

[0495] In some embodiments of the treatment methods disclosed herein, the disease, disorder, or medical condition is osteoporosis.

[0496] In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is selected from the group consisting of RA, IBD, SLE, IgAN, metabolic syndrome, multiple sclerosis, immune thrombocytopenic purpura, primary biliary cirrhosis, transplantation, myasthenia gravis, osteoporosis, and bone resorption (periodontitis).

[0497] In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is selected from the group consisting of systemic lupus erythematosus ("SLE"), rheumatoid arthritis ("RA"), Sjögren's syndrome, lupus nephritis, inflammatory bowel disease ("IBD"), ANCA-associated vasculitis, myositis, IgG4-related disease, bullous pemphigoid, neuromyelitis optica spectrum disorder ("NMOSD"), atopic dermatitis ("AD"), hidradenitis suppurativa ("HS"), , steatosis, nonalcoholic steatohepatitis ("NASH"), primary biliary cirrhosis, leukemia, lymphoma, pancreatic cancer, breast cancer, melanoma, obesity, diabetes, acute kidney injury, IgAN, autosomal dominant polycystic kidney disease ("ADCKD"), membranous nephropathy, osteoporosis, bone resorption (periodontitis), multiple sclerosis ("MS"), immune thrombocytopenic purpura, transplantation, myasthenia gravis, scleroderma, myositis, IgG4-related disease, and bullous pemphigoid.

[0498] In some embodiments, disclosed herein is a method for preventing or controlling an excessive inflammatory response, comprising administering to a subject in need of such treatment an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0499] In some embodiments of the methods disclosed herein, the subject is a human subject.

[0500] The present disclosure also provides a method for modulating NIK activity, comprising exposing NIK to an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0501] In some embodiments, the present disclosure provides a method for inhibiting NIK activity, the method comprising exposing NIK to an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0502] Dosage and administration

[0503] In the methods disclosed herein, an effective amount of at least one compound according to the present disclosure is administered to a subject suffering from or diagnosed with such a disease, disorder, or medical condition. An "effective amount" means an amount or dosage sufficient to produce the desired therapeutic or prophylactic beneficial effect in a patient in need of such treatment for a given disease, disorder, or medical condition. For a 70 kg human, an exemplary range of dosage is about 1 mg / day to 1000 mg / day, measured in single or multiple dose units.

[0504] In some embodiments, the dosage is about 1 mg to 500 mg of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 300 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, or 400 mg of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, or 500 mg of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0505] The dosage administered will be affected by factors such as the route of administration, the health, weight, and age of the recipient, the frequency of treatment, and the presence of concurrent and unrelated treatments.

[0506] It will also be apparent to those skilled in the art that the therapeutically effective dose of a compound of the present invention or its pharmaceutical composition will vary depending on the desired effect. Thus, one skilled in the art can readily determine the optimal dose to be administered, and the optimal dose will vary with the specific compound used, the route of administration, the strength of the formulation, and the progression of the disease condition. In addition, factors related to the specific subject being treated, including subject age, weight, diet, and time of administration, will result in the need to adjust the dose to an appropriate therapeutic level. Therefore, the above-mentioned doses are examples of general circumstances. Of course, there may be individual circumstances where a higher or lower dosage range should be used, and such circumstances are also within the scope of this disclosure.

[0507] Once the patient's disease, disorder, or condition improves, the dosage can be adjusted to a preventative or maintenance treatment. For example, the dosage or frequency of administration, or both, can be reduced to a level that maintains the desired therapeutic or preventative effect, depending on the symptoms. Of course, treatment can be discontinued if symptoms have been alleviated to an appropriate level. However, patients may require long-term intermittent treatment due to any recurrence of symptoms.

[0508] The compounds of the present disclosure or their pharmaceutically acceptable salts can be formulated into pharmaceutical compositions comprising any known pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers commonly used in pharmaceutical compositions are non-toxic, biologically tolerable, and in other words, biologically suitable substances for administration to subjects, such as inert substances, which are added to pharmaceutical compositions or used as vehicles or diluents to promote administration of agents and are compatible therewith. Exemplary carriers include, but are not limited to, any suitable solvents, dispersion media, coatings, antibacterial and antifungal agents, and isotonic agents. Exemplary excipients that can also serve as formulation components include fillers, binders, disintegrants, and lubricants.

[0509] The delivery forms of pharmaceutical compositions containing one or more compounds of the present disclosure can be prepared using pharmaceutically acceptable excipients and compounding techniques known or available to those of ordinary skill in the art. These compositions can be administered in the presently disclosed methods by a suitable delivery route, such as oral, parenteral, rectal, topical, or ocular administration, or by inhalation.

[0510] The preparation can be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations or suppositories. The composition can be formulated for any of a variety of administration routes, such as intravenous infusion, subcutaneous injection, topical administration or oral administration.

[0511] For oral administration, the compounds of the present disclosure can be provided in the form of tablets, capsules or beads, or as solutions, emulsions or suspensions. To prepare oral compositions, the active agent can be formulated to produce, for example, a dosage of about 1 mg / day to 1000 mg / day in a single or multiple dose unit for a 70 kg human as an exemplary range.

[0512] Oral tablets can include compounds of the present disclosure mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrants, binders, lubricants, sweeteners, flavorings, colorants, and preservatives. Suitable inert fillers include sodium carbonate and calcium carbonate, sodium phosphate and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, etc. Illustrative examples of liquid oral excipients include ethanol, glycerol, water, etc. Disintegrants are exemplified by starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid. Binders can include starch and gelatin. Lubricants (when present) can be magnesium stearate, stearic acid, or talc. If desired, tablets can be coated with materials such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or can be coated with enteric coatings. Available additional coatings include coatings designed to release the compound or active agent based on time, pH, or bacterial content.

[0513] Capsules for oral administration include hard gelatin capsules and soft gelatin capsules or (hydroxypropyl) methylcellulose capsules. For the preparation of hard gelatin capsules, one or more active ingredients can be mixed with a solid, semisolid or liquid diluent. Soft gelatin capsules can be prepared by mixing the active ingredient with oils such as peanut oil or olive oil, liquid paraffin, a mixture of monoglycerides and diglycerides of short-chain fatty acids, polyethylene glycol 400 or propylene glycol. Orally administered liquids can be in the form of suspensions, solutions, emulsions or syrups, or can be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicles before use. Such liquid compositions may optionally contain: pharmaceutically acceptable excipients, such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous vehicles, such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethanol or water; preservatives (e.g., methylparaben or propylparaben or sorbic acid); wetting agents, such as lecithin; and, if desired, flavoring or coloring agents.

[0514] The compounds of the present disclosure can also be administered by non-oral routes. For example, the composition can be formulated into suppositories, enemas or foams for rectal administration. For parenteral use, including intravenous, intramuscular, intraperitoneal or subcutaneous routes, the compounds of the present disclosure can be provided in the form of sterile aqueous solutions or suspensions, which are buffered to appropriate pH and isotonicity or in parenteral acceptable oils. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms can be presented in unit dosage forms (such as ampoules or disposable injection devices), in multiple dose forms (such as vials) from which appropriate doses can be extracted, or in solid forms or pre-concentrates that can be used to prepare injectable formulations. Exemplary infusion doses range from about 1 to 1000 μg / kg / minute of an active agent mixed with a pharmaceutically acceptable carrier, over a period of several minutes to several days.

[0515] For topical administration, the compounds of the present disclosure may be mixed with a pharmaceutical carrier.Another way to administer the compounds of the present disclosure may be through the use of a patch to achieve transdermal delivery.

[0516] The compounds of the present disclosure may alternatively be administered in the methods of the present disclosure by inhalation via the nasal or oral routes, for example, in the form of a spray formulation also containing a suitable carrier.

[0517] Although embodiments of the present invention have been described in conjunction with certain specific embodiments for illustrative purposes, embodiments of the present invention are not limited thereto. Therefore, various modifications, adaptations, and combinations of the various features of the described embodiments may be practiced without departing from the scope of the invention as set forth in the claims. In addition, the following examples are illustrative and non-limiting of the compounds, compositions, and methods described herein. Other suitable modifications and adjustments known to those skilled in the art are within the scope of the following examples. Any and all journal articles, patent applications, issued patents, or other cited references are incorporated by reference in their entirety.

[0518] Example

[0519] The following specific examples are provided to further illustrate embodiments within the scope of the present disclosure.

[0520] abbreviation

[0521]

[0522]

[0523]

[0524] In some embodiments, provided herein are methods and intermediates disclosed herein that can be used to prepare the compounds of the present disclosure or pharmaceutically acceptable salts thereof.

[0525] By way of illustration and not limitation, the compounds of the present disclosure are prepared according to the following general preparation procedures provided in schemes 1-7. Those of ordinary skill in the art will recognize that, in order to obtain the various compounds herein, raw materials can be appropriately selected so that, when protected or unprotected as needed, the substituents ultimately required will be carried throughout the reaction scheme to obtain the desired product. Alternatively, the appropriate group replacing the final desired substituent can be subjected to the entire reaction scheme and, where appropriate, substituted with the desired substituent. Unless otherwise indicated, the variables in schemes 1-7 are all as defined above for Formula I.

[0526] Solution 1

[0527]

[0528] The compounds of Formula I of the present disclosure can be prepared, for example, as shown in Scheme 1. 1 is a boron-based coupling agent such as a boronic acid or a boronic ester and when the substituent B in compound XII 2 When B is a halogen such as Cl, Br or I, the coupling is achieved by reaction under Suzuki conditions. 1 is halogen and B in compound XII 2 When a boron-based coupling agent is used, coupling under Suzuki conditions also provides compounds of Formula I. Typical Suzuki coupling conditions involve the use of a palladium catalyst, a base, a suitable solvent, and other optional reagents, including a ligand (e.g., tri-tert-butylphosphine or butyldi(1-adamantyl)phosphine). Examples of suitable palladium catalysts include, but are not limited to, Pd(t-Bu3P)2, Pd(PPh3)4, Pd(dtbpf)Cl2, Pd2(dba)3, RuPhosPdG4, and Pd(dppf)Cl2. Suitable bases include, but are not limited to, K3PO4, KF, Cs2CO3, NaHCO3, Na2CO3, and mixtures thereof. Suitable solvents include, but are not limited to, 1,4-dioxane, 1,2-dioxane, DMF, THF, water, and mixtures thereof. The reaction can be heated to a temperature of about 65°C to about 170°C using microwave or conventional heating for a period of about 1 to 20 hours to provide the compound of Formula I.

[0529] Alternatively, when B 1 is a halogen such as Cl, Br or I, and when B 2 When B is a stannyl group (e.g., Sn(Me) 3 or Sn(n-Bu) 3 ), Stille coupling conditions can be used to couple compound XI to compound XII. Those skilled in the art will recognize that when B1 is a stannyl group and when B 2 When is halogen, coupling under Stille conditions also gives compounds of Formula I. Typical Stille coupling conditions involve the use of a catalyst (usually palladium, but sometimes nickel), a suitable solvent and other optional reagents including a ligand, TEA or CuI. Examples of suitable catalysts include, but are not limited to, Pd(PPh3)4 and PdCl2(PPh3)2. Suitable solvents include, but are not limited to, DMF, toluene and mixtures thereof. The reaction can be heated to a temperature of about 120°C to about 160°C using microwave or conventional heating for a period of about 1 to 16 hours to give a compound of Formula I.

[0530] In the case of the presence of a blocking group or masking group on the compound of formula XI or formula XII, conditions well known to those skilled in the art are adopted to increase the last deprotection step, to provide a compound of formula I. For example, if methyl ester or ethyl ester are used to mask primary amides, reagents such as ammonia can be used to demask them in a solvent such as MeOH or EtOH. Alternatively, if nitrile groups are used to mask primary amides, reagents such as NaOMe can be used in a solvent such as MeOH to convert them into amides. Also alternatively, if carboxylic acid is used to mask primary amides, reagents such as NH4Cl, HATU and TEA can be used in a solvent such as DMF to convert them into amides.

[0531] For example, if tosyl or phthalimide groups are used to protect amino groups, reagents such as ammonia can be used to remove them in solvents such as MeOH or EtOH. Alternatively, if tert-butyloxycarbonyl (Boc) or tetrahydropyran (THP) groups are used to protect amino groups, reagents such as HCl can be used to remove them in solvents such as dioxane and / or MeOH. Also alternatively, if 2-(trimethylsilyl)ethoxymethyl (SEM) groups are used to protect amino groups, reagents such as TBAF can be used to remove them in solvents such as MeOH. Also alternatively, if p-methoxybenzyl (PMB) groups are used to protect amino groups, reagents such as TFA can be used to remove them.

[0532] By way of further example, if a nitro group is used to mask a primary amine, it can be converted to an amine using reagents such as a porous nickel aluminum alloy (e.g., Raney nickel) and hydrazine hydrate in solvents such as ethanol and / or 1,2-dichloroethane. Alternatively, the nitro group can be converted to an amine using reagents such as zinc powder and NHCl in solvents such as MeOH and / or water.

[0533] Option 2

[0534]

[0535] The compounds of Formula I of the present disclosure can be prepared, for example, as shown in Scheme 2. 3 is a boron-based coupling agent such as a boronic acid or a boronic ester and when the substituent B in compound XIV 4 When B is a halogen such as Cl, Br or I, the coupling is achieved by reaction under Suzuki conditions. 3 is halogen and B in compound XIV 4 When a boron-based coupling agent is used, coupling under Suzuki conditions also provides compounds of Formula I. Typical Suzuki coupling conditions involve the use of a palladium catalyst, a base, a suitable solvent, and other optional reagents, including a ligand (e.g., tri-tert-butylphosphine or butyldi(1-adamantyl)phosphine). Examples of suitable palladium catalysts include, but are not limited to, Pd(t-Bu3P)2, Pd(PPh3)4, Pd(dtbpf)Cl2, Pd2(dba)3, RuPhosPdG4, and Pd(dppf)Cl2. Suitable bases include, but are not limited to, K3PO4, KF, Cs2CO3, NaHCO3, Na2CO3, and mixtures thereof. Suitable solvents include, but are not limited to, 1,4-dioxane, 1,2-dioxane, DMF, THF, water, and mixtures thereof. The reaction can be heated to a temperature of about 65°C to about 170°C using microwave or conventional heating for a period of about 1 to 20 hours to provide the compound of Formula I.

[0536] Alternatively, when B 3 is a halogen such as Cl, Br or I, and when B 4 When B is a stannyl group (e.g., Sn(Me) 3 or Sn(n-Bu) 3 ), Stille coupling conditions can be used to couple Compound XIII to Compound XIV. Those skilled in the art will recognize that when B 3 is a stannyl group and when B 4 When is halogen, coupling under Stille conditions also gives compounds of Formula I. Typical Stille coupling conditions involve the use of a catalyst (usually palladium, but sometimes nickel), a suitable solvent and other optional reagents including a ligand, TEA or CuI. Examples of suitable catalysts include, but are not limited to, Pd(PPh3)4 and PdCl2(PPh3)2. Suitable solvents include, but are not limited to, DMF, toluene and mixtures thereof. The reaction can be heated to a temperature of about 120°C to about 160°C using microwave or conventional heating for a period of about 1 to 16 hours to give a compound of Formula I.

[0537] In the event that a protecting or masking group is present on the compound of Formula XIII or Formula XIV, a final deprotection step is added using conditions known to those skilled in the art to provide the compound of Formula I. For example, if the amino group is protected with a 2-(trimethylsilyl)ethoxymethyl (SEM) group, it can be removed using a reagent such as TBAF in a solvent such as MeOH.

[0538] Option 3

[0539]

[0540] When B and R 2 When the bond between is between a carbon atom and a nitrogen atom, the compounds of Formula I of the present disclosure can be prepared, for example, as shown in Scheme 3. In some embodiments, the substituent B 5 is halogen, and the substituent B 6 is with R 2 Alternatively, the substituent B 5 is a hydrogen atom covalently bonded to the nitrogen atom of B, and B 6 For halogen. Compounds XV and XVI can be combined with a suitable catalyst (e.g., palladium or copper catalyst), a suitable base, a suitable solvent and other optional reagents (including ligands). Suitable catalysts include, but are not limited to, Pd2(dba)3 and CuI. Suitable bases include, but are not limited to, t-BuONa and K3PO4. Suitable solvents include, but are not limited to, DMF and toluene. Suitable ligands include, but are not limited to, BINAP and trans-N,N'-dimethylcyclohexane-1,2-diamine. The reaction can be heated to a temperature of about 85°C to about 100°C for a period of about 16 hours to obtain a compound of Formula I.

[0541] Alternatively, compounds XV and XVI can be combined with a suitable base and a suitable solvent. Suitable bases include, but are not limited to, Cs2CO3 and TEA. Suitable solvents include, but are not limited to, DMF and DMA. The reaction can be heated to a temperature of about 100°C to about 140°C for a period of about 3 to 24 hours using microwave or conventional heating to obtain a compound of Formula I.

[0542] Where a protecting or masking group is present on the compound of Formula XV or Formula XVI, a final deprotection step is added using conditions known to those skilled in the art to provide compounds of Formula I. For example, if a methyl or ethyl ester is used to mask the primary amide, it can be demasked using reagents such as ammonia in solvents such as MeOH or EtOH.

[0543] Option 4

[0544]

[0545] The compounds of Formula I of the present disclosure can be prepared, for example, as shown in Scheme 4. In some embodiments, the substituent B 7 is a boron-based coupling agent such as a boronic acid or a boronic ester, and the substituent B 8 is with R 2 The nitrogen atom of the compound XVII and XVIII can be combined with a suitable catalyst (e.g., Cu(OAc) 2), a suitable base (e.g., pyridine), a suitable solvent, and other optional reagents (e.g., molecular sieves). Suitable solvents include, but are not limited to, DMF and chloroform. The reaction can be heated to a temperature of about 40° C. to about 120° C. for a period of about 3 to 72 hours to obtain a compound of Formula I.

[0546] Where protecting or masking groups are present on the compound of Formula XVII or Formula XVIII, a final deprotection step is added using conditions known to those skilled in the art to provide the compound of Formula I. For example, if a methyl or ethyl ester is used to mask the primary amide, it can be demasked using reagents such as ammonia in solvents such as MeOH or EtOH.

[0547] Option 5

[0548]

[0549] The compounds of formula XXI of the present disclosure can be prepared, for example, as shown in Scheme 5. The substituent B in compound XX 9 Is, for example, a halogen such as Cl. Compounds XIX and XX can be combined with a suitable base (e.g., TEA) and a suitable solvent (e.g., DCM). The reaction can be heated to a temperature of about 25° C. to about 40° C. for a period of about 3 to 16 hours to obtain a compound of formula XXI.

[0550] Option 6

[0551]

[0552] The compounds of formula XXIII of the present disclosure can be prepared, for example, as shown in Scheme 6. Substituent B in compound XXII 10 Is, for example, a halogen such as I. Compounds XIX and XXII can be combined with a copper catalyst (e.g., CuI), a ligand (e.g., trans-N,N'-dimethylcyclohexane-1,2-diamine) and NaN3 in a solvent (e.g., DMSO and / or water). Additives such as sodium ascorbate may also be included. The reaction can be allowed to proceed at room temperature for about 16 hours to obtain a compound of formula XXIII.

[0553] In the case where a protecting group or masking group is present on the compound of formula XXII, a final deprotection step is added using conditions known to those skilled in the art to provide the compound of formula XXIII. For example, if a methyl ester or ethyl ester is used to mask the primary amide, it can be demasked using reagents such as ammonia in solvents such as MeOH or EtOH.

[0554] Option 7

[0555]

[0556] The compound of formula XXV of the present disclosure can be prepared, for example, as shown in Scheme 7. Compound XXIV can be combined with p-toluenesulfonylhydrazine and a suitable solvent (e.g., ACN), and the reaction mixture can be allowed to proceed at room temperature for about 3 hours. A suitable base (e.g., NaOH) and a compound of formula XIX can then be added to the reaction mixture. The reaction can then be heated to a temperature of about 50° C. for about 16 hours to obtain a compound of formula XXV.

[0557] In obtaining the compounds and corresponding analytical data described in the Examples below, the following experimental and analytical protocols were followed unless otherwise indicated.

[0558] Unless otherwise specified, the reaction solutions were kept at room temperature under N 2(g) or Ar (g) Stir under a 4% tantalum atmosphere. When solutions were "concentrated to dryness," they were concentrated under reduced pressure using a rotary evaporator. When solutions were dried, they were typically dried over a desiccant such as MgSO4 or Na2SO4. Unless otherwise indicated, normal phase flash column chromatography (FCC) was performed using ethyl acetate (EtOAc) / hexane, CH2Cl2 / MeOH, or CH2Cl2 / 10% 2N NH3 in MeOH as eluents, using a pre-packed silica gel column such as Performed on silica gel.

[0559] Thin layer chromatography using silica gel plates, such as Merck silica gel 60F 254 2.5 cm x 7.5 cm 250 mm or 5.0 cm x 10.0 cm 250 μm pre-coated silica gel plates. Preparative thin layer chromatography uses silica gel plates such as EM Science silica gel 60F 254 The microwave reaction was carried out on a 20 cm x 20 cm 0.5 mm pre-coated plate with a 20 cm x 4 cm concentrating area. Biotage Initiator TM or Optimizer TMThe microwave was used at the specified temperature. Unless otherwise indicated, mass spectra were obtained on a mass spectrometer such as an Agilent 1100 series MSD using electrospray ionization (ESI) in positive ion mode. The calculated masses correspond to the exact masses. NMR spectra were obtained on an NMR spectrometer such as Bruker model DPX400 (400 MHz), DPX500 (500 MHz), DRX600 (600 MHz) spectrometers. 1 The format of H NMR data is as follows: chemical shift (in ppm) downfield from a tetramethylsilane reference (multiplicity, coupling constant J (in Hz), integration).

[0560] When the yield is given in the form of a percentage, such yield refers to the ratio of the mass of the entity for which the yield is given to the maximum amount of the same entity obtainable under specific stoichiometric conditions. Unless otherwise indicated, the concentration of the reagent given in the form of a percentage refers to the mass ratio. Whether or not explicitly stated, the yields given in the following examples are calculated relative to the dry form of the compound for which any such yield is given.

[0561] Chemical names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye).

[0562] Intermediate 1: (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one .

[0563]

[0564] Step A: tert-Butyl 3-(methylamino)propanoate. A 2 L round-bottom flask equipped with an overhead stirrer was charged with methylamine (500 mL, 3.48 mol, 30 wt% solution in EtOH) and EtOH (500 mL), followed by the dropwise addition of tert-butyl acrylate (100 g, 0.78 mol) at 20-25 ° C over 3 hours. The resulting mixture was stirred at room temperature (rt) for 3 hours and then concentrated to dryness to give tert-butyl 3-(methylamino)propanoate (124 g) as a colorless oil. MS (ESI): CH 17 The calculated mass of NO2 is 159.1; the measured m / z is 160.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ2.79 (t, J = 6.5 Hz, 2H), 2.43 (s, 3H), 2.41 (t, J = 6.5 Hz, 2H), 1.44 (s, 9H).

[0565] Step B: tert-Butyl 4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate. A 50 L glass-lined reactor equipped with an overhead stirrer was charged with tert-butyl 3-(methylamino)propionate (900 g, 5.65 mol), diethyl oxalate (827 g, 5.65 mol) and THF (18 L). The resulting mixture was warmed to 50-55 ° C, followed by the addition of t-BuOK (633 g, 5.65 mol) in portions. After stirring for 1 h, the mixture was cooled to 20 ° C, concentrated to dryness, and water (5.00 L) was added to form a suspension. The pH was adjusted to 1-2 with aqueous HCl, and the resulting mixture was stirred at 20-25°C for 1 hour, then filtered and dried to give tert-butyl 4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (940 g, 78%) as an off-white solid. 1 H NMR (300MHz, CDCl3) δ8.99(s,1H),3.94(s,2H),3.10(s,3H),1.56(s,9H).

[0566] Step C:4- hydroxy -1- methyl -5- oxo -2,5- dihydro -1H- pyrrole -3- carboxylic acid. Into a 5L round-bottom flask equipped with an overhead stirrer, 4- hydroxy -1- methyl -5- oxo -2,5- dihydro -1H- pyrrole -3- carboxylic acid tert-butyl ester (500g, 2.34mol) and TFA (2.00L) are loaded. The resulting mixture is stirred at 20-25 ° C for 3 hours and then concentrated to dryness. Acetonitrile (1.50L) ​​is added to the residue under stirring at 20-25 ° C for 1 hour. The product is separated by filtration and dried to obtain 4- hydroxy -1- methyl -5- oxo -2,5- dihydro -1H- pyrrole -3- carboxylic acid (357g, 97%) as an off-white solid. 1 H NMR (300MHz, CD3OD) δ4.04–3.98 (m, 2H), 3.08 (s, 3H).

[0567] Step D: 1-methylpyrrolidine-2,3-dione. A 20 L round-bottom flask equipped with an overhead stirrer was charged with 4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (1000 g, 6.4 mol) and THF (15 L). The resulting mixture was heated to 65 ° C. After 4 hours, the mixture was concentrated to dryness to give 1-methylpyrrolidine-2,3-dione (712 g, 99%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ3.70 (t, J = 5.7 Hz, 2H), 3.13 (s, 3H), 2.72 (t, J = 5.7 Hz, 2H).

[0568] Step E: (R, S) -3- ethynyl -3- hydroxy -1- methylpyrrolidone -2- one. Ethynyl magnesium bromide (3.50 L, 0.5 M THF solution) was loaded into a 10 L round-bottom flask equipped with an overhead stirrer. The flask was purged with nitrogen and cooled to -10 ° C, and then 1- methylpyrrolidine -2,3- dione (120 g, 1.06 mol) was added within 20 minutes. The resulting mixture was warmed to 20-25 ° C and stirred for 16 hours. The resulting mixture was quenched with NH4Cl aqueous solution (120 g in 360 mL H2O) and subsequently diluted with DCM (3.50 L). After slurrying for 1 hour, the suspension was filtered, and the filtrate was dried over anhydrous Na2SO4 (500 g) and treated with activated carbon (24 g). The activated carbon was removed by filtration, and the filtrate was concentrated in vacuo to dryness. The residue was slurried in MTBE (360 mL) at 20-25°C for 1 hour. The product was isolated by filtration and then dried to give (R,S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (81 g, 55%) as a yellow solid. MS (ESI): mass calculated for C7H9NO2: 139.1; m / z found: 140.1 [M+H] + . 1 H NMR (300MHz, CD3OD) δ3.40 (dd, J = 7.7, 5.3Hz, 2H), 3.03 (s, 1H), 2.88 (s, 3H), 2.52–2.41 (m, 1H), 2.21 (dt, J = 12.7, 7.7Hz, 1H).

[0569] Step F: (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one and (S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one. The enantiomers of (R,S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one were separated by chiral preparative SFC using an SFC column such as Separation was performed on an AS-H 5μm, 5×25cm column using a mobile phase (80% CO₂, 20% IPA (0.1% DEA detection), UV = 220-254 nM at 25°C) to afford (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (40%) and (S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 2, 40%). Data for (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one: MS (ESI): Mass calculated for CₐH₄NO₂, 139.1; m / z found, 140.1 [M+H] + . 1H NMR (300MHz, CD3OD) δ3.40 (dd, J = 7.7, 5.3Hz, 2H), 3.03 (s, 1H), 2.88 (s, 3H), 2.52–2.41 (m, 1H), 2.21 (dt, J = 12.7, 7.7Hz, 1H). [α] 20 D =-100.1 (c=1.01 in MeOH).

[0570] Intermediate 2: (S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one .

[0571]

[0572] Chiral separation as described in Step F of Intermediate 1 also yielded (S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (40%). MS (ESI): mass calculated for C7H9NO2: 139.1; m / z found: 140.1 [M+H] + . 1 H NMR (300MHz, CD3OD) δ3.40 (dd, J = 7.7, 5.3Hz, 2H), 3.03 (s, 1H), 2.88 (s, 3H), 2.52–2.41 (m, 1H), 2.21 (dt, J = 12.7, 7.7Hz, 1H). [α] 20 D =+90.5 (c=1.19 in MeOH).

[0573] Intermediate 3: (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one .

[0574]

[0575] Step A: 3-bromobenzaldehyde oxime. To a solution of 3-bromobenzaldehyde (3.0 g, 16 mmol) in EtOH (40 mL) was added NH2OH (50% aqueous solution, 1.1 mL, 19 mmol). The reaction was stirred at 25°C for 4 hours. The reaction mixture was then concentrated under reduced pressure to afford 3-bromobenzaldehyde oxime (3.2 g, 98%) as a white solid. MS (ESI): mass calculated for C7H6BrNO is 199.0; m / z found is 200.1 [M+H] + .

[0576] Step B: 3-bromo-N-hydroxyiminobenzyl chloride. To a solution of 3-bromobenzaldehyde oxime (3.20 g, 16.0 mmol) in anhydrous DCM (20 mL) was added N-chlorosuccinimide (2.56 g, 19.2 mmol) portionwise. The reaction mixture was stirred at 25 ° C for 2 hours and filtered. The filtrate was concentrated to give 3-bromo-N-hydroxyiminobenzyl chloride (3.0 g, 95%) as a yellow solid. MS (ESI): The mass calculated value for C7H5BrClNO was 234.5, and the found value for m / z was 235.2 [M+H] +.

[0577] Step C: (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of 3-bromo-N-hydroxyiminobenzyl chloride (1.50 g, 3.20 mmol) in DCM (20 mL) was added (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1, 4.45 g, 3.20 mmol) followed by TEA (1.24 mL, 9.60 mmol). The reaction mixture was stirred at 25° C. for 16 hours, diluted with DCM (30 mL), washed with brine (20 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1 / 1) to give (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (0.6 g, 55%) as a yellow oil. MS (ESI): C 14 H 13 The calculated mass of BrN2O3 is 336.0; the measured m / z is 337.1 [M+H] + .

[0578] Intermediate 4: (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (2-(4-(2-( ... .

[0579]

[0580] To a flask containing (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 3, 0.60 g, 1.8 mmol) in 1,4-dioxane (10 mL) was charged bis(pinacolato)diboron (0.90 g, 3.56 mmol), Pd(dppf)Cl2.CH2Cl2 (130 mg, 0.180 mmol) and KOAc (540 mg, 5.34 mmol). The reaction mixture was heated at 85° C. under an Ar atmosphere for 16 hours. The mixture was concentrated and the residue was purified by preparative TLC (DCM / MeOH=20 / 1) to give (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (0.62 g, 77%) as a brown solid. MS (ESI): C 20 H 25 The calculated mass of BN2O5 is 384.2; the measured m / z is 385.2 [M+H] + .

[0581] Intermediate 5: (R)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (2-( ... .

[0582]

[0583] Step A: (R)-3-(3-(3-bromophenyl)-3-oxoprop-1-ynyl)-3-hydroxy-1-methylpyrrolidin-2-one. A solution of (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1, 3.00 g, 21.6 mmol) in THF (150 mL) was cooled to -20°C and PdCl(PPh) (0.61 g, 0.86 mmol), CuI (0.21 g, 1.08 mmol) and TEA (4.47 mL, 34.1 mmol) were added. A solution of 3-bromobenzoyl chloride (4.73 g, 21.6 mmol) in THF (10 mL) was added dropwise. The reaction mixture was slowly warmed to 0°C, stirred for 2 hours, diluted with water (80 mL) and extracted with EtOAc (3 x 60 mL). The combined organic solvent extracts were washed with brine (60 mL), dried over Na2SO4 and filtered. The filtrate was concentrated and purified by FCC (DCM / MeOH=100 / 1) to give (R)-3-(3-(3-bromophenyl)-3-oxoprop-1-ynyl)-3-hydroxy-1-methylpyrrolidin-2-one (1.6 g, 23%) as a yellow solid. MS (ESI): C 14 H 12The calculated mass of BrNO3 is 321.0; the measured m / z is 322.0 [M+H] + .

[0584] Step B: (R)-3-(5-(3-bromophenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of (R)-3-(3-(3-bromophenyl)-3-oxoprop-1-ynyl)-3-hydroxy-1-methylpyrrolidin-2-one (1.60 g, 4.37 mmol) in DCM (100 mL) was added NaN (1.42 g, 21.8 mmol). The mixture was cooled to 0°C and AcOH (1.31 g, 21.85 mmol) was added dropwise followed by TEA (1.21 mL, 0.87 mmol). The reaction mixture was stirred at room temperature for 2 days. Saturated aqueous NaHCO (100 mL) was added and the mixture was stirred for 10 minutes. The organic solvent portion was separated and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic solvent extracts were washed with brine (2×100 mL), dried over Na 2 SO 4 and filtered. The filtrate was concentrated by blowing a continuous stream of N 2 through the filtrate, and the residue was purified by FCC (DCM / MeOH=50 / 1) to give (R)-3-(5-(3-bromophenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (0.6 g, 41%) as a gray oil. MS (ESI): C 14 H 13 The calculated mass of BrN2O3 is 336.0; the measured m / z is 337.0 [M+H] + .

[0585] Step C: (R)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one. To a flask containing (R)-3-(5-(3-bromophenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (85 mg, 0.252 mmol) in 1,4-dioxane (5 mL) was charged bis(pinacolato)diboron (128.0 mg, 0.50 mmol), Pd(dppf)Cl2·CHCl2 (18.4 mg, 0.025 mmol), and KOAc (74.2 mg, 0.76 mmol). The mixture was heated at 65°C under Ar for 4 h. The reaction mixture was filtered and concentrated to give (R)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one (0.10 g, 87%) as a brown oil, which was used in the next step without further purification. MS (ESI): C 20 H 25 The calculated mass of BN2O5 is 384.2; the measured m / z is 385.2 [M+H] + .

[0586] Intermediate 6: (R,S)-3-(5-(3-bromophenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one .

[0587]

[0588] (R,S)-3-(5-(3-bromophenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (1.4 g) was prepared using conditions analogous to those described for the preparation of Intermediate 5 ((R)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one) using (R,S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (prepared in Intermediate 1, Step E) instead of (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one. MS (ESI): C 14 H 13 The calculated mass of BrN2O3 is 336.0; the measured m / z is 337.0 [M+H] + .

[0589] Intermediate 7: (R)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidine-2-yl ketone .

[0590]

[0591] Step A: 2-Bromoisonicotinaldehyde oxime. To a solution of 2-bromoisonicotinaldehyde (250 mg, 1.3 mmol) in EtOH (10 mL) was added hydroxylamine (0.095 mL, 50% in water, 1.6 mmol). The reaction mixture was stirred at room temperature for 16 hours and concentrated to dryness to afford 2-bromoisonicotinaldehyde oxime (240 mg, 89%) as a colorless solid. MS (ESI): mass calculated for C6H5BrN2O is 200.0; m / z found is 201.1 [M+H] + .

[0592] Step B: 2-bromo-N-hydroxyisonicotinimidoyl chloride. To a solution of 2-bromoisonicotinaldehyde oxime (140 mg, 0.60 mmol) in DCM (5 mL) was added portionwise N-chlorosuccinimide (120 mg, 0.90 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then DMF (1 mL) was added, and the reaction mixture was stirred for an additional 2 hours. The mixture was diluted with EtOAc (20 mL) and washed with brine (3×20 mL). The organic extract was dried over Na 2 SO 4 , filtered and concentrated to dryness to give 2-bromo-N-hydroxyisonicotinimidoyl chloride (140 mg, 80%) as a white solid. MS (ESI): mass calculated for C 6 H 4 BrClN 2 O is 235.5; m / z found is 199.0 [M-HCl + 1] + .

[0593] Step C: (R)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of bromo-N-hydroxyisonicotinimidoyl chloride (2.80 g, 11.9 mmol) and (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1, 1.64 g, 11.9 mmol) in t-BuOH:H2O (10 mL 1:1) was added a solution of sodium ascorbate (0.24 g, 1.2 mmol) in H2O (1 mL). A solution of CuSO4·5H2O (0.89 g, 3.6 mmol) in H2O (2 mL) was then added, followed by KHCO3 (3.57 g, 1.19 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with water (20 mL), and extracted with EtOAc (3×20 mL). The combined organic solvent extracts were dried, filtered, concentrated to dryness, and purified by preparative TLC (DCM / MeOH=20 / 1) to give (R)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (1.8 g, 45%) as a yellow solid. MS (ESI): C 13 H 12The calculated mass of BrN3O3 is 337.0, and the measured m / z is 338.3 [M+H] + .

[0594] Intermediate 8: (R)-3-hydroxy-1-methyl-3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) alkyl-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)pyrrolidin-2-one.

[0595]

[0596] Step A: (R)-3-(1-(3-bromophenyl)-1H-1,2,3-triazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a suspension of 1-bromo-3-iodobenzene (281 mg, 0.99 mmol) in DMSO (2 mL) was added (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1, 138 mg, 0.993 mmol), sodium azide (71 mg, 1.1 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (28 mg, 0.20 mmol) and copper(I) iodide (38 mg, 0.20 mmol). A solution of sodium ascorbate (39 mg, 0.20 mmol) in water (0.5 mL) was slowly added and the reaction mixture was stirred at room temperature under an Ar atmosphere for 16 hours. The mixture was diluted with EtOAc (20 mL), and the organic phase was washed with brine (3×15 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by FCC (DCM\MeOH=20 / 1) to give (R)-3-(1-(3-bromophenyl)-1H-1,2,3-triazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (200 mg, 76%) as a yellow solid. MS (ESI): C 13 H 13 The calculated mass of BrN4O2 is 336.0; the found m / z is 337.0 [M+H].

[0597] Step B: (R)-3-hydroxy-1-methyl-3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)pyrrolidin-2-one. To a solution of (R)-3-(1-(3-bromophenyl)-1H-1,2,3-triazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (200 mg, 0.593 mmol) in dioxane (10 mL) was added bis(pinacolato)diboron (301 mg, 1.19 mmol) followed by [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (45 mg, 0.059 mmol) and KOAc (175 mg, 1.78 mmol). The reaction mixture was heated at 65° C. under an Ar atmosphere for 2 h. The reaction mixture was then filtered and concentrated under reduced pressure. The residue was purified by FCC (DCM / MeOH=20 / 1) to give (R)-3-hydroxy-1-methyl-3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)pyrrolidin-2-one (260 mg, 68%) as a yellow solid. MS (ESI): C 19 H 25 The calculated mass of BN4O4 is 384.2; the measured m / z is 385.2 [M+H] + .

[0598] Intermediate 9: (R,S)-3-hydroxy-1-methyl-3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxolane) (boran-2-yl)phenyl)-1H-imidazol-4-yl)pyrrolidin-2-one.

[0599]

[0600] Step A: 1-(3-bromophenyl)-4-iodo-1H-imidazole. A mixture of 4-iodoimidazole (3.68 g, 19.0 mmol) in THF (100 mL), 3-bromophenylboronic acid (7.6 g, 38 mmol), di-μ-hydroxyoxo-bis[(N,N,N',N'-tetramethylethylenediamine)copper(II) chloride] (9.7 g, 20.869 mmol) and molecular sieves (250 mg) were stirred at 30 ° C under an O atmosphere for 16 hours. The reaction mixture was then filtered through celite, washed with EtOAc (200 mL) and concentrated under reduced pressure. The residue was purified by FCC (petroleum ether / EA=2 / 1) to give 1-(3-bromophenyl)-4-iodo-1H-imidazole (3.2 g, 48%) as a brown solid. MS (ESI): mass calculated for C9H6BrIN2 is 347.9; m / z found is 349.0 [M+H] + .

[0601] Step B: 3-(1-(3-bromophenyl)-1H-imidazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of 1-(3-bromophenyl)-4-iodo-1H-imidazole (1.35 g, 3.87 mmol) in THF (30 mL) cooled to 0 ° C was added dropwise isopropylmagnesium chloride-lithium chloride solution (3.6 mL, 1.3 M THF solution). After 1 hour, a solution of 1-methylpyrrolidine-2,3-dione (0.87 g, 7.74 mmol) in THF (10 mL) was added, and the mixture was stirred at 0 ° C for 2 hours. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was then cooled to 0 ° C, quenched with ice water (6 mL) and MeOH (10 mL) and concentrated under reduced pressure. The residue was purified using preparative TLC (DCM / MeOH=15 / 1) to give 3-(1-(3-bromophenyl)-1H-imidazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (0.29 mg, 22%) as a brown solid. MS (ESI): C 14 H 14 The calculated mass of BrN3O2 is 336.2; the measured m / z is 336.0 [M+H] + .

[0602] Step C: 3-Hydroxy-1-methyl-3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-4-yl)pyrrolidin-2-one. A mixture of bis(pinacolato)diboron (242 mg, 0.95 mmol), 3-(1-(3-bromophenyl)-1H-imidazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (160 mg, 0.48 mmol), Pd(dppf)Cl2·CHCl2 (36.3 mg, 0.048 mmol) and KOAc (140.1 mg, 1.428 mmol) in dioxane (10 mL) was heated at 80°C under Ar atmosphere for 16 hours. The reaction mixture was used directly in the subsequent reaction. MS (ESI): C 20 H 26 The calculated mass of BN3O4 is 383.3; the measured m / z is 384.0 [M+H] + .

[0603] Intermediate 10: (R)-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl Boric acid .

[0604]

[0605] To a suspension of (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 3, 500 mg, 1.5 mmol) in MeOH (15 mL) was added tetrakis(dimethylamino)diboron (881 mg, 4.45 mmol) followed by chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (43.4 mg, 59.3 mmol) and the reaction was heated at 60 °C under argon atmosphere for 16 h. The mixture was concentrated to dryness and purified by FCC (8% MeOH / DCM) to give (R)-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)boronic acid (160 mg, 36%) as a yellow solid. MS (ESI): C 14 H 15 The calculated mass of BN2O5 is 302.11; the measured m / z is 303.2 [M+H] + .

[0606] Intermediate 11: 5-chloro-3-nitro-1H-pyrazolo[4,3-b]pyridine .

[0607]

[0608] To a flask containing 5-chloro-1H-pyrazolo[4,3-b]pyridine (5.0 g, 32.56 mmol) was added H2SO4 (10 mL) at 0 ° C., followed by KNO3 (8.2 g, 81.397 mmol). The mixture was stirred at room temperature for 3 hours and then heated at 115 ° C. for 8 hours. The reaction mixture was then poured into ice water, and the pH was adjusted to pH 9 using NH4OH aqueous solution. A precipitate was formed and collected by filtration. The filter cake was dried to give 5-chloro-3-nitro-1H-pyrazolo[4,3-b]pyridine (5.2 g, 80%) as a yellow solid. MS (ESI): calculated for C6H3ClN4O2 is 198.6; m / z found is 199.0 [M+H] + .

[0609] Intermediate 12: 5-chloro-1-methyl-3-nitro-1H-pyrazolo[4,3-b]pyridine .

[0610]

[0611] To a solution of 5-chloro-3-nitro-1H-pyrazolo[4,3-b]pyridine (Intermediate 11, 500 mg, 2.5 mmol) and iodomethane (357 mg, 2.52 mmol) in DMF (4 mL) was added potassium carbonate (348 mg, 2.52 mmol). The reactant was stirred at 50 ° C for 2 hours, then diluted with EtOAc (30 mL) and washed with brine (3×10 mL). The organic layers were combined and concentrated to dryness, and the resulting residue was purified by preparative TLC (100% EtOAc) to give 5-chloro-1-methyl-3-nitro-1H-pyrazolo[4,3-b]pyridine (200 mg, 37%) as a yellow solid. MS (ESI): mass calculated for C7H5ClN4O2 is 212.0; m / z found is 213.0 [M+H] + .

[0612] Intermediate 13: 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine .

[0613]

[0614] Step A: Methyl (E)-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxylate A mixture of methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate (3.00 g, 11.4 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.26 g, 11.40 mmol), Pd(dppf)Cl2 (0.43 g, 0.57 mmol), water (10 mL) and Na2CO3 (3.63 g, 34.2 mmol) in THF (70 mL) was heated at 65°C under Ar atmosphere for 16 hours. The reaction mixture was concentrated to dryness, and the residue was purified by FCC, eluting with petroleum ether / ethyl acetate (20 / 1 to 8 / 1, gradient elution) to give (E)-methyl 5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxylate (1.2 g, 41%) as a yellow solid. MS (ESI): C 11 H 14 The calculated mass of N2O3S is 254.1; the found m / z is 255.1 [M+H] + .

[0615] Step B: (E)-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxamide. A mixture of (E)-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxylic acid methyl ester (1.2 g, 4.7 mmol) in NH3 in MeOH (7 M, 12 mL, 84 mmol) was heated in a sealed tube at 80 ° C for 16 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to give (E)-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxamide (950 mg, 84%) as a yellow solid, which was used in the next step without further purification. MS (ESI): C 10 H 13 The calculated mass of N3O2S is 239.1; the found m / z is 240.1 [M+H] + .

[0616] Step C: 2-(Methylthio)pyrido[3,4-d]pyrimidin-8-ol. To a solution of (E)-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxamide (950 mg, 3.97 mmol) in toluene (25 mL) was added p-toluenesulfonic acid monohydrate (113 mg, 0.60 mmol). The resulting mixture was heated at 90 ° C for 2 hours, cooled to room temperature, and then concentrated under reduced pressure to give 2-(methylthio)pyrido[3,4-d]pyrimidin-8-ol (700 mg, 91%) as a yellow solid, which was used in the next step without further purification. MS (ESI): mass calculated for CHNOS is 193.0; m / z found is 194.1 [M+H] + .

[0617] Step D: 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine. A mixture of 2-(methylthio)pyrido[3,4-d]pyrimidin-8-ol (700 mg, 3.62 mmol) in POCl3 (25 mL, 269 mmol) was heated at 70 ° C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was distributed between EtOAc (20 mL) and saturated NaHCO3 aqueous solution (20 mL). The aqueous layer was extracted with EtOAc (2×10 mL), and the combined organic solvent extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was analyzed by preparative TLC (petroleum ether / ethyl acetate=3 / 1, R f =0.4) to give 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine (500 mg, 65%) as a white solid. MS (ESI): mass calculated for C8H6ClN3S is 211.0; m / z found is 212.1 [M+H] + .

[0618] Intermediate 14: 6-(3-iodophenyl)picolinic acid methyl ester .

[0619]

[0620] A mixture of methyl 6-bromopicolinate (1.0 g, 4.63 mmol), (3-iodophenyl)boronic acid (1.0 g, 4.21 mmol), KF (733 mg, 12.6 mmol), PdCl2(dppf) (128 mg, 0.17 mmol), 1,4-dioxane (15 mL) and water (2 mL) was heated at 80 ° C under N2 atmosphere for 15 hours. The mixture was concentrated, diluted with water (35 mL) and extracted with EtOAc (4×35 mL). The combined organic solvent extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=5 / 1) to give methyl 6-(3-iodophenyl)picolinate (89 mg, 6.2%) as a yellow oil. MS (ESI): C 13 H 10 The calculated mass of INO2 is 339.1; the found m / z is 340.0 [M+H] + .

[0621] Intermediate 15: 6-chloro-4-methoxypicolinamide .

[0622]

[0623] To a solution of 6-chloro-4-methoxypicolinic acid (200 mg, 1.07 mmol) in DCM (3 mL) and DMF (3 mL) was added ammonium chloride (160 mg, 2.99 mmol), followed by DIEA (689 mg, 5.33 mmol) and HATU (567 mg, 1.49 mmol). The reaction mixture was stirred at room temperature overnight and then diluted with water (20 mL). The aqueous phase was extracted with EtOAc (3 × 15 mL), concentrated to dryness and purified by FCC (petroleum ether / ethyl acetate = 1: 1) to give 6-chloro-4-methoxypicolinamide (130 mg, 65%) as a yellow solid. MS (ESI): The mass calculated value for C7H7ClN2O2 is 186.0; the found value for m / z is 187.0 [M+H] + .

[0624] Intermediate 16: 6-chloro-2-methylpyrido[3,2-d]pyrimidin-4-amine .

[0625]

[0626] A vial containing 3-amino-6-chloropyridine carbonitrile (100 mg, 0.65 mmol) was charged with acetamidine hydrochloride (57.0 mg, 0.98 mmol), tripotassium phosphate (553 mg, 2.6 mmol) and THF (3 mL). The vial was sealed and heated at 80 ° C for 16 hours. The resulting mixture was cooled to room temperature and concentrated to dryness. Water (3 mL) was added to the residue and the resulting mixture was heated at 70 ° C. After stirring for 30 minutes, the resulting mixture was cooled to room temperature and stirred for another 30 minutes. The resulting solid was separated by filtration and washed with water (3 mL) and Et2O (10 mL) in sequence to give 6-chloro-2-methylpyrido[3,2-d]pyrimidin-4-amine (70 mg, 55%) as a light yellow solid. MS (ESI): The mass calculated value of C8H7ClN4 is 194.0; the found value of m / z is 195.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 8.00 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 6.76 (s, 2H), 2.63 (s, 3H).

[0627] Intermediate 17: 6-chloropyrido[3,2-d]pyrimidin-2-d-4-amine .

[0628]

[0629] A 1L round-bottom flask was charged with 3-amino-6-chloropyridinecarbonitrile (22.0 g, 0.14 mol), formamide-d3 (20.6 g, 0.43 mol), K3PO4 (122 g, 0.57 mol) and cyclopentyl methyl ether (440 mL). The resulting mixture was heated at 65 ° C for 16 hours and then cooled to room temperature. The reaction mixture was then filtered and the filter cake was slurried in water (100 mL) at 20 ° C for 3 hours. The solid was separated by filtration and dried to obtain 6-chloropyrido [3,2-d] pyrimidine-2-d-4-amine (23.9 g, 94%) as a yellow solid. MS (ESI): The mass calculated value of C7H4DClN4 is 181.0; the found value of m / z is 182.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.15 (d, J = 8.8 Hz, 1H), 8.05 (br s, 1H), 7.95 (br s, 1H), 7.88 (d, J = 8.8 Hz, 1H).

[0630] Intermediate 18: 6-(3-iodophenyl)pyrido[3,2-d]pyrimidin-2-d-4-amine .

[0631]

[0632] Step A: 6-(3-(Trimethylsilyl)phenyl)pyrido[3,2-d]pyrimidin-2-d-4-amine. Under N2 atmosphere, a 1 L flask equipped with an overhead stirrer containing 6-chloropyrido[3,2-d]pyrimidin-2-d-4-amine (Intermediate 17, 31 g, 0.14 mol) was charged sequentially with 4-(trimethylsilyl)phenylboronic acid (32 g, 0.17 mol), Pd(dppf)Cl2 (10.2 g, 13.8 mmol), CH3CN (500 mL), and Cs2CO3 aqueous solution (1 M, 125 mL). The resulting mixture was heated at 75 ° C for 3 hours. Water (375 mL) was added, and the reaction mixture was further heated at 65 ° C for 0.5 hours. The resulting mixture was then gradually cooled to room temperature and stirred for 1 hour. The product was isolated by filtration and dried to give 6-(3-(trimethylsilyl)phenyl)pyrido[3,2-d]pyrimidin-2-d-4-amine (39 g, 94%) as a brown solid. MS (ESI): C 16 H 17 The calculated mass of DN4Si is 295.1; the measured m / z is 296.1 [M+H] + . 1 H-NMR (300MHz, DMSO-d6) δ8.46(t,J=8.9Hz,2H),8.39(s,1H),8.15(d,J=8.8Hz,1H) ,8.04(d,J=10.3Hz,2H),7.65(d,J=7.1Hz,1H),7.54(t,J=7.6Hz,1H),0.35(s,9H).

[0633] Step B: 6-(3-iodophenyl)pyrido[3,2-d]pyrimidin-2-d-4-amine. A 10 L round-bottom flask equipped with an overhead stirrer was charged with 6-(3-(trimethylsilyl)phenyl)pyrido[3,2-d]pyrimidin-2-d-4-amine (49.0 g, 0.17 mol) and DCM (980 mL). A solution of ICl (134 g, 0.830 mol) in CHCl (735 mL) was then added dropwise at -5°C, and the reaction mixture was warmed to 15°C and stirred for 1 hour. A precipitate formed and was isolated by filtration and dried under vacuum at 50°C. The resulting solid was combined with several additional batches of this material and dissolved in DMSO (800 mL). Aqueous KHPO (10 wt %) was then added dropwise to the solution and stirring was continued at 20°C for 2 hours. The precipitate was isolated by filtration and then slurried in water (1600 mL) at 20° C. for 4 hours. The solid was isolated and dried to give 6-(3-iodophenyl)pyrido[3,2-d]pyrimidin-2-d-4-amine (135 g) as a light brown solid. MS (ESI): C 13The calculated mass of H8DIN4 is 349.0; the found m / z is 350.0 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ8.84(m,1H),8.47(m,1H),8.40(m,2H),8.12(m,2H),7.86(m,1H),7.34(m,1H).

[0634] Intermediate 19: 3-amino-6-(3-iodophenyl)picolinamide .

[0635]

[0636] Step A: 3-amino-6-(3-(trimethylsilyl)phenyl)picolinamide. To a N2-purged solution of 3-amino-6-chloropicolinamide (1.00 g, 5.83 mmol) and (3-(trimethylsilyl)phenyl)boronic acid (1.11 g, 5.83 mmol) in dioxane (58 mL) and water (15 mL) was added methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1'-biphenyl)]palladium(II) (0.48 g, 0.58 mmol) followed by Cs2CO3 (5.70 g, 17.5 mmol). The reaction mixture was heated at 80° C. for 1 hour, partitioned between EtOAc (40 mL) and water (60 mL), and the organic layer was separated, concentrated to dryness, and purified by FCC (0-40% EtOAc:hexanes) to give 3-amino-6-(3-(trimethylsilyl)phenyl)picolinamide (1.2 g, 73%) as an orange solid. MS (ESI): C 15 H 19 The calculated mass of N3OSi is 285.1; the observed m / z is 286.1 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ8.12-8.03(m,2H),8.02(s,1H),7.87(d,J=8.7Hz,1H),7. 49-7.44(m,1H),7.43-7.37(m,2H),7.25(d,J=8.7Hz,1H),6.95(s,2H),0.30(s,9H).

[0637] Step B: 3-amino-6-(3-iodophenyl)picolinamide. To a solution of 3-amino-6-(3-(trimethylsilyl)phenyl)picolinamide (0.20 g, 0.70 mmol) in DCM (7 mL) was added dropwise ICl solution (3.5 mL, 2 M in DCM, 3.50 mmol) at 0 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. Saturated Na2S2O3 aqueous solution (25 mL) was added and the solid was isolated by filtration. The solid was purified by FCC (0-10% MeOH: DCM) to give 3-amino-6-(3-iodophenyl)picolinamide (133 mg, 56%) as a beige solid. MS (ESI): C 12 H 10 The calculated mass of IN3O is 339.0; the found m / z is 340.0 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δ8.45–8.39(m,1H),8.16(s,1H),8.12–8.01(m,1H),7.87 (d,J=8.7Hz,1H),7.70–7.62(m,1H),7.40(s,1H),7.25–7.17(m,2H),7.03(s,2H).

[0638] Intermediate 20: 2-(5-iodo-2-methylphenyl)thiazolo[5,4-d]pyrimidin-7-amine .

[0639]

[0640] Step A: N-(4-amino-6-oxo-1,6-dihydropyrimidin-5-yl)-5-iodo-2-methylbenzamide. A 2-L round-bottom flask equipped with an overhead stirrer was charged sequentially with 5,6-diaminopyrimidin-4(3H)-one (47.3 g, 375 mmol), 5-iodo-2-methylbenzoic acid (108 g, 412 mmol), DMF (710 mL), and DIEA (153 g, 1.18 mol). The flask was purged with nitrogen and cooled to 0-10°C before adding 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (148 g, 390 mmol). The resulting mixture was stirred at 0-10°C for 1 hour, then warmed to room temperature and stirred for 18 hours. The mixture was diluted with acetonitrile (709 mL) and stirred for 30 minutes. The resulting solid was filtered and washed with CH3CN (190 mL × 3). The filter cake was collected and dried under vacuum at 50 ° C -55 ° C to give N- (4-amino-6-oxo-1,6-dihydropyrimidin-5-yl) -5-iodo-2-methylbenzamide (108 g, 78.0%) as a light brown solid. 1H NMR (400MHz, DMSO-d6) δ11.68(s,1H),8.89(s,1H),8.01(s,1H),7.78(s,1H),7.66(d,J=8.0Hz,1H),7.05(d,J=8.0Hz,1H),6.39(s,2H),2.35(s,3H).

[0641] Step B: 2-(5-iodo-2-methylphenyl)thiazolo[5,4-d]pyrimidin-7-amine. A 2 L round-bottom flask equipped with an overhead stirrer was charged with N-(4-amino-6-oxo-1,6-dihydropyrimidin-5-yl)-5-iodo-2-methylbenzamide (110 g, 297 mmol), pyridine (1.10 L) and P2S5 (165 g, 742 mmol). The resulting mixture was heated at 100 ° C for 1 h and then cooled to RT. The mixture was concentrated to dryness, diluted with acetonitrile (550 mL), and neutralized with 1N HCl aqueous solution (1.20 L). The resulting mixture was stirred for 1 hour, and the suspension was filtered, washed with MeOH (110 mL×3), and dried under vacuum at 50-55 ° C. The resulting solid was further purified by adding MeOH (1150 mL) at 60 ° C and stirring for 1 hour. The solid was collected by filtration and dried in vacuo at 50-55 °C to give 2-(5-iodo-2-methylphenyl)thiazolo[5,4-d]pyrimidin-7-amine (88.4 g, 80.8%) as a light yellow solid. 1 H NMR (300MHz, DMSO-d6) δ8.33(s,1H),8.15(d,J=1.9Hz,1H),7.81(d,J=2.0Hz,2H),7.78(d,J=1.9Hz,1H),7.23(d,J=8.1Hz,1H),2.57(s,3H).

[0642] Intermediate 21: 2-(3-iodophenyl)thiazolo[5,4-d]pyrimidin-7-amine .

[0643]

[0644] Step A: N-(4-amino-6-oxo-1,6-dihydropyrimidin-5-yl)-3-iodobenzamide. To a solution of 5,6-diaminopyrimidin-4-ol and NaOH (2M, 50 mL, 100 mmol) was added 3-iodobenzoyl chloride (4.23 g, 15.9 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 4 hours, allowed to warm to room temperature, and then stirred overnight. The solid was removed by filtration, and the pH of the filtrate was adjusted to pH 4-5 with acetic acid. The resulting precipitate was filtered, washed with water (50 mL), and the resulting solid was suspended in EtOH (100 mL), stirred for 10 minutes and filtered. The filter cake was washed with EtOH (30 mL) and then dried to give N-(4-amino-6-oxo-1,6-dihydropyrimidin-5-yl)-3-iodobenzamide (0.64 g, 23%) as a brown solid. MS (ESI): C 11 The calculated mass of H9IN4O2 is 356.0; the found m / z is 357 [M+H] + .

[0645] Step B: 2-(3-iodophenyl)thiazolo[5,4-d]pyrimidin-7-amine. A solution of N-(4-amino-6-oxo-1,6-dihydropyrimidin-5-yl)-3-iodobenzamide (640 mg, 1.80 mmol), 2,4-bis(4-methoxyphenyl)-2,4-dithio-1,3,2,4-dithiadiphosphatidine (727 mg, 1.80 mmol) in toluene (15 mL) was heated to reflux for 16 hours, cooled to room temperature and the solid was isolated by filtration. The filter cake was washed with toluene (5 mL), the solid was suspended in MeOH (3 mL), stirred for 2 minutes and isolated by filtration to give 2-(3-iodophenyl)thiazolo[5,4-d]pyrimidin-7-amine (420 mg, 66%) as a white solid. MS (ESI): C 11 The calculated mass of H7IN4S is 353.9; the found m / z is 355.0 [M+H] + .

[0646] Intermediate 22: 4-(azetidin-1-yl)-6-chloropyrido[3,2-d]pyrimidine .

[0647]

[0648] To a mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (250 mg, 1.25 mmol), DIPEA (0.87 mL, 5.00 mmol) and DMF (2.5 mL) was added azetidine (71.3 mg, 1.25 mmol) and the resulting mixture was stirred at room temperature. After 1.5 hours, the mixture was filtered and the filter cake was dried under reduced pressure to give 4-(azetidine-1-yl)-6-chloropyrido[3,2-d]pyrimidine (200 mg, 73%). It was a white solid. MS (ESI): C 10 The calculated mass of H9ClN4 is 220.1; the found m / z is 221.1 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.34 (s, 1H), 7.97 (d, J = 8.8Hz, 1H), 7.69 (d, J = 8.8Hz, 1H), 4.88 (t, J = 7.7Hz, 2H), 4.36 (t, J = 7.7Hz, 2H), 2.82-2.21 (m, 2H).

[0649] Intermediate 23: (R)-3-hydroxy-3-(3-(3-iodophenyl)isoxazol-5-yl)-1-methylpyrrolidin-2-one .

[0650]

[0651] Step A: 3-iodobenzaldehyde oxime. To a solution of 3-iodobenzaldehyde (1.5 g, 6.5 mmol) in EtOH (20 mL) was added NH2OH (50% aqueous solution) (0.46 mL, 7.8 mmol). The mixture was stirred at 25 ° C for 16 hours and concentrated to dryness to give 3-iodobenzaldehyde oxime (1500 mg, 6.072 mmol) as a light yellow solid, which was used in the next step without further purification. MS (ESI): mass calculated for C7H6INO is 247.0; m / z found is 248.1 [M+H] + .

[0652] Step B: N-hydroxy-3-iodoiminobenzyl chloride. N-chlorosuccinimide (973 mg, 7.29 mmol) was added portionwise to a solution of 3-iodobenzaldehyde oxime (1.5 g, 6.1 mmol) in anhydrous DCM (30 mL). The reaction mixture was stirred at 25 ° C for 2 hours. The mixture was then concentrated to give N-hydroxy-3-iodoiminobenzyl chloride (1450 mg, 5.151 mmol) as a light yellow oil, which was used in the next step without further purification. MS (ESI): the mass calculated value for C7H5ClINO was 280.9; the found value for m / z was 282.3 [M+H] + .

[0653] Step C: (R)-3-hydroxy-3-(3-(3-iodophenyl)isoxazol-5-yl)-1-methylpyrrolidin-2-one. To a solution of N-hydroxy-3-iodoiminobenzyl chloride (650 mg, 2.31 mmol) in DCM (15 mL) was added (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1, 385 mg, 2.77 mmol) and TEA (934 mg, 9.24 mmol). The mixture was stirred at 50 ° C for 4 hours. The mixture was then cooled to room temperature, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was analyzed by preparative TLC (DCM / MeOH=20 / 1, R f =0.4) to give (R)-3-hydroxy-3-(3-(3-iodophenyl)isoxazol-5-yl)-1-methylpyrrolidin-2-one (110 mg, 0.266 mmol) as a yellow solid. MS (ESI): C 14 H 13 The calculated mass of IN2O3 is 384.0; the found m / z is 385.0 [M+H] + .

[0654] Intermediate 24: 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3- b] tert-Butyl pyridine-1-carboxylate .

[0655]

[0656] Step A: 3-iodo-1H-pyrrolo[2,3-b]pyridine. To a solution of 1H-pyrrolo[2,3-b]pyridine (5 g, 42.324 mmol) in MeCN (60 mL) was added N-iodosuccinimide (11.427 g, 50.789 mmol) portionwise. The mixture was stirred at 25 ° C for 2 hours, and then the solid was collected from the reaction mixture by vacuum filtration. The solid was washed with MeCN (30 mL), and the filtrate was concentrated to give 3-iodo-1H-pyrrolo[2,3-b]pyridine (8.0 g, 31 mmol) as a yellow solid. MS (ESI): The mass calculated value for C7H5IN2 is 244.0; the found value for m / z is 245.1 [M+H] + .

[0657] Step B: tert-butyl 3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. To a solution of 3-iodo-1H-pyrrolo[2,3-b]pyridine (8.00 g, 32.8 mmol), DMAP (0.40 g, 3.28 mmol) and TEA (13.2 g, 131 mmol) in DCM (130 mL) was added di-tert-butyl dicarbonate (8.58 g, 39.3 mmol) dropwise. The mixture was stirred at 25 ° C for 2 hours. The reaction mixture was then diluted with DCM (130 mL) and washed with saturated Na2SO3 aqueous solution (100 mL), then washed with brine (120 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (8 / 1) to give tert-butyl 3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (11.8 g) as a yellow oil. MS (ESI): C 12 H 13 The calculated mass of IN2O2 is 344.0; the found m / z is 345.1 [M+H] + .

[0658] Step C: tert-Butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. To a solution of tert-butyl 3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (11.8 g, 34.3 mmol) in 1,4-dioxane (50 mL) was added bis(pinacolato)diboron (17.4 g, 68.6 mmol), PdCl(dppf) (0.78 g, 1.03 mmol), and KOAc (10.1 g, 103 mmol). The mixture was heated at 85° C. under an argon atmosphere for 16 hours. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), washed with brine (50 mL), dried over NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (gradient 20 / 1 to 8 / 1) to give tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (8 g, 9 mmol) as a light yellow solid. MS (ESI): C 18 H 25 The calculated mass of BN2O4 is 344.2; the measured m / z is 345.3 [M+H] + .

[0659] Intermediate 25: 6-(3-chlorophenyl)pyrido[3,2-d]pyrimidin-2-d-4-amine .

[0660]

[0661] 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (144 mg, 0.22 mmol) was added to a mixture of 6-chloropyrido[3,2-d]pyrimidin-2-d-4-amine (Intermediate 17, 400 mg, 2.20 mmol), (3-chlorophenyl)boronic acid (413 mg, 2.64 mmol), K3PO4 (1.4 g, 6.6 mmol), 1,4-dioxane (6.4 mL) and H2O (1.6 mL). The resulting mixture was aerated with Ar for 5 minutes and then subjected to microwave irradiation at 90 ° C for 1.5 hours. The mixture was then cooled to room temperature and concentrated to dryness under reduced pressure to give the product, which was purified by FCC (eluent: petroleum ether: ethyl acetate = 1:0 to 1:1) to give 6-(3-chlorophenyl)pyrido[3,2-d]pyrimidin-2-d-4-amine (300 mg, 51%) as a yellow solid. MS(ESI):C 13 The calculated mass of H8ClDN4 is 257.7; the measured m / z is 258.1[M+1] + .

[0662] Intermediate 26: (S)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one .

[0663]

[0664] The title compound was prepared using similar conditions as described for Intermediate 3 using Intermediate 2 instead of Intermediate 1 in Step C. MS (ESI): C 14 H 13 The calculated mass of BrN2O3 is 336.0; the measured m / z is 337.1 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.01(t,J=1.8Hz,1H),7.81(td,J=7.8,1.2Hz,1H),7.67-7.61(m,1H),7.41(t,J=7.9Hz, 1H), 6.92-6.89 (m, 1H), 3.62-3.49 (m, 2H), 2.95 (s, 3H), 2.72 (ddd, J = 13.5, 6.8, 5.1Hz, 1H), 2.45-2.33 (m, 1H).

[0665] Intermediate 27: (S)-3-Hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (2-(4-(2-( ... .

[0666]

[0667] The title compound was prepared in a manner analogous to (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Steps AC) using (S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one in Step C and the borylation reaction was similar to (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. MS (ESI): C 20 H 25 The calculated mass of BN2O5 is 384.2; the measured m / z is 385.2 [M+H] + .

[0668] Intermediate 28: (R)-3-hydroxy-1-methyl-3-(3-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxo- (borolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one .

[0669]

[0670] Step A: 3-Bromo-5-methylbenzaldehyde oxime. To a solution of 3-bromo-5-methylbenzaldehyde (2 g, 10.05 mmol) in EtOH (20 mL) was added NH2OH (50% aqueous solution) (0.71 mL, 12.06 mmol). The mixture was stirred at 25°C for 16 hours and concentrated under reduced pressure to give 3-bromo-5-methylbenzaldehyde oxime (2.1 g, 97%) as a white solid. MS (ESI): mass calculated for C8H8BrNO is 214.1; m / z found is 214.1 [M+H]. + .

[0671] Step B: 3-bromo-N-hydroxy-5-methyliminobenzyl chloride. To a solution of 3-bromo-5-methylbenzaldehyde oxime (600 mg, 2.80 mmol) in anhydrous DCM (20 mL) was added N-chlorosuccinimide (450 mg, 3.36 mmol) portionwise. The reaction mixture was stirred at 25 ° C for 2 hours, filtered, and the filtrate was concentrated under reduced pressure to give 3-bromo-N-hydroxy-5-methyliminobenzyl chloride (0.6 g, 86%) as a yellow solid. MS (ESI): mass calculated for CHBrClNO is 248.5; m / z found is 249.1 [M + H] + .

[0672] Step C: (R)-3-(3-(3-bromo-5-methylphenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. A solution of (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1, 336 mg, 2.41 mmol), 3-bromo-N-hydroxy-5-methyliminobenzyl chloride (600 mg, 2.41 mmol) and TEA (0.99 mL, 7.24 mmol) in DCM (20 mL) was stirred at 25° C. for 16 hours. The reaction mixture was diluted with DCM (80 mL), washed with brine (60 mL), dried over anhydrous NaSO, filtered and concentrated. The residue was purified by preparative TLC (DCM / MeOH=20 / 1) to give (R)-3-(3-(3-bromo-5-methylphenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (0.3 g, 35%) as a yellow oil. MS (ESI): C 15 H 15 The calculated mass of BrN2O3 is 351.2; the measured m / z is 351.0 [M+H] + .

[0673] Step D: (R)-3-hydroxy-1-methyl-3-(3-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. A mixture of bis(pinacolato)diboron (398 mg, 1.57 mmol), (R)-3-(3-(3-bromo-5-methylphenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (275 mg, 0.78 mmol), Pd(dppf)Cl2·CHCl2 (59.6 mg, 0.078 mmol), KOAc (230.5 mg, 2.35 mmol) and 1,4-dioxane (8 mL) was heated at 80°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by FCC (DCM / MeOH=60 / 1) to give (R)-3-hydroxy-1-methyl-3-(3-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (0.3 g, 96%) as a yellow solid. MS (ESI): C 21 H 27 The calculated mass of BN2O5 is 398.3; the found m / z is 399.3 [M+H] + .

[0674] Intermediate 29: (R)-3-hydroxy-1-methyl-3-(3-(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxo- (borolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one .

[0675]

[0676] The title compound was prepared in a manner analogous to (R)-3-hydroxy-1-methyl-3-(3-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one steps AD using 5-bromo-2-methylbenzaldehyde instead of 3-bromo-5-methylbenzaldehyde in step A. MS (ESI): C 21 H 27 The calculated mass of BN2O5 is 398.3; the found m / z is 399 [M+H] + .

[0677] Intermediate 30: (R)-3-hydroxy-1-methyl-3-(3-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxo- (borolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one

[0678]

[0679] The title compound was prepared in a manner analogous to (R)-3-hydroxy-1-methyl-3-(3-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one steps AD using 3-bromo-4-methylbenzaldehyde instead of 3-bromo-5-methylbenzaldehyde in step A. MS (ESI): C 21 H 27 The calculated mass of BN2O5 is 398.3; the found m / z is 399 [M+H] + .

[0680] Intermediate 31: (R)-3-hydroxy-3-(3-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxolane) (boran-2-yl)phenyl)isoxazol-5-yl)-1-methylpyrrolidin-2-one.

[0681]

[0682] The title compound was prepared in a manner analogous to (R)-3-hydroxy-1-methyl-3-(3-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one steps AD using 3-bromo-5-methoxybenzaldehyde instead of 3-bromo-5-methylbenzaldehyde in step A. MS (ESI): C 21 H 27 The calculated mass of BN2O6 is 414.2; the measured m / z is 415.2 [M+H] + .

[0683] Intermediate 32: (R)-3-hydroxy-1-methyl-3-(3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) alkyl-2-yl)furan-2-yl)isoxazol-5-yl)pyrrolidin-2-one.

[0684]

[0685] The title compound was prepared in a manner analogous to (R)-3-hydroxy-1-methyl-3-(3-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one steps AD using 5-bromofuran-2-carbaldehyde instead of 3-bromo-5-methylbenzaldehyde in step A. MS (ESI): C 18 H 23 The calculated mass of BN2O6 is 374.2; the measured m / z is 293 [M-C6H 12 ] + .

[0686] Intermediate 33: (R)-3-(3-(5-(6-chloropyridin-2-yl)furan-2-yl)isoxazol-5-yl)-3-hydroxy-1- Methylpyrrolidin-2-one .

[0687]

[0688] Step A: 5-(6-chloropyridin-2-yl)furan-2-carbaldehyde. To a solution of 2-chloro-6-(furan-2-yl)pyridine (1.8 g, 10 mmol) in THF (40 mL) was added LDA (2N, 6 mL, 12 mmol), and the reaction mixture was stirred at -78 ° C for 1 hour. A solution of DMF (1.5 g, 20 mmol) in THF (5 mL) was added dropwise, and the reaction was stirred at -78 ° C for 2 hours, then diluted with water (50 mL). The mixture was allowed to warm to room temperature and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (2×100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated to dryness and then stirred with petroleum ether (50 mL) and EtOAc (5 mL) for 10 minutes. The solid was separated by filtration to give 5-(6-chloropyridin-2-yl)furan-2-carbaldehyde (1.5 g, 72.0%) as a yellow solid. MS (ESI): C 10 The calculated mass of H6ClNO2 is 207.6; the found m / z is 208 [M+H] + .

[0689] Step B: 5-(6-chloropyridin-2-yl)furan-2-carbaldehyde oxime. To a solution of 5-(6-chloropyridin-2-yl)furan-2-carbaldehyde (1.3 g, 6.26 mmol) in EtOH (100 mL) was added hydroxylamine (50% aqueous solution, 827 mg, 12.52 mmol). The mixture was stirred at 25 ° C for 6 hours and then concentrated to give 5-(6-chloropyridin-2-yl)furan-2-carbaldehyde oxime (1.3 g, 93%) as a yellow solid. MS (ESI): C 10The calculated mass of H7ClN2O2 is 222.6; the found m / z is 223.1 [M+H] + .

[0690] Step C: 5-(6-chloropyridin-2-yl)-N-hydroxyfuran-2-carboximidoyl chloride. To a solution of 5-(6-chloropyridin-2-yl)furan-2-carbaldehyde oxime (500 mg, 2 mmol) in anhydrous DMF (8 mL) was added N-chlorosuccinimide (360 mg, 2.7 mmol) portionwise and the reaction was stirred at 30 ° C for 4 hours. The reaction mixture was concentrated to dryness to give 5-(6-chloropyridin-2-yl)-N-hydroxyfuran-2-carboximidoyl chloride (550 mg, 95%) as a yellow solid, which was used in the next step without further purification. MS (ESI): C 10 The calculated mass of H6Cl2N2O2 is 257.1; the found m / z is 257 [M+H] + .

[0691] Step D: (R)-3-(3-(5-(6-chloropyridin-2-yl)furan-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of 5-(6-chloropyridin-2-yl)-N-hydroxyfuran-2-carboimidoyl chloride (550 mg, 2.14 mmol) in DCM (30 mL) was added (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1, 298 mg, 2.14 mmol) and TEA (648 mg, 6.42 mmol). The mixture was stirred at 25° C. for 16 hours. The mixture was washed with brine (2×50 mL), dried over Na 2 SO 4 and filtered. The filtrate was concentrated and the residue was purified by preparative TLC (UV-254, silica, DCM:MeOH / 20:1) to give (R)-3-(3-(5-(6-chloropyridin-2-yl)furan-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (110 mg, 14%) as a brown oil. MS (ESI): C 17 H 14 The calculated mass of ClN3O4 is 359.8; the found m / z is 360 [M+H] + .

[0692] Intermediate 34: (R,S)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidine- 2-Keto .

[0693]

[0694] The title compound (Step A: 700 mg, 30%; Step B: 1.4 g, 69%) was prepared using similar conditions as described in Steps AB for (R)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one, using (R,S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one in Step A instead of (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one. MS (ESI): C 14 H 13 The calculated mass of BrN2O3 is 337.2, and the measured m / z is 337 [M+H] + .

[0695] Intermediate 35: (R,S)-3-(5-(3-aminophenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidine-2-yl ketone .

[0696]

[0697] Step A: (R,S)-3-(5-(3-((diphenylmethylene)amino)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one. A solution of (R,S)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 34, 260 mg, 0.77 mmol), diphenylformimine (210 mg, 0.16 mmol), cesium carbonate (502 mg, 1.54 mmol), BINAP (72 mg, 0.12 mmol) and palladium(II) acetate (17 mg, 0.12 mmol) in dioxane (8 mL) was heated to 100°C for 16 hours. The reaction mixture was cooled to room temperature, concentrated to dryness, and purified by FCC (DCM:MeOH, 20:1) to give (R,S)-3-(5-(3-((diphenylmethylene)amino)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (200 mg, 59% yield) as a yellow oil. MS (ESI): C 27 H 23 The calculated mass of N3O3 is 437.5; the found m / z is 438 [M+H] + .

[0698] Step B: (R,S)-3-(5-(3-aminophenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one. A solution of (R,S)-3-(5-(3-((diphenylmethylene)amino)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (210 mg, 0.48 mmol) in EtOH (10 mL) was treated with aqueous HCl (2.7 mL, 1 M, 2.7 mmol) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with saturated aqueous NaHCO (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated and purified by preparative TLC (DCM:MeOH, 15:1) to give (R,S)-3-(5-(3-aminophenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (95 mg, 72% yield) as a colorless solid. MS (ESI): C 14 H 15 The calculated mass of N3O3 is 273.1; the measured m / z is 274.2 [M+H] + .

[0699] Intermediate 36: (R,S)-(3-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)benzene Boric acid .

[0700]

[0701] Step A: (R,S)-3-Hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one. The reaction mixture was prepared in a manner analogous to step C of (R)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one, using (R,S)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 34) instead of ( The title compound was prepared to give (R,S)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one as a yellow solid (200 mg, 88% yield). MS (ESI): C 20 H 25 The calculated mass of BN2O5 is 384.2; the measured m / z is 385.2 [M+H] + .

[0702] Step B: (R,S)-(3-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)boronic acid. The title compound was synthesized analogously to (R)-3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenylboronic acid using (R,S)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one to give (R,S)-(3-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)boronic acid (40 mg, 61% yield) as a light yellow solid. MS (ESI): C 14 H 15 The calculated mass of BN2O5 is 302.1; the measured m / z is 303.1 [M+H] + .

[0703] Intermediate 37: (5R,8S)-2-(3-formylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyrimidine 4-pyridinecarboxamide .

[0704]

[0705] Step A: (5R,8S)-2-(3-vinylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyrimidine-4-carboxamide. A mixture of (5R,8S)-2-(3-iodophenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyrimidine-4-carboxamide (350 mg, 0.86 mmol), potassium trifluoro(vinyl)borate (173 mg, 1.23 mmol), tetrakis(triphenylphosphine)palladium(0) (99 mg, 0.086 mmol), Na2CO3 (274 mg, 2.58 mmol), 1,4-dioxane (10 mL) and water (1 mL) was stirred at 85°C under nitrogen for 16 hours. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 20 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The product was purified by preparative TLC (DCM / MeOH=40 / 1, silica, UV=254 nm) to give (5R,8S)-2-(3-vinylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyrimidine-4-carboxamide (250 mg, 82.5%) as a yellow solid. MS (ESI): C 18 H 17 The calculated mass of N3O2 is 307.3; the measured m / z is 308 [M+H] + .

[0706] Step B: (5R,8S)-2-(3-formylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyrimidine-4-carboxamide. To a solution of (5R,8S)-2-(3-vinylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyrimidine-4-carboxamide (250 mg, 0.81 mmol) in t-BuOH (4.5 mL), THF (3.0 mL), and H2O (1.5 mL) was added N-methylmorpholine N-oxide (114.4 mg, 0.98 mmol), followed by OsO4 (10 mg, 0.041 mmol). The reaction mixture was stirred at room temperature for 7 hours, followed by the addition of NaHCO3 (820 mg, 9.76 mmol), NaIO4 (557 mg, 2.60 mmol), and H2O (3 mL). The mixture was stirred for 45 minutes and then poured into a saturated aqueous Na2SO3 solution. The mixture was extracted with diethyl ether. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by preparative TLC (DCM / MeOH=40 / 1, silica, UV=254nm) to give (5R,8S)-2-(3-formylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycycloheptyl[d]pyrimidine-4-carboxamide (200 mg, 80%). MS (ESI): C 17 H 15 The calculated mass of N3O3 is 309; the found m / z is 309.8 [M+H] + .

[0707] Intermediate 38: 2-chloro-7-fluoroquinazoline-4-carboxamide .

[0708]

[0709] Step A: 7-Fluoroquinazoline-2,4(1H,3H)-dione. Aqueous potassium nitrate solution (10 mL, 4.8 M, 48.3 mmol) was added dropwise to a mixture of 2-amino-4-fluorobenzoic acid (5.0 g, 32.2 mmol) in AcOH (3.5 g, 58.0 mmol) and water (20 mL). The reaction mixture was heated to 50°C for 16 hours, and then NaOH (5.1 g, 129 mmol) was added portionwise. Stirring was continued at 50°C for 4 hours, and then concentrated HCl was added. (水溶液) The pH was slowly adjusted to pH <1. The precipitate was isolated by filtration and washed with water to afford 7-fluoroquinazoline-2,4(1H,3H)-dione (2.8 g, 48% yield) as a yellow solid. MS (ESI): mass calculated for C8H5FN2O2: 180.0; m / z found: 212.1 [M+H] + .

[0710] Step B: 2,4-dichloro-7-fluoroquinazoline. A mixture of 7-fluoroquinazoline-2,4(1H,3H)-dione (2.8 g, 15.5 mmol), POCl (10 mL, 107.6 mmol), and DIEA (5.36 mL, 31.1 mmol) was heated at reflux for 4 hours. The reaction mixture was concentrated in vacuo and treated with ice water. The precipitate was isolated by filtration, washed with water, and dried under reduced pressure to give 2,4-dichloro-7-fluoroquinazoline (3.0 g, 89% yield) as a brown solid. MS (ESI): mass calculated for CHClFN: 217; m / z found: 217 [M+H].

[0711] Step C: 2-chloro-4-(1-ethoxyvinyl)-7-fluoroquinazoline. To a solution of 2,4-dichloro-7-fluoroquinazoline (3.0 g, 13.8 mmol) in DMF (26 mL) was added tributyl(1-ethoxyvinyl)stannane (5.0 g, 13.8 mmol) followed by dichlorobis(triphenylphosphine)palladium(II) (0.48 g, 0.69 mmol). The reaction mixture was heated to 60°C for 16 hours, cooled to room temperature and eluted with KF. (水溶液) The mixture was quenched. EtOAc was added, the mixture was filtered, and the filtrate was washed with water and then with brine. The product was purified by FCC (ether: EtOAc, 10: 1) to give 2-chloro-4-(1-ethoxyvinyl)-7-fluoroquinazoline (2.2 g, 63% yield) as a yellow solid. MS (ESI): C 12 H 10 The calculated mass of ClFN2O is 252.1; the found m / z is 253 [M+H] + .

[0712] Step D: 2-chloro-7-fluoroquinazoline-4-carboxylic acid. A solution of 2-chloro-4-(1-ethoxyvinyl)-7-fluoroquinazoline (2.2g, 8.7mmol) in dioxane (20mL) was treated with a solution of sodium periodate (3.7g, 17.4mmol) in water (2mL), followed by KMnO (0.69g, 4.4mmol) and stirred at room temperature for 16 hours. The pH was adjusted to 7-8 with saturated K CO aqueous solution, and the precipitate was removed by filtration and washed with DCM. The filtrate was washed with water, and the organic layer was separated, dried and concentrated under reduced pressure. The product was purified by preparative TLC (ether: EtOAc, 3: 1) to obtain 2-chloro-7-fluoroquinazoline-4-carboxylic acid ethyl ester (900mg, 41%). The pH of the aqueous layer was adjusted to pH 1-3 with a 2M HCl aqueous solution, and extracted with DCM (2×20mL). The organic layer was concentrated to give 2-chloro-7-fluoroquinazoline-4-carboxylic acid (0.26 g, 13% yield) as a yellow solid. MS (ESI): mass calculated for C9H4ClFN2O2: 226; m / z found: 226 [M+H] + .

[0713] Step E: 2-chloro-7-fluoroquinazoline-4-carboxamide. A solution of 2-chloro-7-fluoroquinazoline-4-carboxylic acid (150 mg, 0.66 mmol) in DCM (2 mL) was treated with oxalyl chloride (0.17 mL, 1.98 mmol) and DMF (0.036 mL, 0.47 mmol) at 0 ° C. The solution was stirred for 0.5 hours and then treated with 28% NH3 aqueous solution (0.15 mL, 2.29 mmol) and continued stirring at 0 ° C for 0.5 hours. The mixture was diluted with water (10 mL) and extracted with DCM (3×5 mL). The combined organic extracts were concentrated to give 2-chloro-7-fluoroquinazoline-4-carboxamide (60 mg, 40% yield) as a yellow solid. MS (ESI): The mass calculated value for C9H5ClFN3O is 225.0; the found value of m / z is 226 [M+H] + .

[0714] Intermediate 39: Ethyl 2-chloro-7-fluoroquinazoline-4-carboxylate .

[0715]

[0716] The title compound was prepared in a manner similar to steps AD of 2-chloro-7-fluoroquinazoline-4-carboxamide to give ethyl 2-chloro-7-fluoroquinazoline-4-carboxylate (900 mg, 41%). MS (ESI): C 11 The calculated mass of H8ClFN2O2 is 254.7; the found m / z is 255 [M+H] + .

[0717] Intermediate 40: 6-(tributylstannyl)pyridineamide .

[0718]

[0719] To a solution of 6-bromopicolinamide (0.50 g, 2.49 mmol) in toluene (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.14 g, 0.12 mmol), followed by bis(tributyltin) (2.89 g, 4.96 mmol) and the mixture was heated at 100 ° C for 16 hours. The reaction mixture was cooled to room temperature, concentrated to dryness and purified by preparative TLC (DCM: EtOAC 4: 1) to give 6-(tributylstannyl)picolinamide (0.80 g, 78% yield) as a colorless oil. MS (ESI): C 18 H 32 The calculated mass of N2OSn is 412.2; the found m / z is 413 [M+H] + .

[0720] Intermediate 41: 3-amino-6-(tributylstannyl)picolinamide .

[0721]

[0722] The title compound was synthesized using similar conditions to 6-(tributylstannyl)picolinamide, using 3-amino-6-bromopicolinamide instead of 6-bromopicolinamide to give 3-amino-6-(tributylstannyl)picolinamide (0.11 g, 46% yield) as a colorless oil. MS (ESI): C 18 H 33 The calculated mass of N3OSn is 427.2; the observed m / z is 427.0 [M+H] + .

[0723] Intermediate 42: (R)-3-hydroxy-1-methyl-3-(3-(2-(tributylstannyl)pyridin-4-yl)isoxazole- 5-aminobenzoic acid)pyrrolidin-2-one .

[0724]

[0725] The title compound was synthesized using similar conditions as 6-(tributylstannyl)picolinamide using (R)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 7) instead of 6-bromopyridinamide to afford (R)-3-hydroxy-1-methyl-3-(3-(2-(tributylstannyl)pyridin-4-yl)isoxazol-5-yl)pyrrolidin-2-one (0.25 g, 22% yield) as a brown oil. MS (ESI): C 25 H 39The calculated mass of N3O3Sn is 549.2; the found m / z is 550.0 [M+H] + .

[0726] Intermediate 43: (R)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidine-2-yl ketone .

[0727]

[0728] Step A. (E) -6- bromopyridinecarbaldehyde oxime. At room temperature, 6- bromopyridine -2- carboxaldehyde (40g, 215mmol), EtOH (600mL) and NH2OH HCl (17.93g, 258.05mmol) were added to a 1L 3-neck round-bottom flask. Sodium acetate (35.28g, 430.09mmol) was added portionwise to the above mixture at 0°C. The resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The mixture was acidified to pH=7 with saturated NaHCO3 aqueous solution (100mL). The resulting mixture was extracted with EtOAc (2 × 100mL). The combined organic extracts were washed with brine (1 × 150mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by grinding with hexane (80mL). The precipitated solid was collected by filtration and washed with hexane to give the title compound (39 g, 90%) as a white solid.

[0729] Step B. (Z) -6- bromo -N- hydroxypyridinylmethyl iminoyl chloride. To a 2L 4-neck round-bottom flask was added (E) -N- [(6- bromopyridin-2-yl) methylene] hydroxylamine (39g, 194mmol) and DMF (1L) at room temperature. To the above mixture was added NCS (31.09g, 232.8mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The pH of the mixture was then adjusted to pH = 7 with TFA (5L, 1M). The resulting mixture was extracted with MTBE (2 × 1L). The combined organic extracts were washed with brine (1 × 1L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by trituration with hexane (80mL). The precipitated solid was collected by filtration and washed with hexane to give the title compound (41.2607g, 90.19%) as a white solid. LC-MS (ESI): mass calculated for C6H4BrClN2O: 233.9; m / z found: 235 [M+H] + . 1H NMR (300MHz, DMSO-d6) δ12.89(s,1H),7.91(d,J=7.7,1.2Hz,1H),7.85(t,J=7.6Hz,1H),7.76(d,J=7.6,1.2Hz,1H).

[0730] Step C. (R)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (90.0 g, 646.78 mmol, intermediate 1) and (Z)-6-bromo-N-hydroxypyridinylmethylimidoyl chloride (609 g, 2.59 mol) in EtOAc (900 mL) and H O (450 mL) was added NaHCO (326 g, 3.88 mol in 150 mL H O). The mixture was stirred at 25° C. for 24 hours, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate=1 / 0 to 0 / 1). The product was triturated with EtOH (4000 mL) at 25° C. for 12 hours. The above procedure was repeated 4 times. The obtained product was triturated with petroleum ether:ethyl acetate=1:1 (2000 mL) at 25°C for 12 hours and repeated twice to obtain the title compound (490 g, 50.4%) as a white solid. LC-MS (ESI): C 13 H 12 The calculated mass of BrN3O3 is 337.01; the measured m / z is 340.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.04(d,J=7.5Hz,1H),7.92(t,J=7.8Hz,1H),7.79(d,J=7.9Hz,1H),6.94(s,1H),6.77( s,1H),3.52-3.38(m,2H),2.83(s,3H),2.59(ddd,J=4.9,7.8,13.2Hz,1H),2.27(ddd,J=5.8,7.9,13.5Hz,1H).

[0731] Intermediate 44: (R)-3-ethynyl-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one .

[0732]

[0733] Step A. (3E) -1- methyl -3- [(1- phenylethyl) imino] pyrrolidin-2-one. To a 20L 4-neck round-bottom flask was added 1- methylpyrrolidine -2,3- dione (346g, 3060mmol), MgSO4 (368g, 3060mmol) and DCM (7L). Thereto were added (+ / -) -α- methylbenzylamine (389.21g, 3211.74mmol) and TFA (0.2mL). The resulting mixture was stirred at 40 ° C under a nitrogen atmosphere overnight. The mixture was allowed to cool to room temperature. The solid was filtered out and washed with DCM (1×1L). The filtrate was collected and concentrated under reduced pressure. The product was slurried with ether (1.5L). The solid was collected by filtration to give (3E) -1- methyl -3- [(1- phenylethyl) imino] pyrrolidin-2-one (540g) as a purple solid. 1 H NMR (300MHz, DMSO-d6) δ7.39-7.08(m,5H),5.41(d,J=7.0Hz,1H),4.88(t,J=2.4H z,1H),4.30-4.13(m,1H),3.76-3.52(m,2H),2.89(s,3H),1.40(d,J=6.8Hz,3H).

[0734] Step B.4,4-difluoro-3,3-dihydroxy-1-methylpyrrolidin-2-one. To a 10 L 4-neck round-bottom flask was added (3E)-1-methyl-3-[(1-phenylethyl)imino]pyrrolidin-2-one (540 g, 2496.71 mmol), Na2SO4 (511 g, 3600 mmol) and acetonitrile (5.4 L). Select-F (1946 g, 5493 mmol) was added portionwise at 0 ° C. The reaction mixture was stirred at room temperature overnight, and then acetonitrile (5.4 L) was added. HCl (4N, 936 mL) in 1,4-dioxane was added dropwise to the mixture at 0 ° C. The resulting mixture was stirred at room temperature for another 1 hour. The resulting precipitate was filtered and washed with acetonitrile (1×2 L). The filtrate was concentrated under vacuum. The filtration and concentration were repeated 2 more times. The residue was purified by DAC using a C18 column (CH3CN / H2O (0.1% NH4HCO3) = 1% to 15% in 17 minutes) to give 4,4-difluoro-3,3-dihydroxy-1-methylpyrrolidin-2-one (122 g, 23.9% of step A and step B) as an off-white solid. 1 H NMR (300MHz, DMSO-d6) δ7.29 (s, 2H), 3.65 (t, J = 12.0Hz, 2H), 2.80 (s, 3H).

[0735] Step C. (3R)-3-ethynyl-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one. To a 5L 4-neck round-bottom flask was added 4,4-difluoro-3,3-dihydroxy-1-methylpyrrolidin-2-one (122 g, 730.04 mmol), DMF (2440 mL), K2CO3 (10.09 g, 73.00 mmol), trimethylsilylacetylene (143 g, 1460 mmol) and Cu(OAc)2 (26.52 g, 146.01 mmol) at room temperature under N2 atmosphere. The resulting mixture was stirred at 50 °C overnight. The mixture was cooled to room temperature, quenched by the addition of MeOH (500 mL) at room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1 to 1:1) to give (R,S)-3-ethynyl-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one (97 g, 75%) as a yellow solid. The (R) and (S) enantiomers of 3-ethynyl-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one (97 g and 6.2 g synthesized separately) were separated by chiral preparative SFC ( IC-3 (50×4.6 mm), 80% hexanes with 0.1% DEA:20% EtOH) was separated to provide (3R)-3-ethynyl-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one (45.6 g, 88%) as an off-white solid as the first-eluting enantiomer. LC-MS (ESI): mass calculated for C7H7F2NO2: 175.0; m / z found: 176 [M+H] + . 1 HNMR(300MHz,DMSO-d6)δ7.43(s,1H),3.84-3.80(m,3H),2.82(s,3H).

[0736] Intermediate 45: (3R,5S)-3-ethynyl-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one .

[0737]

[0738] Step A.4,4,4-trifluoro-3-(methylamino)butanoic acid ethyl ester To a solution of (E)-4,4,4-trifluorobut-2-enoic acid ethyl ester (4400 g, 26.17 mol, 3.89 L) in THF (18.0 L) was added MeNH2 (3330 g, 32.17 mol, 30% purity). The light yellow solution was stirred at 25 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure to give the product as a yellow liquid (4.64 kg, 89%), which was used in the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.08-4.26 (m, 2H), 3.40-3.56 (m, 1H), 2.61-2.68 (m, 1H), 2.51-2.55 (m, 3H), 2.41-2.50 (m, 1H), 1.22-1.29 (m, 3H).

[0739] Step B.4-hydroxy-1-methyl-5-oxo-2-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester. At 25 ° C under N2 atmosphere, to a solution of 4,4,4-trifluoro-3-(methylamino)butanoic acid ethyl ester (2400g, 12.05mol) in 2-MeTHF (24000mL) was added t-BuOK (1.35kg, 12.05mol) and diethyl oxalate (1.76kg, 12.05mol, 1.65L). Under N2 atmosphere, the reaction mixture was heated at 60 ° C for 3 hours. At 25 ° C, the reaction mixture was quenched by adding NH4Cl (saturated aqueous solution, 10.0L). Then, the pH of the mixture was adjusted to pH=2-3 with 1M HCl aqueous solution (9.00L), and the resulting mixture was extracted twice with EtOAc (5.00L). The combined organic extracts were washed with brine (15.0 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (DCM / MeOH 0% to 3%) to give the title compound (4.20 kg, 16.59 mol, 68.8%) as a brown oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.63 (q, J = 5.0 Hz, 1H), 4.24-4.42 (m, 4H), 3.10-3.14 (m, 3H), 1.19-1.26 (m, 2H).

[0740] Step C. 1-Methyl-5-(trifluoromethyl)pyrrolidine-2,3-dione. A mixture of ethyl 4-hydroxy-1-methyl-5-oxo-2-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylate (2000 g, 7.90 mol) in HCl (10.96 kg, 108.23 mol, 10.75 L, 36% solution) was heated at 110°C for 16 hours. The reaction mixture was cooled to 20°C and extracted with isopropyl acetate (5000 mL x 8). The combined organic extracts were washed with brine (10000 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (5000 mL) at 25°C for 3 hours. The solid was filtered, washed with MTBE (1000 mL), and dried under high vacuum to give the title compound (1.15 kg, 6.35 mol, 40.2%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.28-4.42 (m, 1H), 3.28 (s, 3H), 2.87-3.01 (m, 1H), 2.71-2.83 (m, 1H).

[0741] Step D. 3-Hydroxy-1-methyl-5-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)pyrrolidin-2-one. To a solution of trimethylsilyl acetylene (1.21 kg, 12.3 mol, 1.71 L) in THF (5400 mL) was added n-BuLi (2.5 M, 4.95 L) dropwise at -70°C to -60°C over 30 minutes, and the mixture was stirred at -70°C to -60°C for 1 hour. 1-Methyl-5-(trifluoromethyl)pyrrolidine-2,3-dione (1120 g, 6.18 mol) in THF (9000 mL) was added dropwise to the mixture at -70°C to -60°C over 30 minutes. The black solution was stirred at -70°C to -60°C for 2 hours. The reaction mixture was added dropwise to NH4Cl (saturated aqueous solution, 10000 mL) at 0°C, and the pH of the mixture was adjusted to pH = 5 with 2M HCl aqueous solution (5000 mL) and the aqueous solution was extracted with EtOAc (5000 mL × 3). The combined organic extracts were washed with 5000 mL of brine, dried over Na2SO4, filtered and evaporated to dryness. The title compound (1.50 kg, 86%) was obtained as a red solid and used without further purification. 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.08-4.16 (m, 1H), 2.96-3.06 (m, 3H), 2.72-2.82 (m, 1H), 2.22-2.35 (m, 1H), 0.08-0.21 (m, 8H).

[0742] Step E. (3R,5S)-3-ethynyl-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one. 3-Hydroxy-1-methyl-5-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)pyrrolidin-2-one (1500 g, 5.37 mol) was dissolved in MeOH (10.0 L), and KCO (742 g, 5.37 mol) was added. The black mixture was stirred at 25° C. for 1 hour. The reaction mixture was filtered and the filter cake was washed with CHCl (4000 mL) and poured into water (3000 mL). The organic phase was separated, and the aqueous phase was extracted with CH2Cl2 (3000 mL×2). The combined organic extracts were washed with water (2000 mL) and brine (2000 mL), dried over Na2SO4, and concentrated to dryness under reduced pressure to give a mixture of (3R,5S)-3-ethynyl-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one and (3S,5R)-3-ethynyl-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one. The mixture was purified by column chromatography (PE:EA=10:1 to 3:1) to give a mixture of diastereomers (635 g, 55%, 97.8% purity). Then (3R,5S)-3-ethynyl-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one and (3S,5R)-3-ethynyl-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one were separated by SFC (column: DAICEL AD (250 mm × 50 mm, 10 μm); mobile phase: [0.1% NH 3. H2O EtOH]; B%: 20%-20%, min) to afford the title compound, (3R,5S)-3-ethynyl-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one, as the first eluting peak as a yellow solid (95.0 g, 45.7%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.97-4.08 (m, 1H), 3.03 (d, J = 1.0 Hz, 3H), 2.80 (dd, J = 13.6, 7.5 Hz, 1H), 2.62 (s, 1H), 2.33 (dd, J = 13.7, 7.2 Hz, 1H), 1.23-1.28 (m, 1H).

[0743] Intermediate 46: (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d4 .

[0744]

[0745] Step A: 1-methylpyrrolidin-2-one-3,3,4,4,5,5-d6. NaH (60% in mineral oil, 52g, 1302mmol) is placed in a 1000mL 3-neck round-bottom flask purged and maintained with a nitrogen atmosphere. THF (400mL) is added and the mixture is cooled to 0°C. Pyrrolidin-2-one-3,3,4,4,5,5-d6 (39.5g, 434mmol) is added thereto at 0°C. The resulting solution is stirred at 0°C for 20 minutes, and then iodomethane (184g, 1302mmol) is added dropwise at 0°C. The resulting solution is slowly warmed to room temperature and stirred for 3.5 hours. The resulting solution was poured into ice water (800 mL) and extracted with DCM (15×400 mL). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford 1-methylpyrrolidin-2-one-3,3,4,4,5,5-d6 (67.6 g) as a yellow oil. LC-MS (ESI): mass calculated for C5H3D6NO was 105.1, m / z found was 106 [M+H] + .

[0746] Step B: 3-benzoyl-1-methylpyrrolidin-2-one-4,4,5,5-d4. To a 2000mL 3-neck round-bottom flask purged and maintained with a nitrogen atmosphere, NaH (60% in mineral oil, 26g, 651mmol), toluene (900mL) and methanol (1.82mL) were added. A mixture solution of 1-methylpyrrolidin-2-one-3,3,4,4,5,5-d6 (67.6g, 434mmol) and methyl benzoate (65g, 477mmol) was added dropwise at room temperature. The resulting solution was heated at 110°C overnight. Thereafter, the reaction mixture was cooled to 0°C and HOAc (39g, 651mmol) and water (24g, 1302mmol) were added. After 10 minutes, water was added and the reaction mixture was extracted with 3×600mL of DCM. The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified by silica gel chromatography (eluent: PE / EtOAc, 10 / 1 to 3 / 1). This resulted in 70.5 g (78% of steps A and B) of 3-benzoyl-1-methylpyrrolidin-2-one-4,4,5,5-d4 as a yellow oil. LC-MS (ESI): C 12 The calculated mass of H9D4NO2 is 207.1; the measured m / z is 208 [M+H] + .

[0747] Step C: 3-benzoyl-3-ethynyl-1-methylpyrrolidin-2-one-4,4,5,5-d4. 3-Benzoyl-1-methylpyrrolidin-2-one-4,4,5,5-d4 (70.5 g, 340 mmol) and THF (anhydrous, 1200 mL) are placed in a 2000 mL 4-neck round-bottom flask with a mechanical stirrer purged and maintained with a nitrogen atmosphere. The resulting mixture is cooled to -78 ° C, and 1-((trimethylsilyl)ethynyl)-1λ3-benzo[d][1,2]iodophenol-3(1H)-one (175 g, 510 mmol) is added in one go, and the reaction mixture is stirred at -78 ° C for 10 minutes. TBAF (1 M in THF, 510 mL, 510 mmol) is added dropwise at -78 ° C. The resulting solution was stirred at -70 ° C for 2 hours and then warmed to room temperature for another 2 hours. The resulting mixture was quenched with saturated aqueous NH4Cl solution, extracted with 3×600 mL EtOAc and the organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by silica gel chromatography (PE / EtOAc, 10 / 1 to 5 / 1) to give 53.8 g (62%) of 3-benzoyl-3-ethynyl-1-methylpyrrolidin-2-one-4,4,5,5-d4 as a yellow oil. LC-MS (ESI): C 14 The calculated mass of H9D4NO2 is 231.1; the measured m / z is 232 [M+H] + .

[0748] Step D: 3-ethynyl-1-methyl-2-oxopyrrolidin-3-yl-4,4,5,5-d4 benzoate. 3-Benzoyl-3-ethynyl-1-methylpyrrolidin-2-one-4,4,5,5-d4 (53.8 g, 233 mmol), DCM (3000 mL), KHCO3 (116 g, 1165 mmol) and m-CPBA (236 g, 1165 mmol) were placed in a 5000 mL 4-neck round-bottom flask with a mechanical stirrer. The resulting mixture was stirred at room temperature overnight. The reaction mixture was then quenched with saturated NaHCO3 aqueous solution, stirred for 1 hour, extracted with 2 × 1000 mL DCM and the organic extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by silica gel chromatography (PE / EtOAc, 10 / 1 to 3 / 1) to give 27 g (47%) of 3-ethynyl-1-methyl-2-oxopyrrolidin-3-yl-4,4,5,5-d4 benzoate as a yellow solid. LC-MS (ESI): C 14 The calculated mass of H9D4NO3 is 247.1; the found m / z is 248 [M+H] + .

[0749] Step E: 3-Ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d4. 3-Ethynyl-1-methyl-2-oxopyrrolidin-3-yl-4,4,5,5-d4 benzoate (27 g, 109 mmol) and THF (270 mL) were placed in a 1000 mL 4-necked round-bottom flask and the mixture was cooled to 0°C. A solution of LiOH-H2O (13.8 g, 327 mmol) in H2O (270 mL) was added at 0-10°C and the reaction mixture was stirred at room temperature for 5 hours. The mixture was then cooled to 0°C, the pH was adjusted to pH = 7 with 1M aqueous HCl, and the reaction mixture was concentrated under reduced pressure. The product was purified by silica gel chromatography (DCM / MeOH, 300 / 1 to 100 / 1) to give 15.1 g (87%) of 3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d4 as a yellow solid. LC-MS (ESI): mass calculated for C7H5D4NO2: 143.1; m / z found: 144 [M+H] + .

[0750] Step F: (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d4. The (R) and (S) enantiomers of 3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d4 were separated by SFC (column: 1H, 3×25 cm, 5 μm; mobile phase A: CO 2 , mobile phase B: IPA (0.5% 2M NH 3 -MeOH); flow rate: 100 mL / min; gradient: 10% B; column temperature: 35° C.; back pressure: 100 bar; 220 nm; RT1: 3.62; RT2: 4.82). The first eluting peak is (S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d4, and the second eluting peak is (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d4. (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d4 was then slurried with MTBE (60 mL), and the solid was filtered and collected. The filter cake was washed with MTBE and the filtrate was concentrated to give 6.46 g (79%) of (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d4 as a white solid. LC-MS (ESI): mass calculated for C7H5D4NO2: 143.1; m / z found: 144 [M+H] + .

[0751] Intermediate 47: (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) alkyl-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one-4,4,5,5-d4 .

[0752]

[0753] Step A. (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d4. To a microwave vial containing (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d4 (intermediate 46, 250 mg, 1.75 mmol) and (Z)-3-bromo-N-hydroxyiminobenzyl chloride (409 mg, 1.75 mmol) was added DCM (11 mL) followed by EtN (0.73 mL). The vial was sealed and the resulting homogeneous mixture was stirred at room temperature. After ~10 minutes, a white suspension was produced and after 3.5 hours, the reaction was judged complete by TLC. The contents were filtered through a pad of celite and rinsed with DCM. The colorless eluent was concentrated to give the product as an off-white solid. The material was redissolved in CHCl3-MeOH, and Celite (3 g) was added and concentrated to dryness. The material was purified by FCC (using 100% DCM increasing to 5% MeOH-DCM) to give the title compound as a light yellow solid (405 mg, 67%) after drying. MS (ESI): C 14 H 13 The calculated mass of BrN2O3 is 341.2; the measured m / z is 342.2 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.87 (t, J = 1.8 Hz, 1H), 7.63 (dt, J = 7.9, 1.3 Hz, 1H), 7.54 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 6.64 (s, 1H), 4.25 (s, 1H), 2.99 (s, 3H).

[0754] Step B. (R)-3-Hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one-4,4,5,5-d4. To a microwave vial was added (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d4 (400 mg, 1.17 mmol), bis(pinacolato)diboron (416.8 mg, 1.64 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (92.2 mg, 0.12 mmol), KOAc (460 mg, 4.69 mmol), and 1,4-dioxane (21 mL, degassed with nitrogen for 20 minutes prior to use). The vial was sealed and evacuated / purged with nitrogen, then placed in an aluminum heating mantle at 110°C. After 2.5 hours, the reaction mixture was filtered through a celite pad (while still warm) and rinsed with EtOAc and THF, and the effluent was concentrated to give an orange viscous oil. The substance was dissolved in EtOAc and purified by FCC (using 100% hexane to increase to 100% EtOAc) to give the title compound (223 mg, 49%) as an off-white solid. MS (ESI): C 20 H 25 The calculated mass of BN2O5 is 388.3; the measured m / z is 339.3 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.15 (t, J = 1.5 Hz, 1H), 7.89 (ddt, J = 18.6, 7.4, 1.4 Hz, 2H), 7.44 (t, J = 7.6 Hz, 1H), 6.74 (s, 1H), 3.72 (d, J = 12.3 Hz, 1H), 2.99 (s, 3H), 1.36 (s, 12H).

[0755] Intermediate 48: (3R,5S)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxetane (pentaboran-2-yl)phenyl)isoxazol-5-yl)-5-(trifluoromethyl)pyrrolidin-2-one .

[0756]

[0757] Step A. (3R, 5S) -3- (3- (3- bromophenyl) isoxazol -5- bases) -3- hydroxy -1- methyl -5- (trifluoromethyl) pyrrolidin -2- one. To a 50mL flask containing (3R, 5S) -3- ethynyl -3- hydroxy -1- methyl -5- (trifluoromethyl) pyrrolidin -2- one (intermediate 45, 500mg, 2.41mmol) and (Z) -3- bromo -N- hydroxy imino benzyl chloride (566mg, 2.41mmol) was added DCM (15mL), followed by EtN (1mL). The flask was kept under nitrogen and the resulting homogeneous mixture was stirred at room temperature. After 24 hours, the reaction was judged to be complete by TLC. The contents were filtered through a diatomaceous earth pad and rinsed with DCM. The colorless eluent was concentrated to give the product as a pale solid. The product was dissolved in CHCl3-MeOH (3 g) containing celite, concentrated and purified by FCC (100% hexanes increasing to 100% EtOAc) to give the title compound as an off-white amorphous solid (815 mg, 83.0%) after drying. MS (ESI): C 15 H 12 The calculated mass of BrF3N2O3 is 405.2; the measured m / z is 406.0 [M+H] + . 1 H NMR (500 MHz, CHLOROFORM-d) δ 7.88 (t, J = 1.8 Hz, 1H), 7.65 (ddd, J = 7.8, 1.6, 1.0 Hz, 1H), 7.57 (ddd, J = 8.1, 2.0, 1.0 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 6.70 (s, 1H), 4.35-4.20 (m, 1H), 4.10-3.98 (m, 1H), 3.09 (q, J = 1.2 Hz, 3H), 3.06-2.93 (m, 2H), 2.48 (dd, J = 14.2, 6.8 Hz, 1H).

[0758] Step B. (3R,5S)-3-Hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)-5-(trifluoromethyl)pyrrolidin-2-one. To a microwave vial was added (3R,5S)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one (400 mg, 0.99 mmol), bis(pinacolato)diboron (351 mg, 1.38 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (77 mg, 0.099 mmol), KOAc (387.5 mg, 3.95 mmol), and 1,4-dioxane (18 mL, degassed with nitrogen for 20 minutes before use). The vial was sealed and evacuated / purged with nitrogen, then placed in an aluminum heating mantle at 110°C. After 4 hours, the reaction mixture was filtered through a pad of celite (while still warm) and rinsed with EtOAc and THF, and the mixture was concentrated to give a slightly brown viscous oil. This material was dissolved in EtOAc and purified by FCC (using 100% hexane to increase progressively to 100% EtOAc) to give the title compound (404 mg, 90.0%) as a viscous amber gum. This title compound solidified into an amorphous solid under vacuum, but was not completely pure and used as is by HPLC analysis. MS (ESI): C 21 H 24 The calculated mass of BF3N2O5 is 452.2; the found m / z is 453.3 [M+H] + .

[0759] Intermediate 49: (R)-3-ethynyl-3-hydroxy-1-(methyl-d3)pyrrolidin-2-one .

[0760]

[0761] Step A: 4-((tert-Butyloxycarbonyl)amino)-2-hydroxybutanoic acid. Into a 5 L, 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-amino-2-hydroxybutanoic acid (200 g, 1.67 mol) in water (1 L). KCO (695 g, 4.99 mol) was then added in several portions at 0°C. To this mixture was added dropwise a solution of di-tert-butyl dicarbonate (436 g, 2 mol) in dioxane (1 L) with stirring at 0°C. The resulting solution was stirred at 20°C to 25°C for 24 hours. The resulting mixture was washed with petroleum ether (1 L x 2). The combined aqueous phases were cooled to 0°C using a water / ice bath and adjusted to pH 4-5 with aqueous HCl (6 N). The resulting solution was extracted with ethyl acetate (1 L x 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give 4-((tert-butoxycarbonyl)amino)-2-hydroxybutanoic acid (260 g, 71%) as a yellow oil.

[0762] Step B: Methyl 4-((tert-Butoxycarbonyl)amino)-2-hydroxybutanoate. Into a 5 L, 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-[[(tert-Butoxy)carbonyl]amino]-2-hydroxybutanoic acid (260 g, 1.19 mol) in N,N-dimethylformamide (2.5 L) and Cs2CO3 (503 g, 1.54 mol). After 10 min, iodomethane (202 g, 1.42 mol) was added dropwise to the mixture with stirring at room temperature. After 4.5 h, the mixture was poured into water / ice (2 L) and extracted with ethyl acetate (2 L x 2). The combined organic extracts were washed with brine (1 L x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. This afforded methyl 4-((tert-butoxycarbonyl)amino)-2-hydroxybutanoate (180 g, 65%) as a yellow oil.

[0763] Step C: Methyl 4-((tert-butoxycarbonyl)amino)-2-((tert-butyldimethylsilyl)oxy)butanoate. Into a 5 L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of methyl 4-[[(tert-butoxy)carbonyl]amino]-2-hydroxybutanoate (180 g, 0.77 mol) in dichloromethane (1.8 L) and imidazole (108 g, 1.54 mol). tert-Butyl(chloro)dimethylsilane (231 g, 1.53 mol) was then added in several portions at 0° C. The resulting solution was warmed to RT and stirred for 16 h. Thereafter, the mixture was poured into water / ice (1 L) and extracted with dichloromethane (1.5 L×3). The combined organic extracts were washed with brine (1 L), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified by FCC (1:10, ethyl acetate / petroleum ether) to give methyl 4-((tert-butoxycarbonyl)amino)-2-((tert-butyldimethylsilyl)oxy)butanoate (200 g, 75%) as a pale yellow oil.

[0764] Step D: Methyl 4-((tert-Butoxycarbonyl)(methyl-d3)amino)-2-((tert-butyldimethylsilyl)oxy)butanoate. Into a 1 L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed methyl 4-[[(tert-Butoxy)carbonyl]amino]-2-[(tert-Butyldimethylsilyl)oxy]butanoate (50.0 g, 144 mmol), N,N-dimethylformamide (500 mL) and CD3I (62.6 g, 432 mmol). The resulting solution was cooled to 0°C, and sodium hydride (8.60 g, 358 mmol, 60% in mineral oil) was added in several portions at 0°C. After 2 hours at 0°C, the mixture was poured into saturated aqueous NH4Cl solution (250 mL). The resulting mixture was extracted with ethyl acetate (500 mL x 2). The combined organic extracts were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The above procedure (Step D) was repeated 3 times to give methyl 4-((tert-butoxycarbonyl)(methyl-d3)amino)-2-((tert-butyldimethylsilyl)oxy)butanoate (200 g, 95%) as a light yellow oil.

[0765] Step E: Methyl 4-((tert-butoxycarbonyl)(methyl-d3)amino)-2-hydroxybutanoate. Into a 3 L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed methyl 4-((tert-butoxycarbonyl)(methyl-d3)amino)-2-((tert-butyldimethylsilyl)oxy)butanoate (200 g, 549 mmol), methanol (2 L) and amine hydrofluoride (204 g, 5.51 mol). The resulting solution was heated at 50° C. After 12 h, the resulting solution was cooled to RT, concentrated to dryness, and diluted with water (1 L). The resulting mixture was extracted with ethyl acetate (1 L×3). The combined organic extracts were washed with brine (1 L), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. This afforded methyl 4-((tert-butoxycarbonyl)(methyl-d3)amino)-2-hydroxybutanoate (137 g) as a light yellow oil which was used in the next step without further purification.

[0766] Step F: Methyl 4-((tert-butoxycarbonyl)(methyl-d3)amino)-2-oxobutanoate. A 3 L 3-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with methyl 4-((tert-butoxycarbonyl)(methyl-d3)amino)-2-hydroxybutanoate (137 g, 547 mmol), dichloromethane (1.4 L) and 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benzidoyl-3-(1H)-one (Dess-Martin periodinane, 348 g, 821 mmol) at 5 ° C. The resulting mixture was stirred at room temperature for 3 hours. Thereafter, the mixture was poured into aqueous sodium bicarbonate solution (2 L). The resulting solid was filtered off and the filtrate was extracted with dichloromethane (1.5 L×3). The combined organic extracts were washed with brine (1 L), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified by FCC (1:3, ethyl acetate / petroleum ether) to give methyl 4-((tert-butoxycarbonyl)(methyl-d3)amino)-2-oxobutanoate (81 g, 60%) as a yellow oil. 1 H NMR (300MHz, CDCl3) δ3.90 (s, 3H), 3.56 (t, J = 6.6 Hz, 2H), 3.08 (t, J = 6.6 Hz, 2H), 1.48 (s, 9H).

[0767] Step G: methyl 2-(2-((tert-butoxycarbonyl)(methyl-d3)amino)ethyl)-2-hydroxybut-3-ynoate. Into a 1L 3-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of methyl 4-((tert-butoxycarbonyl)(methyl-d3)amino)-2-oxobutanoate (20 g, 81 mmol) in THF (0.2 L). The solution was cooled to -78°C, followed by the dropwise addition of bromo(ethynyl)magnesium (274 mL, 138 mmol). The resulting solution was stirred at -40°C. After 2 hours, saturated aqueous NH4Cl solution (100 mL) was added dropwise at -70°C. The resulting mixture was then slowly warmed to room temperature and extracted with ethyl acetate (800 mL×3). The combined organic extracts were washed with brine (800 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The above procedure (Step G) was repeated 3 times and the combined residues gave methyl 2-(2-((tert-butoxycarbonyl)(methyl-d3)amino)ethyl)-2-hydroxybut-3-ynoate (82 g) as a yellow oil.

[0768] Step H: Methyl 2-hydroxy-2-(2-((methyl-d3)amino)ethyl)but-3-ynoate as trifluoroacetate. Into a 1 L 3-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of methyl 2-(2-((tert-butoxycarbonyl)(methyl-d3)amino)ethyl)-2-hydroxybut-3-ynoate (70.0 g, 255 mmol), dichloromethane (420 mL) and trifluoroacetic acid (140 mL). The resulting solution was stirred at RT for 1 h. The resulting mixture was concentrated to dryness and used directly in the next step without further purification.

[0769] Step I: (R)-3-ethynyl-3-hydroxy-1-(methyl-d3)pyrrolidin-2-one. Into a 1 L 3-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of methyl 2-hydroxy-2-(2-((methyl-d3)amino)ethyl)but-3-ynoate (70.0 g, 243 mmol), methanol (700 mL) and potassium carbonate (133 g, 964 mmol) as trifluoroacetate. The resulting solution was stirred at room temperature for 3 hours. The resulting solid was filtered off and the filtrate was concentrated to dryness. The resulting residue was purified by FCC (1:5, ethyl acetate / petroleum ether) and then recrystallized from diethyl ether (100 mL) to give racemic 3-ethynyl-3-hydroxy-1-(methyl-d3)pyrrolidin-2-one (16 g, 46%) as a yellow solid. The material was prepared by chiral SFC ( Further purification using AS-H, 5×25 cm, 5 μm; mobile phase, CO₂ (80%) and IPA (0.1% DEA) (20%); detector, UV = 220 nm at 25°C) afforded (R)-3-ethynyl-3-hydroxy-1-(methyl-d₃)pyrrolidin-2-one (5.4 g, 34%, >97% ee) as a brown solid and (S)-3-ethynyl-3-hydroxy-1-(methyl-d₃)pyrrolidin-2-one (5.2 g, 33%, >97% ee) as a brown solid. Data for (R)-3-ethynyl-3-hydroxy-1-(methyl-d₃)pyrrolidin-2-one: MS (ESI): mass calculated for CₐH₆D₃NO₂: 142.1; m / z found: 143.2 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 3.41-3.38 (t, J = 5.2 Hz, 2H), 3.03 (s, 1H), 2.48-2.43 (m, 1H), 2.24-2.17 (m, 1H). (S)-3-ethynyl-3-hydroxy-1-(methyl-d3)pyrrolidin-2-one data: MS (ESI): Mass calculated for C7H6D3NO2: 142.08; m / z found: 143.2 [M+H]. + . 1 H NMR (400MHz, CD3OD) δ3.41-3.38 (t, J = 5.2Hz, 2H), 3.03 (s, 1H), 2.48-2.43 (m, 1H), 2.24-2.17 (m, 1H).

[0770] Intermediate 50: (R)-3-hydroxy-1-(methyl-d3)-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxepin (2-Borolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one .

[0771]

[0772] Step A. (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-(methyl-d3)pyrrolidin-2-one. To a vial containing (R)-3-ethynyl-3-hydroxy-1-(methyl-d3)pyrrolidin-2-one (intermediate 49, 500 mg, 3.52 mmol) and (Z)-3-bromo-N-hydroxyiminobenzyl chloride (800 mg, 3.41 mmol) was added DCM (22 mL) followed by Et3N (1.5 mL). The flask was sealed and the homogeneous mixture was stirred at room temperature. After 24 hours, the contents were filtered through a pad of celite and rinsed with DCM. The mixture was concentrated to give the product as a viscous orange gum. The product was dissolved in DCM (40 mL), water (20 mL) was added and the layers were separated. The aqueous portion was back extracted three times with CHCl 3 (10 mL) and the combined organic extracts were dried over MgSO 4 , filtered and concentrated to give an orange oil which was purified by FCC (100% DCM increasing to 5% MeOH-DCM) to give the title compound as a hygroscopic semisolid (810 mg, 67%), MS (ESI): C 14 H 13 The calculated mass of BrN2O3 is 340.2, and the measured m / z is 341.7 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.87 (t, J = 1.8 Hz, 1H), 7.69-7.47 (m, 2H), 7.27 (t, J = 7.9 Hz, 2H), 6.67 (s, 1H), 4.66 (s, 1H), 3.76 (s, 1H), 3.60-3.67 (m, 1H), 3.57-3.27 (m, 2H), 2.72-2.77 (m, 1H), 2.59-2.38 (m, 2H), 2.25-2.33 (m, 1H).

[0773] Step B. (R)-3-Hydroxy-1-(methyl-d3)-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. To a 50 mL flask containing (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-(methyl-d3)pyrrolidin-2-one (800 mg, 2.35 mmol) was added bis(pinacolato)diboron (836 mg, 3.29 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (185 mg, 0.24 mmol), KOAc (923 mg, 9.41 mmol), and 1,4-dioxane (42 mL, degassed with nitrogen for 20 minutes before use). The flask was equipped with a reflux condenser and evacuated / purged with nitrogen, then placed in an aluminum heating mantle at 105°C. After 4.5 hours, TLC (20% EtOAc-DCM) indicated the reaction was complete. The mixture was filtered through a pad of celite (while still warm) and rinsed with EtOAc and THF, and the filtrate was concentrated to give a slightly brown viscous oil. The substance was dissolved in EtOAc and purified by FCC (100% hexane increasing to 100% EtOAc) to give the title product (211 mg, 23%) as an amber amorphous solid. MS (ESI): C 20 H 25 The calculated mass of BN2O5 is 387.3; the measured m / z is 388.3 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.15 (d, J = 1.6 Hz, 1H), 7.85-7.94 (m, 2H), 7.44 (t, J = 7.6 Hz, 1H), 6.74 (s, 1H), 3.68-3.74 (m, 1H), 3.58-3.66 (m, 1H), 3.42-3.47 (m, 1H), 2.77-2.81 (m, 1H), 2.41-2.50 (m, 1H), 1.36 (s, 12H).

[0774] Intermediate 51: 4-Bromo-6-chloropyridine amide

[0775]

[0776] To a 25 mL round-bottom flask containing 4-bromo-6-chloropyridinecarbonitrile (360 mg, 1.7 mmol) was added acetone (8.3 mL), water (2.8 mL) and K2CO3 (114 mg, 0.8 mmol). Urea-hydrogen peroxide (1.6 g, 16.6 mmol) was then added to the stirred mixture and the resulting mixture was stirred at room temperature. After 90 minutes, the resulting solution was diluted with water and extracted with ethyl acetate. The resulting organic solution was then dried over MgSO4, filtered and evaporated to dryness to give a white solid (320 mg, 82%) which was used without further purification. LC-MS (ESI): mass calculated for C6H4BrClN2O was 233.9; m / z found was 234.9 [M+H] + .

[0777] Intermediate 52: 6-chloro-4-(1-methyl-1H-pyrazol-5-yl)pyridineamide

[0778]

[0779] A mixture consisting of 4-bromo-6-chloropicolinamide (100 mg, 0.43 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (132 mg, 0.63 mmol), K PO (276 mg, 1.27 mmol), 1,4-dioxane (1.1 mL) and water (0.2 mL) was then evacuated and refilled with N 3 times, treated with Pd(dppf)Cl (46 mg, 0.064 mmol) and heated at 100° C. under N for 3 hours. The reaction vessel was removed from the heating mantle and allowed to gradually cool to room temperature. The resulting mixture was diluted with water and extracted with ethyl acetate. The resulting organic solution was then dried over MgSO , filtered and evaporated to dryness. The residue was subjected to flash column chromatography using a gradient of 0% to 10% MeOH in DCM over 15 minutes to give an orange oil (100 mg). MS (ESI): C 10 The calculated mass of H9ClN4O is 236.1; the found m / z is 237.0 [M+H] + .

[0780] Intermediate 53: 6-chloro-4-(isothiazol-5-yl)pyridineamide

[0781]

[0782] The title compound (60 mg, 59%) was prepared using conditions similar to those described for Intermediate 52 using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole instead of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI): mass calculated for C9H6ClN3OS 239.0, m / z found 240.0 [M+H] + .

[0783] Intermediate 54: 6-chloro-4-(thiazol-5-yl)pyridineamide

[0784]

[0785] The title compound (60 mg, 59%) was prepared using conditions similar to those described for Intermediate 52 using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole instead of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI): mass calculated for C9H6ClN3OS 239.0, m / z found 239.9 [M+H] + .

[0786] Intermediate 55: (R)-4-chloro-6-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazole-3-yl)- 1-[4-(2-amino-3-methyl)phenyl)picolinic acid

[0787]

[0788] To a mixture of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 10.0 g, 26.0 mmol) and methyl 4,6-dichloropicolinate (10.7 g, 52.1 mmol) in 1,4-dioxane (75.0 mL) and water (25.0 mL) was added KCO (7.19 g, 52.1 mmol) and Pd(PPh) (1.50 g, 1.30 mmol), and the resulting mixture was degassed and purged with N three times, and then the mixture was heated at 90° C. under N atmosphere for 4 hours. The reaction mixture was diluted with water (40 mL), the pH of the mixture was adjusted to pH 3, and the mixture was extracted with ethyl acetate (50.0 mL×3). The combined organic layers were washed with brine (50.0 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The product was triturated with ethyl acetate (15 mL) at 25°C for 15 minutes. The title compound (8.50 g, 19.3 mmol, 74.2%) was obtained as a white solid. MS (ESI): C 20 H 16 The calculated mass of ClN3O5 is 413.1; the found m / z is 414.1 [M+H] + .

[0789] Intermediate 56: (R)-4-chloro-6-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazole-3-yl)- methyl)phenyl)picolinate

[0790]

[0791] To a solution of (R)-4-chloro-6-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinic acid (16.0 g, 38.7 mmol, intermediate 55) in MeOH (35.0 mL) and THF (35.0 mL) was slowly added trimethylsilyl-diazomethane (2 M, 58.00 mL) at 0 ° C under N2. The mixture was slowly stirred and warmed from 0 ° C to 25 ° C over 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (petroleum ether: ethyl acetate = 1: 0 to 0: 1) to give the product. The product was triturated with MTBE (60 mL, triturated at 25 ° C for 48 hours). The compound (11.8 g, 26.3 mmol, 68.0%) was obtained as a white solid. MS (ESI): C 21 H 18 The calculated mass of ClN3O5 is 427.1; the found m / z is 428.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)d 8.53-8.66(m,2H),8.31(br d,J=7.88Hz,1H),7.99-8.10(m,2H),7.69(t,J=7.75Hz,1H),7.19(s,1H),6.75(s,1H),3.95(s, 3H), 3.38-3.55 (m, 2H), 2.85 (s, 3H), 2.53-2.64 (m, 1H), 2.29 (ddd, J = 13.38, 7.63, 6.00Hz, 1H).

[0792] Intermediate 57: (R)-4-chloro-6-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazole-3-yl)- 1-[4-(2-amino-3-methyl)phenyl)pyridineamide

[0793]

[0794] A solution of ammonia (11.7 mL, 2 M in MeOH) and (R)-methyl 4-chloro-6-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinate (Intermediate 56, 1 g, 2.3 mmol) was stirred in a microwave at 100° C. for 80 minutes. The resulting solution was evaporated to dryness to give a white solid (1 g) which was used as is. MS (ESI): C 20 H 17 The calculated mass of ClN4O4 is 412.1; the found m / z is 413.1 [M+H] + .

[0795] Intermediate 58: 6,8-dichloropyrido[3,2-d]pyrimidin-4-amine .

[0796]

[0797] A flask was charged with a solution of 3-amino-4,6-dichloropyridine carbonitrile (1.21 g, 6.34 mmol), K PO (13.6 g, 64.0 mmol) and 1,4-dioxane (50 mL), followed by acetic acid formamidine (3.87 g, 37.1 mmol). The resulting mixture was heated at 100 ° C for 16 h. The resulting mixture was cooled to RT and concentrated to dryness. The residue was diluted with H 2 O (50 mL) and stirred at room temperature for 16 hours. The resulting mixture was filtered, the filter cake was washed with water (200 mL), and the solid was collected. The resulting solid was added to DCM (50 mL), and the mixture was stirred at room temperature for 40 minutes. The resulting solid was collected by filtration and dried to give 6,8-dichloropyrido [3,2-d] pyrimidine -4-amine (1.35 g, 97.5%) as a white solid. MS (ESI): mass calculated for C7H4Cl2N4: 214.0; m / z found: 215.0 [M+H] +. 1 H NMR (500MHz, CDCl3) δ8.72(s,1H),7.81(s,1H),5.95–5.48(m,2H).

[0798] Intermediate 59: 6-chloropyrido[3,2-d]pyrimidin-4-amine

[0799]

[0800] Acetic acid formamidine (25.0 g, 240 mmol) is added to a solution of 3-amino-6-chloropyridine carbonitrile (8.80 g, 57.3 mmol) and K3PO4 (78.0 g, 367 mmol) in 1,4-dioxane (400 mL). The reaction is heated at 100 ° C for 2 hours. After the reaction mixture is cooled to room temperature, the reaction mixture is concentrated to dryness in vacuo to obtain the product, which is poured into H2O (500 mL) and stirred at room temperature for 16 hours. The suspension is filtered. The filter cake is washed with H2O (100 mL) and the filtrate is poured into CHCl3 (70 mL). The mixture is heated at 50 ° C for 30 minutes. The suspension is separated by filtration, then cooled to room temperature, and the filter cake is washed with CHCl3 (30 mL). The filter cake is then dried in vacuo to obtain the product (7.8 g, 75%) as a yellow solid. 1 HNMR (400MHz, DMSO-d6) δ8.41 (s, 1H), 8.10 (d, J = 8.8Hz, 1H), 8.04-7.90 (m, 2H), 7.84 (d, J = 8.6Hz, 1H).

[0801] Intermediate 60: tert-Butyl 3-((hydroxyimino)methyl)piperidine-1-carboxylate

[0802]

[0803] By 3-formylpiperidine-1-carboxylic acid tert-butyl esters (3.50g, 16.4mmol), hydroxylamine hydrochloride (1.71g, 24.6mmol) and Na cO a mixture of (2.61g, 24.6mmol) in EtOH (50mL) and water (5mL) is heated to 80 DEG C and kept for 16 hours.The reaction vessel is taken out from oil bath and is gradually cooled to room temperature.The mixture is concentrated in vacuo, diluted with water (40mL), and extracted with EtOAc (100mL×3).The organic layer combined is passed through anhydrous Na sO dried, filtered, and concentrated in vacuo to obtain 3-((hydroxyimino)methyl)piperidine-1-carboxylic acid tert-butyl esters (3.2g) as solid, which is directly used in the next step without purification. 1HNMR (400MHz, CDCl3) δ7.36 (d, J = 5.5Hz, 1H), 4.12-3.70 (m, 3H), 2.90-2.79 (m, 2H), 2.44-2.33 (m, 1H), 1.98-1.76 (m, 2H), 1.46 (s, 9H). 1 H NMR(400MHz,MeOD)δ7.26(d,J=5.7Hz,1H),4.01-3.64(m,3H),3.06-2.87(m ,2H),2.34-2.24(m,1H),1.91-1.81(m,1H),1.75-1.62(m,2H),1.43(s,9H).

[0804] Intermediate 61: tert-Butyl 3-(chloro(hydroxyimino)methyl)piperidine-1-carboxylate

[0805]

[0806] NCS (1.87 g, 14.0 mmol) was added to a solution consisting of tert-butyl 3-((hydroxyimino)methyl)piperidine-1-carboxylate (intermediate 60, 3.2 g, 14 mmol) and N,N-dimethylformamide (100 mL), and the resulting mixture was stirred at room temperature under nitrogen for 16 hours. Thereafter, the mixture was diluted with ethyl acetate (200 mL) and washed with water (50 mL×3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-30% EtOAc / petroleum ether) to give tert-butyl 3-(chloro(hydroxyimino)methyl)piperidine-1-carboxylate (1.36 g, 29%) as a colorless oil. MS (ESI): C 11 H 19 The calculated mass of ClN2O3 is 262.1; the measured m / z is 207.1 [M-55] + .

[0807] Intermediate 62: 3-(5-((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)piperidine- tert-Butyl 1-carboxylate

[0808]

[0809] (R) -3-ethynyl -3-hydroxy -1-methylpyrrolidin-2-one (intermediate 1, 500 mg, 3.59 mmol), tert-butyl 3- (chloro (hydroxyimino) methyl) piperidine -1- carboxylate (intermediate 61, 1.3 g, 4.9 mmol) and NaHCO (604 mg, 7.19 mmol) in EtOAc (20 mL) were stirred at room temperature for 16 hours. Afterwards, the mixture was concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (10% -100% EtOAc / petroleum ether) to give tert-butyl 3- (5- ((R) -3-hydroxy -1-methyl -2-oxopyrrolidin-3-yl) isoxazol-3-yl) piperidine -1- carboxylate (1.32 g, 99.8%) as a white solid. MS (ESI): C 18 H 27 The calculated mass of N3O5 is 365.2; the measured m / z is 266.2 [M-99] + .

[0810] Intermediate 63: (3R)-3-Hydroxy-1-methyl-3-(3-(piperidin-3-yl)isoxazol-5-yl)pyrrolidin-2-one

[0811]

[0812] TFA (3.6 mL, 48 mmol) was added to a solution of tert-butyl 3-(5-((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)piperidine-1-carboxylate (intermediate 62, 1.2 g, 3.3 mmol) in DCM (36 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. Thereafter, the mixture was treated with saturated NaHCO3 aqueous solution (50 mL) to reach pH 8-9 and lyophilized to dryness. The residue was ground with DCM / EtOAc / MeOH (200 mL, 10:10:1), filtered, and the filtrate was concentrated in vacuo to dryness to give (3R)-3-hydroxy-1-methyl-3-(3-(piperidin-3-yl)isoxazol-5-yl)pyrrolidin-2-one (4 g) as a sticky solid. The product was used directly in the next step without purification. MS (ESI): C 13 H 19 The calculated mass value of N3O3 is 265.1; the measured m / z value is 266.0[M+1]+.

[0813] Intermediate 64: Ethyl 3-bromo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate

[0814]

[0815] 5,6,7,8-tetrahydroimidazo [1,5-a] pyrazine -1- carboxylic acid ethyl ester hydrochloride (1.0g, 4.3mmol) and MeCN (10mL) are added to a 40mL flask, and NBS (768mg, 4.32mmol) is loaded. The resulting mixture is stirred at room temperature for 2 hours and quenched with saturated Na2S2O3 aqueous solution (20mL) and stirred at room temperature for 15 minutes. Thereafter, the mixture is alkalized to pH=8 with saturated NaHCO3 aqueous solution and concentrated in vacuo to dryness to give a yellow solid. The yellow solid is then subjected to silica gel chromatography (0-10% MeOH / DCM) to give 3- bromo-5,6,7,8-tetrahydroimidazo [1,5-a] pyrazine -1- carboxylic acid ethyl ester (290mg, 21%) as a yellow solid. LCMS (ESI): C9H 12 The calculated mass of BrN3O2 is 273.0; the measured m / z is 276.0 [M+H] + .

[0816] Intermediate 65: (R)-3-(3-(2-chloropyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidine-2-yl ketone.

[0817]

[0818] (R)-3-(3-(2-chloropyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (512 mg) was prepared in a manner similar to Intermediate 7: (R)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one using 2-chloroisonicotinaldehyde instead of 2-bromoisonicotinaldehyde. MS (ESI): C 13 H 12 The calculated mass of ClN3O3 is 293.1; the found m / z is 293.9 [M+H] + .

[0819] Example 1: (R)-3-(3-(3-(4-amino-2-methylpyrido[3,2-d]pyrimidin-6-yl)phenyl)isoxazole- 5-amino)-3-hydroxy-1-methylpyrrolidin-2-one .

[0820]

[0821] To a solution of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 150 mg, 0.39 mmol) in 1,4-dioxane (8 mL) and H2O (1 mL) was added 6-chloro-2-methylpyrido[3,2-d]pyrimidin-4-amine (Intermediate 16, 152 mg, 0.780 mmol) followed by bis(tri-tert-butylphosphine)palladium(0) (20 mg, 0.04 mmol) and KF (68 mg, 1.2 mmol). The mixture was heated at 85°C under N2 atmosphere for 3 h, cooled to room temperature, and then concentrated. The resulting residue was purified by reverse phase HPLC using an HPLC column such as an Xtimate C18 10 μm, 21.2×250 mm column using a 5% to 38% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) to afford (R)-3-(3-(3-(4-amino-2-methylpyrido[3,2-d]pyrimidin-6-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (5.9 mg, 4%) as a white solid. MS (ESI): C 22 H 20 The calculated mass of N6O3 is 416.4; the measured m / z is 417.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.75(s,1H),8.52–8.56(m,2H),8.30(s,1H),8.13(s,1H),8.08(d,J=8.0Hz,1H),8.01(d,J=8.0Hz,1H),7. 93(s,1H),7.67(t,J=7.6Hz,1H),7.32(s,1H),3.41–3.53(m,2H),2.85(s,3H),2.55–2.61(m,1H),2.47(s,3H),2.26–2.33(m,1H).

[0822] Example 2: (R)-3-(3-(3-(4-aminopyrido[3,2-d]pyrimidin-6-yl-2-d)phenyl)isoxazole-5- 1-Methylpyrrolidin-2-one .

[0823]

[0824] To a solution of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 15 mg, 0.39 mmol) in 1,2-dioxane (2 mL) and H2O (0.2 mL) was added 6-chloropyrido[3,2-d]pyrimidin-2-d-4-amine (Intermediate 17, 71 mg, 0.39 mmol) followed by bis(tri-tert-butylphosphine)palladium(0) (20 mg, 0.04 mmol) and K3PO4 (249 mg, 1.17 mmol). The mixture was heated at 90°C under N2 atmosphere for 16 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC using an HPLC column such as Xtimate 10 μm, Purification on a 21.2×250 mm column using a 20% to 35% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) afforded (R)-3-(3-(3-(4-aminopyrido[3,2- d ]pyrimidin-6-yl-2- d )phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one as a brown solid (28 mg, 18%). MS (ESI): C 21 H 17 The calculated mass of DN6O3 is 403.1; the measured m / z is 404.0 [M+H] + . 1 HNMR(400MHz, DMSO-d6)δ8.78(s,1H),8.59(d,J=7.2Hz,2H),8.28(s,1H),8.17(d,J=8.8Hz,1H),8.00-8.10(m,2H),7 .68(t,J=8.0Hz,1H),7.34(s,1H),6.78(s,1H),3.40-3.60(m,2H),2.86(s,3H),2.50-2.60(m,1H),2.20-2.40(m,1H).

[0825] Example 3: (R)-3-(5-(3-(4-amino-2-methylpyrido[3,2-d]pyrimidin-6-yl)phenyl)isoxazole- 3-yl)-3-hydroxy-1-methylpyrrolidin-2-one .

[0826]

[0827] (R)-3-(5-(3-(4-amino-2-methylpyrido[3,2-d]pyrimidin-6-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (57.8 mg, 53%) was prepared using conditions similar to those described in Example 1 using (R)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one (Intermediate 5) instead of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. MS (ESI): C 22 H 20 The calculated mass of N6O3 is 416.4; the measured m / z is 417.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.83(s,1H),8.53-8.56(m,2H),8.17(s,1H),8.08(d,J=8.8Hz,1H),7.94-7.97(m,2H),7.69(t,J= 8.0Hz,1H),7.39(s,1H),6.52(s,1H),3.37-3.49(m,2H),2.85(s,3H),2.63-2.71(m,1H),2.47(s,3H),2.22-2.29(m,1H).

[0828] Example 4: (R)-3-(3-(3-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazole-5-yl 1-Methyl-2-pyrrolidin-3-one.

[0829]

[0830] Step A: (R)-3-hydroxy-1-methyl-3-(3-(3-(3-nitro-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. To a solution of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 50 mg, 0.1 mmol) in dioxane (2 mL) and DMF (1 mL) was added 5-chloro-3-nitro-1H-pyrazolo[4,3-b]pyridine (26 mg, 0.13 mmol) followed by Pd(t-Bu3P)2 (7.0 mg, 0.013 mmol) and K3PO4 (83 mg, 0.39 mmol). The mixture was heated at 95 ° C for 16 hours under N2 atmosphere, then cooled to room temperature and diluted with water (20 mL). The resulting aqueous mixture was extracted with DCM (4×15 mL). The combined organic solvent extracts were concentrated and purified using preparative TLC (DCM / MeOH=20 / 1) to give (R)-3-hydroxy-1-methyl-3-(3-(3-nitro-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (8 mg, 15%) as a brown solid. MS (ESI): C 20 H 16 The calculated mass of N6O5 is 420.4; the found m / z is 421.0 [M+H] + .

[0831] Step B: (R)-3-(3-(3-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of (R)-3-hydroxy-1-methyl-3-(3-(3-(3-nitro-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (15 mg, 0.036 mmol) in ethanol (2 mL) and 1,2-dichloroethane (1 mL) is added a porous nickel aluminum alloy (nickel aluminide) such as Raney nickel (50 mg) followed by hydrazine hydrate (71 mg, 1.4 mmol). The mixture is stirred at 20° C. for 1 hour, then filtered and concentrated. The resulting residue was purified by reverse phase HPLC using an HPLC column such as an Xtimate C18 10 μm, 21.2×250 mm column using a 5% to 35% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) to afford (R)-3-(3-(3-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (5 mg, 36%) as an off-white solid. MS (ESI): C 20 H 18 The calculated mass of N6O3 is 390.4; the found m / z is 391.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.7(s,1H),8.60(s,1H),8.26(d,J=8.0Hz,1H),8.00(d,J=8.8Hz,1H),7.90(d,J=8.0Hz,1H),7.81(d,J=8.8Hz, 1H),7.63(t,J=8.0Hz,1H),7.15(s,1H),6.74(s,1H),5.49(s,2H),3.40-3.50(m,2H),2.86(s,3H),2.50-2.60(m,1H),2.26-2.33(m,1H).

[0832] Example 5: (R)-3-(3-(3-(3-amino-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)iso Oxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one .

[0833]

[0834] Step A: (R)-3-Hydroxy-1-methyl-3-(3-(3-(1-methyl-3-nitro-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. To a solution of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 271 mg, 0.710 mmol) in DMF (2 mL) and H2O (0.2 mL) was added 5-chloro-1-methyl-3-nitro-1H-pyrazolo[4,3-b]pyridine (26 mg, 0.13 mmol) followed by Pd(t-Bu3P)2 (36 mg, 0.071 mmol) and K3PO4 (449 mg, 2.12 mmol). The mixture was heated at 90°C under N2 atmosphere for 16 h. The mixture was cooled to room temperature, filtered and purified by reverse phase HPLC using an HPLC column, such as an Xtimate C18 10 μm, 21.2×250 mm column, using an 18% to 35% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) to give (R)-3-hydroxy-1-methyl-3-(3-(3-(1-methyl-3-nitro-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (37 mg, 12%). MS (ESI): C 21 H 18 The calculated mass of N6O5 is 434.4; the found m / z is 435.0 [M+H] + .

[0835] Step B: (R)-3-(3-(3-(3-amino-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. A solution of (R)-3-hydroxy-1-methyl-3-(3-(3-(1-methyl-3-nitro-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (30 mg, 0.07 mmol), saturated aqueous NH4Cl (10 mL) and zinc powder (45 mg, 0.69 mmol) in MeOH (10 mL) was heated at 37°C for 16 h. The reaction mixture was concentrated to dryness and purified by reverse phase HPLC using an HPLC column such as an Xtimate C18 10 μm, 21.2×250 mm column using a 5% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) for 3 minutes, followed by a 27% to 35% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) to afford (R)-3-(3-(3-(3-amino-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (8.6 mg, 31%) as a yellow solid. MS (ESI): C 21 H 20 The calculated mass of N6O3 is 404.2; the found m / z is 405.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.06(s,1H),8.85(d,J=5.2Hz,1H),8.68(s,1H),8.13(d,J=2.8Hz,1H),7.98(dd,J=1.2,5.2Hz,1H),7.84(s,1H ),7.65(d,J=2.4Hz,1H),7.48(s,1H),6.83(s,1H),4.00(s,3H),3.43-3.52(m,2H),2.86(s,3H),2.56-2.62(m,1H),2.29-2.34(m,1H).

[0836] Example 6: (R)-3-(5-(3-(3-amino-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)iso Oxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one .

[0837]

[0838] (R)-3-(5-(3-(3-amino-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one was prepared using similar conditions to those described in Example 5 using (R)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one (Intermediate 5) instead of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. MS (ESI): C 21 H 20 The calculated mass of N6O3 is 404.2; the found m / z is 405.0 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ12.30(s,1H),8.70(s,1H),8.61(s,1H),8.55(d,J=2.8Hz,1H),8.42(d,J=8.0Hz,1H),8.34(d,J=2.8Hz,1H),7.7 3(d,J=8.0Hz,1H),7.57(t,J=8.0Hz,1H),7.07(s,1H),6.75(s,1H),3.52-3.41(m,2H),2.85(s,3H),2.62-2.55(m,1H),2.32-2.25(m,1H).

[0839] Example 7: (R)-3-amino-6-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazole-3- 1-[4-(2-amino-3-methyl)phenyl)pyridineamide .

[0840]

[0841] To a solution of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 105 mg, 0.270 mmol) in DMF (2 mL) and H2O (0.2 mL) was added 3-amino-6-bromopicolinamide (70 mg, 0.4 mmol) followed by Pd(t-Bu3P)2 (14 mg, 0.026 mmol) and K3PO4 (174 mg, 0.820 mmol). The mixture was heated at 90°C under N2 atmosphere for 16 hours. The mixture was then cooled to room temperature and concentrated. The residue was purified by reverse phase HPLC using an HPLC column such as Xtimate 10 μm, Purification on a 21.2×250 mm column using a 20% to 35% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) afforded (R)-3-amino-6-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinamide as a brown solid (5.2 mg, 5%). MS (ESI): C 20 H 19 The calculated mass of N5O4 is 393.1; the found m / z is 394.0 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ8.44(s,1H),8.26(d,J=8.0Hz,1H),8.20(s,1H),8.00(d,J=8.8Hz,1H),7.83(d,J=8.0Hz,1H),7.55(t,J=8.0Hz,1H),7. 47(s,1H),7.26(d,J=8.8Hz,1H),7.22(s,2H),7.04(s,1H),6.73(s,1H) ,3.51-3.44(m,2H),2.85(s,3H),2.55-2.48(m,1H),2.35-2.25(m,1H).

[0842] Example 8: (R)-6-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)benzene 4-Methoxy-2-pyridinecarboxamide .

[0843]

[0844] (R)-6-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-4-methoxypicolinamide (2 mg, 2%) was prepared using conditions similar to those described in Example 7 using 6-chloro-4-methoxypicolinamide (Intermediate 15) instead of 3-amino-6-bromopicolinamide. MS (ESI): C 21 H 20 The calculated mass of N4O5 is 408.1; the found m / z is 409.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.63(s,1H),8.46(d,J=8.0Hz,1H),8.41(s,1H),7.99(d,J=8.0Hz,1H),7.83(s,1H),7.78(s,1H),7.64(t,J=8 .0Hz,1H),7.56(s,1H),7.30(s,1H),6.77(s,1H),4.00(s,3H),3.60-3.40(m,2H),2.85(s,3H),2.62-2.52(m,1H),2.36-2.23(m,1H).

[0845] Example 9: (R,S)-3-(5-(3-(1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)isoxazol-3-yl)-3- Hydroxy-1-methylpyrrolidin-2-one .

[0846]

[0847] Step A: tert-Butyl 3-(3-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. tert-Butyl 3-(3-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (80 mg, 76%) was prepared using conditions similar to those described in Example 7, using (R,S)-3-(5-(3-bromophenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 6) instead of (R )-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one and prepared using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Intermediate 24) instead of 3-amino-6-bromopicolinamide. MS (ESI): C 26 H 26 The calculated mass of N4O5 is 474.2; the found m / z is 475.2 [M+H] + .

[0848] Step B: (R,S)-3-(5-(3-(1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one. A solution of tert-butyl 3-(3-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (80 mg, 0.17 mmol) in 4M HCl in 1,4-dioxane (15 mL, 60 mmol) was stirred at room temperature for 16 hours and then concentrated to dryness. The residue was diluted with saturated aqueous NaHCO3 and extracted with EtOAc (2×15 mL). The organic solvent extracts were combined, concentrated to dryness and purified by reverse phase HPLC using an HPLC column such as an Agela Durashell C18 10 μm, 21.2×250 mm column using an 18% to 35% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) to afford (R,S)-3-(5-(3-(1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (42 mg, 67%) as a white solid. MS (ESI): C 21 H 18 The calculated mass of N4O3 is 374.1; the found m / z is 375.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ12.05(s,1H),8.35(d,J=8.0Hz,1H),8.30(d,J=4.0Hz,1H),8.18(s,1H),8.08(s,1H),7.88(t,J=8.0Hz,1H),7.74(d,J=8.0H z,1H),7.60(t,J=8.0Hz,1H),7.21(s,1H),7.19(t,J=4.0Hz,1H),6.50(s, 1H),3.45-3.38(m,2H),2.81(s,3H),2.70-2.64(m,1H),2.28-2.23(m,1H).

[0849] Example 10: (R)-3-(3-(3-(8-aminopyrido[3,4-d]pyrimidin-2-yl)phenyl)isoxazol-5-yl)- 3-Hydroxy-1-methylpyrrolidin-2-one .

[0850]

[0851] Step A: (R)-3-(3-(3-(8-chloropyrido[3,4-d]pyrimidin-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a suspension of 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine (Intermediate 13, 90.0 mg, 0.43 mmol), (R)-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)boronic acid (Intermediate 10, 154 mg, 0.51 mmol), and copper(I)thiophene-2-carboxylate (162 mg, 0.85 mmol) in THF (2 mL) was added Pd(PPh) (49 mg, 0.04 mmol). The mixture was heated at 105° C. under a nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=20 / 1, R f =0.4) to give (R)-3-(3-(3-(8-chloropyrido[3,4-d]pyrimidin-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (40 mg, 22%) as a yellow solid. MS (ESI): C 21 H 16 The calculated mass of ClN5O3 is 421.1; the found m / z is 422.1 [M+H] + .

[0852] Step B: (R)-3-(3-(3-(8-aminopyrido[3,4-d]pyrimidin-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of (R)-3-(3-(3-(8-chloropyrido[3,4-d]pyrimidin-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (50 mg, 0.1 mmol) in dioxane (1 mL) was added aqueous ammonium hydroxide (12 N, 5 mL, 60 mmol). The mixture was heated at 70 °C in a sealed tube for 16 hours and then concentrated under reduced pressure. The residue was purified by reverse phase HPLC using an HPLC column such as a Boston pHlex ODS 10 μm, 21.2×250 mm column using a 30% to 54% gradient of CH 3 CN and HO (0.1% FA) to afford (R)-3-(3-(3-(8-aminopyrido[3,4-d]pyrimidin-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (1 mg, 2%) as a yellow solid. MS (ESI): C 21 H 18 The calculated mass of N6O3 is 402.1; the measured m / z is 403.1 [M+H] + .1 H NMR (400MHz, CD3OD) δ9.48(s,1H),9.14-9.16(m,1H),8.78(d,J=8.0Hz,1H),8.03(d,J=8.0Hz,1H),7.96(d,J=5.6Hz,1H),7.7 0(d,J=8.0Hz,1H),7.10(s,1H),7.09(d,J=5.6Hz,1H),3.63-3.60(m,2H),3.00(s,3H),2.80-2.76(m,1H),2.46-2.42(m,1H).

[0853] Example 11: (R)-3-(3-(3-(4-(azetidin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)phenyl) (5-Isoxazolyl)-3-hydroxy-1-methylpyrrolidin-2-one .

[0854]

[0855] To a solution of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 140 mg, 0.36 mmol) in DMF (3 mL) and H2O (0.3 mL) was added 4-(azetidin-1-yl)-6-chloropyrido[3,2-d]pyrimidine (80 mg, 0.4 mmol) followed by Pd(t-Bu3P)2 (18 mg, 0.04 mmol) and K2CO3 (151 mg, 1.09 mmol). The mixture was heated at 105°C under N2 atmosphere for 16 h, then cooled to room temperature and concentrated. The resulting compound was purified using reverse phase HPLC using an HPLC column such as an Xtimate C18 10 μm, 21.2×250 mm column using a 36% to 41% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) to afford (R)-3-(3-(3-(4-(azetidin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (37 mg, 23%) as an off-white solid. MS (ESI): C 24 H 22 The calculated mass of N6O3 is 442.47; the measured m / z is 443.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.68(s,1H),8.56(d,J=8.8Hz,1H),8.45(s,1H),8.34(d,J=7.6,1H),8.17(d,J=8.8Hz,1H),8.01(d,J=7.6,1H),7.17(t,J= 7.6,1H),7.19(s,1H),6.77(s,1H),5.04(t,J=7.2,2H),4.34(t,J=7.2,2 H),3.50-3.44(m,2H),2.86(s,3H),2.62-2.57(m,2H),2.33-2.27(m,2H).

[0856] Example 12: (R)-3-(3-(3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-4-methylphenyl)isothiazolinone oxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0857]

[0858] Step A: 3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-4-methylbenzaldehyde. A mixture of 2-(5-iodo-2-methylphenyl)thiazolo[5,4-d]pyrimidin-7-amine (Intermediate 20, 400 mg, 1 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride DCM complex (44 mg, 0.054 mmol), triethylsilane (379 mg, 3.26 mmol), and NaCO (138 mg, 1.30 mmol) in DMF (8 mL) was heated at 80°C under a CO atmosphere for 24 hours. The reaction mixture was cooled, diluted with EtOAc (20 mL), and washed with brine (3 x 10 mL). The organic solvent fraction was separated, dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH=20 / 1) to give 3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-4-methylbenzaldehyde (0.22 g, 75%) as a yellow solid. MS (ESI): C 13 H 10 The calculated mass of N4OS is 270.3; the found m / z is 271.1 [M+H] + .

[0859] Step B: 3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-4-methylbenzaldehyde oxime. To a solution of 3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-4-methylbenzaldehyde (220 mg, 0.81 mmol) in EtOH (10 mL) was added hydroxylamine (50% aqueous solution) (0.24 mL, 4.07 mmol). The mixture was stirred at 25 ° C for 2 hours and then concentrated to give 3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-4-methylbenzaldehyde oxime (200 mg, 86%) as a white solid. MS (ESI): C 13 H 11 The calculated mass of N5OS is 285.3; the found m / z is 286.1 [M+H] + .

[0860] Step C: 3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-N-hydroxy-4-methyliminobenzyl chloride. To a solution of 3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-4-methylbenzaldehyde oxime (200 mg, 0.7 mmol) in DCM (10 mL) and DMF (15 mL) was added N-chlorosuccinimide (281 mg, 2.10 mmol) portionwise. The reaction mixture was stirred at 25 ° C for 5 hours, then diluted with EtOAc (50 mL) and washed with brine (3×60 mL). The organic solvent portion was dried over Na2SO4, filtered and concentrated to give 3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-N-hydroxy-4-methyliminobenzyl chloride (0.18 g, 80%) as a yellow solid. MS (ESI): C 13 H 10 The calculated mass of ClN5OS is 319.8; the found m / z is 284.1 [M-HCl] + .

[0861] Step D: (R)-3-(3-(3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-4-methylphenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of 3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-N-hydroxy-4-methyliminobenzyl chloride (180 mg, 0.28 mmol) in DCM (15 mL) was added (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1, 39.2 mg, 0.28 mmol) followed by triethylamine (0.12 mL, 0.84 mmol). The reaction mixture was stirred at 25 °C for 16 h, diluted with DCM (30 mL) and washed with brine (20 mL). The organic solvent portion was dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC using an HPLC column such as a Boston pHlex ODS 10 μm, 21.2×250 mm column using a 20% to 60% gradient of CH 3 CN / H 2 O (0.1% FA) to afford (R)-3-(3-(3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-4-methylphenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (1.9 mg, 1%) as a yellow oil. MS (ESI): C 20 H 18 The calculated mass of N6O3S is 422.1; the found m / z is 423.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.43(s,4H),8.29(s,1H),8.20(d,J=1.2Hz,1H),7.87(dd,J=8.0,1.6Hz,1H),8.51(d, J=8.0Hz,1H),6.96(s,1H),3.41-3.47(m,2H),2.84(s,3H),2.66(s,3H),2.54-2.61(m,1H),2.26-2.32(m,1H).

[0862] Example 13: (R)-3-(3-(3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)phenyl)isoxazol-5-yl)- 3-Hydroxy-1-methylpyrrolidin-2-one .

[0863]

[0864] (R)-3-(3-(3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one Using conditions similar to those described in Example 1, using 2-(3-iodophenyl)thiazolo[5,4-d]pyrimidin-7-amine (Intermediate 21) instead of 6-chloro-2-methylpyrido[3,2-d]pyrimidin-4-amine (Intermediate 16). MS (ESI): C 19 H 16 The calculated mass of N6O3S is 408.1; the found m / z is 409 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.56(s,1H),8.33(s,1H),8.17(d,J=8.0Hz,1H),8.08(d,J=8.0Hz,1H),7.85(s,2H),7.74 (t,J=8.0Hz,1H),7.15(s,1H),6.78(s,1H),3.53-3.44(m,2H),2.85(s,3H),2.62-2.55(m,1H),2.33-2.26(m,1H).

[0865] Example 14: (R)-6-(3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-1,2,3-triazole- 1-amino)phenyl)pyridineamide .

[0866]

[0867] Step A: (R)-methyl 6-(3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)picolinate. To a mixture of methyl 6-(3-iodophenyl)picolinate (64 mg, 0.19 mmol), (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1, 32 mg, 0.23 mmol), NaN3 (13.5 mg, 0.210 mmol), CuI (7 mg, 0.04 mmol) and trans-N,N'-dimethyl-cyclohexane-1,2-diamine (5.4 mg, 0.038 mmol) in DMSO (2 mL) was added water (0.5 mL) followed by sodium ascorbate (7.5 mg, 0.038 mmol). The mixture was stirred at room temperature under N2 atmosphere for 16 hours, poured into water (20 mL), and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with salt water (2 × 20 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was analyzed by preparative TLC (EA / petroleum ether=2 / 1, R f=0.5) to give (R)-methyl 6-(3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)picolinate (70 mg, 94%) as a white solid. MS (ESI): C 20 H 19 The calculated mass of N5O4 is 393.4; the found m / z is 394 [M+H] + .

[0868] Step B: (R)-6-(3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)picolinamide. A mixture of (R)-methyl 6-(3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)picolinate (60 mg, 0.15 mmol) and ammonia in MeOH (7N, 5 mL) was heated at 75° C. for 16 hours. The solution was concentrated and purified by reverse phase HPLC using an HPLC column such as an Xtimate 10 μm Purification on a 21.2×250 mm column using a 5% to 33% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) afforded (R)-6-(3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)picolinamide (19 mg, 33%) as a white solid. MS (ESI): C 19 H 18 The calculated mass of N6O3 is 378.4; the found m / z is 379.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.96(s,1H),8.73(s,1H),8.52(s,1H),8.43(d,J=7.6Hz,1H),8.37(d,J=8.0,1H),8.12(t,J=7.6Hz,1H ), 8.05 (d, J = 7.6Hz, 2H), 7.80-7.70 (m, 2H), 6.28 (s, 1H), 3.55-3.45 (m, 2H), 2.83 (s, 3H), 2.80-2.65 (m, 1H), 2.35-2.25 (m, 1H).

[0869] Example 15: (R)-1-(3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-1,2,3-triazole- 1-amino)phenyl)imidazo[1,5-a]pyridine-3-carboxamide .

[0870]

[0871] To a solution of (R)-3-hydroxy-1-methyl-3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)pyrrolidin-2-one (Intermediate 8, 100 mg, 0.26) in DMF (10 mL) and water (1 mL) was added 1-bromoimidazo[1,5-a]pyridine-3-carboxamide (62 mg, 0.26 mmol) followed by Pd(t-Bu3P)2 (13 mg, 0.026 mmol) and K3PO4 (166 mg, 0.78 mmol). The mixture was heated at 90°C under nitrogen for 16 hours, cooled to room temperature, and then concentrated under reduced pressure. The residue was purified by preparative HPLC to give (R)-1-(3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide (19.4 mg, 18%) as a yellow solid. MS (ESI): C 21 H 19 The calculated mass of N7O3 is 417.2; the found m / z is 418.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.51(d,J=7.6Hz,1H),8.79(s,1H),8.45(t,J=2Hz,1H),8.24(d,J=9.2Hz,1H),8.10(d,J=8.4Hz,2H),7.88-7.85(m,1H), 7.74-7.65(m,2H),7.29-7.26(m,1H),7.09(t,J=6.8Hz,1H),6.28(s,1H ),3.51-3.47(m,2H),2.83(s,3H),2.77-2.66(m,1H),2.34-2.26(m,1H).

[0872] Example 16: (R)-3-(5-(3-(4-aminopyrido[3,2-d]pyrimidin-6-yl-2-d)phenyl)isoxazole-3- 1-Methylpyrrolidin-2-one .

[0873]

[0874] A mixture of 6-chloropyrido[3,2-d]pyrimidin-2-d-4-amine (Intermediate 17, 78 mg, 0.43 mmol), (R)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one (Intermediate 5, 110 mg, 0.29 mmol), bis(tri-tert-butylphosphine)palladium(0) (15 mg, 0.029 mmol), K3PO4 (182 mg, 0.86 mmol), 1,4-dioxane (10 mL) and water (1 mL) was heated at 65°C under an argon atmosphere for 16 hours. The reaction mixture was filtered and concentrated. The residue was purified by reverse phase HPLC using an HPLC column such as an Xtimate C18 10 μm, 21.2×250 mm column using a 20% to 35% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) to afford (R)-3-(5-(3-(4-aminopyrido[3,2-d]pyrimidin-6-yl-2-d)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (51 mg, 44%) as a white solid. MS (ESI): C 21 H 17 The calculated mass of DN6O3 is 403.4; the measured m / z is 404.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.86(s,1H),8.61(d,J=4.8Hz,1H),8.57(d,J=8Hz,1H),8.31(s,1H),8.17(d,J=4.8Hz,1H),8.05(s,1H),7.9 8(d,J=8Hz,1H),7.71(t,J=8Hz,1H),7.40(s,1H),6.53(s,1H),3.49-3.38(m,2H),2.82(s,3H),2.72-2.65(m,1H),2.31-2.23(m,1H).

[0875] Example 17: (R)-3-(5-(3-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazole-3-yl 1-Methyl-2-pyrrolidin-3-one.

[0876]

[0877] Step A: (R)-3-(5-(3-(3-nitro-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of (R)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one (Intermediate 5, 100 mg, 0.26 mmol) in 1,4-dioxane (4 mL), HO (1 mL), and DMF (5 mL) was added 5-chloro-3-nitro-1H-pyrazolo[4,3-b]pyridine (103 mg, 0.52 mmol), Pd(t-BuP) (13 mg, 0.026 mmol), and KPO (166 mg, 0.78 mmol). The mixture was heated at 80° C. under Ar atmosphere for 16 h, cooled to room temperature, and then concentrated. The residue was purified by reverse phase HPLC using an HPLC column such as an Xtimate C18 10 μm, 21.2×250 mm column using a 15% to 35% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) to afford (R)-3-(5-(3-(3-nitro-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (20 mg, 18%) as a white solid. MS (ESI): C 20 H 16 The calculated mass of N6O5 is 420.4; the found m / z is 421.2 [M+H] + .

[0878] Step B: (R)-3-(5-(3-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of (R)-3-(5-(3-(3-nitro-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (20 mg, 0.05 mmol) in saturated aqueous NH4Cl (2 mL) and MeOH (2 mL) was added zinc powder (200 mg, 3.06 mmol). The mixture was stirred at 30°C for 1 hour, filtered, and the filtrate was concentrated. The residue was purified by reverse phase HPLC using an HPLC column such as an Xtimate C18 10 μm, 21.2×250 mm column using a 5% to 40% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) to afford (R)-3-(5-(3-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (1 mg, 5%) as a pale yellow solid. MS (ESI): C 20 H 18 The calculated mass of N6O3 is 390.4; the measured m / z is 391.2 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.54 (s, 1H), 8.15 (d, J = 8.0Hz, 1H), 7.95-7.88 (m, 3H), 7.66 (t, J = 8.0 Hz,1H),7.07(s,1H),3.58-3.55(m,2H),2.95(s,3H),2.88-2.80(m,1H),2.41-2.37(m,1H).

[0879] Example 18: (R)-6-(3-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)benzene 1-[4-(2-amino-1-methyl)pyridineamide .

[0880]

[0881] Step A: Methyl (R)-6-(3-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)picolinate. A mixture of methyl 6-bromopicolinate (76 mg, 0.35 mmol), (R)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one (Intermediate 5, 90 mg, 0.23 mmol), bis(tri-tert-butylphosphine)palladium(0) (11.9 mg, 0.02 mmol) and K3PO4 (149 mg, 0.70 mmol) in 1,4-dioxane (8 mL) and water (1 mL) was heated at 75°C under Ar atmosphere for 16 h. The reaction mixture was filtered and concentrated, and the residue was purified by preparative TLC (DCM:MeOH=20:1) to give (R)-methyl 6-(3-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)picolinate (87 mg, 94%) as a white solid. MS (ESI): C 21 H 19 The calculated mass of N3O5 is 393.1; the found m / z is 394.1 [M+H] + .

[0882] Step B: (R)-6-(3-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)picolinamide. A solution of (R)-methyl 6-(3-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)picolinate (75.9 mg, 0.35 mmol) in NH (7N in EtOH, 5 mL) was heated at 75° C. for 16 h. The reaction mixture was concentrated and the residue was purified by reverse phase HPLC using an HPLC column such as an Xtimate 10 μm, 21.2×250 mm column using a 15% to 45% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) to afford (R)-6-(3-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)picolinamide (18 mg, 23%) as a white solid. MS (ESI): C 20 H 18 The calculated mass of N4O4 is 378.1; the found m / z is 379.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.73(s,1H),8.47(s,1H),8.45(s,1H),8.35(d,J=7.6Hz,1H),8.11(t,J=7.6Hz,1H),8.03(d,J=8.0Hz,1H),7.95(d,J=7 .6Hz,1H),7.76(s,1H),7.68(t,J=8.0Hz,1H),7.36(s,1H),6.52(s,1H) ,3.49-3.37(m,2H),2.82(s,3H),2.71-2.65(m,1H),2.29-2.22(m,1H).

[0883] Example 19: (R,S)-2-(3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-imidazole-1- 4-Methyl)phenyl)quinazoline-4-carboxamide .

[0884]

[0885] Step A: Ethyl (R,S)-2-(3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-imidazol-1-yl)phenyl)quinazoline-4-carboxylate. To a solution of (R,S)-3-hydroxy-1-methyl-3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-4-yl)pyrrolidin-2-one (Intermediate 9, 180 mg, 0.47 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) was added ethyl 2-chloroquinazoline-4-carboxylate (222 mg, 0.94 mmol), followed by Pd(t-Bu3P)2 (24.0 mg, 0.05 mmol) and KF (82 mg, 1.41 mmol). The mixture was heated at 85° C. under a N atmosphere overnight. The mixture was concentrated and purified using preparative TLC (DCM / MeOH=15 / 1) to give (R,S)-ethyl 2-(3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-imidazol-1-yl)phenyl)quinazoline-4-carboxylate (150 mg, 69.8%) as a yellow solid. MS (ESI): C 25 H 23 The calculated mass of N5O4 is 457.5; the found m / z is 458.0 [M+H] + .

[0886] Step B: (R,S)-2-(3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-imidazol-1-yl)phenyl)quinazoline-4-carboxamide. A solution of (R,S)-ethyl 2-(3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-imidazol-1-yl)phenyl)quinazoline-4-carboxylate (140 mg, 0.31 mmol) in NH in MeOH (7N, 5 mL) was heated at 75° C. for 16 hours. The reaction mixture was concentrated and the residue was purified by HPLC using an HPLC column such as an Xtimate 10 μm A 21.2×250 mm column was used with a 15% to 45% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) to afford (R,S)-2-(3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-imidazol-1-yl)phenyl)quinazoline-4-carboxamide (40 mg, 31%) as a white solid. MS (ESI): C 23 H 20 The calculated mass of N6O3 is 428.4; the found m / z is 429.0 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ8.91(d,J=8.4Hz,1H),8.79(s,2H),8.64(d,J=8.4Hz,1H),8.31(s,1H),8.10-8.30( m,3H),8.00-7.70(m,4H),5.89(s,1H),3.50-3.30(m,2H),2.80(s,3H),2.70-2.50(m,1H),2.20-2.10(m,1H).

[0887] Example 20: (R)-3-(3-(2-(8-amino-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)pyridin-4-yl)iso Oxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one .

[0888]

[0889] To a solution of (R)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 7, 560 mg, 1.66 mmol) and 5,6,7,8-tetrahydro-2,7-naphthyridin-1-amine (247 mg, 1.66 mmol) in DMF (9 mL) was added Pd2(dba)3 (75.8 mg, 0.08 mmol) followed by BINAP (155 mg, 0.25 mmol) and t-BuONa (477 mg, 4.97 mmol). The reaction mixture was heated at 85 ° C. under an Ar atmosphere for 16 hours, then diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic solvent extracts were concentrated to dryness and then purified by preparative TLC (DCM:MeOH 10:1) and reverse phase HPLC to give (R)-3-(5-(3-(8-amino-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (2.5 mg, 0.4%) as a pale yellow solid. MS (ESI): C 21 H 22 The calculated mass of N6O3 is 406.2; the measured m / z is 407.2 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ8.27(d,J=5.2Hz,1H),7.75(d,J=5.2Hz,1H),7.35(s,1H),7.18(s,1H),7.11(d,J=5.2Hz,1H),6.78(s,1H),6.41(d,J=5.2H z,1H),5.92(s,2H),4.31(s,2H),3.94(t,J=5.2Hz,2H),3.50-3.40(m,2H) ,2.85(s,3H),2.75(t,J=5.2Hz,2H),2.60-2.54(m,1H),2.33-2.25(m,1H).

[0890] Example 21: (R)-4'-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)-4-methyl Oxy-[2,2'-bipyridine]-6-carboxamide .

[0891]

[0892] Step A: 4-methoxy-6-(tributylstannyl)picolinamide. To a solution of 6-bromo-4-methoxypicolinamide (400.0 mg, 1.730 mmol) in toluene (10 mL) was added bis(tributyltin) (2 g, 3.5 mmol), followed by Pd(Ph3P)4 (100 mg, 0.09 mmol), and the reaction mixture was heated at 90 ° C under N2 atmosphere for 16 hours. Saturated KF aqueous solution (20 mL) was added and stirring was continued at room temperature for 2 hours. The mixture was extracted with EtOAc (3×20 mL), and the combined organic solvent extracts were washed with brine (3×20 mL) and concentrated to dryness. The residue was purified by FCC (DCM:MeOH, 20: 1) to give 4-methoxy-6-(tributylstannyl)picolinamide (185 mg, 18%) as a yellow solid. MS (ESI): C 19 H 34 The calculated mass of N2O2Sn is 442.2; the found m / z is 443.1 [M+H] + .

[0893] Step B: (R)-4'-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)-4-methoxy-[2,2'-bipyridine]-6-carboxamide. A solution of 4-methoxy-6-(tributylstannyl)picolinamide (185 mg, 0.42 mmol), (R)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 7, 212 mg, 0.06 mmol), and Pd(Ph3P)4 (48.5 mg, 0.04 mmol) in DMF (3 mL) was heated at 125°C under N2 for 16 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL), and washed with brine (3 x 15 mL). The organic layer was concentrated to dryness and purified by reverse phase HPLC using an HPLC column such as Xtimate 10 μm Purification on a 21.2×250 mm column using a 5% to 36% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) afforded (R)-4′-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)-4-methoxy-[2,2′-bipyridine]-6-carboxamide (12 mg, 7%) as a white solid. MS (ESI): C 20 H 19 The calculated mass of N5O5 is 409.2; the found m / z is 410.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.63(s,1H),8.46(d,J=8.0Hz,1H),8.41(s,1H),7.99(d,J=8.0Hz,1H),7.83(s,1H),7.78(s,1H),7.64 (t,J=8.0Hz,1H),7.56(s,1H),7.30(s,1H),4.00(s,3H),3.60-3.40(m,2H),2.85(s,3H),2.62-2.52(m,1H),2.36-2.23(m,1H).

[0894] Example 22: (R)-1-(4-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)pyrrolidone (2-pyridin-1H-indazole-3-carboxamide) .

[0895]

[0896] Step A: (R)-1-(4-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)pyridin-2-yl)-1H-indazole-3-carboxylic acid methyl ester. To a solution of 1H-indazole-3-carboxylic acid methyl ester (65 mg, 0.67 mmol) in toluene (5 mL) was added (R)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 7, 124 mg, 0.37 mmol), followed by the addition of (1S,2S)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (10.5 mg, 0.074 mmol), CuI (3.5 mg, 0.02 mmol) and K 3 PO 4 (165 mg, 0.78 mmol). The reaction mixture was heated at 100 ° C. under N 2 atmosphere for 16 hours, then concentrated to dryness and purified by FCC (DCM: MeOH, 20: 1) to give (R) -1- (4- (5- (3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl) isoxazol-3-yl) pyridin-2-yl) -1H-indazole-3-carboxylic acid methyl ester (60 mg, 77%) as a yellow solid. MS (ESI): C 22 H 19 The calculated mass of N5O5 is 433.1; the found m / z is 434.1 [M+H] + .

[0897] Step B: (R)-1-(4-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)pyridin-2-yl)-1H-indazole-3-carboxamide. A solution of (R)-methyl 1-(4-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)pyridin-2-yl)-1H-indazole-3-carboxylate (60 mg, 0.14 mmol) in NH3 (7N in MeOH, 5 mL, 35 mmol) was heated at 75°C for 16 hours. The mixture was cooled to room temperature, concentrated to dryness and purified by reverse phase HPLC using an HPLC column such as an Xtimate 10 μm Purification on a 21.2×250 mm column using a 40% to 45% gradient of CH 3 CN / (10 mM NH 4 HCO 3 and 0.025% NH 4 OH in H 2 O) afforded (R)-1-(4-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)pyridin-2-yl)-1H-indazole-3-carboxamide (33 mg, 55%) as a white solid. MS (ESI): C 21 H 18 The calculated mass of N6O4 is 418.1; the found m / z is 419.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.84(d,J=8.8Hz,1H),8.76(d,J=5.2Hz,1H),8.69(s,1H),8.35-8.32(m,2H),7.88-7.86(m,1H),7.74(s,1H),7.6 5(t,J=7.2Hz,1H),7.46(t,J=7.2Hz,1H),7.30(s,1H),6.85(s,1H),3.52-3.45(m,2H),2.86(s,3H),2.62-2.57(m,1H),2.35-2.30(m,1H).

[0898] Example 23: (R)-1-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)benzene yl)imidazo[1,5-a]pyridine-3-carboxamide .

[0899]

[0900] To a large vial was added (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 200 mg, 0.52 mmol), 1-bromoimidazo[1,5-a]pyridine-3-carboxamide (190 mg, 0.79 mmol), and Pd(PPh3)4 (61 mg, 0.05 mmol). A mixture of 1,4-dioxane (20 mL) and 2M K2CO3 (1.2 mL, 2.4 mmol) was then degassed with N2 for 20 minutes and added to the reaction mixture. The vial was sealed and evacuated / purged with nitrogen three times before being placed in an aluminum heating mantle at 100°C. After 2 hours, the mixture was heated at 80°C overnight. After 18 hours, the reaction mixture was filtered through a pad of celite (while still warm) and further rinsed with EtOAc and THF, and the eluate was concentrated to give a brown viscous oil. The substance was redissolved in CHCl and purified by FCC with a 0-90% gradient of EtOAc in DCM to give (R)-1-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide (151 mg, 70%) as an off-white fluffy solid. MS (ESI): C 19 H 16 The calculated mass of N6O2 is 417.4; the measured m / z is 418.1 [M+H] + . 1 HNMR(500MHz,CD3OD)δ9.48(dt,J=7.2,1.1Hz,1H),8.46-8.32(m,1H),8.11-7.99(m,2H),7.81 -7.77(m,1H),7.67-7.51(m,1H),7.21-7.18(m,1H),7.01-6.91(m,2H) ,3.65-3.47(m,2H),2.96(s,3H),2.78-2.72(m,1H),2.43-2.37(m,1H).

[0901] Example 24: (R)-3-(3-(3-(1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)isoxazol-5-yl)-3- Hydroxy-1-methylpyrrolidin-2-one .

[0902]

[0903] Step A: (R)-tert-Butyl 3-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. To a solution of (R)-3-hydroxy-3-(3-(3-iodophenyl)isoxazol-5-yl)-1-methylpyrrolidin-2-one (Intermediate 23, 90 mg, 0.234 mmol) in 1,4-dioxane (10 mL) and water (1.5 mL) was added tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Intermediate 24, 604 mg, 0.70 mmol), bis(tri-tert-butylphosphine)palladium(0) (12 mg, 0.02 mmol) and K3PO4 (149 mg, 0.70 mmol). The mixture was heated at 75°C for 16 h, then diluted with H2O (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic solvent extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative TLC (DCM / MeOH=20 / 1) to give (R)-tert-butyl 3-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (50 mg, 0.086 mmol) as a yellow solid. MS (ESI): C 26 H 26 The calculated mass of N4O5 is 474.2; the found m / z is 475.2 [M+H] + .

[0904] Step B: (R)-3-(3-(3-(1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. A solution of (R)-tert-butyl 3-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (50.0 mg, 0.11 mmol) in HCl solution (8 mL, 7 M in 1,4-dioxane) was stirred at 25°C for 2 hours and then concentrated to dryness. The residue was dissolved in H2O (10 mL) and the pH of the solution was adjusted to pH >7 with saturated aqueous NaHCO3. The solution was then extracted with DCM / i-PrOH (3 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH=20 / 1, R f=0.35) to give (R)-3-(3-(3-(1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (9 mg, 22%) as a white solid. MS (ESI): C 21 H 18 The calculated mass of N4O3 is 374.1; the measured m / z is 375.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.01(s,1H),8.29-8.33(m,2H),8.16(s,1H),8.04(s,1H),7.86(d,J=7.6Hz,1H),7.75(d,J=7.6Hz,1H),7.57 (t,J=8.0Hz,1H),7.20-7.17(m,1H),7.13(s,1H),6.71(s,1H),3.49-3.40(m,2H),2.84(s,3H),2.60-2.54(m,1H),2.32-2.25(m,1H).

[0905] Example 25: (R)-3-Hydroxy-1-methyl-3-(3-(3-(4-methylpyrido[3,2-d]pyrimidin-6-yl)benzene 1-[2-[(1-[(2-( ... .

[0906]

[0907] Step A: 6-chloro-4-methylpyrido[3,2-d]pyrimidine. Trimethylaluminum (1.25 mL, 2M in THF, 3.00 mmol) was added to a mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (500 mg, 2.50 mmol) and THF (20 mL) cooled to 0°C. The mixture was purged with N2 for 5 minutes, treated with Pd(PPh3)4 (144 mg, 0.13 mmol), purged with N2 for another 5 minutes, and then heated at 80°C under N2 atmosphere for 8 hours. The mixture was then cooled to room temperature, diluted with saturated aqueous NH4Cl solution (20 mL), and extracted with ethyl acetate (100 mL). The organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel FCC (eluent: petroleum ether:ethyl acetate=1:0 to 3:1) to give 6-chloro-4-methylpyrido[3,2-d]pyrimidine (270 mg, 60%) as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ9.24 (s, 1H), 8.27 (d, J = 8.8Hz, 1H), 7.78 (d, J = 8.8Hz, 1H), 3.06 (s, 3H).

[0908] Step B: (R)-3-Hydroxy-1-methyl-3-(3-(3-(4-methylpyrido[3,2-d]pyrimidin-6-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. A mixture of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 360 mg, 0.94 mmol), 6-chloro-4-methylpyrido[3,2-d]pyrimidine (168 mg, 0.935 mmol), K3PO4 (597 mg, 2.81 mmol), 1,4-dioxane (4 mL) and HO (1 mL) was purged with Ar for 5 minutes, then treated with 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (61 mg, 0.09 mmol) and purged with Ar for an additional 5 minutes. The resulting mixture was subjected to microwave irradiation at 90°C for 1 hour. The mixture was then cooled to room temperature and concentrated under reduced pressure. The product was purified by preparative HPLC using an HPLC column such as a Phenomenex Gemini-NX, 150 mm x 30 mm x 5 μm column (eluent: 27% to 51%, water (0.04% NH4OH + 10 mM NH4HCO3)-CH3CN). The product was suspended in water (10 mL) and the mixture was frozen by inserting into a -78°C bath and then lyophilized to dryness to afford (R)-3-hydroxy-1-methyl-3-(3-(3-(4-methylpyrido[3,2-d]pyrimidin-6-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (99 mg, 26%) as a red solid. MS (ESI): C 22 H 19 The calculated mass of N5O3 is 401.2; the found m / z is 402.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.21(s,1H),8.83-8.69(m,2H),8.54-8.44(m,2H),8.11-8.03(m,1H),7.79-7.69(m,1H ),7.22(s,1H),6.78(s,1H),3.52-3.44(m,2H),3.09(s,3H),2.86(s,3H),2.64-2.57(m,1H),2.37-2.26(m,1H).

[0909] Example 26: (R)-3-(3-(3-(4-amino-8-methylpyrido[3,2-d]pyrimidin-6-yl)phenyl)isothiazolinone oxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one .

[0910]

[0911] Step A: 3-amino-4-bromo-6-chloropyridine carbonitrile. N-bromosuccinimide (3.4 g, 19 mmol) is added to a solution of 3-amino-6-chloropyridine carbonitrile (2.7 g, 18 mmol) and DMF (50 mL). The resulting mixture is heated at 90 ° C for 2 hours. The mixture is then cooled to room temperature, treated with saturated Na2SO3 aqueous solution (100 mL) and stirred for 1 hour. The resulting mixture is treated with saturated NaHCO3 aqueous solution (100 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic extracts are washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure. The resulting residue is purified by FCC (eluent: petroleum ether: ethyl acetate = 1: 0 to 1: 1) to obtain 3-amino-4-bromo-6-chloropyridine carbonitrile (1.3 g, 30%) as a yellow solid. MS (ESI): mass calculated for C6H3BrClN3: 230.9; m / z found: 233.7 [M+H] + .

[0912] Step B: 3-Amino-6-chloro-4-methylpyridinecarbonitrile. 3-Amino-4-bromo-6-chloropyridinecarbonitrile (1.2 g, 5.2 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.8 mL, 5.7 mmol), KCO (13 mL, 2.0 M aqueous solution, 26 mmol), and 1,4-dioxane (30 mL) were added to a 100 mL round-bottom flask. The mixture was sparged with Ar for 5 minutes and then treated with PdCl(dppf)·CHCl (0.5 g, 0.5 mmol). The mixture was sparged with Ar for an additional 5 minutes, and the resulting mixture was heated at 80°C for 2 hours. The mixture was then cooled to room temperature, diluted with H2O (100 mL), and extracted with ethyl acetate (60 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure. The resulting residue was purified by FCC (eluent: petroleum ether: ethyl acetate = 5: 1 to 1: 1) to give 3-amino-6-chloro-4-methylpyridinecarbonitrile (600 mg, 69%) as a yellow solid.

[0913] Step C: 6-Chloro-8-methylpyrido[3,2-d]pyrimidin-4-amine. 3-Amino-6-chloro-4-methylpyridinecarbonitrile (1.05 g, 6.27 mmol), formamidine acetate (5.22 g, 50.1 mmol), K3PO4 (13.3 g, 62.7 mmol), and 1,4-dioxane (30 mL) were added to a 100 mL round-bottom flask. The reaction mixture was heated at 90°C for 2 hours. The mixture was then cooled to room temperature, diluted with H2O (100 mL), and extracted with ethyl acetate (60 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give the product, which was purified by FCC (eluent: petroleum ether: ethyl acetate = 1:0 to 1:1) to give 6-chloro-8-methylpyrido[3,2-d]pyrimidin-4-amine (1.0 g, 82%) as a yellow solid. MS (ESI): mass calculated for C8H7ClN4 is 194.0; m / z found is 195.1 [M+H] + .

[0914] Step D: (R)-3-(3-(3-(4-amino-8-methylpyrido[3,2-d]pyrimidin-6-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. A mixture of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 250 mg, 0.651 mmol), 6-chloro-8-methylpyrido[3,2-d]pyrimidin-4-amine (152 mg, 0.781 mmol), K3PO4 (414 mg, 1.95 mmol), 1,4-dioxane (4 mL), and HO (1 mL) was sparged with Ar for 5 minutes, treated with 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (42 mg, 0.064 mmol), and sparged with Ar for an additional 5 minutes. The resulting mixture was subjected to microwave irradiation at 90°C for 1 hour. The resulting mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC using an HPLC column such as Welch Xtimate C18, 150 mm × 25 mm × 5 μm column (eluent: 20% to 50%, water (0.04% NH4OH)-CH3CN) to give the product. The product was suspended in water (10 mL), and the mixture was frozen by inserting into a -78°C bath and then lyophilized to dryness to give (R)-3-(3-(3-(4-amino-8-methylpyrido[3,2-d]pyrimidin-6-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (100 mg, 35%) as a yellow solid. MS (ESI): C22 H 20 The calculated mass of N6O3 is 416.2; the measured m / z is 417.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.73 (s, 1H), 8.57 (d, J = 7.9Hz, 1H), 8.50-8.39 (m, 2H), 8.17 (br s,1H),8.06-7.88(m,2H),7.72-7.61(m,1H),7.31(s,1H),6.99-6.50(m,1H),3. 52-3.40(m,2H),2.85(s,3H),2.68(s,3H),2.62-2.55(m,1H),2.36-2.22(m,1H).

[0915] Example 27: (S)-3-(3-(3-(4-amino-8-methylpyrido[3,2-d]pyrimidin-6-yl)phenyl)isothiazolinone oxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0916]

[0917] Step A: (S)-3-Hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bis(1,3,2-dioxaborolane) (300 mg, 1.18 mmol) was added to (S)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 26, 200 mg, 0.6 mmol) and KOAc (380 mg, 1.79 mmol) in 1,4-dioxane (5 mL). The resulting mixture was aerated with Ar for 5 minutes and then treated with PdCl2(dppf) (43.0 mg, 0.06 mmol) to give a reaction mixture. The reaction mixture was aerated with Ar for another 5 minutes and then subjected to microwave irradiation at 100 ° C for 1 hour. Thereafter, the reaction mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated to dryness under reduced pressure to give the product, which was purified by FCC (eluent: petroleum ether: ethyl acetate = 1: 0 to 0: 1) to give (S) -3-hydroxy-1-methyl-3- (3- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) phenyl) isoxazol-5-yl) pyrrolidin-2-one (156 mg, 62%) as a yellow oil. MS (ESI): C 20 H 25 The calculated mass of BN2O5 is 384.2; the measured m / z is 385.2 [M+H] + .

[0918] Step B: (S)-3-(3-(3-(4-amino-8-methylpyrido[3,2-d]pyrimidin-6-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. 6-Chloro-8-methylpyrido[3,2-d]pyrimidin-4-amine (Example 26, Step C, 51 mg, 0.26 mmol), (S)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (100 mg, 0.26 mmol), K3PO4 (166 mg, 0.78 mmol), 1,4-dioxane (2 mL) and H2O (0.5 mL) were added to a 5 mL microwave tube. The resulting mixture was aerated with Ar for 5 minutes, treated with Pd(dtbpf)Cl2 (17 mg, 0.03 mmol), and aerated with Ar for another 5 minutes to obtain a reaction mixture. The reaction mixture was subjected to microwave irradiation at 90°C for 1 hour. Thereafter, the reaction mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated to dryness under reduced pressure to obtain the product, which was purified by preparative HPLC using an HPLC column such as Welch Xtimate C18 150×25 mm×5 μm column (eluent: 23% to 43% CH3CN and H2O with (0.04% NH4OH+10 mM NH4HCO3)) and by SFC using an SFC column such as DAICEL The product was further purified by AS250mm×30mm, 10μm column (isocratic elution: EtOH (containing 0.1% of 25% NH3): supercritical CO2, 45%: 55%). The fractions containing the product were collected and concentrated under reduced pressure. The product was suspended in water (10mL), and the mixture was frozen by inserting into a -78°C bath and then lyophilized to dryness to give (S)-3-(3-(3-(4-amino-8-methylpyrido[3,2-d]pyrimidin-6-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (36.1mg, 33%) as a colorless solid. MS (ESI): C 22 H 20 The calculated mass of N6O3 is 416.2; the measured m / z is 417.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.70 (s, 1H), 8.53 (d, J = 7.8Hz, 1H), 8.47-8.37 (m, 2H), 8.13 (br s,1H),8.02-7.85(m,2H),7.68-7.57(m,1H),7.26(s,1H),6.72(br s,1H),3.47-3.37(m,2H),2.82(s,3H),2.64(s,3H),2.57-2.52(m,1H),2.30-2.22(m,1H).

[0919] Example 28: (R)-6-(3-(2-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)thiazol-5-yl)phenyl) Pyridineamide .

[0920]

[0921] Step A: 5-(3-bromophenyl)thiazole. Tricyclohexylphosphine tetrafluoroborate (4.3 g, 12 mmol) was added to a mixture of thiazole (5.0 g, 59 mmol), 1,3-dibromobenzene (10.7 mL, 88.1 mmol), PivOH (1.80 g, 17.6 mmol), K2CO3 (12.2 g, 88.1 mmol) and DMA (100 mL). The mixture was purged with Ar three times and then treated with Pd(OAc)2 (1.32 mg, 5.87 mmol). The resulting mixture was heated at 100 ° C for 2 hours. Thereafter, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give the product, which was purified by FCC (eluent: petroleum ether: ethyl acetate = 1:0 to 10:1) to give 5-(3-bromophenyl)thiazole (1.9 g, 13%) as an orange oil. MS (ESI): mass calculated for C9H6BrNS 240.1; m / z found 242.0 [M+H] + .

[0922] Step B: (R,S)-3-(5-(3-bromophenyl)thiazol-2-yl)-3-hydroxy-1-methylpyrrolidin-2-one. Lithium diisopropylamide (5.94 mL, 11.9 mmol, 2.0 M in hexanes) was added to 5-(3-bromophenyl)thiazole (1.9 g, 7.9 mmol) in THF (10 mL) cooled to -72°C. The resulting mixture was stirred at -72°C for 30 minutes, treated with a solution of 1-methylpyrrolidine-2,3-dione (1.07 g, 9.50 mmol) in THF (10 mL) and stirred at -72°C for 1 hour. Afterwards, the reaction mixture was quenched with H2O (50 mL) and extracted with DCM / MeOH (10:1) (50 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by FCC (eluent: methylene chloride:methanol=1:0 to 10:1) to give (R,S)-3-(5-(3-bromophenyl)thiazol-2-yl)-3-hydroxy-1-methylpyrrolidin-2-one (741 mg, 25%) as a brown oil. MS (ESI): C 14 H 13 The calculated mass of BrN2O2S is 350.0; the measured m / z is 353.1 [M+H] + .

[0923] Step C: (R,S)-3-Hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-yl)pyrrolidin-2-one. (R,S)-3-(5-(3-br...

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: A is optionally selected from one to three of -C (1-4) Alkyl and -C (1-4) A 5-membered heteroaryl group substituted with a haloalkyl group; B is furanyl, piperidinyl or a group having the following structure: W is CH2, CHF or CF2; V is N, CH or CR V ; X is N, CH or CR X ; Y is N, CH or CR Y ; Z is N, CH or CR Z ; R V , R X , R Y and R Z are each independently halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl or -OC (1-4) alkyl; R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl; R 2 is -N(H)(5- to 10-membered heteroaryl), -C (6-10) aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, wherein the -N(H)(5- to 10-membered heteroaryl), the -C (6-10) The aryl group, the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or the 5- to 10-membered heteroaryl group are each optionally substituted by one to five R 3 Group substitution; Each R 3 are independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-10) Cycloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 )、-C(O)OH、-C(O)N(R N1 )(R N4 ),-C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (1-3) alkyl (phenyl), 3 to 8 membered heterocyclyl or 5 to 6 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-10) Cycloalkyl, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (1-3) Alkyl (phenyl), 3 to 8 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to five selected from halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C (3-6) Cycloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C (1-4) Alkyl OC (1-4) Alkyl radical substitution; R N1 is hydrogen or C (1-4) alkyl; R N2 , R N3 and R N4 Each occurrence is independently hydrogen, -C (1-4) Alkyl, -C (3-6) Cycloalkyl, -C(O)C (1-4) Alkyl, -C (1-4) alkyl (4 to 6 membered heterocyclyl), 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, wherein the 4 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to three selected from -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) alkyl, -OC (1-4) Haloalkyl and -C(O)C (1-4) Alkyl radical substitution; Provided that at least two of V, X, Y and Z are CH; and The prerequisite is that if R 2 is pyrimidinyl, the pyrimidinyl is replaced by a (1-6) Alkyl and -C(O)N(R N1 )(R N4 ) and optionally further substituted by one to two R 3 Group substitution.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: A is optionally selected from one to three of -C (1-4) Alkyl and -C (1-4) A 5-membered heteroaryl group substituted with a haloalkyl group; B is furanyl, piperidinyl or a group having the following structure: W is CH2 or CF2; V is N, CH or CR V ; X is N, CH or CR X ; Y is N, CH or CR Y ; Z is N, CH or CR Z ; R V , R X , R Y and R Z are each independently halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl or -OC (1-4) alkyl; R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl; R 2 is -N(H)(5- to 10-membered heteroaryl), -C (6-10) aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, wherein: the -N(H)(5- to 10-membered heteroaryl) is optionally substituted by one to five R 3a The -C (6-10) The aryl group is optionally substituted by one to five R 3b The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 3c and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 3d Group substitution; R 3a and R 3b Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 ) or -C(O)N(R N1 )(R N4 ); R 3c and R 3d Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-10) Cycloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 )、-C(O)OH、-C(O)N(R N1 )(R N4 ),-C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (1-3) alkyl (phenyl), 3 to 8 membered heterocyclyl or 5 to 6 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-10) Cycloalkyl, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (1-3) Alkyl (phenyl), 3 to 8 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to five selected from halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C (3-6) Cycloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C (1-4) Alkyl OC (1-4) Alkyl radical substitution; R N1 is hydrogen or C (1-4) alkyl; R N2 , R N3 and R N4 Each occurrence is independently hydrogen, -C (1-4) Alkyl, -C (3-6) Cycloalkyl, -C(O)C (1-4) Alkyl, -C (1-4) alkyl (4 to 6 membered heterocyclyl), 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, wherein the 4 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to three selected from -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) alkyl, -OC (1-4) Haloalkyl and -C(O)C (1-4) Alkyl radical substitution; Provided that at least two of V, X, Y and Z are CH; and The prerequisite is that if R 2 is pyrimidinyl, the pyrimidinyl is replaced by a (1-6) Alkyl and -C(O)N(R N1 )(R N4 ) and optionally further substituted by one to two R 3d Group substitution.

3. The compound according to claim 1 or claim 2 or a pharmaceutically acceptable salt thereof, wherein: A is optionally selected from one to three of -C (1-4) Alkyl and -C (1-4) A 5-membered heteroaryl group substituted with a haloalkyl group; B is furanyl, piperidinyl or a group having the following structure: W is CH2 or CF2; V is N, CH or CR V ; X is N, CH or CR X ; Y is N, CH or CR Y ; Z is N, CH or CR Z ; R V is a halo group; R X , R Y and R Z are each independently halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl or -OC (1-4) alkyl; R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl; R 2 is -N(H)(5- to 10-membered heteroaryl), -C (6-10) aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, wherein: the -N(H)(5- to 10-membered heteroaryl) is optionally substituted by one to five R 3a The -C (6-10) The aryl group is optionally substituted by one to five R 3b The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 3c and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 3d Group substitution; R 3a and R 3b Each occurrence is independently -N(R N1 )(R N2 ) or -C(O)N(R N1 )(R N4 ); Each R 3c Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 )、-C(O)OH、-C(O)N(R N1 )(R N4 ) or -C (1-3) Alkyl(phenyl); Each R 3d Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-10) Cycloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 )、-C(O)N(R N1 )(R N4 ),-C (1-3) alkyl(3 to 8 membered heterocyclyl), 3 to 8 membered heterocyclyl or 5 to 6 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-10) Cycloalkyl, -C (1-3) Alkyl (3 to 8 membered heterocyclyl), 3 to 8 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C (3-6) Cycloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C (1-4) Alkyl OC (1-4) Alkyl radical substitution; R N1 is hydrogen or C (1-4) alkyl; R N2 It is hydrogen, -C (1-4) Alkyl, -C (3-6) Cycloalkyl, -C(O)C (1-4) Alkyl, -C (1-4) alkyl (4 to 6 membered heterocyclyl), 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, wherein the 4 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to three selected from -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C(O)C (1-4) Alkyl radical substitution; R N3 It is hydrogen, -C (3-6) Cycloalkyl or 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is optionally further substituted with one to three -C (1-4) Alkyl group substitution; R N4 It is hydrogen, -C (1-4) Alkyl or 4 to 6 membered heterocyclic group; Provided that at least two of V, X, Y and Z are CH; and The prerequisite is that if R 2 is pyrimidinyl, the pyrimidinyl is replaced by a (1-6) Alkyl and -C(O)N(R N1 )(R N4 ) and optionally further substituted by one to two R 3d Group substitution.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein: A is optionally replaced by one to three -C (1-4) 5-membered heteroaryl substituted with an alkyl group; B is furanyl, piperidinyl or a group having the following structure: W is CH2 or CF2; V is N, CH or CR V ; X is N, CH or CR X ; Y is N, CH or CR Y ; Z is N, CH or CR Z ; R V is a halo group; R X , R Y and R Z are each independently halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl or -OC (1-4) alkyl; R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl; R 2 is -N(H)(5- to 10-membered heteroaryl), -C (6-10) aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, wherein: the -N(H)(5- to 10-membered heteroaryl) is optionally replaced by one -N(R N1 )(R N2 ) group, the -C (6-10) The aryl group is optionally substituted with a -C(O)N(R N1 )(R N4 ) group, wherein the 5 to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 3c and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 3d Group substitution; Each R 3c Each occurrence is independently -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -C(O)OH, -C(O)N(R N1 )(R N4 ) or -C (1-3) Alkyl(phenyl); Each R 3d Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 )、-C(O)N(R N1 )(R N4 ),-C (1-3) alkyl (3 to 8 membered heterocyclyl), 3 to 8 membered heterocyclyl or 5 to 6 membered heteroaryl, wherein the 3 to 8 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to five selected from halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C (3-6) Cycloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C (1-4) Alkyl OC (1-4) Alkyl radical substitution; R N1 is hydrogen or C (1-4) alkyl; R N2 It is hydrogen, -C (1-4) Alkyl, -C (3-6) Cycloalkyl, -C(O)C (1-4) Alkyl, -C (1-4) alkyl (4 to 6 membered heterocyclyl), 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, wherein the 4 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to three selected from -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C(O)C (1-4) Alkyl radical substitution; R N3 It is hydrogen, -C (3-6) Cycloalkyl or 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is optionally further substituted with one to three -C (1-4) Alkyl group substitution; R N4 It is hydrogen, -C (1-4) Alkyl or 4 to 6 membered heterocyclic group; Provided that at least two of V, X, Y and Z are CH; and The prerequisite is that if R 2 is pyrimidinyl, the pyrimidinyl is replaced by a (1-6) Alkyl and -C(O)N(R N1 )(R N4 ) and optionally further substituted by one to two R 3d Group substitution.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein: A is optionally replaced by a-C (1-4) 5-membered heteroaryl substituted with an alkyl group; B is: W is CH2 or CF2; V is N, CH or CF; X is N, CH or CR X ; Y is N, CH or CR Y ; Z is N, CH or CR Z ; R X , R Y and R Z are each independently fluorine, -CH3 or -OCH3; R 1 is hydrogen or -CF3; R 2 is -N(H)(5- to 10-membered heteroaryl), -C (6-10) aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, wherein: the -N(H)(5- to 10-membered heteroaryl) is optionally substituted with one -NH2 group, the -C (6-10) The aryl group is optionally substituted with a -C(O)NH2 group, and the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with one to five R 3c and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 3d Group substitution; Each R 3c Each occurrence is independently -NH2, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -C(O)OH, -C(O)NH2 or -C (1-3) Alkyl(phenyl); Each R 3d Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 )、-C(O)N(R N1 )(R N4 ),-C (1-3) alkyl (3 to 8 membered heterocyclyl), 3 to 8 membered heterocyclyl or 5 to 6 membered heteroaryl, wherein the 3 to 8 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to five selected from halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C (3-6) Cycloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C (1-4) Alkyl OC (1-4) Alkyl radical substitution; R N1 It is hydrogen; R N2 It is hydrogen, -C (1-4) Alkyl, -C (3-6) Cycloalkyl, -C(O)C (1-4) Alkyl, -C (1-4) alkyl (4 to 6 membered heterocyclyl), 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, wherein the 4 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to three selected from -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C(O)C (1-4) Alkyl radical substitution; R N3 It is hydrogen, -C (3-6) Cycloalkyl or 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is optionally further substituted with one to three -C (1-4) Alkyl group substitution; R N4 It is hydrogen, -C (1-4) Alkyl or 4 to 6 membered heterocyclic group; Provided that at least two of V, X, Y and Z are CH; and The prerequisite is that if R 2 is pyrimidinyl, the pyrimidinyl is replaced by a (1-6) Alkyl and -C(O)N(R N1 )(R N4 ) and optionally further substituted by one to two R 3d Group substitution.

6. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted by a -C (1-4) A 5-membered heteroaryl substituted with an alkyl group.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein A is oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl or triazolyl, each of which is optionally substituted with a methyl group. 8 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is isoxazolyl or pyrazolyl.

9. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein A is:

10. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein A is 11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein W is CH2.

12. A compound according to any one of claims 1 to 4 or 6 to 11, or a pharmaceutically acceptable salt thereof, wherein B is:

13. A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein B is 14. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein R V , R X , R Y and R Z Each is independently fluorine, -CH3 or -OCH3.

15. The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein V is N, CH or CF; X is N, CH, CF or C-CH3; Y is N, CH, CF, C-CH3 or C-OCH3; and Z is N, CH, CF or C-CH3.

16. A compound according to any one of claims 1 to 12, 14 or 15, or a pharmaceutically acceptable salt thereof, wherein B is:

17. A compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein B is 18. A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein R 1 It is hydrogen or -CF3.

19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of any one of formulas Id-1 to Id-5:

20. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of any one of formulas Ie-1 to Ie-6:

21. A compound according to any one of claims 2 to 20, or a pharmaceutically acceptable salt thereof, wherein R 2 is optionally replaced by one to five R 3a -N(H)(5- to 10-membered heteroaryl) substituted with a group.

22. A compound according to any one of claims 2 to 21 or a pharmaceutically acceptable salt thereof, wherein R 2 is optionally replaced by one to five R 3a -N(H)(9- to 10-membered heteroaryl) substituted with a group.

23. A compound according to any one of claims 2 to 22, or a pharmaceutically acceptable salt thereof, wherein R 3a Yes-N(R N1 )(R N2 ).

24. A compound according to any one of claims 2 to 23, or a pharmaceutically acceptable salt thereof, wherein R 3a It is -NH2.

25. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R 2 yes 26. A compound according to any one of claims 2 to 20, or a pharmaceutically acceptable salt thereof, wherein R 2 is optionally replaced by one to five R 3b -C (6-10) Aryl.

27. A compound according to any one of claims 2 to 20 or 26, or a pharmaceutically acceptable salt thereof, wherein R 3b Yes-C(O)N(R N1 )(R N4 ).

28. A compound according to any one of claims 2 to 20, 26 or 27, or a pharmaceutically acceptable salt thereof, wherein R 3b It is -C(O)NH2.

29. A compound according to any one of claims 1 to 20 or 26 to 28, or a pharmaceutically acceptable salt thereof, wherein R 2 yes 30. A compound according to any one of claims 2 to 20, or a pharmaceutically acceptable salt thereof, wherein R 2 is optionally replaced by one to five R 3c A 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms which is substituted by a radical.

31. A compound according to any one of claims 2 to 20 or 30, or a pharmaceutically acceptable salt thereof, wherein R 2 yes:

32. A compound according to any one of claims 2 to 20, 30 or 31, or a pharmaceutically acceptable salt thereof, wherein R 2 yes:

33. A compound according to any one of claims 2 to 3, 6 to 20 or 30 to 32, or a pharmaceutically acceptable salt thereof, wherein R 3c Each occurrence is independently -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -C(O)OH, -C(O)N(R N1 )(R N4 ) or -C (1-3) Alkyl(phenyl).

34. A compound according to any one of claims 2 to 20 or 30 to 33, or a pharmaceutically acceptable salt thereof, wherein R 3c Each occurrence is independently -NH2, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -C(O)OH, -C(O)NH2 or -C (1-3) Alkyl(phenyl).

35. A compound according to any one of claims 1 to 20 or 30 to 34, or a pharmaceutically acceptable salt thereof, wherein R 2 yes:

36. A compound according to any one of claims 1 to 20 or 30 to 34, or a pharmaceutically acceptable salt thereof, wherein R 2 yes:

37. A compound according to any one of claims 2 to 20, or a pharmaceutically acceptable salt thereof, wherein R 2 is optionally replaced by one to five R 3d A 5- to 10-membered heteroaryl group is substituted with a moiety.

38. A compound according to any one of claims 2 to 20 or 37, or a pharmaceutically acceptable salt thereof, wherein R 2 is a 5- to 6-membered monocyclic heteroaryl or a 9- to 10-membered bicyclic heteroaryl, each of which is optionally substituted by one to five R 3d Group substitution.

39. A compound according to any one of claims 2 to 20, 37 or 38, or a pharmaceutically acceptable salt thereof, wherein R 2 is pyrazolyl, imidazolyl, furanyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, indazolyl, benzimidazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolopyridazinyl, pyrrolotriazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, triazolopyridinyl, quinazolinyl, isoquinolinonyl, quinazolinonyl, pyridopyrimidinyl, pyridopyrimidonyl, pyrimidopyrimidinyl, benzoxazolyl, thiazolopyrimidinyl, furopyridinyl or thienopyrimidinyl, each of which is optionally substituted by one to three R 3d Group substitution.

40. A compound according to any one of claims 2 to 20 or 37 to 39, or a pharmaceutically acceptable salt thereof, wherein R 2 is thiazolyl, pyridyl, pyrimidinyl, indazolyl, pyrazolopyrimidinyl or imidazopyridinyl, each of which is optionally substituted by one to three R 3d Group substitution.

41. A compound according to any one of claims 2 to 20 or 37 to 39, or a pharmaceutically acceptable salt thereof, wherein R 2 yes:

42. A compound according to any one of claims 2 to 20 or 37 to 41, or a pharmaceutically acceptable salt thereof, wherein each R 3d Each occurrence is independently halo, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl-N(R N1 )(R N3 )、-C(O)N(R N1 )(R N4 ),-C (1-3) alkyl (3 to 8 membered heterocyclyl), 3 to 8 membered heterocyclyl or 5 to 6 membered heteroaryl, wherein the 3 to 8 membered heterocyclyl and 5 to 6 membered heteroaryl are optionally further substituted by one to five selected from halo, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -C (3-6) Cycloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl and -C (1-4) Alkyl OC (1-4) Alkyl radicals are substituted.

43. A compound according to any one of claims 2 to 20 or 37 to 42, or a pharmaceutically acceptable salt thereof, wherein each R 3d Each occurrence is independently -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -C(O)N(R N1 )(R N4 ) or a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heteroaryl group is optionally further substituted with one to three -C (1-4) Alkyl group substitution.

44. A compound according to any one of claims 1 to 20, 37 to 39, 41 or 42, or a pharmaceutically acceptable salt thereof, wherein R 2 yes:

45. A compound according to any one of claims 1 to 20, 37 to 39, 41, 42 or 44, or a pharmaceutically acceptable salt thereof, wherein R 2 yes:

46. ​​A compound according to any one of claims 1 to 20 or 37 to 44, or a pharmaceutically acceptable salt thereof, wherein R 2 yes:

47. A compound according to any one of claims 1 to 20 or 37 to 46, or a pharmaceutically acceptable salt thereof, wherein R 2 yes 48. A compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein R N1 It's hydrogen.

49. A compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein R N2 is hydrogen, 4 to 6 membered heterocyclyl or 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is optionally further substituted with one to three -C (1-4) Alkyl group substitution.

50. A compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein R N4 It's hydrogen.

51. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula If: in: A is isoxazolyl; Z is N or CH; R 2 is optionally replaced by one to three R 3d substituted 5- to 10-membered heteroaryl; Each R 3d Each occurrence is independently -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-10) Cycloalkyl, -C(O)N(R N1 )(R N4 ) or a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heteroaryl group is optionally further substituted with one to three -C (1-4) Alkyl group substitution; R N1 It is hydrogen; R N2 is hydrogen, 4 to 6 membered heterocyclyl or 5 to 6 membered heteroaryl, wherein the 5 to 6 membered heteroaryl is optionally further substituted with one to three -C (1-4) Alkyl group substituted; and R N4 It is hydrogen; The prerequisite is that if R 2 is a pyrimidinyl group, the pyrimidinyl group is replaced by a -C(O)N(R N1 )(R N4 ) group and optionally further substituted by one to two R 3d Group substitution.

52. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having a structure selected from the group consisting of those in any one of Table 1A to Table 1J.

53. The compound according to claim 52, or a pharmaceutically acceptable salt thereof, having a structure selected from the group consisting of:

54. The compound according to claim 53 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

55. The compound according to claim 53 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

56. The compound according to claim 53 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

57. The compound according to claim 53 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

58. The compound according to claim 53 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

59. The compound according to claim 53 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

60. The compound according to claim 53 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

61. The compound according to claim 53 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

62. The compound according to claim 53 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

63. The compound according to claim 53 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

64. A pharmaceutical composition comprising a compound according to any one of claims 1 to 63 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

65. A method of treating a disease, disorder or medical condition mediated by NIK activity, the method comprising administering to a subject in need of such treatment an effective amount of (i) a compound according to any one of claims 1 to 63 or a pharmaceutically acceptable carrier thereof, or (ii) a pharmaceutical composition according to claim 64.

66. The method of claim 65, wherein the disease, disorder or medical condition mediated by NIK activity is selected from the group consisting of an inflammatory disorder and an autoimmune disorder.

67. The method of claim 66, wherein the disease, disorder or medical condition mediated by NIK activity is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome and lupus nephritis.

68. The method of claim 65, wherein the disease, disorder or medical condition mediated by NIK activity is selected from the group consisting of an inflammatory disorder, an autoimmune disorder, cancer, a metabolic disorder and osteoporosis.

69. The method of claim 68, wherein the disease, disorder or medical condition mediated by NIK activity is selected from the group consisting of systemic lupus erythematosus ("SLE"), rheumatoid arthritis ("RA"), Sjögren's syndrome, lupus nephritis, inflammatory bowel disease ("IBD"), ANCA-associated vasculitis, myositis, IgG4-associated disease, bullous pemphigoid, neuromyelitis optica spectrum disorder ("NMOSD"), atopic dermatitis ("AD"), hidradenitis suppurativa ( "HS"), steatosis, nonalcoholic steatohepatitis ("NASH"), primary biliary cirrhosis, leukemia, lymphoma, pancreatic cancer, breast cancer, melanoma, obesity, diabetes, acute kidney injury, IgAN, autosomal dominant polycystic kidney disease ("ADCKD"), membranous nephropathy, osteoporosis, bone resorption (periodontitis), multiple sclerosis ("MS"), immune thrombocytopenic purpura, transplantation, myasthenia gravis, scleroderma, myositis, IgG4-related disease, and bullous pemphigoid.

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