Pyrrolidone derivatives as inhibitors of NF-kB-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 / 364,549, filed May 11, 2022, the entire disclosure of which is hereby incorporated by reference herein. 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 particularly discloses compounds of formula I':

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein A, W, X, Y, R 1 、R 2 , L, R 3 、R 4 and R 5 As defined herein.

[0009] The present application also discloses compounds of formula I:

[0010]

[0011] or a pharmaceutically acceptable salt thereof, wherein A, W, X, Y, R 1 、R 2 , L and R 3 As defined herein.

[0012] The present application also discloses a pharmaceutical composition comprising a compound of Formula I' or Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0013] 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 Formula I or a pharmaceutically acceptable carrier thereof, or (ii) a pharmaceutical composition comprising a compound of Formula I' or 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. DETAILED DESCRIPTION

[0014] 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.

[0015] 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.

[0016] 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 one method to alleviate or eliminate the adverse effects associated with this increase is NIK inhibition.

[0017] 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.

[0018] 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 initiated by preformed antibodies and requires only intact neutrophils and the complement system 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).

[0019] 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., Invest. 2002; 109(1):59-68) and proliferative lupus glomerulonephritis (DT Boumpas et al., Arthritis & Rheumatism 2003; 48(3):719-27).

[0020] definition

[0021] 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.

[0022] 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.

[0023] As used herein, the terms "including," "containing," and "comprising" are used in their open, non-limiting sense.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] The term "alkylene" refers to a group derived from a group having 1 to 12 carbon atoms (i.e., (C1-C 12 )alkylene), a straight or branched chain saturated divalent hydrocarbon portion of an alkane of 1 to 6 carbon atoms (i.e., (C1-C6)alkylene), 1 to 4 carbon atoms (i.e., (C1-C4)alkylene), or 1 to 3 carbon atoms (i.e., (C1-C3)alkylene). Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), -C(CH3)H-, propylene (-CH2CH2CH2-), isopropylene (-CH(CH3)CH2-), and -CH2CH(CH3)-. In one embodiment, alkylene refers to C (1-4) In another embodiment, alkylene refers to C (1-2) Alkylene.

[0033] The term "halo" or "halogen" refers to bromo (-Br), chloro (-Cl), fluoro (-F), or iodo (-I). In one embodiment, halo refers to fluoro.

[0034] 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 replacing one or more H with a halo group. 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.

[0035] 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.

[0036] The term "cycloalkylene" refers to a group derived from a group having, for example, 3 to 10 carbon atoms (ie, C (3-10) cycloalkylene), 3 to 8 carbon atoms (i.e., C (3-8) cycloalkylene) or 3 to 6 carbon atoms (i.e., C(3-6) All divalent saturated or partially unsaturated carbon ring systems of cycloalkanes (cycloalkylene), wherein the cycloalkyl ring system has a single ring or multiple rings in a spiro or bridged configuration. Examples of alkylene include, but are not limited to In one embodiment, cycloalkylene refers to a C (3-10) In another embodiment, cycloalkylene refers to C (3-8) In another embodiment, cycloalkyl refers to C (3-6) Cycloalkylene.

[0037] 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.

[0038] The term "heterocyclyl" 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 (such as lactones) and cyclic amides (such as lactams). Exemplary heterocycles include but are not limited to oxetanes, aziridines, azetidinyls, pyrrolidinyls, pyrrolidonyls, piperidyls, piperazinyls, morpholinyls, tetrahydropyranyls, tetrahydrofuranyls and thiomorpholinyls. Unless otherwise indicated, heterocyclyl groups are connected to their side groups at any heteroatom or carbon atom producing a stable structure. In one embodiment, heterocyclyl refers to a 3 to 10 yuan heterocyclyl. In another embodiment, heterocyclyl refers to a 3 to 8 yuan heterocyclyl. In another embodiment, heterocyclyl refers to a 3 to 6 yuan heterocyclyl.

[0039] 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 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 aromatic. 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.

[0040] 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 the case of a 5-membered ring, in some embodiments, the heteroaryl ring contains one member of nitrogen, oxygen, or sulfur, and in addition up to 3 additional nitrogens. In the case of a 6-membered ring, in some embodiments, the heteroaryl ring contains 1 to 3 nitrogen atoms. For cases where the 6-membered ring has 3 nitrogen atoms, 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.

[0041] 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.

[0042] 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.

[0043] "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of one another.

[0044] "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.

[0045] 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.

[0046] 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.

[0047] Certain examples contain chemical structures depicted or labeled as (*R) or (*S). When (*R) or (*S) is used in the name of a compound or in the chemical representation of a compound, it is intended to indicate that the compound is a pure single isomer at that stereocenter; however, the absolute configuration at that stereocenter has not been determined. Thus, a compound designated as (*R) refers to a compound having the (R) or (S) absolute configuration at that stereocenter as a pure single isomer, and a compound designated as (*S) refers to a compound having the (R) or (S) absolute configuration at that stereocenter as a pure single isomer. For example, (R)-3-hydroxy-1-methan-3-(3-(6-(2-(((*S)-6-methyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)amino)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one:

[0048] means one of the following compounds:

[0049]

[0050] Although pseudoasymmetric stereogenic centers are treated in the same manner as chiral centers, the former are given lowercase letter symbols, r or s (Angew. Chem. Int. Ed. Engl. 1982, 21, 567-583).

[0051] 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.

[0052] 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 3H (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 (ie, tritium or T). For example, the group Also covers Etc. Similarly, references to carbon and oxygen include within their scope 12 C. 13 C and 14 C and 15 O. 16 O. 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.

[0053] 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.

[0054] 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.

[0055] "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", J Pharm 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.

[0056] Compounds of the present disclosure

[0057] The present application discloses a compound of formula I':

[0058]

[0059] or a pharmaceutically acceptable salt thereof, wherein:

[0060] A is optionally replaced by one or more -C (1-4) a 5-membered heteroaryl substituted with an alkyl group;

[0061] W is CH2, CHF, CF2 or CHR W ;

[0062] X is N, CH or CR X ;

[0063] Y is N, CH or CR Y ;

[0064] R W -C (1-4) Alkyl or -C (1-4) alkyl halide;

[0065] R X is a halogenated group, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl or -C (1-4) Alkyl-OC (1-4) alkyl;

[0066] R Y is a halogenated group, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl or -C (1-4) Alkyl-OC (1-4) alkyl;

[0067] R 1 For hydrogen, -C (1-4) Alkyl or -C (1-4) haloalkyl; or wherein R W and R 1 Together with the carbon atoms to which they are attached to form C (3-5) Cycloalkyl;

[0068] R 2 is hydrogen or -C (1-4) alkyl;

[0069] L does not exist, is -C (1-4) Alkylene or -C (3-6) Cycloalkylene, wherein the -C (1-4) Alkylene and -C (3-6) Cycloalkylene is optionally substituted by one to three groups selected from halo, -OH, -N(R N1 )(R N2 ),-C (1-3) Alkyl, -C (1-3) Haloalkyl, -C (3-5) Cycloalkyl and -OC (1-3) Alkyl radical substitution;

[0070] R 3 -C (1-10) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, -C (6-10) Aryl, 5- to 10-membered heteroaryl, or -C(O)N(R N3 )(R N4 ), where -C (1-10) Alkyl, -C (3-10)Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, -C (6-10) Aryl and 5- to 10-membered heteroaryl are each optionally substituted by one to five R 3x group substitution;

[0071] Each R 3x Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-8) Alkyl, -C (1-8) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-8) Alkyl, -OC (1-8) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-8) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-8) Alkyl, -C(O)C (1-8) Alkyl, -S(O)2C (1-8) Alkyl, -S(O)2C (3-8) Cycloalkyl, -N(H)S(O)2C (1-8) Alkyl, -C (0-8) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-8) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5- to 10-membered heteroaryl, wherein the -C (1-8) Alkyl, -C (1-8) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-8) Alkyl, -OC (1-8) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-8) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-8) Alkyl, -C(O)C (1-8) Alkyl, -S(O)2C (1-8) Alkyl, -S(O)2C (3-8) Cycloalkyl, -N(H)S(O)2C (1-8) Alkyl, 3 to 8 membered heterocyclic group, -C (1-8) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C(1-8) Alkyl, -C (1-8) Haloalkyl, -OC (1-8) Alkyl, -OC (1-8) a haloalkyl group and a 3- to 5-membered heterocyclic group; or

[0072] R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic group, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, each of which is optionally further substituted by one to three groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-8) Alkyl and -OC (1-8) Alkyl groups substituted, wherein the -C (1-8) Alkyl and -OC (1-8) The alkyl group is optionally further substituted with one to five halo groups;

[0073] R 4 is hydrogen, halo or -C (1-4) alkyl;

[0074] R 5 is hydrogen, halo or -C (1-4) alkyl;

[0075] R N1 and R N2 Each occurrence is independently hydrogen, -C (1-8) Alkyl or -C (1-8) alkyl halide;

[0076] R N3 is hydrogen or -C (1-8) alkyl; and

[0077] R N4 For hydrogen, -C (1-8) Alkyl or phenyl; or R N3 and R N4 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic group, which is optionally substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-8) Alkyl, -C (1-8) Haloalkyl, -OC (1-8) Alkyl and -OC (1-8) The haloalkyl group is substituted.

[0078] In some embodiments, disclosed herein are compounds of formula I' as described above, wherein if R 3-C(O)N(R N3 )(R N4 ), then L does not exist.

[0079] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0080] A is optionally replaced by one or more -C (1-4) a 5-membered heteroaryl substituted with an alkyl group;

[0081] W is CH2, CHF, CF2 or CHR W ;

[0082] X is N, CH or CR X ;

[0083] Y is N, CH or CR Y ;

[0084] R W -C (1-4) Alkyl or -C (1-4) alkyl halide;

[0085] R X is a halo group;

[0086] R Y is a halogenated group, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl or -C (1-4) Alkyl-OC (1-4) alkyl;

[0087] R 1 For hydrogen, -C (1-4) Alkyl or -C (1-4) haloalkyl; or wherein R W and R 1 Together with the carbon atoms to which they are attached to form C (3-5) Cycloalkyl;

[0088] R 2 is hydrogen or -C (1-4) alkyl;

[0089] L does not exist, is -C (1-4) Alkylene or -C (3-6) Cycloalkylene, wherein the -C (1-4) Alkylene and -C (3-6) Cycloalkylene is optionally substituted by one to three groups selected from halo, -OH, -N(R N1 )(R N2 ),-C(1-3) Alkyl, -C (1-3) Haloalkyl, -C (3-5) Cycloalkyl and -OC (1-3) Alkyl radical substitution;

[0090] R 3 -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, -C (6-10) Aryl, 5- to 10-membered heteroaryl, or -C(O)N(R N3 )(R N4 ), where -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, -C (6-10) Aryl and 5- to 10-membered heteroaryl are each optionally substituted by one to five R 3x group substitution;

[0091] Each R 3x Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -S(O)2C (3-8) Cycloalkyl, -N(H)S(O)2C (1-4) Alkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5- to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8)Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -S(O)2C (3-8) Cycloalkyl, -N(H)S(O)2C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) a haloalkyl group and a 3- to 5-membered heterocyclic group; or

[0092] R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic group, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, each of which is optionally further substituted by one to three groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl and -OC (1-6) Alkyl groups substituted, wherein the -C (1-6) Alkyl and -OC (1-6) The alkyl group is optionally further substituted with one to five halo groups;

[0093] R 4 is hydrogen, halo or -C (1-4) alkyl;

[0094] R 5 is hydrogen, halo or -C (1-4) alkyl;

[0095] R N1 and R N2 Each occurrence is independently hydrogen, -C (1-3) Alkyl or -C (1-3) alkyl halide;

[0096] R N3 is hydrogen or -C (1-4) alkyl; and

[0097] R N4For hydrogen, -C (1-4) Alkyl or phenyl; or R N3 and R N4 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic group, which is optionally substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl radical substitution;

[0098] If R 3 -C(O)N(R N3 )(R N4 ), then L does not exist.

[0099] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0100] A is optionally replaced by a -C (1-4) a 5-membered heteroaryl substituted with an alkyl group;

[0101] W is CH2, CF2 or CHR W ;

[0102] X is N, CH or CR X ;

[0103] Y is N, CH or CR Y ;

[0104] R W -C (1-4) Alkyl, -C (1-4) Haloalkyl, or R W and R 1 Together with the carbon atoms to which they are attached to form C (3-5) Cycloalkyl;

[0105] R X is a halo group;

[0106] R Y is a halogenated group, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl or -C (1-4) Alkyl-OC (1-4) alkyl;

[0107] R 1 For hydrogen, -C (1-4)Alkyl or -C (1-4) alkyl halide;

[0108] R 2 is hydrogen;

[0109] L does not exist, is -C (1-4) Alkylene or -C (3-6) Cycloalkylene, wherein the -C (1-4) Alkylene and -C (3-6) Cycloalkylene is optionally substituted by one to three groups selected from halo, -OH, -N(R N1 )(R N2 ),-C (1-3) Alkyl, -C (1-3) Haloalkyl, -C (3-5) Cycloalkyl and -OC (1-3) Alkyl radical substitution;

[0110] R 3 -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, -C (6-10) Aryl, 5- to 10-membered heteroaryl, or -C(O)N(R N3 )(R N4 ), where: (1-6) The alkyl group is optionally substituted by one to five R 3a Group substitution; the -C (3-10) The cycloalkyl group is optionally substituted by one to five R 3b The 3 to 10 membered heterocyclic group is optionally substituted by one to five R 3c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 3d Replace; the -C (6-10) The aryl group is optionally substituted by one to five R 3e and the 5- to 10-membered heteroaryl is optionally substituted by one to five R 3f group substitution;

[0111] Each R 3a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) alkyl or 3 to 8 membered heterocyclic group, wherein the -C(3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl and 3 to 8 membered heterocyclic groups are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl radical substitution;

[0112] 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 (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -S(O)2C (3-8) Cycloalkyl, -N(H)S(O)2C (1-4) Alkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8-membered heterocyclyl or 5 to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) The haloalkyl, 3- to 8-membered heterocyclyl and 5- to 10-membered heteroaryl groups are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl radical substitution;

[0113] R 3e and R 3f Each occurrence is independently halo, -OH, -N(R N1)(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5- to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) a haloalkyl group and a 3- to 5-membered heterocyclic group; or

[0114] R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally substituted by one to three substituted radicals selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) haloalkyl radical substitution;

[0115] R 4 is hydrogen, halo or -C (1-4) alkyl;

[0116] R 5 is hydrogen, halo or -C (1-4) alkyl;

[0117] R N1 and R N2 Each occurrence is independently hydrogen or -C (1-3) alkyl;

[0118] R N3 is hydrogen or -C (1-4) alkyl; and

[0119] R N4 For hydrogen, -C (1-4) Alkyl or phenyl; or R N3 and R N4 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic group, which is optionally substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl radical substitution;

[0120] If R 3 -C(O)N(R N3 )(R N4 ), then L does not exist.

[0121] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0122] A is optionally replaced by a -C (1-4) a 5-membered heteroaryl substituted with an alkyl group;

[0123] W is CH2, CF2 or CHR W ;

[0124] X is N, CH or CR X ;

[0125] Y is N, CH or CR Y ;

[0126] R W -C (1-4) Alkyl, -C (1-4) Haloalkyl, or R W and R1 Together with the carbon atoms to which they are attached to form C (3-5) Cycloalkyl;

[0127] R X is a halo group;

[0128] R Y -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl or -C (1-4) Alkyl-OC (1-4) alkyl;

[0129] R 1 For hydrogen, -C (1-4) Alkyl or -C (1-4) alkyl halide;

[0130] R 2 is hydrogen;

[0131] L does not exist, is -C (1-4) Alkylene or -C (3-6) Cycloalkylene, wherein the -C (1-4) Alkylene and -C (3-6) Cycloalkylene is optionally substituted by one to three groups selected from halo, -OH, -N(R N1 )(R N2 ),-C (1-3) Alkyl, -C (1-3) Haloalkyl, -C (3-5) Cycloalkyl and -OC (1-3) Alkyl radical substitution;

[0132] R 3 -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, -C (6-10) Aryl, 5- to 10-membered heteroaryl, or -C(O)N(R N3 )(R N4 ), where: (1-6) The alkyl group is optionally substituted by one to five R 3a Group substitution; the -C (3-10) The cycloalkyl group is optionally substituted by one to five R 3b The 3 to 10 membered heterocyclic group is optionally substituted by one to five R 3c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 3d substituted; and the 5- to 10-membered heteroaryl is optionally substituted by one to five R 3f group substitution;

[0133] Each R 3a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ),-CN,-OC (1-6) Alkyl or -OC (1-6) alkyl halide;

[0134] 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 (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -S(O)2C (1-4) Alkyl or -S(O)2C (3-8) Cycloalkyl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) The haloalkyl group is optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN and -OC (1-4) Alkyl radical substitution;

[0135] Each R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5- to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6)Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) a haloalkyl group and a 3- to 5-membered heterocyclic group; or

[0136] R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, each of which is optionally further substituted by one to three groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) haloalkyl radical substitution;

[0137] R 4 is hydrogen, halo or -C (1-4) alkyl;

[0138] R 5 is hydrogen, halo or -C (1-4) alkyl;

[0139] R N1 and R N2 Each occurrence is independently hydrogen or -C (1-3) alkyl;

[0140] R N3 is hydrogen or -C (1-4) alkyl; and

[0141] R N4 For hydrogen, -C (1-4) Alkyl or phenyl; or R N3 and R N4Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic group, which is optionally substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl radical substitution;

[0142] If R 3 -C(O)N(R N3 )(R N4 ), then L does not exist.

[0143] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0144] A is a 5-membered heteroaryl group optionally substituted with one -CH3 group;

[0145] W is CH2, CF2 or CHR W ;

[0146] X is N, CH or CR X ;

[0147] Y is N, CH or CR Y ;

[0148] R W -C (1-4) Alkyl, -C (1-4) Haloalkyl, or R W and R 1 Together with the carbon atoms to which they are attached to form C (3-5) Cycloalkyl;

[0149] R X is a halo group;

[0150] R Y -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl or -C (1-4) Alkyl-OC (1-4) alkyl;

[0151] R 1 For hydrogen, -C (1-4) Alkyl or -C (1-4) alkyl halide;

[0152] R 2 is hydrogen;

[0153] L does not exist, is -C (1-4) Alkylene or -C (3-6) Cycloalkylene, wherein the -C (1-4) The alkylene group is optionally substituted by one to three groups selected from halo, -OH, -N(R N1 )(R N2 ) and cyclopropyl;

[0154] R 3 -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, phenyl, 5- to 10-membered heteroaryl, or -C(O)N(R N3 )(R N4 ); where: the -C (1-6) The alkyl group is optionally substituted by one to five R 3a Group substitution; the -C (3-10) The cycloalkyl group is optionally substituted by one to five R 3b The 3 to 10 membered heterocyclic group is optionally substituted by one to five R 3c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 3d substituted; and the 5- to 10-membered heteroaryl is optionally substituted by one to five R 3f group substitution;

[0155] Each R 3a Each occurrence is independently halo, -OH, -OC (1-6) Alkyl or -OC (1-6) alkyl halide;

[0156] Each R 3b Each occurrence is independently halo, -OH, -C (1-6) Haloalkyl or -OC (1-6) alkyl;

[0157] Each R 3c Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -S(O)2C (1-4) Alkyl or -S(O)2C (3-8) Cycloalkyl, wherein the -C (1-6)Alkyl and -OC (1-6) The alkyl group is optionally further substituted by one to five groups selected from halo and -OC (1-4) Alkyl radical substitution;

[0158] Each R 3d Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl or -C (1-3) Alkyl C (3-10) Cycloalkyl;

[0159] Each R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) alkyl (3 to 8 membered heterocyclic) or 5 to 10 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclyl) and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ),-C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) a haloalkyl group and a 3- to 5-membered heterocyclic group; or

[0160] R 2 and LR 3Together with the nitrogen atom to which they are attached, they form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, each of which is optionally further substituted by one to three rings selected from -N(R N1 )(R N2 ) and -C (1-6) Alkyl radical substitution;

[0161] R 4 is hydrogen, halo or -C (1-4) alkyl;

[0162] R 5 is hydrogen, halo or -C (1-4) alkyl;

[0163] R N1 and R N2 Each occurrence is independently hydrogen or -C (1-3) alkyl;

[0164] R N3 is hydrogen or -C (1-4) alkyl; and

[0165] R N4 For hydrogen, -C (1-4) Alkyl or phenyl; or R N3 and R N4 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic group, which is optionally substituted by one to five substituted radicals selected from halo, -C (1-4) Alkyl and -C (1-4) haloalkyl radical substitution;

[0166] If R 3 -C(O)N(R N3 )(R N4 ), then L does not exist.

[0167] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0168] A is pyrazolyl, imidazolyl, triazolyl, thiazolyl, isoxazolyl, thiazolyl or thiadiazolyl, wherein the pyrazolyl is optionally substituted with one -CH3 group;

[0169] W is CH2, CF2 or CHR W , where W is CHR W When R W and R 1 Together with the carbon atoms to which they are attached to form C (3-5) Cycloalkyl;

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

[0171] Y is N, CH or CR Y ;

[0172] R X For fluorine;

[0173] R Y is CH3, -CHF2, -CF3, -OCH3 or -CH2OCH3;

[0174] R 1 is hydrogen, -CH3 or -CF3;

[0175] R 2 is hydrogen;

[0176] L does not exist, is -C (1-4) Alkylene or -C (3-6) Cycloalkylene, wherein the -C (1-4) The alkylene group is optionally substituted by one to three groups selected from halo, -OH, -N(R N1 )(R N2 ) and cyclopropyl;

[0177] R 3 -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, phenyl, 5- to 10-membered heteroaryl, or -C(O)N(R N3 )(R N4 ); where: the -C (1-6) The alkyl group is optionally substituted by one to five R 3a Atomic substitution; the -C (3-10) The cycloalkyl group is optionally substituted by one to five R 3b The 3 to 10 membered heterocyclic group is optionally substituted by one to five R 3c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 3d and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 3f group substitution;

[0178] Each R 3a Each occurrence is independently halo, -OH or -OC (1-6) alkyl;

[0179] Each R 3b Each occurrence is independently halo, -OH, -C (1-6) Haloalkyl or -OC (1-6) alkyl;

[0180] Each R 3c Each occurrence is independently halo, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -S(O)2C (1-4) Alkyl or -S(O)2C (3-8) Cycloalkyl, wherein the -C (1-6) Alkyl and -OC (1-6) The alkyl group is optionally further substituted by one to five groups selected from halo and -OC (1-4) Alkyl radical substitution;

[0181] Each R 3d Each occurrence is independently -C (1-6) Alkyl, -C (1-6) Haloalkyl or -C (1-3) Alkyl C (3-10) Cycloalkyl;

[0182] Each R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) alkyl (3 to 8 membered heterocyclic) or 5 to 10 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclyl) and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ),-C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) a haloalkyl group and a 3- to 5-membered heterocyclic group; or

[0183] R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, each of which is optionally further substituted by one to three rings selected from -N(R N1 )(R N2 ) and -C (1-6) Alkyl radical substitution;

[0184] R 4 is hydrogen, chlorine, fluorine or -CH3;

[0185] R 5 is hydrogen, chlorine, fluorine or -CH3;

[0186] R N1 and R N2 Each occurrence is independently hydrogen or -C (1-3) alkyl;

[0187] R N3 is hydrogen or -C (1-4) alkyl; and

[0188] R N4 For hydrogen, -C (1-4) Alkyl or phenyl; or R N3 and R N4 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic group, which is optionally substituted by one to five substituted radicals selected from halo, -C (1-4) Alkyl and -C (1-4) haloalkyl radical substitution;

[0189] If R 3 -C(O)N(R N3 )(R N4 ), then L does not exist.

[0190] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, the compound having a structure according to Formula I:

[0191]

[0192] The present application also discloses compounds of formula I:

[0193]

[0194] or a pharmaceutically acceptable salt thereof, wherein:

[0195] A is optionally replaced by one or more -C (1-4) a 5-membered heteroaryl substituted with an alkyl group;

[0196] W is CH2, CHF or CF2;

[0197] X is N or CH;

[0198] Y is N, CH or CR Y ;

[0199] R Y is a halogenated group, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl or -OC (1-4) alkyl halide;

[0200] R 1 For hydrogen, -C (1-4) Alkyl or -C (1-4) alkyl halide;

[0201] R 2 is hydrogen or -C (1-4) alkyl;

[0202] L does not exist, is -C (1-4) Alkylene or -C (3-6) Cycloalkylene, wherein the -C (1-4) Alkylene and -C (3-6) Cycloalkylene is optionally substituted by one to three groups selected from halo, -C (1-3) Alkyl and -OC (1-3) Alkyl radical substitution;

[0203] R 3 -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, -C (6-10) aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one to five R 3x group substitution;

[0204] Each R 3x Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3)Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, -C(0-3)alkylC(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5- to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl group substitution; or

[0205] R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally substituted by one to three substituted radicals selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) and R N1 and R N2 Each occurrence is independently hydrogen, -C (1-3) Alkyl or -C (1-3) Halogenated alkyl.

[0206] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0207] A is optionally replaced by a -C (1-4) a 5-membered heteroaryl substituted with an alkyl group;

[0208] W is CH2 or CF2;

[0209] X is N or CH;

[0210] Y is N, CH or CR Y ;

[0211] R Y -C (1-4) Alkyl or -C (1-4) alkyl halide;

[0212] R 1 For hydrogen, -C (1-4) Alkyl or -C (1-4) alkyl halide;

[0213] R 2 is hydrogen;

[0214] L does not exist, is -C (1-4) Alkylene or -C (3-6) Cycloalkylene, wherein the -C (1-4) Alkylene and -C (3-6) Cycloalkylene is optionally substituted by one to three groups selected from halo, -C (1-3) Alkyl and -OC (1-3) Alkyl radical substitution;

[0215] R 3 -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, -C (6-10) aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one to five R 3x group substitution;

[0216] Each R 3x Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3)Alkyl C (3-10) Cycloalkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5- to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl group substitution; or

[0217] R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, each of which is optionally substituted by one to three groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) haloalkyl; and

[0218] R N1 and R N2 Each occurrence is independently hydrogen or -C (1-3) Alkyl or -C (1-3) Halogenated alkyl.

[0219] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0220] A is a 5-membered heteroaryl group;

[0221] W is CH2 or CF2;

[0222] X is N or CH;

[0223] Y is N, CH or CR Y ;

[0224] R Y -C (1-4) Alkyl or -C (1-4) alkyl halide;

[0225] R 1 For hydrogen, -C (1-4) Alkyl or -C (1-4) alkyl halide;

[0226] R 2 is hydrogen;

[0227] L does not exist, is -C (1-4) Alkylene or -C (3-6) cycloalkylene;

[0228] R 3 -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, -C (6-10) aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one to five R 3x group substitution;

[0229] Each R 3x Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) alkyl (3 to 8 membered heterocyclic) or 5 to 10 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C(1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclyl) and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl group substitution; or

[0230] R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, each of which is optionally substituted by one to three rings selected from -N(R N1 )(R N2 ) and -C (1-6) alkyl radicals; and

[0231] R N1 and R N2 Each occurrence is independently hydrogen or -C (1-3) alkyl.

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

[0233] A is pyrazolyl, triazolyl, thiazolyl or isoxazolyl;

[0234] W is CH2 or CF2;

[0235] X is N or CH;

[0236] Y is CH or CR Y ;

[0237] R Y is -CF3;

[0238] R 1 is hydrogen or -CF3;

[0239] R 2 is hydrogen;

[0240] L does not exist, is -C (1-4) Alkylene or -C (3-6) cycloalkylene;

[0241] R 3 -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, -C(6-10) aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one to five R 3x group substitution;

[0242] Each R 3x Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) alkyl (3 to 8 membered heterocyclic) or 5 to 10 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclyl) and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl group substitution; or

[0243] R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 5,6-fused bicyclic ring system containing one or more heteroatoms, or a 5-membered heteroaryl group, each of which is optionally substituted by one to three selected from -N(R N1 )(R N2 ) and -C (1-6) alkyl radicals; and

[0244] R N1 and R N2 Each occurrence is independently hydrogen or -C (1-3) alkyl.

[0245] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0246] A is optionally replaced by one or more -C (1-4) a 5-membered heteroaryl substituted with an alkyl group;

[0247] W is CH2, CHF or CF2;

[0248] X is N or CH;

[0249] Y is N, CH or CR Y ;

[0250] R Y is a halogenated group, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl or -OC (1-4) alkyl halide;

[0251] R 1 For hydrogen, -C (1-4) Alkyl or -C (1-4) alkyl halide;

[0252] R 2 is hydrogen or -C (1-4) alkyl;

[0253] L does not exist, is -C (1-4) Alkylene or -C (3-6) Cycloalkylene, wherein the -C (1-4) Alkylene and -C (3-6) Cycloalkylene is optionally substituted by one to three groups selected from halo, -C (1-3) Alkyl and -OC (1-3) Alkyl radical substitution;

[0254] R 3 -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, -C (6-10) Aryl or 5- to 10-membered heteroaryl, wherein: the -C (1-6) The alkyl group is optionally substituted by one to five R 3a Group substitution; the -C (3-10) The cycloalkyl group is optionally substituted by one to five R 3b The 3 to 10 membered heterocyclic group is optionally substituted by one to five R 3c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 3d Replace; the -C (6-10) The aryl group is optionally substituted by one to five R 3e and the 5- to 10-membered heteroaryl is optionally substituted by one to five R 3f group substitution;

[0255] R 3a 、R 3b 、R 3c 、R 3d 、R 3e and R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, -C(0-3)alkylC(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5- to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4)haloalkyl group substitution; or

[0256] R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally substituted by one to three substituted radicals selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) haloalkyl; and

[0257] R N1 and R N2 Each occurrence is independently hydrogen, -C (1-3) Alkyl or -C (1-3) Halogenated alkyl.

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

[0259] A is optionally replaced by a -C (1-4) a 5-membered heteroaryl substituted with an alkyl group;

[0260] W is CH2 or CF2;

[0261] X is N or CH;

[0262] Y is N, CH or CR Y ;

[0263] R Y is a halogenated group, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl or -OC (1-4) alkyl halide;

[0264] R 1 For hydrogen, -C (1-4) Alkyl or -C (1-4) alkyl halide;

[0265] R 2 is hydrogen;

[0266] L does not exist, is -C (1-4) Alkylene or -C (3-6) Cycloalkylene, wherein the -C (1-4) Alkylene and -C (3-6) Cycloalkylene is optionally substituted by one to three groups selected from halo, -C(1-3) Alkyl and -OC (1-3) Alkyl radical substitution;

[0267] R 3 -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, -C (6-10) Aryl or 5- to 10-membered heteroaryl, wherein: the -C (1-6) The alkyl group is optionally substituted by one to five R 3a Group substitution; the -C (3-10) The cycloalkyl group is optionally substituted by one to five R 3b The 3 to 10 membered heterocyclic group is optionally substituted by one to five R 3c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 3d Replace; the -C (6-10) The aryl group is optionally substituted by one to five R 3e and the 5- to 10-membered heteroaryl is optionally substituted by one to five R 3f group substitution;

[0268] Each R 3a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) alkyl or 3 to 8 membered heterocyclic group, wherein the -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl and 3 to 8 membered heterocyclic groups are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl radical substitution;

[0269] R 3b 、R 3c and R 3d Each occurrence is independently halo, -OH, -N(RN1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8-membered heterocyclyl or 5 to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) The haloalkyl, 3- to 8-membered heterocyclyl and 5- to 10-membered heteroaryl groups are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl radical substitution;

[0270] R 3e and R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5- to 10-membered heteroaryl, wherein the -C(1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl group substitution; or

[0271] R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally substituted by one to three substituted radicals selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) haloalkyl; and

[0272] R N1 and R N2 Each occurrence is independently hydrogen or -C (1-3) alkyl.

[0273] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0274] A is optionally replaced by a -C (1-4) a 5-membered heteroaryl substituted with an alkyl group;

[0275] W is CH2 or CF2;

[0276] X is N or CH;

[0277] Y is N, CH or CR Y ;

[0278] R Y -C (1-4)Alkyl, -C (1-4) Haloalkyl or -OC (1-4) alkyl;

[0279] R 1 For hydrogen, -C (1-4) Alkyl or -C (1-4) alkyl halide;

[0280] R 2 is hydrogen;

[0281] L does not exist, is -C (1-4) Alkylene or -C (3-6) Cycloalkylene, wherein the -C (1-4) Alkylene and -C (3-6) Cycloalkylene is optionally substituted by one to three groups selected from halo, -C (1-3) Alkyl and -OC (1-3) Alkyl radical substitution;

[0282] R 3 -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3 to 10 membered heterocyclyl, 5 to 12 membered bicyclic or tricyclic ring system containing one or more heteroatoms, or 5 to 10 membered heteroaryl, wherein: the -C (1-6) The alkyl group is optionally substituted by one to five R 3a Group substitution; the -C (3-10) The cycloalkyl group is optionally substituted by one to five R 3b The 3 to 10 membered heterocyclic group is optionally substituted by one to five R 3c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 3d substituted; and the 5- to 10-membered heteroaryl is optionally substituted by one to five R 3f group substitution;

[0283] Each R 3a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ) or -CN;

[0284] 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, -OC (1-6) Alkyl or -OC (1-6) haloalkyl, wherein the -C (1-6) Alkyl, -C(1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) The haloalkyl group is optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ) and -CN groups;

[0285] Each R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group) or -C (6-10) Aryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group) and -C (6-10) The aryl group is optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl group substitution; or

[0286] R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, each of which is optionally substituted by one to three groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C(1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) haloalkyl; and

[0287] R N1 and R N2 Each occurrence is independently hydrogen or -C (1-3) alkyl.

[0288] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0289] A is a 5-membered heteroaryl group;

[0290] W is CH2 or CF2;

[0291] X is N or CH;

[0292] Y is N, CH or CR Y ;

[0293] R Y -C (1-4) Alkyl, -C (1-4) Haloalkyl or -OC (1-4) alkyl;

[0294] R 1 For hydrogen, -C (1-4) Alkyl or -C (1-4) alkyl halide;

[0295] R 2 is hydrogen;

[0296] L does not exist, is -C (1-4) Alkylene or -C (3-6) cycloalkylene;

[0297] R 3 -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3 to 10 membered heterocyclyl, 5 to 12 membered bicyclic or tricyclic ring system containing one or more heteroatoms, or 5 to 10 membered heteroaryl; wherein: the -C (1-6) The alkyl group is optionally substituted with one to five halo groups; the -C (3-10) The cycloalkyl group is optionally substituted with one to five -OH groups; the 5 to 12 membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with one to five R 3d substituted; and the 5- to 10-membered heteroaryl is optionally substituted by one to five R 3f group substitution;

[0298] Each R 3dEach occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl or -OC (1-6) alkyl halide;

[0299] Each R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group or -C (1-3) Alkyl (3 to 8 membered heterocyclic group), wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group and -C (1-3) The alkyl (3 to 8 membered heterocyclic group) is optionally further substituted by one to five groups selected from halo, -OH, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl group substitution; or

[0300] R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, each of which is optionally substituted by one to three rings selected from -N(R N1 )(R N2 ) and -C (1-6) alkyl radicals; and

[0301] R N1 and R N2 Each occurrence is independently hydrogen or -C (1-3) alkyl.

[0302] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0303] A is pyrazolyl, triazolyl, thiazolyl or isoxazolyl;

[0304] W is CH2 or CF2;

[0305] X is N or CH;

[0306] Y is CH or CR Y ;

[0307] R Y is -CF3;

[0308] R 1 is hydrogen or -CF3;

[0309] R 2 is hydrogen;

[0310] L does not exist, is -C (1-4) Alkylene or -C (3-6) cycloalkylene;

[0311] R 3 -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3 to 10 membered heterocyclyl, 5 to 12 membered bicyclic or tricyclic ring system containing one or more heteroatoms, or 5 to 10 membered heteroaryl; wherein: the -C (1-6) The alkyl group is optionally substituted with one to five fluorine atoms; the -C (3-10) Cycloalkyl is optionally substituted with one -OH group; a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with one to five -C (1-6) alkyl group, and the 5- to 10-membered heteroaryl is optionally substituted by one to five R 3f group substitution;

[0312] Each R 3f Each occurrence is independently -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group or -C (1-3) Alkyl (3 to 8 membered heterocyclic group), wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group and -C(1-3) The alkyl (3 to 8 membered heterocyclic group) is optionally further substituted by one to five groups selected from halo, -OH, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl group substitution; or

[0313] R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, each of which is optionally substituted by one to three rings selected from -N(R N1 )(R N2 ) and -C (1-6) alkyl radicals; and

[0314] R N1 and R N2 Each occurrence is independently hydrogen or -C (1-3) alkyl.

[0315] 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′:

[0316]

[0317] 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':

[0318]

[0319] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ia-1:

[0320]

[0321] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ia-2:

[0322]

[0323] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein A is replaced by a -C (1-4)alkyl group substituted 5-membered heteroaryl. In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein A is a 5-membered heteroaryl. In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein A is pyrazolyl, triazolyl, thiazolyl, or isoxazolyl. In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein A is triazolyl or isoxazolyl. In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein A is pyrazolyl. In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein A is triazolyl. In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein A is thiazolyl. In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein A is isoxazolyl.

[0324] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein A is

[0325] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein A is

[0326] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein A is

[0327] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein A is

[0328] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein A is

[0329] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein A is

[0330] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein A is

[0331] 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':

[0332]

[0333] 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':

[0334]

[0335] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ib-3':

[0336]

[0337] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ib-1:

[0338]

[0339] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ib-2:

[0340]

[0341] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ib-3:

[0342]

[0343] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein W is CH2, CDH, CD2, CF2 or CHR W . In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein W is CH2, CDH, CD2, or CF2. In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein W is CH2 or CF2. In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein W is CH2. In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein W is CF2. In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein W is CHR W .

[0344] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein X is N. Disclosed herein are compounds of Formula I' or 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 N, CH, or CF.

[0345] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein Y is N, CH, C-CH3, C-CHF2, C-CF3, C-OCH3, or C-CH2OCH3. In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein Y is N. In some embodiments, disclosed herein are compounds of Formula I' or 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 Formula I, or pharmaceutically acceptable salts thereof, wherein Y is CH or C-CF3. In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein Y is CH. In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein Y is CR Y . In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein Y is C-CH3. In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein Y is C-CHF2. In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein Y is C-CF3. In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein Y is C-OCH3. In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein Y is C-CH2OCH3.

[0346] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R W -C (1-4) In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R W -C (1-4) In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein when W is CHRW When R W and R 1 Together with the carbon atoms to which they are attached to form C (3-5) In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein when W is CHR W When R W and R 1 Together with the carbon atoms to which they are attached to form C (3) Cycloalkyl.

[0347] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R X In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R X For fluorine.

[0348] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R Y -C (1-4) Alkyl, -C (1-4) Haloalkyl or -OC (1-4) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R Y -C (1-4) Alkyl or -C (1-4) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R Y -C (1-4) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R Y In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R Y -C (1-4) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R Y It is -CF3.

[0349] 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':

[0350]

[0351] 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':

[0352]

[0353] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ic-1:

[0354]

[0355] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ic-2:

[0356]

[0357] In some embodiments, disclosed herein are compounds of Formula I' or 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 Formula I, or pharmaceutically acceptable salts thereof, wherein R 1 In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 1 In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 1 In some embodiments, disclosed herein are compounds of Formula I' or 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 W and R 1 Together with the carbon atoms to which they are attached to form C (3-5) In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R W and R1 together with the carbon atom to which they are attached to form C (3) Cycloalkyl.

[0358] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of any one of Formula Id-1 to Formula Id-7:

[0359]

[0360] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of any one of Formula Id-1 to Formula Id-5:

[0361]

[0362] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 2 For hydrogen.

[0363] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein L is absent, -C (1-4) Alkylene or -C (3-6) Cycloalkylene, wherein the -C (1-4) The alkylene group is optionally substituted by one to three groups selected from halo, -OH, -N(R N1 )(R N2 In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein L is absent, -C (1-4) Alkylene or -C (3-6) Cycloalkylene, wherein the -C (1-4) The alkylene group is optionally replaced by a -OC (1-3) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein L is absent, -C (1-4) Alkylene or -C (3-6) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein L is absent, -C (1-4) Alkylene or cyclopropylene.

[0364] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein L is absent, is

[0365] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein L is absent, is

[0366] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein L is absent, is

[0367] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein L is absent or is

[0368] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein L is absent.

[0369] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein L is

[0370] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein L is

[0371] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein L is

[0372] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein L is

[0373] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein L is

[0374] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein L is

[0375] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein L is

[0376] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of any one of Formulas Ie-1 to Ie-10:

[0377]

[0378] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of any one of Formulas If-1 to If-10:

[0379]

[0380]

[0381] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 -C (3-10) Cycloalkyl, 3 to 10 membered heterocyclyl, 5 to 12 membered bicyclic or tricyclic ring system containing one or more heteroatoms, or 5 to 10 membered heteroaryl, each of which is optionally substituted by one to five R 3x Group substitution.

[0382] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is a 5- to 12-membered bicyclic 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 3x Group substitution.

[0383] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3x Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5- to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) The haloalkyl group is substituted.

[0384] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3x Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) alkyl (3 to 8 membered heterocyclic) or 5 to 10 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclyl) and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) The haloalkyl group is substituted.

[0385] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3x Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) alkyl (3 to 8 membered heterocyclic) or 5 to 10 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6)Haloalkyl, -OC (3-8) Cycloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclyl) and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) The haloalkyl group is substituted.

[0386] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, wherein: the 5- to 12-membered bicyclic ring system containing one or more heteroatoms is optionally replaced by one to five R 3d substituted, and the 5- to 10-membered heteroaryl is optionally substituted by one to five R 3f Group substitution.

[0387] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is optionally replaced by one to five R 3a -C substituted with a group (1-6) alkyl.

[0388] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, -C(0-3)alkylC(O)N(R N1 )(R N2), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5- to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) The haloalkyl group is substituted.

[0389] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) alkyl or 3 to 8 membered heterocyclic group, wherein the -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl and 3 to 8 membered heterocyclic groups are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC(1-4) Alkyl and -OC (1-4) The haloalkyl group is substituted.

[0390] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3a Each occurrence is independently halo, -OH, -OC (1-6) Alkyl or -OC (1-6) Halogenated alkyl.

[0391] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ),-CN,-OC (1-6) Alkyl or -OC (1-6) Halogenated alkyl.

[0392] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ) or -CN.

[0393] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3a Each occurrence is independently halo, -OH or -OC (1-6) alkyl.

[0394] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3a In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3a In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3a In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3a Yes-OC (1-6) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3a It is -OCH3.

[0395] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R3 for:

[0396]

[0397] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for

[0398] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is optionally replaced by one to five R 3b -C substituted with a group (3-10) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is optionally replaced by one to three R 3b -C (3-10) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is optionally replaced by one to three R 3b A cyclopentyl group substituted with a group.

[0399] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3b Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, -C(0-3)alkylC(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5- to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C(3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) The haloalkyl group is substituted.

[0400] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein each R 3b Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -S(O)2C (3-8) Cycloalkyl, -N(H)S(O)2C (1-4) Alkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8-membered heterocyclyl or 5 to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) The haloalkyl, 3- to 8-membered heterocyclyl and 5- to 10-membered heteroaryl groups are optionally further substituted by one to five groups selected from halo, -OH, -N(RN1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) The haloalkyl group is substituted.

[0401] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3b Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8-membered heterocyclyl or 5 to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) The haloalkyl, 3- to 8-membered heterocyclyl and 5- to 10-membered heteroaryl groups are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) The haloalkyl group is substituted.

[0402] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein each R 3b Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl C(3-10) Cycloalkyl, -S(O)2C (1-4) Alkyl or -S(O)2C (3-8) Cycloalkyl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) The haloalkyl group is optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN and -OC (1-4) Alkyl groups are substituted.

[0403] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3b Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl or -OC (1-6) haloalkyl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) The haloalkyl group is optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ) and -CN groups.

[0404] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3b Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl or -OC (1-6) Halogenated alkyl.

[0405] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3b Each occurrence is independently halo, -OH, -C (1-6) Haloalkyl or -OC (1-6) alkyl.

[0406] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R3b In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3b In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3b In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3b -C (1-6) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3b In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3b Yes-OC (1-6) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3b It is -OCH3.

[0407] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is -C optionally substituted by one -OH group (3-10) Cycloalkyl.

[0408] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for:

[0409]

[0410] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for

[0411] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is optionally replaced by one to five R 3c A 3- to 10-membered heterocyclic group substituted by a group.

[0412] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein each R 3c Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C(3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -S(O)2C (3-8) Cycloalkyl, -N(H)S(O)2C (1-4) Alkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5- to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -S(O)2C (3-8) Cycloalkyl, -N(H)S(O)2C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) Substitution of haloalkyl and 3- to 5-membered heterocyclic groups

[0413] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3c Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C(1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, -C(0-3)alkylC(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5- to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) The haloalkyl group is substituted.

[0414] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein each R 3c Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6)Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -S(O)2C (3-8) Cycloalkyl, -N(H)S(O)2C (1-4) Alkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8-membered heterocyclyl or 5 to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) The haloalkyl, 3- to 8-membered heterocyclyl and 5- to 10-membered heteroaryl groups are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) The haloalkyl group is substituted.

[0415] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3c Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8-membered heterocyclyl or 5 to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6)The haloalkyl, 3- to 8-membered heterocyclyl and 5- to 10-membered heteroaryl groups are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) The haloalkyl group is substituted.

[0416] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein each R 3c Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -S(O)2C (1-4) Alkyl or -S(O)2C (3-8) Cycloalkyl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) The haloalkyl group is optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN and -OC (1-4) Alkyl groups are substituted.

[0417] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein each R 3c Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -S(O)2C (1-4) Alkyl or -S(O)2C (3-8) Cycloalkyl, wherein the -C (1-6) Alkyl and -OC (1-6)The alkyl group is optionally further substituted by one to five groups selected from halo and -OC (1-4) Alkyl groups are substituted.

[0418] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3c Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl or -OC (1-6) haloalkyl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) The haloalkyl group is optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ) and -CN groups.

[0419] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein each R 3c Each occurrence is independently halo, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -S(O)2C (1-4) Alkyl or -S(O)2C (3-8) Cycloalkyl, wherein the -C (1-6) Alkyl and -OC (1-6) The alkyl group is optionally further substituted by one to five groups selected from halo and -OC (1-4) Alkyl groups are substituted.

[0420] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3c In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3c Each occurrence is independently optionally further substituted by one to five groups selected from halo and -OC (1-4) Alkyl group substituted -C (1-6) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3c Each occurrence is independently -C (1-6)In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3c Each occurrence is independently -C (3-8) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3c Each occurrence is independently optionally further substituted by one to five groups selected from halo and -OC (1-4) Alkyl group substituted -OC (1-6) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3c Each occurrence is independently -S(O)2C (1-4) alkyl.

[0421] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein each R 3c Each occurrence is independently -S(O)2C (3-8) Cycloalkyl.

[0422] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 3 for:

[0423]

[0424]

[0425] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for

[0426] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is optionally replaced by one to five R 3d In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is optionally replaced by one to five R 3d A 5- to 12-membered bicyclic ring system containing one or more heteroatoms which is substituted by a group.

[0427] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3is a 5- to 12-membered bicyclic ring system containing one to five heteroatoms selected from O, N and S, wherein the 5- to 12-membered bicyclic ring system is optionally replaced by one to five R 3d In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is optionally replaced by one to five R 3d The 5- to 12-membered bicyclic ring system containing one or more heteroatoms is substituted by a group, wherein the 5- to 12-membered bicyclic ring system is a 5,6-fused bicyclic ring system.

[0428] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3d Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, -C(0-3)alkylC(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5- to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C(6-10) Aryl and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) The haloalkyl group is substituted.

[0429] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3d Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8-membered heterocyclyl or 5 to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) The haloalkyl, 3- to 8-membered heterocyclyl and 5- to 10-membered heteroaryl groups are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) The haloalkyl group is substituted.

[0430] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein each R 3d Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC(1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -S(O)2C (1-4) Alkyl or -S(O)2C (3-8) Cycloalkyl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) The haloalkyl group is optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN and -OC (1-4) Alkyl groups are substituted.

[0431] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3d Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl or -OC (1-6) haloalkyl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) The haloalkyl group is optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ) and -CN groups.

[0432] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3d Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl or -C (1-3) Alkyl C (3-10) Cycloalkyl.

[0433] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3d Each occurrence is independently halo, -OH, -N(R N1)(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl or -OC (1-6) Halogenated alkyl.

[0434] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3d Each occurrence is independently -C (1-6) Alkyl, -C (1-6) Haloalkyl or -C (1-3) Alkyl C (3-10) Cycloalkyl.

[0435] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3d -C (1-6) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3d In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3d -C (1-6) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3d In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3d -C (1-3) Alkyl C (3-10) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3d It is -CH2-cyclopropyl.

[0436] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for:

[0437]

[0438] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for:

[0439]

[0440] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is optionally replaced by one to five R 3e -C substituted with a group (6-10) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 It is phenyl.

[0441] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3e Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, -C(0-3)alkylC(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5- to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10)Aryl and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) The haloalkyl group is substituted.

[0442] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3e Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5- to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) The haloalkyl group is substituted.

[0443] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3e Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl or -OC (1-6) Halogenated alkyl.

[0444] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is optionally replaced by one to five R 3f In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is a 5- to 6-membered monocyclic heteroaryl or a 9-membered bicyclic heteroaryl, each of which is optionally substituted by one to three R 3f Group substitution.

[0445] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl or a 9-membered fused nitrogen-containing bicyclic heteroaryl, each of which is optionally substituted by one to three R 3f In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazolopyridinyl or pyrazolopyrimidinyl, each of which is optionally substituted by one to three R 3f In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is pyrazolyl, triazolyl, isoxazolyl, pyridinyl, pyrazolopyridinyl or pyrazolopyrimidinyl, each of which is optionally substituted by one to three R 3f Group substitution.

[0446] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is pyrazolyl, isoxazolyl or pyrazolopyrimidinyl, each of which is optionally substituted by one to three R 3fIn some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is optionally replaced by one to three R 3f In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is optionally replaced by one to three R 3f In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is optionally replaced by one to three R 3f In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 is optionally replaced by one to three R 3f A pyrazolopyrimidinyl group substituted with a group.

[0447] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for:

[0448]

[0449]

[0450] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for:

[0451]

[0452] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for:

[0453]

[0454] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for:

[0455]

[0456] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for:

[0457]

[0458] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for:

[0459]

[0460] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, -C(0-3)alkylC(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5- to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C(1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) The haloalkyl group is substituted.

[0461] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5- to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) The alkyl radicals are substituted with haloalkyl and 3- to 5-membered heterocyclic radicals.

[0462] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3fEach occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5- to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) The haloalkyl group is substituted.

[0463] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8)Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5- to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) The alkyl radicals are substituted with haloalkyl and 3- to 5-membered heterocyclic radicals.

[0464] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group) or -C (6-10) Aryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC(1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group) and -C (6-10) The aryl group is optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) The haloalkyl group is substituted.

[0465] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) alkyl (3 to 8 membered heterocyclic) or 5 to 10 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclyl) and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 ),-C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) The alkyl radicals are substituted with haloalkyl and 3- to 5-membered heterocyclic radicals.

[0466] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group or -C (1-3) Alkyl (3 to 8 membered heterocyclic group), wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group and -C (1-3) The alkyl (3 to 8 membered heterocyclic group) is optionally further substituted by one to five groups selected from halo, -OH, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) The haloalkyl group is substituted.

[0467] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group or -C (1-3) Alkyl (3 to 8 membered heterocyclic group), wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group and -C (1-3) The alkyl (3 to 8 membered heterocyclic group) is optionally further substituted by one to five groups selected from halo, -OH, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4)The haloalkyl group is substituted.

[0468] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently halo, -C (1-6) Alkyl, -OC (3-8) Cycloalkyl, -OC (1-6) Alkyl or -OC (3-8) Cycloalkyl, wherein the -C (1-6) Alkyl, -OC (3-8) Cycloalkyl, -OC (1-6) Alkyl and -OC (3-8) The cycloalkyl group is optionally further substituted with one to five groups selected from halo and -OH.

[0469] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl or -OC (3-8) cycloalkyl groups, each of which is optionally further substituted with one to three -OH groups.

[0470] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently -C (1-6) Alkyl, -OC (3-8) Cycloalkyl, -OC (1-6) Alkyl or -OC (3-8) cycloalkyl, each of which is optionally further substituted with one to five groups selected from fluoro and -OH.

[0471] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently -C optionally further substituted with one to five groups selected from fluoro and -OH (1-6) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently -C (1-6) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3f It's methyl.

[0472] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently -OC optionally further substituted with one to five groups selected from fluoro and -OH (3-8) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently -OC (3-8) Cycloalkyl.

[0473] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently -OC optionally further substituted with one to five groups selected from fluoro and -OH (1-6) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently -OC (1-6) alkyl.

[0474] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently -OC optionally further substituted with one to five groups selected from fluoro and -OH (3-8) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently -OC (3-8) Cycloalkyl.

[0475] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently:

[0476]

[0477] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently:

[0478]

[0479] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently:

[0480]

[0481] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently:

[0482]

[0483] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein each R 3f Each occurrence is independently:

[0484]

[0485] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for:

[0486]

[0487]

[0488]

[0489] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for:

[0490]

[0491] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for:

[0492]

[0493]

[0494] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 3 for:

[0495]

[0496]

[0497] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for:

[0498]

[0499] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for:

[0500]

[0501]

[0502] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for:

[0503]

[0504] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for:

[0505]

[0506] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for:

[0507]

[0508] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for

[0509] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for

[0510] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 3 for

[0511] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally substituted by one to three substituted radicals selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C(1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) The haloalkyl group is substituted.

[0512] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, each of which is optionally substituted by one to three groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) The haloalkyl group is substituted.

[0513] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, each of which is optionally substituted by one to three rings selected from -N(R N1 )(R N2 ) and -C (1-6) Alkyl groups are substituted.

[0514] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 5,6-fused bicyclic ring system containing one or more heteroatoms, or a 5-membered heteroaryl group, each of which is optionally substituted by one to three selected from -N(R N1 )(R N2 ) and -C (1-6) Alkyl groups are substituted.

[0515] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R 2 and LR 3 Combined with the nitrogen atoms to which they are attached, they form:

[0516]

[0517] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R2 and LR 3 Combined with the nitrogen atoms to which they are attached, they form:

[0518]

[0519] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 3 -C(O)N(R N3 )(R N4 ).

[0520] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R N3 is hydrogen or -C (1-4) In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R N3 is hydrogen or -CH3. In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R N3 In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R N3 -C (1-4) In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R N3 is -CH3.

[0521] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R N4 For hydrogen, -C (1-4) In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R N4 is hydrogen, -CH3 or phenyl. In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R N4 In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R N4 -C (1-4) In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R N4 In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R N4 It is phenyl.

[0522] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R N3 and R N4Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic group, which is optionally substituted by one to five substituted radicals selected from halo, -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 N3 and R N4 Together with the nitrogen atom to which they are attached, they form a 4- to 6-membered heterocyclic group, which is optionally substituted with one to five groups selected from fluorine, -CH3 and -CF3.

[0523] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 3 for:

[0524]

[0525] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R N1 and R N2 Each occurrence is independently H or -C (1-3) In some embodiments, disclosed herein are compounds of Formula I' or Formula I, or pharmaceutically acceptable salts thereof, wherein R N1 and R N2 Each is hydrogen.

[0526] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 is hydrogen, chlorine, fluorine or -CH3. In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 is -CH3.

[0527] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 5is hydrogen, chlorine, fluorine or -CH3. In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 5 In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 5 In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 5 In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 5 In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 5 In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 5 is -CH3.

[0528] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 is hydrogen, and R 5 is hydrogen; R 4 is fluorine, and R 5 is hydrogen; R 4 is -CH3; and R 5 is hydrogen; R 4 is hydrogen, and R 5 is chlorine; or R 4 is hydrogen, and R 5 is -CH3.

[0529] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ih:

[0530]

[0531] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ih-1:

[0532]

[0533] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ih-2:

[0534]

[0535] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ih-3:

[0536]

[0537] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ig-1:

[0538]

[0539] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ig-2:

[0540]

[0541] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ig-1:

[0542]

[0543]

[0544] in:

[0545] W is CH2 or CF2;

[0546] X is N or CH;

[0547] R 1 is hydrogen;

[0548] R 2 is hydrogen;

[0549] L does not exist or is -C (1-4) alkylene;

[0550] R 3 is optionally replaced by one to five R 3e a 5- to 10-membered heteroaryl group substituted with a group;

[0551] Each R 3e Independently -C (1-6) Alkyl, -OC (3-8) Cycloalkyl, -OC (1-6) Alkyl or -OC (3-8) cycloalkyl, each of which is optionally further substituted with one to five groups selected from fluoro and -OH.

[0552] In some embodiments, disclosed herein is a compound of Formula I', or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ii:

[0553]

[0554] in:

[0555] A is triazolyl or isoxazolyl;

[0556] X is N or CH;

[0557] R 3 is optionally replaced by one to five R 3e a 5-membered heteroaryl substituted with a group;

[0558] Each R 3e Independently -C (1-6) Alkyl, -OC (3-8) Cycloalkyl, -OC (1-6) Alkyl or -OC (3-8) cycloalkyl, each of which is optionally further substituted with one to five groups selected from fluoro and -OH;

[0559] R 5 For hydrogen ( 1 H) or deuterium ( 2 H).

[0560] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, having a structure as shown in any one of Tables 1A to 1D.

[0561] Table 1A

[0562]

[0563]

[0564] Table 1B

[0565]

[0566]

[0567] Table 1C

[0568]

[0569]

[0570]

[0571] Table 1D

[0572]

[0573]

[0574] In some embodiments, disclosed herein is a compound or a pharmaceutically acceptable salt thereof having a structure as shown in any one of Table 1E to Table 1U.

[0575] Table 1E

[0576]

[0577]

[0578] Table 1F

[0579]

[0580]

[0581]

[0582] Table 1G

[0583]

[0584]

[0585]

[0586] Table 1H

[0587]

[0588]

[0589]

[0590] Table II

[0591]

[0592]

[0593]

[0594] Table 1J

[0595]

[0596]

[0597]

[0598] Table 1K

[0599]

[0600]

[0601] Table 1L

[0602]

[0603]

[0604]

[0605] Table 1M

[0606]

[0607]

[0608] Table 1N

[0609]

[0610]

[0611]

[0612] Table 10

[0613]

[0614]

[0615] Table 1P

[0616]

[0617]

[0618]

[0619] Table 1Q

[0620]

[0621]

[0622] Table 1R

[0623]

[0624]

[0625]

[0626] Table 1S

[0627]

[0628]

[0629] Table 1T

[0630]

[0631]

[0632] Table 1U

[0633]

[0634]

[0635]

[0636]

[0637] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, having a structure as shown in any one of Tables 2A to 2D.

[0638] Table 2A

[0639]

[0640]

[0641]

[0642] Table 2B

[0643]

[0644]

[0645] Table 2C

[0646]

[0647]

[0648]

[0649] Table 2D

[0650]

[0651]

[0652]

[0653] In some embodiments, disclosed herein is a compound or a pharmaceutically acceptable salt thereof having a structure as shown in any one of Tables 2E to 2T.

[0654] Table 2E

[0655]

[0656]

[0657]

[0658] Table 2F

[0659]

[0660]

[0661]

[0662] Table 2G

[0663]

[0664]

[0665]

[0666]

[0667] Table 2H

[0668]

[0669]

[0670]

[0671]

[0672] Table 2I

[0673]

[0674]

[0675]

[0676] Table 2J

[0677]

[0678]

[0679] Table 2K

[0680]

[0681]

[0682] Table 2L

[0683]

[0684]

[0685]

[0686] Table 2M

[0687]

[0688]

[0689]

[0690] Table 2N

[0691]

[0692]

[0693]

[0694] Table 2O

[0695]

[0696]

[0697]

[0698] Table 2P

[0699]

[0700]

[0701]

[0702] Table 2Q

[0703]

[0704]

[0705] Table 2R

[0706]

[0707]

[0708]

[0709] Table 2S

[0710]

[0711]

[0712]

[0713] Table 2T

[0714]

[0715]

[0716] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

[0717]

[0718] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

[0719]

[0720] In some embodiments, disclosed herein are compounds of Formula I' or Formula I having the following structure:

[0721]

[0722] or a pharmaceutically acceptable salt thereof.

[0723] In some embodiments, disclosed herein are compounds of Formula I' or Formula I having the following structure:

[0724]

[0725] or a pharmaceutically acceptable salt thereof.

[0726] In some embodiments, disclosed herein are compounds of Formula I' or Formula I having the following structure:

[0727]

[0728] or a pharmaceutically acceptable salt thereof.

[0729] In some embodiments, disclosed herein are compounds of Formula I' or Formula I having the following structure:

[0730]

[0731] or a pharmaceutically acceptable salt thereof.

[0732] In some embodiments, disclosed herein are compounds of Formula I' or Formula I having the following structure:

[0733]

[0734] or a pharmaceutically acceptable salt thereof.

[0735] In some embodiments, disclosed herein are compounds of Formula I' or Formula I having the following structure:

[0736]

[0737] or a pharmaceutically acceptable salt thereof.

[0738] In some embodiments, disclosed herein are compounds of Formula I' or Formula I having the following structure:

[0739]

[0740] or a pharmaceutically acceptable salt thereof.

[0741] In some embodiments, disclosed herein are compounds of Formula I' or Formula I having the following structure:

[0742]

[0743] or a pharmaceutically acceptable salt thereof.

[0744] In some embodiments, disclosed herein are compounds of Formula I' or Formula I having the following structure:

[0745]

[0746] or a pharmaceutically acceptable salt thereof.

[0747] In some embodiments, disclosed herein are compounds of Formula I' or Formula I having the following structure:

[0748]

[0749] or a pharmaceutically acceptable salt thereof.

[0750] In some embodiments, disclosed herein are compounds of Formula I' or Formula I having the following structure:

[0751]

[0752] or a pharmaceutically acceptable salt thereof.

[0753] In some embodiments, disclosed herein are compounds of Formula I' or Formula I having the following structure:

[0754]

[0755] or a pharmaceutically acceptable salt thereof.

[0756] In some embodiments, disclosed herein are compounds of Formula I' or Formula I having the following structure:

[0757]

[0758] or a pharmaceutically acceptable salt thereof.

[0759] In some embodiments, disclosed herein are compounds of Formula I' or Formula I having the following structure:

[0760]

[0761] or a pharmaceutically acceptable salt thereof.

[0762] In some embodiments, disclosed herein are compounds of Formula I' or Formula I having the following structure:

[0763]

[0764] or a pharmaceutically acceptable salt thereof.

[0765] In some embodiments, disclosed herein are compounds of Formula I' or Formula I having the following structure:

[0766]

[0767] or a pharmaceutically acceptable salt thereof.

[0768] In some embodiments, disclosed herein are compounds of Formula I' or Formula I having the following structure:

[0769]

[0770] or a pharmaceutically acceptable salt thereof.

[0771] In some embodiments, disclosed herein are compounds of Formula I' or Formula I having the following structure:

[0772]

[0773] or a pharmaceutically acceptable salt thereof.

[0774] In some embodiments, disclosed herein are compounds of Formula I' or Formula I having the following structure:

[0775]

[0776] or a pharmaceutically acceptable salt thereof.

[0777] In some embodiments, disclosed herein are compounds of Formula I' or Formula I having the following structure:

[0778]

[0779] or a pharmaceutically acceptable salt thereof.

[0780] In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound of Formula I' or Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0781] Therapeutic uses

[0782] 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.

[0783] The present disclosure also relates to a method for preventing 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 pharmaceutical composition of the present disclosure. In some embodiments, the compounds disclosed herein may be used in combination with another therapeutic agent.

[0784] 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, 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.

[0785] In some embodiments of the treatment methods disclosed herein, the disease, disorder, or medical condition is selected from an inflammatory disorder and an autoimmune disorder.

[0786] 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.

[0787] In some embodiments of the treatment methods 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.

[0788] 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").

[0789] 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.

[0790] 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.

[0791] 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.

[0792] 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.

[0793] 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.

[0794] In some embodiments of the treatment methods disclosed herein, the disease, disorder, or medical condition is osteoporosis.

[0795] In some embodiments of the treatment methods 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).

[0796] 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.

[0797] 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.

[0798] In some embodiments of the methods disclosed herein, the subject is a human subject.

[0799] 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.

[0800] 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.

[0801] Dosage and administration

[0802] 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. "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.

[0803] 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.

[0804] 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.

[0805] 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.

[0806] 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.

[0807] 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.

[0808] 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 disclosed methods by a suitable delivery route, such as oral, parenteral, rectal, topical, or ocular administration, or by inhalation.

[0809] 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.

[0810] 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.

[0811] 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.

[0812] 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.

[0813] 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.

[0814] 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.

[0815] 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.

[0816] 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.

[0817] Example

[0818] The following specific examples are provided to further illustrate embodiments within the scope of the present disclosure.

[0819] abbreviation

[0820] Herein and throughout this application, the following abbreviations may be used.

[0821]

[0822]

[0823]

[0824]

[0825] 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.

[0826] By way of illustration and not limitation, compounds of the present disclosure, i.e. compounds of Formula I' or Formula I, are prepared according to the following general preparation procedures given in Schemes 1-6. One of ordinary skill in the art will recognize that, in order to obtain the various compounds herein, the starting materials can be appropriately selected so that, with or without protection as required, the desired substituents will be carried throughout the reaction scheme to obtain the desired product. Alternatively, suitable groups replacing the desired substituents can be subjected to the entire reaction scheme and, where appropriate, substituted with the desired substituents. Unless otherwise indicated, the variables in Schemes 1-6 are all as defined above for Formula I' or Formula I.

[0827] Solution 1

[0828]

[0829] The compounds of formula I' of the present disclosure can be prepared, for example, as shown in Scheme 1. 1 is halogen (e.g., Cl, Br or I) and when the substituent B in compound XII 2 When B is a stannyl group (e.g., Sn(Me) 3 or Sn(n-Bu) 3 ), the coupling is achieved by reaction under Stille conditions. Those skilled in the art will recognize that when B in compound XI is 1 is a stannyl group and B in compound XII 2 When is a 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 such as CuI and TEA. Examples of suitable catalysts include, but are not limited to, Pd(dppf)Cl2, Pd(PPh3)4, and Pd(P(Cy)3)2Cl2. Suitable solvents include, but are not limited to, 1,4-dioxane, toluene, and DMF. The reaction can be heated to a temperature of about 100°C to about 120°C for a period of about 1 to 16 hours using microwave or conventional heating to give compounds of Formula I'.

[0830] Alternatively, when B 1 is a boron-based coupling agent such as boric acid or boric ester and when B 2 When B is a halogen such as Cl, Br or I, compound XI can be coupled to compound XII using Suzuki coupling conditions. Those skilled in the art will recognize that when B1 When halogen and when B 2 When a boron-based coupling agent is used, coupling under Suzuki conditions also yields compounds of Formula I'. Typical Suzuki coupling conditions involve the use of a palladium catalyst (e.g., Pd(dtbpf)Cl2), a base (e.g., K3PO4), and a suitable solvent (e.g., 1,4-dioxane, water, or a mixture thereof). The reaction can be heated to a temperature of about 80°C for about 1 hour using microwave or conventional heating to yield compounds of Formula I'.

[0831] Alternatively, when B 1 is a boron-based coupling agent such as boric acid or boric ester and when B 2 When is a halide such as Cl, Br or I, compound XI can be coupled to compound XII using Buchwald coupling conditions.

[0832] In the event that a protecting group is present on the compound of Formula XI or XII, 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 (trimethylsilyl)ethoxymethyl (SEM) group is used to protect the nitrogen atom, it can be removed using a reagent such as TFA in a solvent such as DCM.

[0833] Option 2

[0834]

[0835] The compounds of Formula I' of the present disclosure can be prepared, for example, as shown in Scheme 2. Compounds XIII and XIV can be mixed with a suitable acid such as TFA or TsOH in a solvent such as DMSO or 1,4-dioxane. The reaction can be heated to a temperature of about 115°C to about 150°C for a period of about 1.5 to 16 hours to obtain compounds of Formula I'.

[0836] Alternatively, compounds XIII and XIV can be combined with a suitable base such as TEA or DIPEA in a solvent such as DMSO or DMA. The reaction mixture can be heated to a temperature of about 120°C to about 150°C for a period of about 1.5 to 3.5 hours to provide the compound of Formula I'.

[0837] Option 3

[0838]

[0839] The compounds of formula I' of the present disclosure can be prepared, for example, as shown in Scheme 3. 3When halogen (e.g., Cl, Br, or I) is present, compounds of Formula I' can be prepared under Buchwald-Hartwig amination conditions. A typical Buchwald-Hartwig reaction involves the use of a catalyst (usually palladium, such as Pd2(dba)3, but sometimes other metals); a base (e.g., Cs2CO3), and a suitable solvent (e.g., THF). A phosphate ligand, such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, may also be included. The reaction may be heated to a temperature of about 120°C for a period of about 16 hours to provide a compound of Formula I'.

[0840] Option 4

[0841]

[0842] The compounds of Formula I' of the present disclosure can be prepared, for example, as shown in Scheme 4. Substituent B in Compound XVI 4 is, for example, a halogenated compound such as F or Cl. Compounds XVI and XIV can be combined with a suitable base such as DIPEA in a solvent such as DMA or NMP. The reaction can be heated to a temperature of about 80° C. to about 150° C. for a period of about 1 hour using microwave or conventional heating to provide a compound of Formula I′.

[0843] Option 5

[0844]

[0845] The compounds of Formula I' of the present disclosure wherein A is a triazole ring can be prepared, for example, as shown in Scheme 5. Substituent B in Compound XVIII 5 is, for example, a halogen such as Cl, Br or I. Compounds XVII and XVIII can be reacted with a copper catalyst (eg, CuI), a ligand (eg, (1S,2S)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine) and NaN3 are combined in a solvent such as DMSO. Additives such as sodium ascorbate may also be included. The reaction may be allowed to proceed at room temperature for about 16 hours to obtain a compound of Formula XIX.

[0846] Option 6

[0847]

[0848] The compounds of formula I' of the present disclosure can be prepared, for example, as shown in Scheme 6. 6 is halogen (e.g., Cl, Br or I) and when the substituent B in compound XXI 7When B is a stannyl group (e.g., Sn(Me) 3 or Sn(n-Bu) 3 ), the coupling is achieved by reaction under Stille conditions. Those skilled in the art will recognize that when B in compound XX is 6 is a stannyl group and B in compound XXI 7 When is a 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 such as CuI and TEA. Examples of suitable catalysts include, but are not limited to, Pd(dppf)Cl2, Pd(PPh3)4, and Pd(P(Cy)3)2Cl2. Suitable solvents include, but are not limited to, 1,4-dioxane, toluene, and DMF. The reaction can be heated to a temperature of about 100°C to about 120°C for a period of about 1 to 16 hours using microwave or conventional heating to give compounds of Formula I'.

[0849] Alternatively, when B 6 is a boron-based coupling agent such as boric acid or boric ester and when B 7 When B is a halogen such as Cl, Br or I, compound XX can be coupled to compound XXI using Suzuki coupling conditions. Those skilled in the art will recognize that when B 6 When halogen and when B 7 When a boron-based coupling agent is used, coupling under Suzuki conditions also yields compounds of Formula I'. Typical Suzuki coupling conditions involve the use of a palladium catalyst (e.g., Pd(dtbpf)Cl2), a base (e.g., K3PO4), and a suitable solvent (e.g., 1,4-dioxane, water, or a mixture thereof). The reaction can be heated to a temperature of about 80°C for about 1 hour using microwave or conventional heating to yield compounds of Formula I'.

[0850] In the event that a protecting group is present on the compound of Formula XX or XXI, 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 (trimethylsilyl)ethoxymethyl (SEM) group is used to protect the nitrogen atom, it can be removed using a reagent such as TFA in a solvent such as DCM.

[0851] In the case where the compounds are obtained as salts, they can be converted to the corresponding free bases by techniques known in the art. For example, those compounds obtained as TFA salts can be converted to the corresponding free bases by methods such as passing through a carbonate column.

[0852] In obtaining the compounds and corresponding analytical data described in the Examples below, the following experimental and analytical protocols were followed unless otherwise indicated.

[0853] 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.

[0854] The compounds described in the examples can also be purified via preparative reversed-phase HPLC. Typical HPLC chromatographic separation ranges from about 10 minutes to about 20 minutes. Suitable solvent gradients and purification conditions can be determined by those skilled in the art. Unless otherwise noted, when using reversed-phase HPLC to purify the compounds described in one of the following examples, the solvent used was an acetonitrile aqueous solution with a gradient of 10% to 80%. When purified in "acidic conditions" or "acidic medium", acetonitrile and water both contained 0.16% TFA. When carried out in "alkaline conditions" or "alkaline medium", the pH of acetonitrile and water was adjusted to pH 10 with ammonium hydroxide. The following column abbreviations are also used throughout the examples:

[0855] Column Type C1 Waters XSelect CSH C18, 5μm, 19×100mm C2 Waters XBridge BEH C18, 5μm, 19×100mm C3 Waters XSelect CSH C18, 5μm, 19×150mm C4 Waters XBridge BEH C18, 5μm, 19×150mm C5 Waters XSelect CSH Fluoro Phenyl, 5μm, 19×100mm C6 Waters XSelect CSH Fluoro Phenyl, 5μm, 19×150mm C7 Waters XSelect CSH C18, 5μm, 30×150mm C8 Waters XBridge BEH C18, 5μm, 30×150mm

[0856]

[0857]

[0858] 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. a 、Biotage Initiator TM or Optimizer TMThe microwave was carried out at the indicated 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).

[0859] 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.

[0860] Chemical names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye).

[0861] Intermediate 1: (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d4.

[0862]

[0863] 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, and concentrated under reduced pressure to obtain 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: 105.1; m / z found: 106 [M+H] + .

[0864] 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] + .

[0865] 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 NH4Cl solution, extracted with 3×600 mL EtOAc 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 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] + .

[0866] 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 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] + .

[0867] 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 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] + .

[0868] 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*25cm, 5μm; mobile phase A: CO2, mobile phase B: IPA (0.5% 2M NH3-MeOH); flow rate: 100mL / min; gradient: 10% B; column temperature: 35°C; back pressure: 100 bar; 220nm; 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 (60mL), 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] + .

[0869] Intermediate 2: (R)-3-ethynyl-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one

[0870]

[0871] 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 diethyl 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 HNMR(300MHz,DMSO-d6)δ7.39-7.08(m,5H),5.41(d,J=7.0Hz,1H),4.88(t,J=2.4 Hz, 1H), 4.30-4.13 (m, 1H), 3.76-3.52 (m, 2H), 2.89 (s, 3H), 1.40 (d, J = 6.8Hz, 3H).

[0872] Step B.4,4-difluoro-3,3-dihydroxy-1-methylpyrrolidin-2-one. To a 10 L 4-necked round-bottom flask was added (3E)-1-methyl-3-[(1-phenylethyl)imino]pyrrolidin-2-one (540 g, 2497 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 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).

[0873] Step C. (R)-3-ethynyl-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one. To a 5 L 4-neck round-bottom flask at room temperature under N2 atmosphere was added 4,4-difluoro-3,3-dihydroxy-1-methylpyrrolidin-2-one (122 g, 730 mmol), DMF (2440 mL), K2CO3 (10.09 g, 73.00 mmol), trimethylsilylacetylene (143 g, 1460 mmol) and Cu(OAc)2 (26.52 g, 146.0 mmol). 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 x 4.6 mm, 80% hexane with 0.1% DEA:20% EtOH) was separated and obtained as the first-eluting enantiomer (R)-3-ethynyl-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one (45.6 g, 88%) as an off-white solid. 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).

[0874] Intermediate 3: (3R,5S)-3-ethynyl-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one

[0875]

[0876] 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).

[0877] 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. The reaction mixture was quenched by adding NH4Cl (saturated, 10.0L) at 25 ° C, the pH of the mixture was adjusted to pH = 2-3 with 1M HCl (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 anhydrous 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).

[0878] 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 anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was triturated with MTBE (5000 mL) at 25°C for 3 hours. The solid was filtered and 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).

[0879] 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, adjusted to pH = 5 with 2M HCl (5000 mL) and the aqueous solution was extracted with EtOAc (5000 mL x 3). The combined organic extracts were washed with 5000 mL of brine, dried over anhydrous Na2SO4 and evaporated to dryness. The title compound (1.50 kg, 86%) was obtained as a red solid and used without further purification. 1 HNMR (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).

[0880] 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 anhydrous 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) (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).

[0881] Intermediate 4: (Z)-6-Bromo-N-hydroxypyridinylmethylimidoyl chloride

[0882]

[0883] Step A. (E) -6- bromopyridinecarbaldehyde oxime. At room temperature, 6- bromopyridine -2- carboxaldehyde (40.0 g, 215 mmol), EtOH (600 mL) and NH2OHπHCl (17.93 g, 258.1 mmol) are added to a 1L 3-neck round-bottom flask. Sodium acetate (35.28 g, 430.1 mmol) is added portionwise to the above mixture at 0 ° C. The resulting mixture is stirred at room temperature overnight and then concentrated under reduced pressure. The mixture is acidified to pH = 7 with saturated NaHCO3 (100 mL). The resulting mixture is extracted with EtOAc (2 × 100 mL). The combined organic extracts are washed with brine (1 × 150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate is concentrated under reduced pressure to obtain a residue. The residue is purified by grinding with hexane (80 mL). The precipitated solid is collected by filtration and washed with hexane to obtain the title compound (39 g, 90%) as a white solid.

[0884] 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 (39.0 g, 194 mmol) and DMF (1 L) at room temperature. To the above mixture was added NCS (31.09 g, 232.8 mmol) 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 (5 L, 1 M). The resulting mixture was extracted with MTBE (2 × 1 L). The combined organic extracts were washed with brine (1 × 1 L) 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 (80 mL). The precipitated solid was collected by filtration and washed with hexane to give the title compound (41.3 g, 90.2%) as a white solid. LC-MS (ESI): mass calculated for C6H4BrClN2O: 233.9; m / z found: 235 [M+H] + . 1 H 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).

[0885] Intermediate 5: (Z)-6-chloro-N-hydroxy-4-(trifluoromethyl)picolinimidoyl chloride

[0886]

[0887] Step A. (E) -6-chloro-4- (trifluoromethyl) pyridine carboxaldehyde oxime. In a 50 mL round-bottom flask containing anhydrous ethanol (7.9 mL) were added hydroxylamine hydrochloride (182 mg, 2.63 mmol), sodium acetate (391 mg, 4.80 mmol) and 6-chloro-4- (trifluoromethyl) pyridine carboxaldehyde (500 mg, 2.4 mmol). The resulting mixture was stirred at room temperature under nitrogen for 12 hours. Water (50 mL) was then added, followed by EtOAc (50 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate and evaporated to dryness to give the title compound (600 mg) as a white foam. LC-MS (ESI): The mass calculated value for C7H4ClF3N2O is 224.0; the found value for m / z is 225.0 [M+H] + .

[0888] Step B. (Z) -6- chloro- N- hydroxy -4- (trifluoromethyl) pyridinyl methyl iminoyl chloride. In a 50mL round-bottom flask, DMF (anhydrous, 11mL) is added, followed by addition of (E) -6- chloro- 4- (trifluoromethyl) pyridine carboxaldehyde oxime (500mg, 2.2mmol) and NCS (387mg, 2.90mmol). The resulting solution is stirred at room temperature for 12 hours, after which the solution is distributed between EtOAc (30mL) and water (30mL). The aqueous portion is further extracted with EtOAc, the organic layer is merged and dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain yellow foam. The residue is subjected to flash column chromatography, with the eluent of 0% to 100% EtOAc in hexane, to obtain the title compound as a yellow solid. LC-MS (ESI): mass calculated for C7H3Cl2F3N2O: 258.0; m / z found: 258.9 [M+H] + .

[0889] Intermediate 6: (R)-3-hydroxy-1-methyl-3-(3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one

[0890]

[0891] Step A. (R)-3-(3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a 25 mL round-bottom flask was added EtOAc (11.2 mL), water (1.1 mL), NaHCO (564 mg, 6.7 mmol), (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (623 mg, 4.5 mmol), and (Z)-6-chloro-N-hydroxy-4-(trifluoromethyl)picolyl iminoyl chloride (580 mg, 2.2 mmol). The resulting mixture was stirred at room temperature for 12 hours. The solution was then partitioned between additional EtOAc (10 mL) and water (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give a yellow residue. The residue was subjected to flash column chromatography eluting with a gradient of 0% to 10% MeOH in DCM to give the title compound as a yellow solid (700 mg, 86%). LC-MS (ESI): C 14 H 11 The calculated mass of ClF3N3O3 is 361.0; the found m / z is 362.0 [M+H] + .

[0892]

[0266] Step B. (R)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one. A large microwave vial charged with DMF (9 mL, anhydrous) was sparged under nitrogen for 15 minutes, followed by the addition of 2-(methylthio)-4-(tributylstannyl)pyrimidine (791 mg, 1.9 mmol), tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.173 mmol), and (R)-3-(3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (627 mg, 1.7 mmol). The vial was sealed and microwaved at 140°C for 90 minutes. Afterwards, the resulting black solution was partitioned between EtOAc and water. The organic solution was dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give a dark brown residue. The residue was subjected to flash column chromatography using 0% to 10% MeOH in DCM as eluent to give the title compound (470 mg, 60%) as an orange foam. LC-MS (ESI): C 19 H 16 The calculated mass of F3N5O3S is 451.1; the found m / z is 452.2 [M+H] + .

[0893] Step C. (R)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one. (R)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one (470 mg, 1.0 mmol) was dissolved in acetone (2.2 mL), water (2.2 mL), THF (2.2 mL), and MeOH (2.2 mL). Potassium peroxymonosulfate (1.92 g, 3.10 mmol) was added to the mixture and the resulting mixture was stirred at room temperature for 12 hours. Ice water (20 mL) was added to the mixture. After 10 minutes, the solid was removed by filtration, rinsed with water (100 mL), and dried under vacuum for several hours to give the title compound (300 mg, 60%) as a white solid. 1 H NMR (600MHz, DMSO-d6) δ9.34(d,J=5.1Hz,1H),8.88(d,J=5.1Hz,1H),8.79(d,J=1.4Hz,1H),8.50(d,J=1.4Hz,1H),7.39(s,1H),6 .84(s,1H),3.58(s,3H),3.54–3.42(m,2H),2.87(s,3H),2.64(ddd,J=13.0,7.7,5.0Hz,1H),2.33(ddd,J=13.5,8.0,5.5Hz,1H).

[0894] Intermediate 7: (R)-4,4-difluoro-3-hydroxy-1-methyl-3-(3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one

[0895]

[0896] Step A. (R)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one. To a 25 mL round-bottom flask was added EtOAc (7.3 mL), water (0.73 mL), NaHCO (642 mg, 6.6 mmol), (R)-3-ethynyl-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 2, 535 mg, 3.1 mmol), and (Z)-6-bromo-N-hydroxypicolinimidoyl chloride (Intermediate 4, 600 mg, 2.6 mmol). The mixture was stirred at room temperature for 12 hours, after which the solution was partitioned between EtOAc (10 mL) and water (10 mL). The organic portion was extracted, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give a yellow residue which was subjected to flash column chromatography using 0% to 10% MeOH in DCM as eluent to give the title compound as a yellow solid. LC-MS (ESI): C 13 H 10 The calculated mass of BrF2N3O3 is 373.0; the measured m / z is 374.0 [M+H] + .

[0897]

[0266] Step B. (R)-4,4-difluoro-3-hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one. A large microwave vial charged with DMF (7.5 mL, anhydrous) was sparged under nitrogen for 15 minutes, followed by the addition of 2-(methylthio)-4-(tributylstannyl)pyrimidine (683 mg, 1.6 mmol), tetrakis(triphenylphosphine)-palladium(0) (173 mg, 0.15 mmol), and (R)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one (560 mg, 1.5 mmol). The vial was sealed and microwaved at 140 °C for 90 minutes. After this time, the resulting black solution was partitioned between EtOAc and water, and the aqueous portion was extracted with EtOAc. The organic portion was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give a dark brown residue. The residue was purified by flash column chromatography (0% to 10% MeOH in DCM) to give the title compound (650 mg) as an orange foam. LC-MS (ESI): C 18 H 15 The calculated mass of F2N5O3S is 419.1; the found m / z is 420.2 [M+H] + .

[0898] Step C. (R)-4,4-Difluoro-3-hydroxy-1-methyl-3-(3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one. (R)-4,4-Difluoro-3-hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one (650 mg, 1.6 mmol) was dissolved in acetone (3.3 mL), water (3.3 mL), THF (3.3 mL), and MeOH (3.3 mL). Potassium peroxomonosulfate (2.86 g, 4.70 mmol) was added and the resulting clear mixture was stirred at room temperature for 12 hours. Ice water (20 mL) was then added to the flask and the solid was filtered off after 10 minutes, rinsed with water (100 mL), and dried under vacuum for several hours to give the title compound (540 mg, 77%) as a white solid. 1 HNMR(600MHz,DMSO-d6)δ9.27(d,J=5.2Hz,1H),8.86(d,J=5.2Hz,1H),8.71–8.64(m,1H),8. 32–8.25(m,2H),7.99(s,1H),7.43(s,1H),4.03(t,J=12.2Hz,2H),3.55(s,3H),2.98(s,3H).

[0899] Intermediate 8: (3R,5S)-3-hydroxy-1-methyl-3-(3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)-5-(trifluoromethyl)pyrrolidin-2-one.

[0900]

[0901] Step A. (3R,5S)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one. To a 25 mL round-bottom flask was added EtOAc (4.2 mL), water (0.42 mL), NaHCO (214 mg, 2.5 mmol), (3R,5S)-3-ethynyl-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one (211 mg, 1.0 mmol, Intermediate 3), and (Z)-6-bromo-N-hydroxypyridinylmethylimidoyl chloride (Intermediate 4, 200 mg, 0.85 mmol). The mixture was stirred at room temperature for 12 hours. The solution was then partitioned between EtOAc (10 mL) and water (10 mL). The organic portion was extracted, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give a yellow residue. The residue was purified by flash column chromatography (0% to 10% MeOH in DCM as eluent) to give the title compound (360 mg) as a yellow solid. LC-MS (ESI): C 14 H 11 The calculated mass of BrF3N3O3 is 405.0; the measured m / z is 406.0 [M+H] + .

[0902] Step B. (3R,5S)-3-hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)-5-(trifluoromethyl)pyrrolidin-2-one. A 50 mL round-bottom flask was charged with DMF (21 mL, anhydrous) and sparged under nitrogen for 15 minutes, followed by the addition of 2-(methylthio)-4-(tributylstannyl)pyrimidine (1.2 g, 4.6 mmol), tetrakis(triphenylphosphine)-palladium(0) (484 mg, 0.42 mmol), and (3R,5S)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one (1.7 g, 1.5 mmol). The vial was then sealed and microwaved at 140 °C for 90 minutes. After this, the resulting black solution was partitioned between EtOAc and water, and the aqueous portion was extracted with EtOAc. The organic portion was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give a dark brown residue. This residue was subjected to flash column chromatography (0% to 10% MeOH in DCM as eluent) to give the title compound (1.8 g) as an orange foam.

[0903] Step C. (3R,5S)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)-5-(trifluoromethyl)pyrrolidin-2-one. (3R,5S)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)-5-(trifluoromethyl)pyrrolidin-2-one (1.8 g, 4.1 mmol) was placed in a 100 mL flask and dissolved in acetone (10.2 mL), water (10.2 mL), THF (10.2 mL), and MeOH (10.2 mL). Potassium peroxomonosulfate (7.5 g, 12.3 mmol) was added to the mixture and the resulting clear mixture was stirred at room temperature for 12 hours. Ice water (100 mL) was added to the white reaction mixture. After 10 minutes, the solid was filtered, rinsed with water (100 mL), and dried under reduced pressure to give the title compound as a white solid which was used without further purification (2.8 g). 1 H NMR(600MHz,DMSO-d6)δ9.29(d,J=5.1Hz,1H),8.81(d,J=5.1Hz,1H),8.69–8.61(m,1H),8.28–8.27(m,1H),7.36(s,1H) ,7.15(s,1H),4.70–4.57(m,1H),3.56(s,3H),3.07(dd,J=14.6,8.8Hz,1H),2.96(s,3H),2.35(dd,J=14.7,4.4Hz,1H). LC-MS(ESI):C 19 H 16 The calculated mass of F3N5O5S is 483.1; the found m / z is 484.3 [M+H] + .

[0904] Intermediate 9: (R)-3-hydroxy-1-methyl-3-(3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one-4,4,5,5-d4

[0905]

[0906] Step A. (R)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d4. The title compound (1.49 g, 102%) was prepared using conditions similar to those described in Intermediate 8, Step A, using (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d4 (Intermediate 6) instead of (3R,5S)-3-ethynyl-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one. LC-MS (ESI): C 13 The calculated mass of H8D4BrN3O3 is 341.0; the found m / z is 342.1 [M+H] + .

[0907] Step B. (R)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one-4,4,5,5-d4. The title compound (1.6 g, 100%) was prepared using conditions analogous to those described in Intermediate 8, Step B, using (R)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d4 instead of (3R,5S)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one. LC-MS (ESI): C 18 H 13 The calculated mass of D4N5O3S is 341.0; the found m / z is 342.1 [M+H] + .

[0908] Step C. (R)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one-4,4,5,5-d4. The title compound (1.9 g) was prepared using conditions analogous to those described in Intermediate 8, Step C, using (R)-3-hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one-4,4,5,5-d4 in place of (3R,5S)-3-hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)-5-(trifluoromethyl)pyrrolidin-2-one. LC-MS (ESI): C 18 H 13 The calculated mass of D4N5O5S is 419.6; the found m / z is 420.3 [M+H] + .

[0909] Intermediate 10: N-(1-methyl-1H-pyrazol-3-yl)-4-(trimethylstannyl)pyrimidin-2-amine

[0910]

[0911] A mixture of 4-chloro-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine (7.50 g, 35.8 mmol, Example 25, Step B), tetrakis(triphenylphosphine)palladium(0) (4.13 g, 3.58 mmol), hexamethylditin (17.2 g, 52.5 mmol) and 1,4-dioxane (250 mL) was heated at 100° C. for 16 hours. The mixture was cooled to room temperature, diluted with aqueous KF solution (2 M, 150 mL) and stirred for 1 hour. The mixture was then extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give N-(1-methyl-1H-pyrazol-3-yl)-4-(trimethylstannyl)pyrimidin-2-amine (15.3 g, approximately 38% purity, 48%) as a brown powder, which was used without further purification. LC-MS (ESI): C 11 H 17 The calculated mass of N5Sn is 339.1; the found m / z is 339.5 [M+H] + .

[0912] Intermediate 11: (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.

[0913]

[0914] 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 give 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] + .

[0915] 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): mass calculated for C7H5BrClNO is 234.5; m / z found is 235.2 [M + H] + .

[0916] 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 (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] + .

[0917] Step D: (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. To a flask containing (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (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)Cl2πCHCl2 (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 h. 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] + .

[0918] Intermediate 12. (R)-3-(3-(3-(2-chloropyrimidin-4-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one

[0919]

[0920] To a 100 mL round-bottom flask under N2 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 11, 1.5 g, 3.9 mmol), 4-bromo-2-chloropyrimidine (906 mg, 4.69 mmol), K2CO3 (9.76 mL, 1 M, 9.76 mmol), PdCl2(dppf) (143 mg, 0.195 mmol), and 1,4-dioxane (30 mL). The reaction was heated at 50°C for 1 hour. After cooling the reaction mixture to room temperature, it was extracted with ethyl acetate (3 x 100 mL) from brine (saturated aqueous NaCl) (100 mL). The organic extract was dried over MgSO4, filtered, and concentrated to dryness under reduced pressure. The product was purified by chromatography using 0-100% ethyl acetate in hexanes as eluent to give (R)-3-(3-(3-(2-chloropyrimidin-4-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (1.522 g). LCMS (ESI): C 18 H 15 The calculated mass of ClN4O3 is 370.8; the found m / z is 372 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ8.89(d,J=5.1Hz,1H),8.64(s,1H),8.39–8.23(m,2H),8.12(d,J=7.7Hz,1H),7.73(t,J=7.8Hz, 1H),7.20(s,1H),6.77(s,1H),3.54–3.48(m,1H),3.48–3.43(m,1H),2.87(s,3H),2.67–2.54(m,1H),2.37–2.24(m,1H).

[0921] Intermediate 13. (R)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one

[0922]

[0923] Step A. (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) and (Z)-6-bromo-N-pyridinylmethylimidoyl chloride (Intermediate 4, 609 g, 2.59 mol) in EtOAc (900 mL) and H2O (450 mL) was added NaHCO3 (326 g, 3.88 mol in 150 mL H2O). 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).

[0924] Step B. (R)-3-Hydroxy-1-methyl-3-(3-(6-(tributylstannyl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one. A mixture of (R)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (270 g, 798 mmol), (SnBu3)2 (926 g, 1.60 mol, 798 mL), LiCl (169 g, 3.99 mol), tricyclohexylphosphine (22.3 g, 79.8 mmol, 25.8 mL), and Pd(PPh3)2Cl2 (28.0 g, 39.9 mmol) in 1,4-dioxane (2200 mL) was degassed and purged with N2 three times, and then the mixture was heated at 110°C under N2 for 12 hours. The residue was diluted with H2O (500mL) and extracted with EtOAc (3000mL, 1000mL×3). The combined organic layers were washed with brine (800mL×1), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent of 0% to 50% ethyl acetate / petroleum ether gradient) to give the title compound (320g, 49.1%) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 7.85 (dd, J = 0.9, 7.9 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.42 (dd, J = 0.9, 7.4 Hz, 1H), 7.00 (s, 1H), 3.79-3.71 (m, 1H), 3.70-3.59 (m, 1H), 3.46 (dt, J = 2.1, 9.5 Hz ,1H),2.99(s,3H),2.77(ddd,J=2.0,7.0,13.3Hz,1H),2.48(td,J=8.7,13.2Hz,1H),1. 70-1.50(m,7H),1.35(qd,J=7.3,14.7Hz,7H),1.23-1.05(m,6H),0.90(t,J=7.3Hz,9H).

[0925] Step C. (R)-3-hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one. A mixture of (R)-3-hydroxy-1-methyl-3-(3-(6-(tributylstannyl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one (320 g, 583 mmol), 4-iodo-2-(methylthio)pyrimidine (161 g, 641 mmol) and Pd(PPh3)4 (23.6 g, 20.4 mmol) in DMF (3200 mL) was degassed and purged with N2 three times, then the mixture was heated at 130°C under N2 atmosphere for 12 hours. The reaction mixture was cooled to 25°C, then concentrated under reduced pressure to remove DMF and diluted with EtOAc (2000 mL). To the mixture was then added KF (67.81 g, 1.17 mol, 27.34 mL) in H2O (1500 mL) and stirred at 25 ° C for 0.5 hours. The mixture was filtered and the filtrate was extracted with EtOAc (1500 mL × 3). The combined organic layers were washed with brine (800 mL × 1), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The product was triturated with ethyl acetate: petroleum ether (1: 2, 1200 mL) at 25 ° C for 30 minutes to give the title compound (180 g, 53%) as a white solid. 1 H NMR(400MHz, DMSO-d6)δ8.83(d,J=5.1Hz,1H),8.59-8.46(m,1H),8.28-8.08(m,3H),7.20(s,1H) ), 6.78 (s, 1H), 3.58-3.39 (m, 2H), 2.85 (s, 3H), 2.63 (s, 4H), 2.30 (ddd, J = 5.7, 7.8, 13.4Hz, 1H). LC-MS(ESI):C 18 H 17 The calculated mass of N5O3S is 383.1; the found m / z is 384.0 [M+H] + .

[0926] Step D. (R)-3-hydroxy-1-methyl-3-(3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one. To a solution of (R)-3-hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one (130 g, 339 mmol) in THF (260 mL), acetone (260 mL), H2O (260 mL), and MeOH (260 mL) was added potassium peroxymonosulfate (416 g, 678 mmol). The mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with ice-cold H2O (3000 mL). The resulting precipitate was collected by filtration and concentrated under reduced pressure to give a residue. The residue was triturated with H2O (2000 mL) at 25°C for 1.0 h. The trituration was repeated twice. The resulting residue was further triturated with MeOH (700 mL) at 25°C for 0.5 h to give the title compound (190 g, 87.9%) as a white solid. 1 HNMR (400MHz, DMSO-d6) δ9.27(d,J=5.1Hz,1H),8.81(d,J=5.3Hz,1H),8.68-8.60(m,1H),8.26(d,J=4.5Hz,2H),7.27(s,1H),6. 79(s,1H),3.55(s,3H),3.53-3.42(m,2H),2.85(s,3H),2.62(ddd,J=5.1,7.7,13.2Hz,1H),2.31(ddd,J=5.8,7.8,13.4Hz,1H). LC-MS(ESI):C 18 H 17 The calculated mass of N5O5S is 415.1; the found m / z is 416.0 [M+H] + .

[0927] Intermediate 14. 3-Cyclopropyloxy-1-(2,2-difluoroethyl)-1H-pyrazol-4-amine

[0928]

[0929] Step A. 1,4-Dinitro-1H-pyrazole. KNO3 (0.89 g, 8.84 mmol), 4-nitro-1H-pyrazole (1.00 g, 8.84 mmol) and anhydrous CH2Cl2 (5 mL) were added to a 50 mL round-bottom flask. The mixture was cooled to 15 ° C, treated with a solution of 2,2,2-trifluoroacetic anhydride (2.46 mL, 17.7 mmol) and CH2Cl2 (5 mL), and stirred at room temperature under N2 for 5 hours. Afterwards, the light yellow mixture was poured into ice water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a light yellow oil. The light yellow oil was purified by silica gel chromatography (0-20% EtOAc / petroleum ether) to give 1,4-dinitro-1H-pyrazole (1.2 g, 86%) as a yellow oil.

[0930] 1 H NMR (400MHz, CDCl3) δ8.97 (d, J = 0.8Hz, 1H), 8.15-8.09 (m, 1H).

[0931] Step B.3-cyclopropyloxy-4-nitro-1H-pyrazole. NaH (1.35 g, 33.7 mmol, 60 wt % in mineral oil) was added portionwise to a 100 mL three-necked round-bottom flask containing cyclopropanol (1.96 g, 33.7 mmol) and 2-MeTHF (15 mL) at 0 ° C. The reaction was stirred at room temperature for 10 minutes and then added dropwise to another solution consisting of 1,4-dinitro-1H-pyrazole (8.00 g, 50.6 mmol) and 2-MeTHF (15 mL) at -78 ° C. The resulting mixture was stirred at -78 ° C for 1 hour, then allowed to warm to room temperature and stirred for 5 hours. Thereafter, the gray mixture was poured into water, treated with aqueous HCl (10 mL, 3.0 N) and extracted with CH2Cl2 (20 mL × 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a yellow oil. The oil was purified by silica gel chromatography (0-30% EtOAc / petroleum ether) to give 3-cyclopropyloxy-4-nitro-1H-pyrazole (1.1 g, 19%) as a yellow oil. 1 HNMR (400MHz, CDCl3) δ8.30-8.17(m,1H),6.47(s,1H),4.27-4.23(m,1H),1.03-0.94(m,2H),0.88-0.79(m,2H).

[0932] Step C.3-cyclopropyloxy-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole. 2-(tributylphosphoranylidene)acetonitrile (3.00 g, 12.4 mmol) was added to a 100 mL three-necked round-bottom flask containing a solution of 3-cyclopropyloxy-4-nitro-1H-pyrazole (700 mg, 4.14 mmol), 2,2-difluoroethanol (1.02 g, 12.4 mmol) and anhydrous toluene (30 mL) at room temperature under N2. The red mixture was heated at 60 ° C for 12 hours. The reaction vessel was removed from the oil bath and allowed to gradually cool to room temperature. The mixture was concentrated in vacuo to dryness to give a red oil. The red oil was purified by silica gel chromatography (20%-50% EtOAc / petroleum ether) to give 3-cyclopropyloxy-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole (500 mg, 52%) as a red solid. 1 H NMR (400MHz, CDCl3) δ8.10(s,1H),6.34-5.94(m,1H),4.38-4.30(m,2H),4.22-4.19(m,1H),0.96-0.90(m,2H),0.84-0.78(m,2H).

[0933] Step D.3-cyclopropyloxy-1-(2,2-difluoroethyl)pyrazol-4-amine. To a 250 mL 3-neck round-bottom flask was added 3-cyclopropyloxy-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole (9 g, 38.59 mmol), EtOH (129 mL), H2O (26 mL), Fe (10.78 g, 192.99 mmol) and NH4Cl (8.26 g, 154.39 mmol) at room temperature. The resulting mixture was stirred at 70 ° C for 3 hours. The resulting mixture was filtered and the filter cake was washed with MeOH (1×250 mL). The filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (100 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water (3×500 mL) and brine (3×500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give 3-cyclopropyloxy-1-(2,2-difluoroethyl)pyrazol-4-amine (3.124 g, 40%) as a brown oil. 1 H NMR (300 MHz, DMSO-d -6)δδ6.99(s,1H),6.18(tt,J=55.4,4.0Hz,1H),4.27(td,J=14.8,4.0Hz,2H),4. 00(tt,J=6.0,3.3Hz,1H),3.47(s,2H),0.64(dddd,J=9.6,5.7,2.3,1.2Hz,4H). 19 F NMR (282MHz, DMSO-d6, ppm) δ-122.30. LC-MS(ESI):C8H 11 The calculated mass of F2N3O is 203.1; the found m / z is 204.0 [M+H] + .

[0934] Intermediate 15. 2-(4-amino-3-methoxypyrazol-1-yl)ethanol

[0935]

[0936] Step A.1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-methoxy-4-nitropyrazole. To a stirred solution of 3-methoxy-4-nitro-1H-pyrazole (10.00 g, 69.88 mmol), 2-[(tert-butyldimethylsilyl)oxy]ethanol (30.81 g, 174.7 mmol) and triphenylphosphine (45.82 g, 174.7 mmol) in tetrahydrofuran (100 mL) was added dropwise DIAD (22.87 g, 174.7 mmol) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 60°C under a nitrogen atmosphere overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine (2×100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give 1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-methoxy-4-nitropyrazole (11 g, 52%) as a pale yellow oil.

[0937] Step B. 1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-methoxypyrazol-4-amine. In a 500 mL round-bottom flask, to a solution of 1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-methoxy-4-nitropyrazole (11 g, 36.49 mmol) in EtOH (250 mL) was added Pd / C (10%, 7.77 g) under nitrogen atmosphere. The mixture was stirred overnight using a hydrogen balloon under a hydrogen atmosphere, filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10: 1) to give 1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-methoxypyrazol-4-amine (8.7 g, 87.83%) as a brown oil. LCMS (ESI): C 12 H 25 The calculated mass of N3O2Si is 271.2; the measured m / z is 272 [M+H] + .

[0938] Step C. 2-(4-amino-3-methoxypyrazol-1-yl)ethanol. A solution of 1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-methoxypyrazol-4-amine (8.7 g, 32.05 mmol) and TBAF (10.06 g, 38.46 mmol) in tetrahydrofuran (87 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to give 2-(4-amino-3-methoxypyrazol-1-yl)ethanol (2.258 g, 44.86%) as an off-white solid. LCMS (ESI): CH 11 The calculated mass of N3O2 is 157.1; the found m / z is 158 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ6.94 (s, 1H), 4.74 (t, J = 5.4Hz, 1H), 3.80 (t, J = 5.8Hz, 2H), 3.75 (s, 3H), 3.60 (q, J = 5.6Hz, 2H), 3.31 (br, 2H).

[0939] Intermediate 16. 3-Methoxy-1-(1-methylpiperidin-4-yl)pyrazol-4-amine

[0940]

[0941] Step A.4-(3-methoxy-4-nitropyrazole-1-yl)-1-methylpiperidine. To a stirred solution of 3-methoxy-4-nitro-1H-pyrazole (5 g, 34.9 mmol), triphenylphosphine (13.75 g, 52.41 mmol) and 1-methyl-4-piperidinol (6.04 g, 52.4 mmol) in tetrahydrofuran (50 mL) was added DIAD (10.60 g, 52.42 mmol) dropwise at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. The reaction was quenched by adding water / ice (100 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 (3×100 ml). The combined organic extracts were washed with brine (1×100 mL) and water (1×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (10:1) to give 4-(3-methoxy-4-nitropyrazol-1-yl)-1-methylpiperidine (3.2 g, 38.12%) as a pale yellow solid. LCMS (ESI): C 10 H 16 The calculated mass of N4O3 is 240.1; the found m / z is 241 [M+H] + .

[0942] Step B. 3-methoxy-1-(1-methylpiperidin-4-yl)pyrazol-4-amine. To a solution of 4-(3-methoxy-4-nitropyrazol-1-yl)-1-methylpiperidine (3.2 g, 13.31 mmol) in EtOH (40 mL) was added Pd / C (10%, 0.5 g) in a 250 mL round-bottom flask under nitrogen. The mixture was stirred for 4 hours using a hydrogen balloon under a hydrogen atmosphere, filtered through a celite pad and the filtrate was concentrated under reduced pressure. This gave 3-methoxy-1-(1-methylpiperidin-4-yl)pyrazol-4-amine (2.25 g, 78%) as a brown oil. LCMS (ESI): C 10 H 18 The calculated mass of N4O is 210.2; the measured m / z is 210[M] + . 1 H NMR (300MHz, DMSO-d6) δ6.97 (s, 1H), 3.75 (s, 3H), 3.69 (dt, J = 10.8, 4.6Hz, 1H), 2.79 ( dt,J=11.9,3.2Hz,2H),2.17(s,3H),1.97(td,J=11.6,2.8Hz,2H),1.90-1.69(m,4H).

[0943] Intermediate 17. 3-(4-amino-3-methyl-1H-pyrazol-1-yl)cyclobutan-1-ol

[0944]

[0945] Step A.3-(benzyloxy)cyclobutan-1-ol. At room temperature under N2 atmosphere, 3-(benzyloxy)cyclobutan-1-one (15 g, 85.12 mmol) and MeOH (150 mL) were added to a 500 mL 3-neck round-bottom flask. NaBH4 (3.2 g, 84.58 mmol) was added portionwise to the above mixture at 0°C. The resulting mixture was stirred for another hour at 0°C and then concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL), the organic layer was washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 3-(benzyloxy)cyclobutan-1-ol (12 g, 79%) as a yellow oil.

[0946] Step B. 3-(Benzyloxy)cyclobutyl-4-methylbenzenesulfonate. To a 250 mL 3-neck round-bottom flask at room temperature under N2 atmosphere, 3-(benzyloxy)cyclobutan-1-ol (12 g, 67.32 mmol), DCM (120 mL), DMAP (0.82 g, 6.71 mmol) and DIEA (13 g, 100.58 mmol) were added. TsCl (15.3 g, 80.25 mmol) was added portionwise to the above mixture at 0°C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was washed with H2O (2 x 80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. This gave 3-(benzyloxy)cyclobutyl-4-methylbenzenesulfonate (16 g, 71.49%) as a yellow oil.

[0947] Step C. 1-[3-(Benzyloxy)cyclobutyl]-3-methyl-4-nitropyrazole. To a 500 mL 3-necked round-bottom flask at room temperature under N2 atmosphere was added 3-(benzyloxy)cyclobutyl-4-methylbenzenesulfonate (16 g, 48.1 mmol), DMF (160 mL), 3-methyl-4-nitro-1H-pyrazole (4.7 g, 36.97 mmol) and Cs2CO3 (18 g, 55.24 mmol). The resulting mixture was heated at 100°C for 3 hours and then diluted with H2O (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL), and the combined organic extracts were washed with H2O (3 x 100 mL) and brine (1 x 100 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1-3:1) to give 1-[3-(benzyloxy)cyclobutyl]-3-methyl-4-nitropyrazole (9 g, 65%) as a yellow solid. LCMS (ESI): C 15 H 17 The calculated mass of N3O3 is 287.1; the found m / z is 288 [M+H] + .

[0948] Step D. 3-(4-amino-3-methyl-1H-pyrazol-1-yl)cyclobutan-1-ol. To a 250 mL round-bottom flask was added 1-[3-(benzyloxy)cyclobutyl]-3-methyl-4-nitropyrazole (9 g, 31.32 mmol), EtOH (100 mL) and Pd / C (10%, 4 g) at room temperature. The mixture was degassed three times with H2. The resulting mixture was stirred at room temperature under 1 atmosphere of H2 overnight, then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (100:0-1:1) to give the product. The product was further purified by SFC (column: IF, 3*25cm, 5μm; mobile phase A: CO2, mobile phase B: MeOH (0.1% 2M NH3-MeOH); flow rate: 80mL / min; gradient: isocratic 30% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220nm; first peak isolated at 3.5 minutes; sample solvent: MeOH-HPLC; injection volume: 3mL;) to give 3-(4-amino-3-methylpyrazol-1-yl)cyclobutan-1-ol (2.527g, 48.25%) as a brown solid. LCMS (ESI): CH 13 The calculated mass of N3O is 167.1; the found m / z is 168 [M+H] + . 1H NMR (300MHz, DMSO-d6) δ6.99 (s, 1H), 5.09 (d, J = 5.0Hz, 1H), 4.72-4.54 (m, 1H), 4. 44-4.26(m,1H),3.55(s,2H),2.59-2.41(m,2H),2.30-2.13(m,2H),1.99(s,3H).

[0949] Intermediate 18. 3-Methyl-1-(oxan-4-yl)pyrazol-4-amine

[0950]

[0951] Step A.3-Methyl-4-nitro-1-(oxan-4-yl)pyrazole. To a 1L 3-neck round-bottom flask was added 3-methyl-4-nitro-1H-pyrazole (15 g, 118.01 mmol), oxan-4-ol (30.13 g, 295.03 mmol), THF (150 mL) and PPh3 (77.39 g, 295.03 mmol) at room temperature. To the above mixture was added DIAD (59.66 g, 295.03 mmol) dropwise at 0°C. The resulting mixture was heated at 60°C overnight. After the reaction mixture was cooled to room temperature, it was diluted with ice / water (200 mL) and extracted with EA (3×100 mL). The combined organic extracts were washed with brine (1×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE / EA (5:1) to give 3-methyl-4-nitro-1-(oxan-4-yl)pyrazole (12 g, 48%) as a black oil.

[0952] Step B.3-methyl-1-(oxan-4-yl)pyrazole-4-amine. In a 250mL round-bottom flask under a nitrogen atmosphere, Pd / C (10%, 7g) was added to a solution of 3-methyl-4-nitro-1-(oxan-4-yl)pyrazole (12g, 56.81mmol) in EtOH (120mL). A hydrogen atmosphere was placed above the reaction mixture using a hydrogen balloon, and the reaction was stirred overnight. The reaction mixture was filtered through a celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / MeOH (95:5) to give the product. The product was further purified by SFC (SC 100×4.6mm3.0μm, co-solvent B: 10% MeOH (20mM NH3), peak 1.413 minutes, total flow rate:

[0953] 3.0000 mL / min) to give 3-methyl-1-(oxan-4-yl)pyrazol-4-amine (2.57 g, 24.96%) as a brown solid. LCMS (ESI): C9H 15 The calculated mass of N3O is 181; the found m / z is 182.1 [M+H] + . 1 HNMR(300MHz,DMSO-d6)δ7.01(s,1H),4.08(tt,J=10.6,5.6Hz,1H),3.98-3 .85(m,2H),3.50-3.33(m,2H),3.34(s,2H),1.99(s,3H),1.91-1.71(m,4H).

[0954] Intermediate 19. 1-(4-Amino-3-methoxy-1H-pyrazol-1-yl)-2-methylpropan-2-ol

[0955]

[0956] Step A. 1-(3-Methoxy-4-nitro-1H-pyrazol-1-yl)-2-methylpropan-2-ol. 3-Methoxy-4-nitro-1H-pyrazole (2.00 g, 14.0 mmol), DMF (30 mL), 2,2-dimethyloxirane (2.02 g, 28.0 mmol) and Cs2CO3 (13.7 g, 41.9 mmol) were added to a 100 mL round-bottom flask. The mixture was heated at 100 °C for 5 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give a white solid. The solid was purified by flash silica gel chromatography (0-30% EtOAc / petroleum ether gradient eluent) to give 1-(3-methoxy-4-nitro-1H-pyrazol-1-yl)-2-methylpropan-2-ol (2.0 g, 63%) as a white solid. LCMS (ESI): C8H 13 The calculated mass of N3O4 is 215.1; the measured m / z is 216.1 [M+H] + .

[0957] Step B. 1-(4-amino-3-methoxy-1H-pyrazol-1-yl)-2-methylpropan-2-ol. Pd / C (0.544 g, 10 wt%, 0.511 mmol), 1-(3-methoxy-4-nitro-1H-pyrazol-1-yl)-2-methylpropan-2-ol (2.20 g, 10.2 mmol) and MeOH (30 mL) were added to a 100 mL round-bottom flask and the resulting mixture was stirred under H (15 psi) at room temperature for 3 hours. The suspension was filtered through a pad of celite and the pad was washed with EtOAc (100 mL) to give a nearly black, viscous oil. The oil was purified by flash silica gel chromatography (0-50% EtOAc / petroleum ether gradient eluent) to give 1-(4-amino-3-methoxy-1H-pyrazol-1-yl)-2-methylpropan-2-ol (1850.5 mg, 96%) as a blue syrupy solid. LCMS (ESI): C8H 15 The calculated mass of N3O2 is 185.1; the measured m / z is 186.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): 6.94(s,1H), 4.54(s,1H), 3.74(s,3H), 3.67(s,2H), 1.01(s,6H).

[0958] Intermediate 20. 3-Methoxy-1-(oxetan-3-yl)-1H-pyrazol-4-amine

[0959]

[0960] Step A. 3-Methoxy-4-nitro-1-(oxetane-3-yl)-1H-pyrazole. 3-Methoxy-4-nitro-1H-pyrazole (1.00 g, 6.99 mol), DMF (15 mL), 3-iodooxetane (2.57 g, 14.0 mol) and Cs2CO3 (6.83 g, 21.0 mol) were added to a 50 mL round-bottom flask. The mixture was heated at 100°C for 5 hours. The mixture was cooled to room temperature, then diluted with water (30 mL) and extracted with EtOAc (3 x 40 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford a yellow solid, which was purified by silica gel chromatography (0-50% EtOAc / petroleum ether) to afford 3-methoxy-4-nitro-1-(oxetan-3-yl)-1H-pyrazole (1.2 g, 62%) as a white solid. LCMS (ESI): mass calculated for C7H9N3O4 is 199.1; m / z found is 200.2 [M+H]. + .

[0961] Step B.3-methoxy-1-(oxetanes-3-yl)-1H-pyrazole-4-amine. 3-methoxy-4-nitro-1-(oxetanes-3-yl)-1H-pyrazole (2.00 g, 10.0 mmol), wet Pd / C (1 g, 10% Pd, 50% water) and anhydrous EtOH (30 mL) are added to a 100 mL round-bottom flask. The resulting mixture is sprayed with H2 3 times, then stirred at room temperature for 4 hours under an H2 atmosphere (15 Psi). The mixture is filtered and the filtrate is concentrated in vacuo to dryness to obtain a viscous oil close to black, which is subjected to silica gel chromatography (0-100% ethyl acetate / petroleum ether) to obtain 3-methoxy-1-(oxetanes-3-yl)-1H-pyrazole-4-amine (1 g, 56%) close to a viscous oil close to black. 1 H NMR (400MHz, DMSO-d6) δ7.10-7.04(m,1H),5.25-5.15(m,1H),4.81-4.74(m,4H),3.81(s,3H),3.51-3.43(m,2H).

[0962] Intermediate 21. (R)-3-Hydroxy-1-methyl-3-(5-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)isoxazol-3-yl)pyrrolidin-2-one.

[0963]

[0964] Step A. (R)-3-ethynyl-1-methyl-3-((trimethylsilyl)oxy)pyrrolidin-2-one. To a solution of (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (15.0 g, 107.8 mmol) and imidazole (22.0 g, 323.4 mmol) in DMF (50 mL) was added trimethylchlorosilane (20.5 mL, 161.7 mmol) at room temperature. The reaction was heated to 60° C. and stirred overnight. The mixture was poured into a separatory funnel with a mixture of water (50 mL) and saturated aqueous NaHCO₃ (100 mL) and extracted twice with DCM (1×100 mL, then 1×50 mL). The combined organic layers were washed with water (3×50 mL), dried (Na₂SO₄), filtered, and concentrated. The product was purified by FCC (eluent: 10%-70% EtOAc / hexanes) to give 18.788 g (82%) of (R)-3-ethynyl-1-methyl-3-((trimethylsilyl)oxy)pyrrolidin-2-one as a colorless oil which solidified upon standing. LCMS (ESI): C 10 H 17The calculated mass of NO2Si is 211.10; the measured m / z is 212.1[M+1] + .

[0965] Step B. (R)-3-(3-(6-chloropyridin-2-yl)-3-oxoprop-1-yn-1-yl)-1-methyl-3-((trimethylsilyl)oxy)pyrrolidin-2-one. To a solution of (R)-3-ethynyl-1-methyl-3-((trimethylsilyl)oxy)pyrrolidin-2-one (16.4 g, 77.6 mmol) in THF (275 mL) at -20°C was added DIPEA (26.7 mL, 155.2 mmol), Pd(PPh3)4 (2.72 g, 5 mol%), and CuI (739 mg, 5 mol%). The mixture was stirred for several minutes while purging the flask with a stream of N2. A solution of the acid chloride, 6-chloropicolinoyl chloride (19.1 g, 108.6 mmol) in THF (25 mL) was added via syringe at -20°C. The reaction is warming up to 0 ℃ and stirred overnight. The reaction mixture is a stirred suspension of precipitation. Add DIPEA (7mL) again, and make the reaction mixture pass through a 1 inch silica gel plug in a sintered glass funnel, elute with THF, until the product is completely eluted from the plug. The filtrate containing the product is concentrated, causing a thin dark solid precipitation. This material is dissolved among the EtOAc and filtered through a diatomaceous earth plug. The filtrate containing the product is concentrated and purified by FCC (eluent: 30%-70% EtOAc / hexane) to obtain 4.72g dark brown oily substance, which is a mixture of starting silyl-lactam and desired product in a 40:60 mol ratio. The mixture was 76% by weight of (R)-3-(3-(6-chloropyridin-2-yl)-3-oxoprop-1-yn-1-yl)-1-methyl-3-((trimethylsilyl)oxy)pyrrolidin-2-one, giving a yield of 3.59 g (13%) of the desired product. The mixture was used as is in the next step. LCMS (ESI): C 16 H 19 The calculated mass of ClN2O3Si is 350.08; the measured m / z is 351.1 [M+1] + .

[0966]

[0266] Step C. (R)-3-(5-(6-chloropyridin-2-yl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one. A mixture from the previous step containing (R)-3-(3-(6-chloropyridin-2-yl)-3-oxoprop-1-yn-1-yl)-1-methyl-3-((trimethylsilyl)oxy)pyrrolidin-2-one (3.59 g, 10.2 mmol) was stirred in THF (100 mL) at room temperature while NaN (4.0 g, 61.4 mmol), AcOH (3.5 mL, 61.4 mmol), and EtN (0.57 mL, 4.1 mmol) were added. The mixture was allowed to stir overnight. A 1.0 M solution of TBAF in THF (30.7 mL, 30.7 mmol) was added and the mixture was allowed to stir overnight to complete the removal of the silyl group. The reaction mixture was poured into an aqueous sodium carbonate solution (10.8 g Na2CO3, 102 mmol in 110 mL of water) and stirred for 10 minutes. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to give the product as a dark brown oil. The substance was purified by FCC (eluent: 0-25% MeOH in 1:1 EtOAc / hexane). The desired product was separated into a 1.36 g mixture containing desilylated lactam raw material with a product / starting lactam molar ratio of 83:17. The product mixture was 91 wt% of (R)-3-(5-(6-chloropyridin-2-yl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one, giving a yield of 1.24 g (41%) of the desired product. LCMS (ESI): C 13 H 12 The calculated mass of ClN3O3 is 293.06; the measured m / z is 294.1[M+1] + .

[0967] Step D. (R)-3-Hydroxy-1-methyl-3-(5-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-3-yl)pyrrolidin-2-one. A mixture containing (R)-3-(5-(6-chloropyridin-2-yl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (1.2 g, 4.1 mmol), Pd(PPh3)4 (330 mg, 7 mol%), and DMF (16 mL) was added to a 100 mL round-bottom flask. The flask was capped with a septum and flushed with N2 for 15 minutes. Stannane, 2-(ethylthio)-4-(tributylstannyl)pyrimidine (1.53 mL, 4.5 mmol) were added, and the reaction was heated at 100°C overnight. LCMS analysis showed almost complete conversion of the starting pyridyl chloride. The reaction mixture was cooled and poured into a two-phase mixture of EtOAc (60 mL) and a KF aqueous solution (1.2 g KF / 60 mL water), and stirred for 30 minutes. The mixture was filtered through a diatomaceous earth plug containing excessive EtOAc. EtOAc was partially removed in a vacuum, and the remaining two-phase mixture was poured into a separating funnel and separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated to obtain the product in the residual DMF. First, this material was purified by FCC (eluent: 0-10% MeOH / DCM) and partially separated. The mixed fractions were merged and purified by FCC (eluent: 0-100% 5% MeOH in TBME / DCM) again. All pure fractions were combined to give (R)-3-hydroxy-1-methyl-3-(5-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-3-yl)pyrrolidin-2-one (0.65 g, 41%) as an off-white solid. LCMS (ESI): C 18 H 17 The calculated mass of N5O2S is 383.11; the measured m / z is 384.1[M+1] + .

[0968] Step E. (R)-3-Hydroxy-1-methyl-3-(5-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)isoxazol-3-yl)pyrrolidin-2-one. (R)-3-Hydroxy-1-methyl-3-(5-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-3-yl)pyrrolidin-2-one (0.2 g, 0.52 mmol) was placed in a 25 mL flask and dissolved in acetone (1.7 mL), water (1.7 mL), THF (1.7 mL), and MeOH (1.7 mL). Potassium peroxymonosulfate (0.96 g, 1.6 mmol) was added to the mixture and the resulting clear mixture was stirred at room temperature for 12 hours. Ice water (10 mL) was added to the white reaction mixture and stirred for 10 minutes, then the solid was filtered, rinsed with water (20 mL), and dried under reduced pressure to give a white solid which was used without further purification (0.16 g). LC-MS (ESI): C 18 H 17 The calculated mass of N5O5S is 415.1; the found m / z is 415.8 [M+H] + .

[0969] Intermediate 22 and Intermediate 23. (R)-3-Hydroxy-1-methyl-3-(1-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one and (S)-3-Hydroxy-1-methyl-3-(1-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one.

[0970]

[0971] Step A.2-chloro-6-(4-iodo-1H-pyrazol-1-yl)pyridine. The following reaction was carried out in five batches. 4-iodo-1H-pyrazole (200 g, 1.03 mol) and DMF (4000 mL) were added to a 5000 mL flask charged with 2,6-dichloropyridine (381 g, 2.58 mol) and Cs2CO3 (1.01 kg, 3.09 mol). The mixture was heated at 100 ° C for 3 hours. The reaction mixture was filtered and the solid was washed with EtOAc. The filtrate was then diluted with H2O (8000 mL) and extracted with MTBE (5000 mL×3). The organic layer was washed with brine (5000 mL×1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether:ethyl acetate = 2:1 (2000 mL) at 25°C for 1 hour to give 2-chloro-6-(4-iodo-1H-pyrazol-1-yl)pyridine (1.04 kg, 3.10 mol, 60%, 91.0% purity) as a white solid. LCMS (ESI): mass calculated for C8H5ClIN3 is 304.9, m / z found is 305.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.67 (s, 1H), 8.06 (t, J = 7.9 Hz, 1H), 7.99-7.95 (m, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H).

[0972] Step B.3-(1-(6-chloropyridin-2-yl)-1H-pyrazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of 2-chloro-6-(4-iodo-1H-pyrazol-1-yl)pyridine (1000 g, 3.27 mol) in THF (15000 mL) was added iPrMgCl-LiCl (1.30 M, 2.64 L) at 0 ° C under N2 atmosphere. The mixture was stirred at 0 ° C for 0.5 hours. 1-Methylpyrrolidine-2,3-dione (314 g, 2.78 mol) dissolved in THF (5000 mL) was added, and the resulting mixture was stirred at 25 ° C for another 12 hours. The reaction mixture was quenched by adding NH4Cl (saturated aqueous solution, 10 L) at 0 ° C and extracted with EtOAc15000 mL (5000 mL×3). The combined organic layers were washed with brine (5000 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give 3- (1- (6-chloropyridin-2-yl) -1H-pyrazol-4-yl) -3-hydroxy-1-methylpyrrolidin-2-one (330 g, 1.07 mol, 32%, 95.0% purity) as a yellow solid. LCMS (ESI): C 13 H 13 The calculated mass of ClN4O2 is 292.1; the found m / z is 293.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.47(s,1H),8.08-7.98(m,1H),7.90-7.82(m,2H),7.46(d,J=7.8H z,1H),6.00(s,1H),3.45-3.36(m,1H),3.35-3.28(m,3H),2.78(s,3H),2.26-2.17(m,1H).

[0973] Step C. 3-Hydroxy-1-methyl-3-(1-(6-(tributylstannyl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one. A mixture of 3-(1-(6-chloropyridin-2-yl)-1H-pyrazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (280 g, 956 mmol), (SnBu3)2 (1.11 kg, 1.91 mol, 956 mL), LiCl (202 g, 4.78 mol), Cy3P (26.8 g, 95.6 mmol, 31.0 mL), and Pd(PPh3)2Cl2 (33.5 g, 47.8 mmol) in 1,4-dioxane (2500 mL) was degassed and purged with N2 three times. The mixture was stirred at 110°C under N2 for 36 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H2O (1000mL) and extracted with EtOAc (1000mL×3). The combined organic layer was washed with brine (800mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent of 0-46% ethyl acetate / petroleum ether gradient) to give 3-hydroxy-1-methyl-3-(1-(6-(tributylstannyl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one (225g, 411mmol, 42%) as a yellow oil. LCMS (ESI): C 25 H 40 The calculated mass of N4O2Sn is 548.1; the found m / z is 549.2 [M+H] + . 1 H NMR: (400MHz, DMSO-d6)δ8.57(s,1H),7.76-7.68(m,2H),7.61-7.52(m,1H),7.27(s,1H),3.41-3.25(m,3H),2. 88(s,3H),2.54-2.40(m,2H),1.63-1.46(m,7H),1.37-1.23(m,7H),1.14-1.03(m,6H),0.85(t,J=7.3Hz,10H).

[0974] Step D. (R) and (S) enantiomers of 3-hydroxy-1-methyl-3-(1-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one. A mixture of 3-hydroxy-1-methyl-3-(1-(6-(tributylstannyl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one (200 g, 365 mmol), 4-iodo-2-(methylthio)pyrimidine (101 g, 401 mmol) and Pd(PPh) (14.7 g, 12.7 mmol, 0.035 equiv) in DMF (1600 mL) was degassed and purged with N for three times, and then the mixture was heated at 120° C. under N for 12 h. The reaction mixture was cooled at 25 ° C and then diluted with EtOAc (3000 mL). To the mixture was added KF (42.2 g) in H2O (800 mL) and stirred at 25 ° C for 0.5 hours. The mixture was filtered and the filtrate was extracted with EtOAc (1500 mL × 3). The combined organic layer was washed with brine (800 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. It was then ground with EtOAc (500 mL) at 25 ° C for 60 minutes to give (R, S) -3-hydroxy -1-methyl -3- (1- (6- (2- (methylthio) pyrimidin-4-yl) pyridin-2-yl) -1H- pyrazol-4-yl) pyrrolidin-2-one (90 g) as a yellow solid. The (R) and (S) enantiomers of (R,S)-3-hydroxy-1-methyl-3-(1-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one were purified by SFC (DAICEL CHIRALPAK AS (250 mm × 50 mm, 10 μm); mobile phase: 65% [0.1% NH3H2O ​​in EtOH], 35% CO2), yielding two eluting peaks. The second eluting peak was designated as enantiomer 1 of 3-hydroxy-1-methyl-3-(1-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one. LCMS (ESI): C 18 H 18 The calculated mass of N6O2S is 382.1; the found m / z is 383.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 8.88-8.80 (m, 2H), 8.36 (d, J = 7.6Hz, 1H), 8.23-8.20 (m, 1H),8.19-8.16(m,1H),8.07(d,J=8.0Hz,1H),7.88(s,1H),6.01(s,1H),3.42(br dd,J=4.5,8.1Hz,1H),3.39-3.35(m,1H),2.80(s,3H),2.63(s,3H),2.61-2.54(m,1H),2.30-2.21(m,1H). The first eluting peak (retention time = 2.25 minutes) was assigned as enantiomer 2 of 3-hydroxy-1-methyl-3-(1-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one (39.0 g, 98.9 mmol, 97.0% purity) and was obtained as a white solid. LCMS (ESI): C 18 H 18 The calculated mass of N6O2S is 382.1; the found m / z is 383.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.88-8.80(m,2H),8.36(d,J=7.6Hz,1H),8.23-8.20(m,1H),8.19-8.16(m,1H),8.07(d,J=8.0Hz,1H),7.88( s,1H),6.01(s,1H),3.42(dd,J=4.5,8.1Hz,1H),3.39-3.35(m,1H),2.80(s,3H),2.63(s,3H),2.61-2.54(m,1H),2.30-2.21(m,1H).

[0975] Step E: To a solution of enantiomer 1 of 3-hydroxy-1-methyl-3-(1-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one (33.0 g, 86.2 mmol) in a mixture of THF (495 mL) / acetone (495 mL) / H2O (495 mL) was added potassium peroxymonosulfate (159.14 g, 258 mmol). The mixture was stirred at 25°C for 12 hours. The reaction mixture was then diluted with H2O (1500 mL) and extracted with CHCl (1500 mL x 3). The combined extracts were washed with brine (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with H2O (500 mL) at 25°C for 1 hour and then isolated. The isolated product was then triturated a second time with MeOH (500 mL) at 25° C. for 1 hour to afford Enantiomer 1 of 3-hydroxy-1-methyl-3-(1-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one (Intermediate 22, 29.0 g, 66.4 mmol, 77%, 95.0% purity) as a white solid. LCMS (ESI): C 18 H 18 The calculated mass of N6O4S is 414.1; the found m / z is 415.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.28(d,J=5.1Hz,1H),8.89(s,1H),8.83(d,J=5.3Hz,1H),8.4 6(d,J=7.5Hz,1H),8.25(t,J=7.9Hz,1H),8.14(d,J=8.1Hz,1H),7.90(s,1H),6.02(br s,1H),3.55(s,3H),3.48-3.41(m,1H),3.40-3.35(m,1H),2.80(s,3H),2.66-2.53(m,1H),2.36-2.21(m,1H).

[0976] Step F: Enantiomer 2 of 3-hydroxy-1-methyl-3-(1-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one (Intermediate 23) was prepared in a manner analogous to Intermediate 22 using Enantiomer 2 of 3-hydroxy-1-methyl-3-(1-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one (prepared in Step D) instead of Enantiomer 1 of 3-hydroxy-1-methyl-3-(1-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one. LCMS (ESI): C 18 H 18 The calculated mass of N6O4S is 414.1; the found m / z is 415.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.28(d,J=5.3Hz,1H),8.89(s,1H),8.83(d,J=5.1Hz,1H),8.46(d,J=7.5Hz,1H),8.25(t,J=7.9Hz,1H),8.13(d,J=8.3Hz,1H ),7.90(s,1H),6.02(s,1H),3.55(s,3H),3.49-3.41(m,1H),3.40-3.34(m ,1H),2.80(s,3H),2.59(ddd,J=4.6,7.6,12.7Hz,1H),2.33-2.21(m,1H).

[0977] Intermediate 24. N-(1-Methyl-1H-pyrazol-3-yl)-4-(tributylstannyl)pyrimidin-2-amine.

[0978]

[0979] 4-Chloro-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine (300 mg, 1.43 mmol, Example 25, Step B), LiCl (364 mg, 8.59 mmol), 1,1,1,2,2,2-hexabutylditinane (1.79 g, 3.09 mmol) and 1,4-dioxane (10 mL) were added to a 50 mL flask equipped with a reflux condenser. The resulting mixture was purged with N2 three times and then treated with Pd2(dba)3 (66 mg, 0.072 mmol) and tricyclohexylphosphine (40 mg, 0.14 mmol). The resulting mixture was purged with N2 three more times and then heated at 120 ° C for 16 hours. Thereafter, the reaction vessel was removed from the oil bath and allowed to gradually cool to room temperature. The reaction mixture was quenched with saturated KF (30 mL), stirred for 1 hour and extracted with EtOAc (20 mL×3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a brown solid. The solid was chromatographed on silica gel (0-30% EtOAc / petroleum ether) to give N-(1-methyl-1H-pyrazol-3-yl)-4-(tributylstannyl)pyrimidin-2-amine (350 mg, 53%) as a white solid. MS (ESI + ):m / z=466.0.

[0980] Intermediate 25. 3-(2-(6-chloropyridin-2-yl)thiazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one

[0981]

[0982] Step A. 3-(2-bromothiazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. 2,5-Dibromothiazole (2.8 g, 11.5 mmol) and anhydrous THF (30 mL) were added to a 100 mL three-necked round-bottom flask and the mixture was cooled to -78°C. Then, the mixture was added dropwise. i-PrMgClπLiCl (9.5mL, 1.3M hexane solution, 12.4mmol). The resulting mixture was stirred at -78 ° C for 30 minutes, and then 1-methylpyrrolidine-2,3-dione (1.0g, 8.8mmol) in THF (10mL) was added dropwise to the mixture. The resulting mixture was stirred for 16 hours while gradually warming to room temperature. Thereafter, the mixture was poured into water (80mL) and extracted with ethyl acetate (80mL×3). The organic extract was washed with brine (60mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to dryness to give a brown oil. The oil was purified by silica gel chromatography (0-100% EtOAc / petroleum ether) to give 3- (2-bromothiazol-5-yl) -3-hydroxy-1-methylpyrrolidin-2-one (560mg, 19%) as a yellow oil. LCMS (ESI): mass calculated for C8H9BrN2O2S: 276.0; m / z found: 276.9 [M+1] + .

[0983] Step B. 3-(2-(6-chloropyridin-2-yl)thiazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. 3-(2-Bromothiazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (560 mg, 2.0 mmol), 1,4-dioxane (8 mL), H2O (2 mL), 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (580 mg, 2.4 mmol) and K2CO3 (590 mg, 6.0 mmol) were added to a 10 mL flask purged with nitrogen and charged with Pd(dppf)Cl2 (150 mg, 0.21 mmol). The resulting mixture was purged with N2 for 3 minutes and then heated at 90°C for 5 hours. After this, the mixture was cooled to room temperature, poured into water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic extracts were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to dryness to give a brown oil. The oil was then subjected to silica gel chromatography (0-100% EtOAc / petroleum ether) to give 3- (2- (6- chloropyridin-2-yl) thiazol-5-yl) -3- hydroxy -1- methylpyrrolidin-2-one (180 mg, 20%) as a yellow solid. LCMS (ESI): C 13 H 12 The calculated mass of ClN3O2S is 309.0; the measured m / z is 309.8 [M+1] + .

[0984] Intermediate 26. 3-(2-(6-chloropyridin-2-yl)thiazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one

[0985]

[0986] Step A.6-chloropyridine-2-carbothioamide. 6-Chloropyridinecarboxamide (1.0 g, 6.4 mmol) and THF (20 mL) were added to a nitrogen-purged 40 mL flask and charged with Lawesson's reagent (1.3 g, 3.2 mmol). The resulting mixture was heated at 45 ° C for 2 hours. The mixture was concentrated to dryness under reduced pressure to obtain a yellow solid. The solid was then subjected to silica gel chromatography (0-35% EtOAc / petroleum ether) to obtain 6-chloropyridine-2-carbothioamide (1 g, 90%) as a yellow solid. LCMS (ESI): The mass calculated value of C6H5ClN2S is 172.0; the measured value of m / z is 172.7 [M+1] + .

[0987] Step B.3-(1-Ethoxyvinyl)-3-hydroxy-1-methylpyrrolidin-2-one. Ethoxyethylene (12.0 mL, 125 mmol) and THF (50 mL) were added to a 250 mL three-necked round-bottom flask that was oven-dried and purged with nitrogen. The flask was then cooled to -72°C and the resulting mixture was treated portionwise with t-BuLi (40 mL, 1.3 M in pentane, 52 mmol) over 5 minutes. The mixture was warmed to 0°C and stirred until the color of the solution turned pale yellow. Thereafter, 1-methylpyrrolidine-2,3-dione (2.00 g, 17.7 mmol) was added to the mixture. The mixture was stirred at -72°C for 1 hour and then at room temperature for 12 hours. The reaction mixture was then diluted with EtOAc (150 mL), washed with H2O (60 mL×3), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a yellow oil. The oil was then chromatographed on silica gel (0-80% EtOAc / petroleum ether) to give 3-(1-ethoxyvinyl)-3-hydroxy-1-methylpyrrolidin-2-one (400 mg, 12%) as a yellow oil. LCMS (ESI): C9H 15 The calculated mass of NO3 is 185.1; the measured m / z is 186.2[M+1] + .

[0988] Step C.3-(2-bromoacetyl)-3-hydroxy-1-methylpyrrolidin-2-one. 3-(1-ethoxyvinyl)-3-hydroxy-1-methylpyrrolidin-2-one (370 mg, 2.00 mmol) and acetone / H2O=9:1 (5 mL) were added to a nitrogen-purged 40 mL flask and NBS (370 mg, 2.1 mmol) was loaded at 0 ° C. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then diluted with water (20 mL) and extracted with EtOAc (10 mL×3). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to dryness to give 3-(2-bromoacetyl)-3-hydroxy-1-methylpyrrolidin-2-one (330 mg) as a yellow oil. LCMS (ESI): C7H 10 The calculated mass of BrNO3 is 235.0; the measured m / z is 235.6[M+1] + .

[0989] Step D. 3-(2-(6-chloropyridin-2-yl)thiazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one. 3-(2-Bromoacetyl)-3-hydroxy-1-methylpyrrolidin-2-one (330 mg, 1.4 mmol) and EtOH (7 mL) were added to a 40 mL flask and charged with 6-chloropyridine-2-carbothioamide (270 mg, 1.6 mmol). The resulting mixture was stirred at 100 °C for 1.5 hours. Thereafter, the mixture was cooled to room temperature, diluted with EtOAc (50 mL), washed with H2O (20 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to dryness to give a yellow solid. The solid was then chromatographed on silica gel (0-100% EtOAc / petroleum ether) to give 3-(2-(6-chloropyridin-2-yl)thiazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (270 mg, 57%) as a yellow solid. LCMS (ESI): C 13 H 12 The calculated mass of ClN3O2S is 309.0; the measured m / z is 309.9 [M+1] + .

[0990] Intermediate 27. 3-(5-(6-chloropyridin-2-yl)thiazol-2-yl)-3-hydroxy-1-methylpyrrolidin-2-one

[0991]

[0992] Step A.3-hydroxy-1-methyl-3-(thiazol-2-yl)pyrrolidin-2-one. 2-Bromothiazole (1.0 mL, 11 mmol) and anhydrous THF (20 mL) were added to a 100 mL three-necked round-bottom flask cooled to -78 ° C, and then i-PrMgClπLiCl (8.80 mL, 1.3 M in hexane, 11.4 mmol) was added dropwise. The resulting mixture was stirred at -78 ° C for 30 minutes, and then 1-methylpyrrolidine-2,3-dione (1.00 g, 8.8 mmol) in THF (10 mL) was added dropwise to the mixture. The resulting mixture was stirred at room temperature for 3 hours. Thereafter, the mixture was quenched with water (40 mL) and extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a yellow oil. The oil was then chromatographed on silica gel (0-100% EtOAc / petroleum ether) to give 3-hydroxy-1-methyl-3-(thiazol-2-yl)pyrrolidin-2-one (460 mg, 25%) as a yellow solid. LCMS (ESI): C8H 10 The calculated mass of N2O2S is 198.1; the found m / z is 199.0 [M+H] + .

[0993] Step B.3-(5-bromothiazol-2-yl)-3-hydroxy-1-methylpyrrolidin-2-one. 3-Hydroxy-1-methyl-3-(thiazol-2-yl)pyrrolidin-2-one (500 mg, 2.52 mmol), NBS (500 mg, 2.8 mmol) and ACN (15 mL) were added to a 40 mL flask, and the resulting mixture was heated at 40 ° C for 16 hours. After that, the mixture was concentrated to dryness in vacuo to give a white solid. The solid was then subjected to silica gel chromatography (0-100% EtOAc / petroleum ether) to give 3-(5-bromothiazol-2-yl)-3-hydroxy-1-methylpyrrolidin-2-one (530 mg, 69%) as a white solid. LCMS (ESI): The mass calculated value for C8H9BrN2O2S is 276.0; the found value for m / z is 276.9 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.80(s,1H),7.35-6.69(m,1H),3.48-3.43(m,1H),3.56-3.32(m,1H),3.17(s,1H),2.79(s,3H),2.70-2.61(m,1H),2.50(br s,1H),2.29-2.17(m,1H).

[0994] Step C. 3-(5-(6-Chloropyridin-2-yl)thiazol-2-yl)-3-hydroxy-1-methylpyrrolidin-2-one. 3-(5-Bromothiazol-2-yl)-3-hydroxy-1-methylpyrrolidin-2-one (450 mg, 1.6 mmol), 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (790 mg, 3.3 mmol), KCO (680 mg, 4.9 mmol) and 1,4-dioxane / H0 (4:1) (20 mL) were added to a 100 mL round-bottom flask, which was subsequently evacuated and refilled with argon (×3), then treated with Pd(dppf)Cl (130 mg, 0.18 mmol) and the resulting mixture was heated at 110° C. for 16 h. After this, the mixture was cooled to room temperature, poured into water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic extracts were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to dryness to give a brown solid. The solid was then subjected to silica gel chromatography (0-10% MeOH / DCM) to give 3-(5-(6-chloropyridin-2-yl)thiazol-2-yl)-3-hydroxy-1-methylpyrrolidin-2-one (420 mg, 61%) as a black solid. LCMS (ESI): C 13 H 12 The calculated mass of ClN3O2S is 309.0; the found m / z is 310.0 [M+H] + .

[0995] Intermediate 28. N-(1-Methyl-1H-pyrazol-3-yl)-4-(6-(tributylstannyl)pyridin-2-yl)pyrimidin-2-amine.

[0996]

[0997] Step A. 4-(6-Bromopyridin-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine. N-(1-methyl-1H-pyrazol-3-yl)-4-(tributylstannyl)pyrimidin-2-amine (Intermediate 24, 4.66 g, 10 mmol), 2,6-dibromopyridine (2.8 g, 12 mmol), TEA (2.8 mL, 20 mmol) and toluene (50 mL) were added to a 250 mL round-bottom flask and charged with Pd(PPh3)4 (1.2 g, 1.0 mmol). The mixture was sparged with Ar for 5 minutes and then stirred at 120°C for 16 hours. The reaction vessel was removed from the oil bath and allowed to gradually cool to room temperature. The reaction was then diluted with water (80 mL), extracted with ethyl acetate (100 mL × 3), and the combined extracts were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to dryness to give a yellow solid. The yellow solid was then subjected to silica gel chromatography (0-100% ethyl acetate / petroleum ether) to give 4-(6-bromopyridin-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine (2.28 g, 43%) as a yellow solid. LCMS (ESI): C 13 H 11 The calculated mass of BrN6 is 330.0, and the measured m / z is 333.1 [M+H] + .

[0998] Step B N-(1-methyl-1H-pyrazol-3-yl)-4-(6-(tributylstannyl)pyridin-2-yl)pyrimidin-2-amine. 4-(6-Bromopyridin-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine (2.0 g, 6.0 mmol), LiCl (1.5 g, 35 mmol) and 1,4-dioxane (50 mL) were added to a 250 mL flask equipped with a reflux condenser and charged with 1,1,1,2,2,2-hexabutyldistanane (5.83 g, 10.1 mmol). The resulting mixture was purged with N2 three times and then treated with Pd2(dba)3 (273 mg, 0.298 mmol) and tricyclohexylphosphine (167 mg, 0.596 mmol). The resulting mixture was purged with N2 again three times and then heated at 120 °C for 16 hours. The mixture was cooled to room temperature and quenched with saturated KF (20 mL), and stirred for 1 hour. The reaction mixture was then diluted with water (30 mL), extracted with ethyl acetate (60 mL × 3), and the combined extracts were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to dryness to give a yellow solid. The yellow solid was then subjected to silica gel chromatography (0-50% ethyl acetate / petroleum ether) to give N- (1- methyl -1H- pyrazol-3-yl) -4- (6- (tributylstannyl) pyridin-2-yl) pyrimidine -2-amine (1.26 g, 37%) as a yellow solid. LCMS (ESI): C 25 H 38 The calculated mass of N6Sn is 542.22; the measured m / z is 543.15 [M+H] + .

[0999] Intermediate 29. 3-(3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[1000]

[1001] Step A. 3,5-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole. 3,5-Dibromo-1H-pyrazole (8.0 g, 35 mmol), TEA (7.4 mL, 53 mmol) and DCM (100 mL) were added to a 250 mL flask. SEM-Cl (8.8 mL, 50 mmol) was added to the mixture. After stirring at room temperature for 30 min, the mixture was concentrated to dryness under reduced pressure to give a colorless oil, which was then subjected to HPLC (Xtimate C18 column, 10 μm, 150×40 mm; 65%-95% ACN / water containing 0.04% NH 3 π HO + 10 mM NH 4 HCO 3 ) to give 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (6.1 g, 48%) as a colorless oil after lyophilization. LCMS (ESI): C9H 16 The calculated mass of Br2N2OSi is 353.94; the measured m / z is 354.9 [M+H] + .

[1002] Step B. 3-(3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. Tetrahydrofuran (30 mL) and 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (6.0 g, 17 mmol) were added to a 250 mL three-necked flask purged with N2. The mixture was cooled to -72°C. n-Butyllithium (7.41 mL, 2.5 M in hexanes, 18.5 mmol) was added dropwise to the mixture. The mixture was stirred at -72°C for 30 minutes, treated with a solution consisting of 1-methylpyrrolidine-2,3-dione (2.29 g, 20.2 mmol) and THF (50 mL), and then stirred at -72°C for 1 hour. Afterwards, the mixture was quenched with H2O (80 mL) and extracted with EtOAc (80 mL×3). The combined organic extracts were concentrated to dryness under reduced pressure to give a brown oil, which was subjected to HPLC (Xtimate C18 column, 10 μm, 150×40 mm; 40%-70% (v / v) ACN / water (0.05% NH3πH2O+10 mM NH4HCO3)) to give 3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (3.2 g, 49%) as a white solid after lyophilization. LCMS (ESI): C 14 H 24 The calculated mass of BrN3O3Si is 389.1; the measured m / z is 390.0 [M+H] + .

[1003] Intermediate 30. 3-(1-(6-Chloropyridin-2-yl)-1H-imidazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[1004]

[1005] Step A.2-chloro-6-(4-iodo-1H-imidazoles-1-yl)pyridine.A mixture of 4-iodoimidazoles (1.0g, 5.2mmol), 2,6-dichloropyridine (1.91g, 12.9mmol), cesium carbonate (5.04g, 15.5mmol) and DMA (20mL) was heated at 100 DEG C for 2 hours.The reaction mixture was cooled to room temperature and then poured into 150mL water, resulting in the formation of a precipitate. The precipitate was collected by vacuum filtration and washed with water. The filter cake was collected and purified by FCC (silicon dioxide, 40%-100% EtOAc in hexane) to obtain 2-chloro-6-(4-iodo-1H-imidazoles-1-yl)pyridine (685mg, 43%) as a white solid. 1 H NMR (500MHz, DMSO-d6) δ 8.51-8.40 (m, 1H), 8.18-8.12 (m, 1H), 8.08 (t, J = 7.9Hz, 1H), 7.82 (d, J = 8.0Hz, 1H), 7.52 (d, J = 7.8Hz, 1H). LCMS(ESI + ):m / z=306.0.

[1006] Step B. 3-(1-(6-chloropyridin-2-yl)-1H-imidazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of 2-chloro-6-(4-iodo-1H-imidazol-1-yl)pyridine (540 mg, 1.768 mmol) in THF (10 mL) at 0°C was added isopropylmagnesium chloride-lithium chloride complex (1.36 mL, 1.3 M in THF, 1.77 mmol) dropwise over 2 minutes. The resulting mixture was stirred for 10 minutes, then 1-methylpyrrolidine-2,3-dione (220 mg, 1.94 mmol) was added as a solid all at once. The resulting mixture was stirred for 50 minutes, then diluted with saturated aqueous NH4Cl solution, water, and extracted with ethyl acetate. The organic extract was dried over MgSO4, filtered, and concentrated. The residue was purified by FCC (silica, 0-10% MeOH in EtOAc) to give 3-(1-(6-chloropyridin-2-yl)-1H-imidazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (81 mg, 15.6%) as a white solid. 1H NMR (400MHz, CDCl3) δ8.25(d,J=1.5Hz,1H),7.73(t,J=7.9Hz,1H),7.69(d,J=1.5Hz,1H),7.22(d,J=7.8Hz,1H),7.19( d,J=8.0Hz,1H),4.61(s,1H),3.64-3.52(m,1H),3.51-3.39(m,1H),2.96(s,3H),2.84-2.71(m,1H),2.48-2.29(m,1H). LCMS(ESI + ):m / z=293.1.

[1007] Intermediate 31. (R)-3-(3-(6-(2-chloropyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[1008]

[1009] TMPMgClπLiCl solution (1.00M THF solution, 813mL, 813mmol) is cooled in a dry ice EtOH bath. Over 2 hours, a solution of 2-chloropyrimidine (84.6g, 739mmol) in THF (1000mL) is added dropwise using a constant pressure funnel. The resulting solution is stirred for another 2 hours in a dry ice EtOH bath. Over 2 hours, ZnCl2 (1.00M THF solution, 1.11L, 1.11mol) is added using a constant pressure funnel. The mixture is then slowly warmed to 25°C and stirred for 12 hours. The resulting solution was added to another flask containing (R)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (from Step A in the preparation of Intermediate 13, 100 g, 295.72 mmol), Pd(PPh3)4 (42.7 g, 36.9 mmol) and THF (800 mL) at 60°C using a constant pressure funnel over 6 hours. The resulting mixture was stirred for another hour. The reaction was cooled to 25°C, poured into saturated aqueous NH4Cl solution (4000 mL) and extracted with ethyl acetate (2000 mL×3). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated. The residue was triturated with MeOH (500 mL) at 25°C for 12 hours. The reaction was carried out in eight batches. (R)-3-(3-(6-(2-chloropyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one was obtained as a yellow solid (670 g, 1.78 mol, 61.0%). 1H NMR (400MHz, DMSO-d6) δ8.97(d,J=5.1Hz,1H),8.55(d,J=5.1Hz,1H),8.50-8.43(m,1H),8.24-8.17(m,2H),7.22(s,1H),6.78 (s,1H),3.57-3.40(m,2H),2.85(s,3H),2.62(ddd,J=5.1,7.8,13.2Hz,1H),2.30(ddd,J=5.8,7.8,13.4Hz,1H),1.98(s,1H). LCMS(ESI + ):m / z=371.9.

[1010] Intermediate 32. (R)-3-(1-(6-(2-chloropyrimidin-4-yl)pyridin-2-yl)-1H-1,2,3-triazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one

[1011]

[1012] (R)-3-(1-(6-(2-chloropyrimidin-4-yl)pyridin-2-yl)-1H-1,2,3-triazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a stirred solution of 2-chloropyrimidine (103 g, 899 mmol) in tetrahydrofuran (1200 mL) was added TMPMgClπLiCl (1.0 M in THF, 1174 mL) dropwise at -72 °C under a nitrogen atmosphere. The resulting mixture was stirred at -72 °C under a nitrogen atmosphere for 2 hours. Zinc chloride (1927 mL, 1349 mmol, 0.7 M in THF) was added dropwise to the above mixture at -72 °C. The resulting mixture was stirred at room temperature overnight. To the above mixture was added dropwise a solution of (R)-3-(1-(6-bromopyridin-2-yl)-1H-1,2,3-triazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (152 g, 450 mmol, intermediate 51) and tetrakis(triphenylphosphine)palladium(0) (52 g, 45 mmol) in tetrahydrofuran (1500 mL) at 60 ° C under a nitrogen atmosphere. The final reaction mixture was stirred at 60 ° C under a nitrogen atmosphere for 1 hour. The mixture was cooled to room temperature. The reaction was quenched by adding water (3 L) at room temperature. The resulting mixture was extracted with EtOAc (3 × 2 L). The combined organic layers were washed with brine (1 × 1 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (20:1) to give (3R)-3-{1-[6-(2-chloropyrimidin-4-yl)pyridin-2-yl]-1,2,3-triazol-4-yl}-3-hydroxy-1-methylpyrrolidin-2-one (126.1 g, 75%) as an off-white solid. 1 H NMR: (300MHz, DMSO-d6) δ9.11-8.98(m,2H),8.64(t,J=5.1Hz,1H),8.49(dd,J=5.8,2.8Hz,1H),8.4 0-8.31(m,2H),6.33(s,1H),3.50(t,J=6.6Hz,2H),2.91-2.69(m,4H),2.29(dt,J=13.4,6.9Hz,1H). LCMS(ESI + ):m / z=372.

[1013] Intermediate 33. (1R,4R,5S)-4-(3-(6-Bromopyridin-2-yl)isoxazol-5-yl)-4-hydroxy-2-methyl-2-azabicyclo[3.1.0]hexan-3-one.

[1014]

[1015] A solution of (Z)-6-bromo-N-hydroxypicolinimidoyl chloride (Intermediate 4, 1 g, 4.2 mmol), (1R,4R,5S)-4-ethynyl-4-hydroxy-2-methyl-2-azabicyclo[3.1.0]hexan-3-one (0.8 g, 5.1 mmol), NaHCO (1 g, 12.7 mmol), EtOAc (4.2 mL, 0.2 M, 0.83 mmol) and water (distilled, 0.83 mL, 1.7 mmol) was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with 70 mL of water and extracted with ethyl acetate (3 x 70 mL). The organic extract was dried over MgSO, filtered and concentrated under reduced pressure. The product was purified via FCC (12 g silica, 0-15% EtOAc in hexanes) to afford (1R,4R,5S)-4-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-4-hydroxy-2-methyl-2-azabicyclo[3.1.0]hexan-3-one (846.9 mg, 57%).

[1016] 1 H NMR (500MHz, CDCl3) δ8.04–8.00(m,1H),7.65(t,J=7.8Hz,1H),7.54(dd,J=7.9,0.9Hz,1H),7.06–7. 04(m,1H),3.32–3.28(m,1H),3.17–3.13(m,1H),2.98(s,3H),2.17–2.11(m,1H),1.10–1.05(m,1H). MS(ESI + ):m / z=351.9.

[1017] Intermediate 34. (1R,4R,5S)-4-(3-(6-(2-chloropyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)-4-hydroxy-2-methyl-2-azabicyclo[3.1.0]hexan-3-one.

[1018]

[1019] A solution of (1R, 4R, 5S) -4- (3- (6- bromopyridin-2-yl) isoxazol-5-yl) -4-hydroxy-2-methyl-2-azabicyclo [3.1.0] hexan-3-one (intermediate 33, 75 mg, 0.2 mmol), 2-chloro-4- (tributylstannyl) pyrimidine (100 mg, 0.2 mmol), Pd (PPh 3 ) 4 (12 mg, 0.01 mmol), DMF (1 mL, 14.5 mmol) and lithium chloride (11 mg, 0.26 mmol) was subjected to microwave irradiation at 130 ° C under a nitrogen atmosphere for 1 hour. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted in EtOAc and water and vigorously stirred with potassium fluoride (17 mg, 0.26 mmol) for 1 hour. The solid was filtered off and the mixture was transferred to a separatory funnel and aqueously extracted with EtOAc (3×75 mL) and water (100 mL). The organic layer was dried over MgSO 4 , filtered and concentrated under reduced pressure. The product was purified by FCC (4 g silica, 0-100% ethyl acetate in hexane) to give (1R, 4R, 5S) -4- (3- (6- (2-chloropyrimidin-4-yl) pyridin-2-yl) isoxazol-5-yl) -4-hydroxy-2-methyl-2-azabicyclo [3.1.0] hexan-3-one (35 mg, 43%). 1 H NMR (500MHz, DMSO-d6) δ8.98(d,J=5.1Hz,1H),8.58(d,J=5.1Hz,1H),8.50(dd,J=6.7,2.1Hz,1H),8.24–8.23(m,1H),8.22–8. 20(m,1H),7.24(s,1H),6.68(s,1H),3.46–3.43(m,1H),2.86(s,3H),2.11–2.06(m,1H),0.98–0.94(m,1H),0.85–0.81(m,1H). MS(ESI + ):m / z=383.2.

[1020] Intermediate 35. (3R,5R)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1,5-dimethylpyrrolidin-2-one.

[1021]

[1022] A solu...

Claims

1. A compound of formula I': or a pharmaceutically acceptable salt thereof, wherein: A is optionally replaced by one or more -C (1-4) 5-membered heteroaryl substituted with an alkyl group; W is CH2, CHF, CF2 or CHR W ; X is N, CH or CR X ; Y is N, CH or CR Y ; R W For -C (1-4) Alkyl or -C (1-4) Haloalkyl; R X is a halogenated group, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl or -C (1-4) Alkyl-OC (1-4) alkyl; R Y is a halogenated group, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl or -C (1-4) Alkyl-OC (1-4) alkyl; R 1 Hydrogen, -C (1-4) Alkyl or -C (1-4) haloalkyl; or wherein R W and R 1 Together with the carbon atom to which they are attached, they form C (3-5) Cycloalkyl; R 2 is hydrogen or -C (1-4) alkyl; L does not exist, is -C (1-4) Alkylene or -C (3-6) Cycloalkylene, wherein the -C (1-4) Alkylene and -C (3-6) The cycloalkylene group is optionally substituted by one to three groups selected from halo, -OH, -N(R N1 )(R N2 ),-C (1-3) Alkyl, -C (1-3) Haloalkyl, -C (3-5) Cycloalkyl and -OC (1-3) Alkyl radical substitution; R 3 For -C (1-10) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, -C (6-10) aryl, 5- to 10-membered heteroaryl, or -C(O)N(R N3 )(R N4 ), wherein said -C (1-10) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, -C (6-10) Aryl and 5- to 10-membered heteroaryl are each optionally substituted by one to five R 3x group substitution; Each R 3x Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-8) Alkyl, -C (1-8) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-8) Alkyl, -OC (1-8) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-8) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-8) Alkyl, -C(O)C (1-8) Alkyl, -S(O)2C (1-8) Alkyl, -S(O)2C (3-8) Cycloalkyl, -N(H)S(O)2C (1-8) Alkyl, -C (0-8) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-8) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5 to 10 membered heteroaryl, wherein the -C (1-8) Alkyl, -C (1-8) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-8) Alkyl, -OC (1-8) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-8) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-8) Alkyl, -C(O)C (1-8) Alkyl, -S(O)2C (1-8) Alkyl, -S(O)2C (3-8) Cycloalkyl, -N(H)S(O)2C (1-8) Alkyl, 3 to 8 membered heterocyclic group, -C (1-8) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5- to 10-membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-8) Alkyl, -C (1-8) Haloalkyl, -OC (1-8) Alkyl, -OC (1-8) haloalkyl and 3 to 5 membered heterocyclic groups; or R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic group, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, each of which is optionally further substituted by one to three groups selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-8) Alkyl and -OC (1-8) Alkyl group substituted, wherein the -C (1-8) Alkyl and -OC (1-8) The alkyl group is optionally further substituted with one to five halo groups; R 4 is hydrogen, halo or -C (1-4) alkyl; R 5 is hydrogen, halo or -C (1-4) alkyl; R N1 and R N2 Each occurrence is independently hydrogen, -C (1-8) Alkyl or -C (1-8) Haloalkyl; R N3 is hydrogen or -C (1-8) Alkyl; and R N4 Hydrogen, -C (1-8) Alkyl or phenyl; or R N3 and R N4 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic group, which is optionally substituted by one to five substituted groups selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-8) Alkyl, -C (1-8) Haloalkyl, -OC (1-8) Alkyl and -OC (1-8) haloalkyl radical substitution; If R 3 -C(O)N(R N3 )(R N4 ), then L does not exist.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: A is optionally replaced by one or more -C (1-4) 5-membered heteroaryl substituted with an alkyl group; W is CH2, CHF, CF2 or CHR W ; X is N, CH or CR X ; Y is N, CH or CR Y ; R W For -C (1-4) Alkyl or -C (1-4) Haloalkyl; R X is a halo group; R Y is a halogenated group, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) Haloalkyl or -C (1-4) Alkyl-OC (1-4) alkyl; R 1 Hydrogen, -C (1-4) Alkyl or -C (1-4) haloalkyl; or wherein R W and R 1 Together with the carbon atom to which they are attached, they form C (3-5) Cycloalkyl; R 2 is hydrogen or -C (1-4) alkyl; L does not exist, is -C (1-4) Alkylene or -C (3-6) Cycloalkylene, wherein the -C (1-4) Alkylene and -C (3-6) The cycloalkylene group is optionally substituted by one to three groups selected from halo, -OH, -N(R N1 )(R N2 ),-C (1-3) Alkyl, -C (1-3) Haloalkyl, -C (3-5) Cycloalkyl and -OC (1-3) Alkyl radical substitution; R 3 For -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, -C (6-10) aryl, 5- to 10-membered heteroaryl, or -C(O)N(R N3 )(R N4 ), wherein said -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, -C (6-10) Aryl and 5- to 10-membered heteroaryl are each optionally substituted by one to five R 3x group substitution; Each R 3x Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -S(O)2C (3-8) Cycloalkyl, -N(H)S(O)2C (1-4) Alkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5 to 10 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -S(O)2C (3-8) Cycloalkyl, -N(H)S(O)2C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5- to 10-membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) haloalkyl and 3 to 5 membered heterocyclic groups; or R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic group, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, each of which is optionally further substituted by one to three groups selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl and -OC (1-6) Alkyl group substituted, wherein the -C (1-6) Alkyl and -OC (1-6) The alkyl group is optionally further substituted with one to five halo groups; R 4 is hydrogen, halo or -C (1-4) alkyl; R 5 is hydrogen, halo or -C (1-4) alkyl; R N1 and R N2 Each occurrence is independently hydrogen, -C (1-3) Alkyl or -C (1-3) Haloalkyl; R N3 is hydrogen or -C (1-4) Alkyl; and R N4 Hydrogen, -C (1-4) Alkyl or phenyl; or R N3 and R N4 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic group, which is optionally substituted by one to five substituted groups selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl radical substitution; If R 3 -C(O)N(R N3 )(R N4 ), then L does not exist.

3. A compound according to claim 1 or claim 2, which is a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: A is optionally replaced by one or more -C (1-4) 5-membered heteroaryl substituted with an alkyl group; W is CH2, CHF or CF2; X is N or CH; Y is N, CH or CR Y ; R Y is a halogenated group, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl or -OC (1-4) Haloalkyl; R 1 Hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl; R 2 is hydrogen or -C (1-4) alkyl; L does not exist, is -C (1-4) Alkylene or -C (3-6) Cycloalkylene, wherein the -C (1-4) Alkylene and -C (3-6) Cycloalkylene is optionally substituted by one to three groups selected from halo, -C (1-3) Alkyl and -OC (1-3) Alkyl radical substitution; R 3 For -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, -C (6-10) aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one to five R 3x group substitution; Each R 3x Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, -C(0-3)alkylC(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5 to 10 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (3-10) Cycloalkyl C (1-3) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5- to 10-membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl radical substitution; or R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic group, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, each of which is optionally further substituted by one to three groups selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl and -OC (1-6) Alkyl group substituted, wherein the -C (1-6) Alkyl and -OC (1-6) The alkyl group is optionally further substituted with one to five halo groups; and R N1 and R N2 Each occurrence is independently hydrogen, -C (1-3) Alkyl or -C (1-3) Halogenated alkyl.

4. The compound according to claim 1 or claim 2 or a pharmaceutically acceptable salt thereof, wherein: A is optionally replaced by a -C (1-4) 5-membered heteroaryl substituted with an alkyl group; W is CH2, CF2 or CHR W ; R W For -C (1-4) Alkyl, -C (1-4) A haloalkyl group, or R W and R 1 Together with the carbon atom to which they are attached, they form C (3-5) Cycloalkyl; R 2 is hydrogen; R 3 For -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, -C (6-10) aryl, 5- to 10-membered heteroaryl, or -C(O)N(R N3 )(R N4 ), wherein: said -C (1-6) The alkyl group is optionally substituted by one to five R 3a Group substitution; said -C (3-10) The cycloalkyl group is optionally substituted by one to five R 3b The 3 to 10 membered heterocyclic group is optionally substituted by one to five R 3c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 3d Substitution; said -C (6-10) The aryl group is optionally substituted by one to five R 3e and the 5- to 10-membered heteroaryl is optionally substituted by one to five R 3f group substitution; Each R 3a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) alkyl or a 3 to 8-membered heterocyclic group, wherein the -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) The cycloalkyl and 3 to 8 membered heterocyclic groups are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl radical substitution; 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 (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -S(O)2C (3-8) Cycloalkyl, -N(H)S(O)2C (1-4) Alkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), a 3- to 8-membered heterocyclyl or a 5- to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) The haloalkyl, 3- to 8-membered heterocyclyl and 5- to 10-membered heteroaryl groups are optionally further substituted with one to five radicals selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl radical substitution; R 3e and R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) aryl or 5 to 10 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5- to 10-membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) haloalkyl and 3 to 5 membered heterocyclic groups; or R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally substituted by one to three substituted radicals selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) haloalkyl radical; and R N1 and R N2 Each occurrence is independently hydrogen or -C (1-3) alkyl.

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; W is CH2 or CF2; R 2 is hydrogen; R 3 For -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, -C (6-10) Aryl or 5 to 10 membered heteroaryl, wherein: the -C (1-6) The alkyl group is optionally substituted by one to five R 3a Group substitution; said -C (3-10) The cycloalkyl group is optionally substituted by one to five R 3b The 3 to 10 membered heterocyclic group is optionally substituted by one to five R 3c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 3d Substitution; said -C (6-10) The aryl group is optionally substituted by one to five R 3e and the 5- to 10-membered heteroaryl is optionally substituted by one to five R 3f group substitution; Each R 3a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) alkyl or a 3 to 8-membered heterocyclic group, wherein the -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) The cycloalkyl and 3 to 8 membered heterocyclic groups are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl radical substitution; 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 (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), a 3- to 8-membered heterocyclyl or a 5- to 10-membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) The haloalkyl, 3- to 8-membered heterocyclyl and 5- to 10-membered heteroaryl groups are optionally further substituted with one to five radicals selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl radical substitution; R 3e and R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6 - 10) aryl or 5 to 10 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5- to 10-membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl radical substitution; or R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally substituted by one to three substituted radicals selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) haloalkyl radical; and R N1 and R N2 Each occurrence is independently hydrogen or -C (1-3) alkyl.

6. The compound according to any one of claims 1, 2 or 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; R Y For -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl or -C (1-4) Alkyl-OC (1-4) alkyl; R 3 For -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, -C (6-10) aryl, 5- to 10-membered heteroaryl, or -C(O)N(R N3 )(R N4 ), wherein: said -C (1-6) The alkyl group is optionally substituted by one to five R 3a Group substitution; said -C (3-10) The cycloalkyl group is optionally substituted by one to five R 3b The 3 to 10 membered heterocyclic group is optionally substituted by one to five R 3c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 3d and the 5- to 10-membered heteroaryl is optionally substituted by one to five R 3f group substitution; Each R 3a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ),-CN,-OC (1-6) Alkyl or -OC (1-6) Haloalkyl; 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 (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -S(O)2C (1-4) Alkyl or -S(O)2C (3-8) Cycloalkyl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) The haloalkyl group is optionally further substituted with one to five groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN and -OC (1-4) Alkyl radical substitution; Each R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6 - 10) aryl or 5 to 10 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group), -C (6-10) Aryl and 5- to 10-membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) haloalkyl and 3 to 5 membered heterocyclic groups; or R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, each of which is optionally further substituted with one to three groups selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) haloalkyl radical; and R N1 and R N2 Each occurrence is independently hydrogen or -C (1-3) alkyl.

7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein: A is optionally replaced by a -C (1-4) 5-membered heteroaryl substituted with an alkyl group; R Y For -C (1-4) Alkyl, -C (1-4) Haloalkyl or -OC (1-4) alkyl; R 3 For -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3 to 10 membered heterocyclyl, 5 to 12 membered bicyclic or tricyclic ring system containing one or more heteroatoms, or 5 to 10 membered heteroaryl, wherein: the -C (1-6) The alkyl group is optionally substituted by one to five R 3a Group substitution; said -C (3-10) The cycloalkyl group is optionally substituted by one to five R 3b The 3 to 10 membered heterocyclic group is optionally substituted by one to five R 3c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 3d and the 5- to 10-membered heteroaryl is optionally substituted by one to five R 3f group substitution; Each R 3a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ) or -CN; 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, -OC (1-6) Alkyl or -OC (1-6) haloalkyl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) The haloalkyl group is optionally further substituted with one to five groups selected from halo, -OH, -N(R N1 )(R N2 ) and -CN; Each R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group) or -C (6-10) Aryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group) and -C (6-10) The aryl group is optionally further substituted with one to five groups selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl radical substitution; or R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, each of which is optionally further substituted with one to three groups selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1-6) haloalkyl radical; and R N1 and R N2 Each occurrence is independently hydrogen or -C (1-3) alkyl.

8. A compound according to any one of claims 1, 2, 4 or 6, or a pharmaceutically acceptable salt thereof, wherein: A is a 5-membered heteroaryl group optionally substituted with one -CH3 group; W is CH2, CF2 or CHR W , R W For -C (1-4) Alkyl, -C (1-4) A haloalkyl group, or R W and R 1 Together with the carbon atom to which they are attached, they form C (3-5) Cycloalkyl; R 2 is hydrogen; L does not exist, is -C (1-4) Alkylene or -C (3-6) Cycloalkylene, wherein the -C (1-4) The alkylene group is optionally substituted by one to three groups selected from halo, -OH, -N(R N1 )(R N2 ) and cyclopropyl; R 3 For -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, phenyl, 5- to 10-membered heteroaryl, or -C(O)N(R N3 )(R N4 ); wherein: said -C (1-6) The alkyl group is optionally substituted by one to five R 3a Group substitution; said -C (3-10) The cycloalkyl group is optionally substituted by one to five R 3b The 3 to 10 membered heterocyclic group is optionally substituted by one to five R 3c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 3d and the 5- to 10-membered heteroaryl is optionally substituted by one to five R 3f group substitution; Each R 3a Each occurrence is independently halo, -OH, -OC (1-6) Alkyl or -OC (1-6) Haloalkyl; Each R 3b Each occurrence is independently halo, -OH, -C (1-6) Haloalkyl or -OC (1-6) alkyl; Each R 3c Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -S(O)2C (1-4) Alkyl or -S(O)2C (3-8) Cycloalkyl, wherein the -C (1-6) Alkyl and -OC (1-6) The alkyl group is optionally further substituted with one to five groups selected from halo and -OC (1-4) Alkyl radical substitution; Each R 3d Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl or -C (1-3) Alkyl C (3-10) Cycloalkyl; Each R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) alkyl (3 to 8 membered heterocyclyl) or 5 to 10 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) The alkyl (3 to 8 membered heterocyclyl) and 5 to 10 membered heteroaryl groups are optionally further substituted with one to five groups selected from halo, -OH, -N(R N1 )(R N2 ),-C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) haloalkyl and 3 to 5 membered heterocyclic groups; or R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, each of which is optionally further substituted by one to three selected from -N(R N1 )(R N2 ) and -C (1-6) Alkyl radical substitution; R N1 and R N2 Each occurrence is independently hydrogen or -C (1-3) alkyl; R N3 is hydrogen or -C (1-4) Alkyl; and R N4 Hydrogen, -C (1-4) Alkyl or phenyl; or R N3 and R N4 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic group, which is optionally substituted by one to five substituted groups selected from halo, -C (1-4) Alkyl and -C (1-4) The haloalkyl group is substituted.

9. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein: A is a 5-membered heteroaryl group; W is CH2 or CF2; R 2 is hydrogen; L does not exist, is -C (1-4) Alkylene or -C (3-6) Cycloalkylene; R 3 For -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3 to 10 membered heterocyclyl, 5 to 12 membered bicyclic or tricyclic ring system containing one or more heteroatoms, or 5 to 10 membered heteroaryl; wherein: the -C (1-6) The alkyl group is optionally substituted with one to five halo groups; (3-10) The cycloalkyl group is optionally substituted with one to five -OH groups; the 5 to 12 membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with one to five R 3d and the 5- to 10-membered heteroaryl is optionally substituted by one to five R 3f group substitution; Each R 3d Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl or -OC (1-6) Haloalkyl; Each R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group or -C (1-3) Alkyl (3 to 8 membered heterocyclic group), wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group and -C (1-3) The alkyl (3 to 8 membered heterocyclic group) is optionally further substituted by one to five groups selected from halo, -OH, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl radical substitution; or R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, each of which is optionally further substituted by one to three selected from -N(R N1 )(R N2 ) and -C (1-6) Alkyl radical substitution; and R N1 and R N2 Each occurrence is independently hydrogen or -C (1-3) alkyl.

10. The compound according to any one of claims 1, 2, 4, 6 or 8, or a pharmaceutically acceptable salt thereof, wherein: A is pyrazolyl, imidazolyl, triazolyl, thiazolyl, isoxazolyl, thiazolyl or thiadiazolyl, wherein the pyrazolyl is optionally substituted with one -CH3 group; W is CH2, CF2 or CHR W , where W is CHR W When R W and R 1 Together with the carbon atom to which they are attached, they form C (3-5) Cycloalkyl; R X For fluorine; R Y is CH3, -CHF2, -CF3, -OCH3 or -CH2OCH3; R 1 is hydrogen, -CH3 or -CF3; R 2 is hydrogen; L does not exist, is -C (1-4) Alkylene or -C (3-6) Cycloalkylene, wherein the -C (1-4) The alkylene group is optionally substituted by one to three groups selected from halo, -OH, -N(R N1 )(R N2 ) and cyclopropyl; R 3 For -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, phenyl, 5- to 10-membered heteroaryl, or -C(O)N(R N3 )(R N4 ); wherein: said -C (1-6) The alkyl group is optionally substituted by one to five R 3a Atomic substitution; the -C (3-10) The cycloalkyl group is optionally substituted by one to five R 3b The 3 to 10 membered heterocyclic group is optionally substituted by one to five R 3c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 3d and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 3f group substitution; Each R 3a Each occurrence is independently halo, -OH or -OC (1-6) alkyl; Each R 3b Each occurrence is independently halo, -OH, -C (1-6) Haloalkyl or -OC (1-6) alkyl; Each R 3c Each occurrence is independently halo, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -S(O)2C (1-4) Alkyl or -S(O)2C (3-8) Cycloalkyl, wherein the -C (1-6) Alkyl and -OC (1-6) The alkyl group is optionally further substituted with one to five groups selected from halo and -OC (1-4) Alkyl radical substitution; Each R 3d Each occurrence is independently -C (1-6) Alkyl, -C (1-6) Haloalkyl or -C (1-3) Alkyl C (3-10) Cycloalkyl; Each R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) alkyl (3 to 8 membered heterocyclyl) or 5 to 10 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) The alkyl (3 to 8 membered heterocyclyl) and 5 to 10 membered heteroaryl groups are optionally further substituted with one to five groups selected from halo, -OH, -N(R N1 )(R N2 ),-C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) haloalkyl and 3 to 5 membered heterocyclic groups; or R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, each of which is optionally further substituted by one to three selected from -N(R N1 )(R N2 ) and -C (1-6) Alkyl radical substitution; R 4 is hydrogen, chlorine, fluorine or -CH3; R 5 is hydrogen, chlorine, fluorine or -CH3; R N1 and R N2 Each occurrence is independently hydrogen or -C (1-3) alkyl; R N3 is hydrogen or -C (1-4) Alkyl; and R N4 Hydrogen, -C (1-4) Alkyl or phenyl; or R N3 and R N4 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclic group, which is optionally substituted by one to five substituted groups selected from halo, -C (1-4) Alkyl and -C (1-4) The haloalkyl group is substituted.

11. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein: A is pyrazolyl, triazolyl, thiazolyl or isoxazolyl; W is CH2 or CF2; Y is CH or CR Y ; R Y is -CF3; R 1 is hydrogen or -CF3; R 2 is hydrogen; L does not exist, is -C (1-4) Alkylene or -C (3-6) Cycloalkylene; R 3 For -C (1-6) Alkyl, -C (3-10) Cycloalkyl, 3 to 10 membered heterocyclyl, 5 to 12 membered bicyclic or tricyclic ring system containing one or more heteroatoms, or 5 to 10 membered heteroaryl; wherein: the -C (1-6) The alkyl group is optionally substituted with one to five fluorine atoms; (3-10) The cycloalkyl group is optionally substituted with one -OH group; the 5 to 12 membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with one to five -C (1-6) alkyl group, and the 5- to 10-membered heteroaryl is optionally substituted by one to five R 3f group substitution; Each R 3f Each occurrence is independently -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group or -C (1-3) Alkyl (3 to 8 membered heterocyclic group), wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group and -C (1-3) The alkyl (3 to 8 membered heterocyclic group) is optionally further substituted by one to five groups selected from halo, -OH, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl radical substitution; or R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl group, each of which is optionally further substituted by one to three selected from -N(R N1 )(R N2 ) and -C (1-6) Alkyl radical substitution; and R N1 and R N2 Each occurrence is independently hydrogen or -C (1-3) alkyl. 12 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is triazolyl or isoxazolyl.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein A is isoxazolyl.

14. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein A is 15. The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula Ib-1:

16. The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula Ib-2:

17. The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula Ib-3:

18. The compound according to any one of claims 1, 2, 4 to 17, or a pharmaceutically acceptable salt thereof, wherein X is N, CH or CF.

19. A compound according to any one of claims 1, 2, 4-6, 8-10 or 12-18, or a pharmaceutically acceptable salt thereof, wherein Y is N, CH, C-CH3, C-CHF2, C-CF3, C-OCH3 or C-CH2OCH3.

20. A compound according to any one of claims 1 to 10 or 12 to 19, or a pharmaceutically acceptable salt thereof, wherein Y is CH or C-CF3.

21. A compound according to any one of claims 1 to 14 or 18 to 20, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula Ic-1:

22. A compound according to any one of claims 1 to 14 or 18 to 20, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula Ic-2:

23. A compound according to any one of claims 1 to 10 or 12 to 22, or a pharmaceutically acceptable salt thereof, wherein R 1 It is hydrogen or -CF3.

24. A compound according to any one of claims 1, 2, 4, 6, 8, 10, 12 to 14 or 18 to 20, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of any one of Formula Id-1 to Formula Id-7:

25. A compound according to any one of claims 1 to 14, 18 to 20 or 23, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of any one of Formula Id-1 to Formula Id-5:

26. The compound according to any one of claims 1, 2, 4 or 6, or a pharmaceutically acceptable salt thereof, wherein L is absent, -C (1-4) Alkylene or -C (3-6) Cycloalkylene, wherein the -C (1-4) The alkylene group is optionally substituted by one to three groups selected from halo, -OH, -N(R N1 )(R N2 ) and cyclopropyl groups.

27. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein L is absent, -C (1-4) Alkylene or cyclopropylene.

28. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein L is absent, is 29. A compound according to any one of claims 1 to 14, 18 to 20, 23 or 26-28, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of any one of Formula Ie-1 to Formula Ie-10:

30. A compound according to any one of claims 1 to 14, 18 to 20, 23 or 26-28, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of any one of Formula If-1 to Formula If-10:

31. A compound according to any one of claims 4 to 8, 10 or 12 to 30, or a pharmaceutically acceptable salt thereof, wherein R 3 is optionally represented by one to five R 3a -C (1-6) alkyl.

32. A compound according to any one of claims 4 to 6, 8, 10 or 12 to 31, or a pharmaceutically acceptable salt thereof, wherein each R 3a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ) or -CN.

33. A compound according to any one of claims 4 to 6, 8, 10 or 12 to 31, or a pharmaceutically acceptable salt thereof, wherein each R 3a Each occurrence is independently halo, -OH or -OC (1-6) alkyl.

34. A compound according to any one of claims 4 to 8, 10 or 12 to 31, or a pharmaceutically acceptable salt thereof, wherein R 3a For fluorine.

35. A compound according to any one of claims 1 to 6, 8 or 12 to 31, or a pharmaceutically acceptable salt thereof, wherein R 3 for:

36. A compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R 3 for 37. A compound according to any one of claims 4 to 8, 10 or 12 to 30, or a pharmaceutically acceptable salt thereof, wherein R 3 is optionally represented by one to five R 3b -C (3-10) Cycloalkyl.

38. A compound according to any one of claims 4 to 8, 10, 12 to 30 or 37, or a pharmaceutically acceptable salt thereof, wherein R 3 is optionally replaced by one to three R 3b -C (3-6) Cycloalkyl.

39. A compound according to any one of claims 4 to 8, 10, 12 to 30, 37 or 38, or a pharmaceutically acceptable salt thereof, wherein R 3 is optionally replaced by one to three R 3b A cyclopentyl group substituted with a radical.

40. A compound according to any one of claims 4 to 8, 10, 12 to 30 or 37 to 39, or a pharmaceutically acceptable salt thereof, wherein each R 3b Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl or -OC (1-6) Halogenated alkyl.

41. A compound according to any one of claims 4 to 8, 10, 12 to 30 or 37 to 40, or a pharmaceutically acceptable salt thereof, wherein R 3b Each occurrence is independently halo, -OH, -C (1-6) Haloalkyl or -OC (1-6) alkyl.

42. A compound according to any one of claims 4 to 8, 10, 12 to 30 or 37 to 41, or a pharmaceutically acceptable salt thereof, wherein R 3b It is -OH.

43. A compound according to any one of claims 1 to 8, 10, 12 to 30, 37 or 38, or a pharmaceutically acceptable salt thereof, wherein R 3 for:

44. A compound according to any one of claims 1 to 30 or 37 to 43, or a pharmaceutically acceptable salt thereof, wherein R 3 for 45. A compound according to any one of claims 4 to 8, 10 or 12 to 30, or a pharmaceutically acceptable salt thereof, wherein R 3 is optionally represented by one to five R 3c A 3- to 10-membered heterocyclic group substituted by a group.

46. ​​A compound according to any one of claims 4, 6, 8, 10, 12 to 30 or 45, or a pharmaceutically acceptable salt thereof, wherein R 3c Each occurrence is independently halo, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -S(O)2C (1-4) Alkyl or -S(O)2C (3-8) Cycloalkyl, wherein the -C (1-6) Alkyl and -OC (1-6) The alkyl group is optionally further substituted with one to five groups selected from halo and -OC (1-4) Alkyl radicals are substituted.

47. A compound according to any one of claims 1, 2, 4, 6, 8, 10, 12 to 30, 45 or 46, or a pharmaceutically acceptable salt thereof, wherein R 3 for:

48. A compound according to any one of claims 1 to 30 or 45 to 47, or a pharmaceutically acceptable salt thereof, wherein R 3 for 49. A compound according to any one of claims 4 to 10 or 12 to 30, or a pharmaceutically acceptable salt thereof, wherein R 3 is optionally represented by one to five R 3d A 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms which is substituted by a radical.

50. A compound according to any one of claims 4 to 30 or 49, or a pharmaceutically acceptable salt thereof, wherein R 3 is a 5- to 12-membered bicyclic ring system containing one to five heteroatoms selected from O, N and S, wherein the 5- to 12-membered bicyclic ring system is optionally replaced by one to five R 3d Group substitution.

51. A compound according to any one of claims 4 to 30, 49 or 50, or a pharmaceutically acceptable salt thereof, wherein R 3 is optionally represented by one to five R 3d The 5- to 12-membered bicyclic ring system containing one or more heteroatoms substituted by a radical, wherein the 5- to 12-membered bicyclic ring system is a 5,6-fused ring system.

52. A compound according to any one of claims 4 to 8, 10, 12 to 30 or 49 to 51, or a pharmaceutically acceptable salt thereof, wherein each R 3d Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl or -OC (1-6) Halogenated alkyl.

53. A compound according to any one of claims 4, 6, 8, 10, 12 to 30 or 49 to 52, or a pharmaceutically acceptable salt thereof, wherein R 3d Each occurrence is independently -C (1-6) Alkyl, -C (1-6) Haloalkyl or -C (1-3) Alkyl C (3-10) Cycloalkyl.

54. A compound according to any one of claims 4 to 10, 12 to 30 or 49 to 53, or a pharmaceutically acceptable salt thereof, wherein each R 3d For -C (1-6) alkyl.

55. A compound according to any one of claims 1, 2, 4, 6, 8, 10, 12 to 30 or 49 to 54, or a pharmaceutically acceptable salt thereof, wherein R 3 for:

56. A compound according to any one of claims 1 to 30 or 49 to 55, or a pharmaceutically acceptable salt thereof, wherein R 3 for:

57. A compound according to any one of claims 4 to 30, or a pharmaceutically acceptable salt thereof, wherein R 3 is optionally represented by one to five R 3f A 5- to 10-membered heteroaryl group is substituted with a moiety.

58. A compound according to any one of claims 4 to 30 or 57, or a pharmaceutically acceptable salt thereof, wherein R 3 is a 5- to 6-membered monocyclic heteroaryl or a 9-membered bicyclic heteroaryl, each of which is optionally substituted by one to three R 3f Group substitution.

59. A compound according to any one of claims 4 to 30, 57 or 58, or a pharmaceutically acceptable salt thereof, wherein R 3 is pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl or a 9-membered fused nitrogen-containing bicyclic heteroaryl, each of which is optionally substituted by one to three R 3f Group substitution.

60. A compound according to any one of claims 4 to 30 or 57 to 59, or a pharmaceutically acceptable salt thereof, wherein R 3 is pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazolopyridinyl or pyrazolopyrimidinyl, each of which is optionally substituted by one to three R 3f Group substitution.

61. A compound according to any one of claims 4 to 30 or 57 to 60, or a pharmaceutically acceptable salt thereof, wherein R 3 is pyrazolyl, isoxazolyl or pyrazolopyrimidinyl, each of which is optionally substituted by one to three R 3f Group substitution.

62. A compound according to any one of claims 4 to 30 or 57 to 61, or a pharmaceutically acceptable salt thereof, wherein R 3 for 63. A compound according to any one of claims 4 to 30 or 57 to 62, or a pharmaceutically acceptable salt thereof, wherein R 3 for:

64. A compound according to any one of claims 4 to 6, 12 to 30 or 57 to 63, or a pharmaceutically acceptable salt thereof, wherein each R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group) or -C (6-10) Aryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (1-3) Alkyl C (3-10) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) Alkyl (3 to 8 membered heterocyclic group) and -C (6-10) The aryl group is optionally further substituted with one to five groups selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1 - 4) The haloalkyl group is substituted.

65. A compound according to any one of claims 4, 6, 8, 10, 12 to 30 or 57 to 63, or a pharmaceutically acceptable salt thereof, wherein each R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, -C (0-3) Alkyl C(O)N(R N1 )(R N2 ), 3 to 8 membered heterocyclic group, -C (1-3) alkyl (3 to 8 membered heterocyclyl) or 5 to 10 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group, -C (1-3) The alkyl (3 to 8 membered heterocyclyl) and 5 to 10 membered heteroaryl groups are optionally further substituted with one to five groups selected from halo, -OH, -N(R N1 )(R N2 ),-C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-4) The alkyl radicals are substituted with haloalkyl and 3- to 5-membered heterocyclic radicals.

66. A compound according to any one of claims 4 to 8, 12 to 30 or 57 to 65, or a pharmaceutically acceptable salt thereof, wherein each R 3f Each occurrence is independently halo, -OH, -N(R N1 )(R N2 ),-C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group or -C (1 - 3) Alkyl (3 to 8 membered heterocyclic group), wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl, 3 to 8 membered heterocyclic group and -C (1-3) The alkyl (3 to 8 membered heterocyclic group) is optionally further substituted by one to five groups selected from halo, -OH, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) The haloalkyl group is substituted.

67. A compound according to any one of claims 4 to 30 or 57 to 65, or a pharmaceutically acceptable salt thereof, wherein each R 3f Each occurrence is independently -C (1-6) Alkyl, -OC (3-8) Cycloalkyl, -OC (1-6) Alkyl or -OC (3-8) Cycloalkyl, each of which is optionally further substituted with one to five groups selected from fluorine and -OH.

68. A compound according to any one of claims 4, 6, 8, 10, 12 to 30 or 57 to 63, or a pharmaceutically acceptable salt thereof, wherein R 3f Each occurrence is independently:

69. A compound according to any one of claims 4 to 30, 57 to 63 or 68, or a pharmaceutically acceptable salt thereof, wherein R 3f Each occurrence is independently:

70. A compound according to any one of claims 1, 2, 4, 6, 8, 10, 12 to 30 or 57 to 59, or a pharmaceutically acceptable salt thereof, wherein R 3 for:

71. A compound according to any one of claims 1, 2, 4, 6, 8, 10, 12 to 30 or 57 to 59, or a pharmaceutically acceptable salt thereof, wherein R 3 for:

72. A compound according to any one of claims 1, 2, 4, 6, 8, 10, 12 to 30 or 57 to 59, or a pharmaceutically acceptable salt thereof, wherein R 3 for:

73. A compound according to any one of claims 1, 2, 4, 6, 8, 10, 12 to 30 or 57 to 59, or a pharmaceutically acceptable salt thereof, wherein R 3 for:

74. A compound according to any one of claims 1 to 30 or 57 to 59, or a pharmaceutically acceptable salt thereof, wherein R 3 for:

75. A compound according to any one of claims 1 to 5 or 12 to 30, or a pharmaceutically acceptable salt thereof, wherein R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally substituted by one to three substituted radicals selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl and -OC (1 - 6) The haloalkyl group is substituted.

76. A compound according to any one of claims 1 to 30 or 75, or a pharmaceutically acceptable salt thereof, wherein R 2 and LR 3 Together with the nitrogen atom to which they are attached, they form a 5,6-fused bicyclic ring system containing one or more heteroatoms, or a 5-membered heteroaryl group, each of which is optionally substituted by one to three selected from -N(R N1 )(R N2 ) and -C (1-6) Alkyl radicals are substituted.

77. A compound according to any one of claims 1 to 30, 75 or 76, or a pharmaceutically acceptable salt thereof, wherein R 2 and LR 3 Together with the nitrogen atoms to which they are attached, they form:

78. A compound according to any one of claims 1 to 30 or 75 to 77, or a pharmaceutically acceptable salt thereof, wherein R 2 and LR 3 Together with the nitrogen atoms to which they are attached, they form:

79. A compound according to any one of claims 1, 2, 4, 6, 8, 10 or 12 to 30, or a pharmaceutically acceptable salt thereof, wherein R 3 -C(O)N(R N3 )(R N4 ).

80. A compound according to any one of claims 1, 2, 4, 6, 8, 10, 12 to 30 or 79, or a pharmaceutically acceptable salt thereof, wherein R N3 is hydrogen or -CH3; and R N4 is hydrogen, -CH3 or phenyl; or R N3 and R N4 Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered heterocyclic group which is optionally substituted by one to five groups selected from fluorine, -CH3 and -CF3.

81. A compound according to any one of claims 1, 2, 4, 6, 8, 10, 12 to 30, 79 or 80, or a pharmaceutically acceptable salt thereof, wherein R 3 for:

82. A compound according to any one of claims 1, 2, 4, 6, 8, 10, or 12 to 14, 18 to 20, 23, 26 to 28, or 30 to 81, or a pharmaceutically acceptable salt thereof, wherein: R 4 is hydrogen, chlorine, fluorine or -CH3; and R 5 It is hydrogen, chlorine, fluorine or -CH3.

83. A compound according to any one of claims 1, 2, 4, 6, 8, 10, or 12 to 14, 18 to 20, 23, 26 to 28, or 30 to 81, or a pharmaceutically acceptable salt thereof, wherein: R 4 is hydrogen, and R 5 is hydrogen; R 4 is fluorine, and R 5 is hydrogen; R 4 is -CH3; and R 5 is hydrogen; R 4 is hydrogen, and R 5 is chlorine; or R 4 is hydrogen, and R 5 It is -CH3.

84. A compound according to any one of claims 1 to 14, 18 to 20, 23, 26 to 28 or 30 to 81, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula Ih:

85. The compound according to claim 84, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of any one of Formula Ih-1 to Formula Ih-3:

86. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula Ig-1: in: W is CH2 or CF2; X is N or CH; R 1 is hydrogen; R 2 is hydrogen; L does not exist or is -C (1-4) Alkylene; R 3 is optionally represented by one to five R 3e substituted 5- to 10-membered heteroaryl; Each R 3e Independently -C (1-6) Alkyl, -OC (3-8) Cycloalkyl, -OC (1-6) Alkyl or -OC (3-8) Cycloalkyl, each of which is optionally further substituted with one to five groups selected from fluorine and -OH.

87. A compound according to any one of claims 1, 2, 4, 6, 8 or 10, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula Ii: in: A is triazolyl or isoxazolyl; X is N or CH; R 3 is optionally represented by one to five R 3e a 5-membered heteroaryl substituted with a radical; Each R 3e Independently -C (1-6) Alkyl, -OC (3-8) Cycloalkyl, -OC (1-6) Alkyl or -OC (3-8) Cycloalkyl, each of which is optionally further substituted with one to five groups selected from fluorine and -OH; R 5 For hydrogen ( 1 H) or deuterium ( 2 H).

88. A compound having a structure selected from the compounds in Tables 2A-2T, or a pharmaceutically acceptable salt thereof.

89. The compound of claim 88, or a pharmaceutically acceptable salt thereof, having a structure selected from the group consisting of:

90. The compound of claim 88, or a pharmaceutically acceptable salt thereof, having a structure selected from the group consisting of:

91. The compound of claim 88, or a pharmaceutically acceptable salt thereof, having a structure selected from the group consisting of:

92. The compound according to claim 88 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

93. The compound according to claim 88 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

94. The compound according to claim 88 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

95. The compound according to claim 88 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

96. The compound according to claim 88 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

97. The compound according to claim 88 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

98. The compound according to claim 88 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

99. The compound according to claim 88 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

100. The compound according to claim 88 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

101. The compound according to claim 88 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

102. The compound according to claim 88 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

103. The compound according to claim 88 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

104. The compound according to claim 88 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

105. The compound according to claim 88 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

106. The compound according to claim 88 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

107. The compound according to claim 88 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

108. The compound according to claim 88 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

109. The compound according to claim 88 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

110. The compound according to claim 88 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

111. The compound according to claim 88 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

112. A pharmaceutical composition comprising a compound according to any one of claims 1 to 111 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

113. 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 1-111, or a pharmaceutically acceptable carrier thereof, or (ii) a pharmaceutical composition according to claim 112.

114. The method of claim 113, 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.

115. The method of claim 114, 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.

116. The method of claim 113, 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.

117. The method of claim 113, 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.

Images