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

Abstract

The present disclosure relates to compounds of formula (I) that inhibit NIK and pharmaceutical compositions comprising such compounds and methods of use thereof. These compounds and pharmaceutical compositions are useful for the prevention or treatment of diseases such as, but not limited to, inflammatory and autoimmune disorders. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 364,550, filed May 11, 2022, which is hereby incorporated by reference in its entirety. Technical Field

[0003] The present disclosure relates to the fields of chemistry and medicine. More specifically, the present disclosure relates to NF-κB inducing kinase inhibitors and their use in medical treatments. 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 effect, inhibition of NIK 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, e.g., SV Navarra et al., The Lancet, 2011; 377(9767):721-31. One way to reduce or eliminate adverse effects associated with NIK activity is to increase NIK inhibition.

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

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

[0007]

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

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

[0010] The present application also discloses a method for treating a disease, disorder or medical condition mediated by NIK activity, the method comprising administering to a subject in need of such treatment an effective amount of (i) a compound of Formula I or a pharmaceutically acceptable carrier thereof, or (ii) a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In some embodiments, the disease, disorder or medical condition mediated by NIK activity is selected from the group consisting of: inflammatory disorders, autoimmune disorders, cancer, metabolic disorders and osteoporosis. In some embodiments, the disease, disorder or medical condition mediated by NIK activity is selected from the group consisting of: systemic lupus erythematosus ("SLE"), rheumatoid arthritis ("RA"), 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"), suppurative Hidradenitis (“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

[0011] 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 of the present disclosure disclosed or claimed.

[0012] NF-κB inducing kinase (known 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. 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, but not limited to, inflammatory disorders and autoimmune disorders.

[0013] NIK-dependent transcriptional activation is a strictly controlled signal transduction pathway, through continuous events including phosphorylation and protein degradation. In the NIK activation pathway, which is called the non-classical pathway, activation is accomplished by phosphorylating the catalytic complex subunit IKKα, resulting in 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 but not limited to CD40 ligand, B cell activating factor (BAFF), lymphotoxin beta receptor ligand, TNF-related weak inducer of apoptosis (TWEAK) cytokines, and receptor activator of nuclear factor kappa-B ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11). It has been confirmed that NIK is 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 strictly 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-related factors (TRAF2 and TRAF3), which are ubiquitin ligases and cause 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 FR2010, 21, 213-226). NIK plays a role in promoting immune response disorders, so the increase in NIK levels is undesirable, and a method of alleviating or eliminating the adverse effects associated with this increase is NIK inhibition.

[0014] 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 SLE patients (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-classical activation pathways such as but not limited to 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.

[0015] NIK has been described as "important in the immune and bone-destructive components of inflammatory arthritis and represents a possible therapeutic target for these diseases." K. Aya et al. (J. Clin. Invest. 2005, 115, 1848-1854). Mice lacking functional NIK have no peripheral lymph nodes, have defective B cells and T cells, and have impaired receptor activators for NIK ligand-stimulated osteoclastogenesis. K. Aya et al. (J. Clin. Invest. 2005, 115, 1848-1854) used NIK- / - mice to study the role of NIK in a murine model of inflammatory arthritis. The serum transfer arthritis model is triggered by preformed antibodies and requires only intact neutrophils and complement systems in the recipient. Although NIK- / - mice have inflammation comparable to NIK+ / + controls, Ada et al. (as cited above) revealed a significant reduction in periarticular osteoclastogenesis and reduced bone erosion. In contrast, NIK- / - mice are completely resistant to antigen-induced arthritis (AIA), which requires complete antigen presentation and lymphocyte function, but does not require lymph nodes. In addition, the transfer of NIK+ / + splenocytes or T cells to Rag2- / - mice confers susceptibility to AIA, while the transfer of NIK- / - cells does not have this effect. NIK- / - mice are also resistant to genetic, spontaneous forms of arthritis, which are produced in mice expressing both KRN T cell receptors and H-2g7. Transgenic mice are 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).

[0016] 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).

[0017] definition

[0018] 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 the present disclosure belongs. Otherwise, certain terms used herein have the meanings described in this specification.

[0019] In order to help the reader of the application, the specification is divided into each paragraph or chapter, or relates to each embodiment of the application. These divisions should not be considered as the main content of a paragraph or chapter or embodiment being separated from the main content of another paragraph or chapter or embodiment. On the contrary, it will be appreciated by those skilled in the art that this specification has a wide range of applications, and encompasses all combinations of conceivable chapters, paragraphs and sentences. The discussion of any embodiment is intended to be exemplary only, and is not intended to indicate that the scope of the disclosure (including claims) is limited to these examples.

[0020] 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.

[0021] As used herein, the terms "including," "containing," and "comprising" are used in their open, non-limiting sense.

[0022] 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, whether or not the term "about" is explicitly used, each amount given herein is intended to refer to the actual given value, and it is also intended to refer to the approximate values ​​of these given values ​​that can be reasonably inferred according to the general technology in the art, including the equivalent values ​​and approximate values ​​of these given values ​​caused by experimental and / or measurement conditions.

[0023] In the context of 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.

[0024] The term "subject" refers to a patient, which may 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., more preferably humans.

[0025] The term "therapeutically effective amount" or "effective amount" means the 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 prevention, treatment or amelioration of the symptoms of the syndrome, disorder or disease being treated.

[0026] As used herein, the term "treatment" 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); the purpose of applying or administering is to cure, heal, alleviate, relieve, alter, remedy, improve, ameliorate, or affect 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.

[0027] 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.

[0028] The term "C (a-b) "" (where a and b are integers, referring to the specified 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 (including a and b) carbon atoms, wherein alkyl appears as a prefix root. For example, C (1-4) denotes a group containing 1, 2, 3 or 4 carbon atoms.

[0029] The term "alkyl" is a straight or branched chain saturated hydrocarbon. For example, an alkyl group may have 1 to 12 carbon atoms (i.e., (C 1 -C 12 ) alkyl), 1 to 6 carbon atoms (i.e., (C 1 -C 6 ) alkyl), 1 to 4 carbon atoms (i.e., (C 1 -C 4 ) alkyl) or 1 to 3 carbon atoms (i.e., (C 1 -C 3 Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH3 ), isopropyl (i-Pr, i-propyl, -CH (CH 3 ) 2 ), 1-butyl (n-bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-butyl (s-bu, s-butyl, -CH (CH 3 )CH 2 CH 3 ), tert-butyl (t-bu, t-butyl, -CH (CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), neopentyl (-CH 2 C(CH 3 ) 3 )、1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), heptyl (-(CH 2 ) 6 CH 3 ), octyl (-(CH 2 ) 7 CH 3 )、2,2,4-trimethylpentyl (-CH 2 C(CH 3 ) 2 CH 2 CH(CH 3 ) 2 ), nonyl (-(CH 2 ) 8 CH 3 ), decyl (-(CH 2 ) 9 CH 3 ), undecyl (-(CH 2 ) 10CH 3 ) and dodecyl (-(CH 2 ) 11 CH 3 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.

[0030] The term "alkylene" refers to a radical derived from a group having 1 to 12 carbon atoms (i.e., (C 1 -C 12 ) alkylene), 1 to 6 carbon atoms (i.e., (C 1 -C 6 ) alkylene), 1 to 4 carbon atoms (i.e., (C 1 -C 4 ) alkylene) or 1 to 3 carbon atoms (i.e., (C 1 -C 3 ) alkylene) is a straight or branched saturated divalent hydrocarbon portion of an alkane. Examples of alkylene groups include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), -C(CH 3 )H-, propylene (-CH 2 CH 2 CH 2 -), isopropylidene (-CH(CH 3 )CH 2 -) and -CH 2 CH(CH 3 )-. In one embodiment, alkylene refers to C (1-4) In another embodiment, alkylene refers to C (1-2) Alkylene.

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

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

[0033] The term "cycloalkyl" refers to a cycloalkyl group having, for example, 3 to 10 carbon atoms (i.e., 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 cycloalkyl (cycloalkyl), wherein the cycloalkyl ring system has a single ring or multiple rings in a spirocyclic or bridged configuration. Exemplary cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Some cycloalkyls may exist as spirocycloalkyls, 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 C (3-10) In another embodiment, cycloalkyl refers to C (3-8) In another embodiment, cycloalkyl refers to C (3-6) Cycloalkyl.

[0034] The term "cycloalkylene" refers to a radical derived from a group having, for example, 3 to 10 carbon atoms (i.e., 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 C (3-10)In another embodiment, cycloalkylene refers to C (3-8) In another embodiment, cycloalkyl refers to C (3-6) Cycloalkylene.

[0035] Unless otherwise specified, the term "aryl" refers to a polyunsaturated (typically aromatic) hydrocarbon radical which may 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 radicals include phenyl, naphthyl, anthracenyl. In one embodiment, aryl refers to C (6-10) Aryl. In another embodiment, aryl refers to phenyl.

[0036] The term "heterocyclyl" or "heterocycloalkyl" refers to a single saturated or partially unsaturated ring having 3 to 12 ring members, 3 to 10 ring members, 3 to 8 ring members, or 3 to 6 ring members and containing carbon atoms and at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of N, O, and S. The terms "heterocyclyl" and "heterocycloalkyl" include cyclic esters (e.g., lactones) and cyclic amides (e.g., lactams). Exemplary heterocycles include, but are not limited to, oxetane, aziridine, azetidinyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, and thiomorpholinyl. Unless otherwise specified, a heterocyclyl group is attached to its side group at any heteroatom or carbon atom that produces a stable structure. In one embodiment, heterocyclyl refers to a 3 to 10-membered heterocyclyl. In another embodiment, heterocyclyl refers to a 3 to 8-membered heterocyclyl. In another embodiment, heterocyclyl refers to a 3 to 6-membered heterocyclyl.

[0037] 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 spiro polycyclic 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 the group consisting of N, O and S. The ring system can include a completely unsaturated aromatic ring; however, at least one other ring in the polycyclic ring system must be saturated or partially saturated. In some embodiments, the term refers to a fused bicyclic ring system. In some embodiments, the term refers to a fused bicyclic ring system in which one ring is an aromatic ring. The term includes cyclic esters (e.g., lactones) and cyclic amides (e.g., lactams). Non-limiting examples of 5- to 12-membered bicyclic or tricyclic ring systems containing one or more heteroatoms include 3-oxabicyclo[3.1.0]hexyl, indolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 4,5,6,7-tetrahydro-1H-indazolyl, 6,7-dihydro-5H-cyclopenta[c]pyridazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, 3-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazinyl, and 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-onyl. Unless otherwise indicated, a bicyclic or tricyclic ring system is attached to its side group at any heteroatom or carbon atom that results in a stable structure. In one embodiment, a 5 to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms refers to a 5 to 12-membered bicyclic ring system containing one or more heteroatoms. In another embodiment, a 5 to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms refers to a 7 to 12-membered bicyclic ring system containing one or more heteroatoms. In another embodiment, a 5 to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms refers to a 7 to 10-membered bicyclic ring system containing one or more heteroatoms.

[0038] 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 a member in 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 the case where the 6-membered ring has 3 nitrogens, at most 2 nitrogen atoms are adjacent. The example of heteroaryl group includes furanyl, 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 limited terms can also be selected. Unless otherwise specified, heteroaryl is connected to its side group on any heteroatom or carbon atom causing a stable structure. In one embodiment, heteroaryl refers to 5 to 10 yuan of heteroaryl. In another embodiment, heteroaryl refers to 5 to 8 membered heteroaryl. In another embodiment, heteroaryl refers to 5 to 6 membered heteroaryl. In another embodiment, heteroaryl refers to 5 membered heteroaryl.

[0039] The term "substituted" means that the specified group or moiety carries one or more substituents. The term "unsubstituted" means that the specified group does not carry a substituent. 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 the substitution occurs at any valence-allowed position on the system.

[0040] 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.

[0041] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of one another.

[0042] "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 a mixture of enantiomers in a ratio other than 1:1.

[0043] 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, but not limited to, preparative chromatography. These compounds can be prepared in racemic form, non-racemic mixtures, or individual enantiomers can be prepared by enantiospecific synthesis or by resolution. For example, these compounds can be resolved into their component enantiomers by standard techniques, such as by forming a salt with an optically active acid (such as, but not limited to, (-)-di-p-toluoyl-D-tartaric acid and / or (+)-di-p-toluoyl-L-tartaric acid), followed by fractional crystallization and regeneration of the free base. The compounds can also be resolved by forming diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, these compounds can be resolved 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 H NMR spectra.

[0044] Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. It is known that the chiral center of the absolute configuration is marked by the prefixes R and S specified using the standard order rule program, and when necessary, by the appropriate position priority (Pure & Appl. Chem. 45, 1976, 11-30). Certain enantiomers and diastereomers appear together in the embodiments. These enantiomers / diastereomers can be specified and characterized as enantiomer 1 or enantiomer 2 (or, alternatively, diastereomer 1 or diastereomer 2) in the following synthesis method. Presenting stereoisomers in this way conveys that the compound is prepared or separated separately as a pure single enantiomer or diastereomer at a determined stereocenter. However, unless otherwise stated, 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 is the opposite enantiomer, regardless of the order in which the IUPAC names or chemical structures of the compounds appear, unless otherwise stated in the subsequent methods and characterizations.

[0045] Although pseudoasymmetric stereogenic centers are treated in the same manner as chiral centers, the former are given lower case letter symbols, r or s (Angew. Chem. Int. Ed. Engl. 1982, 21, 567-583).

[0046] In any of the processes for preparation of the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups in any of the molecules concerned. This may be achieved by conventional protecting groups such as, but not limited to, those described in: Protective Groups in Organic Chemistry ”, JFWMcOmie, ed., Plenum Press, 1973; and TWGreene and PGM Wuts, “ Protective Groups in Organic Synthesis ”, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known in the art.

[0047] Furthermore, within the scope of the present disclosure, any element, particularly when referred to in relation to a compound of the present disclosure or a pharmaceutically acceptable salt thereof, is intended to include all isotopes or isotopic mixtures (naturally occurring or synthetically produced) of the element in its natural abundance or in its isotopically enriched form. For example, a reference to hydrogen or "H" includes within its scope 1 H. 2 H (i.e. deuterium or D) and 3 H (ie, tritium or T). In some embodiments, the compounds described herein include 2 H (i.e. deuterium) isotope. For example, -C (1-6) Alkyl groups include not only -C 1 H 3 , and includes C 1 HD 2 , C 1 H 2 D. CD 3 and other isotopic forms; not only C 1 H 2 C 1 H 3 , C 1 HDC 1 HD 2 , C 1 HDC 1 H 2 D. C 1 H 2 C 1 H 3 , CD 2 CD 3Likewise, where unspecified hydrogen atoms are present in a chemical structure, those hydrogen atoms may be 1 H. 2 H (i.e., deuterium or D) or 3 H (i.e., tritium or T). For example, the group Also covers Similarly, references to carbon and oxygen include within their scope 12 C. 13 C and 14 C and 15 O and 16 O and 17 O and 18 O. The isotope may be radioactive or non-radioactive. The radiolabeled compounds of the present disclosure may include a radioisotope selected from the group consisting of: 3 H. 11 C. 18 F. 35 S. 122 I. 123 I. 125 I. 131 I. 75 Br, 76 Br, 77 Br and 82 Br. In some embodiments, the radioisotope is selected from the group consisting of 3 H. 11 C and 18 F's group.

[0048] Reference to a compound herein represents a 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 considered when referring to the compound. For example, reference herein to a compound such as, but not limited to, 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 the compound in a solvent, such as but not limited to the dissociated form of the compound in an aqueous environment, whether such dissociated form is derived from R-COOH, a salt thereof, or from 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, for example, but not limited to, R-COOH. (aq) and / or R-COO - (aq) Substances such as, wherein the subscript "(aq)" represents "containing water" according to its conventional meaning in chemistry and biochemistry. In these naming examples, the carboxylic acid functional group is selected; however, this selection is not intended to be limiting, but only to illustrate. 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.

[0049] The term "pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or equivalent in countries 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.

[0050] "Pharmaceutically 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 have the desired pharmacological activity of the parent compound. Generally, see GS Paulekuhn et al., "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database", J. Med. Chem., 2007, 50: 6665-72, SM Berge et al., "Pharmaceutical Salts", JPharm Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with patient tissues without undue toxicity, irritation, or allergic reactions. 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.

[0051] Compounds of the Disclosure

[0052] The present application discloses compounds of formula I:

[0053]

[0054] or a pharmaceutically acceptable salt thereof, wherein:

[0055] A is optionally replaced by one to three -C (1-4) 5- to 6-membered heteroaryl substituted with an alkyl group;

[0056] W is CH 2 , CHF or CF 2 ;

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

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

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

[0060] RX , R Y and R Z are independently halo, -CN, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0061] R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0062] R 2 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0063] R 3 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0064] 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;

[0065] R 4 It is hydrogen, -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(O)-(3- to 10-membered heterocyclyl), -C (6-10) aryl or 5 to 10 membered heteroaryl, wherein the -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(O)-(3- to 10-membered heterocyclyl), -C (6-10) Aryl and 5- to 10-membered heteroaryl are each optionally substituted by one to five R 4x group substitution;

[0066] Each R 4x 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, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 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, 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 (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radical substitution; and

[0067] R N1 and R N2 Each occurrence is independently H, -C (1-3) Alkyl or -C (1-3) Haloalkyl;

[0068] The prerequisite is that at least one of X, Y and Z is CH.

[0069] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein:

[0070] A is optionally replaced by a-C (1-4) 5- to 6-membered heteroaryl substituted with an alkyl group;

[0071] W is CH 2 or CF 2 ;

[0072] X is N, CH or CR X ;

[0073] Y is N, CH or CR Y ;

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

[0075] R X , R Y and R Z are independently halo, -CN, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0076] R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0077] R 2 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0078] R 3 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0079] 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;

[0080] R 4 Yes-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(O)-(3- to 10-membered heterocyclyl), -C (6-10)aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one to five R 4x group substitution;

[0081] Each R 4x 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, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 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 (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radical substitution; and

[0082] R N1 and R N2 Each occurrence is independently H or -C (1-3) alkyl;

[0083] The prerequisite is that at least one of X, Y and Z is CH.

[0084] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein:

[0085] A is a 5- to 6-membered heteroaryl group optionally substituted with one methyl group;

[0086] W is CH 2 or CF 2 ;

[0087] X is N, CH or CR X ;

[0088] Y is N, CH or CR Y ;

[0089] Z is N, CH or CR Z ;

[0090] R X , R Y and R Z are independently halo, -CN, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0091] R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0092] R 2 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0093] R 3 is hydrogen or -C (1-4) alkyl;

[0094] 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 with a -OC (1-3) Alkyl group substitution;

[0095] R 4 Yes-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(O)-(3- to 10-membered heterocyclyl), -C (6-10) aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one to five R 4x group substitution;

[0096] Each R 4x 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, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 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, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-6) Haloalkyl and -C(O)N(R N1 )(R N2 ) is substituted with a group; and

[0097] R N1 and R N2 Each occurrence is independently H or -C (1-3)alkyl;

[0098] The prerequisite is that at least one of X, Y and Z is CH.

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

[0100] A is a 5- to 6-membered heteroaryl group optionally substituted with one methyl group;

[0101] W is CH 2 or CF 2 ;

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

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

[0104] Z is N, CH or CR Z ;

[0105] R X , R Y and R Z are independently halo, -CN, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0106] R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0107] R 2 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0108] R 3 is hydrogen or -C (1-4) alkyl;

[0109] 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 with a -OC (1-3) Alkyl group substitution;

[0110] R 4 Yes-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, each of which is optionally substituted by one to five R 4x group substitution;

[0111] Each R 4x Each occurrence is independently halo, -OH, -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, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) 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, -C (1-3) Alkyl C (3-10) Cycloalkyl and 3 to 8 membered heterocyclic groups 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, -OC (1-6) Haloalkyl and -C(O)N(R N1 )(R N2 ) is substituted with a group; and

[0112] R N1 and R N2 Each occurrence is independently H or -C (1-3) alkyl;

[0113] The prerequisite is that at least one of X, Y and Z is CH.

[0114] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein:

[0115] A is optionally replaced by one to three -C (1-4) 5- to 6-membered heteroaryl substituted with an alkyl group;

[0116] W is CH 2 , CHF or CF 2 ;

[0117] X is N, CH or CR X ;

[0118] Y is N, CH or CR Y ;

[0119] Z is N, CH or CR Z ;

[0120] R X , R Y and R Z are independently halo, -CN, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0121] R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0122] R 2 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0123] R 3 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0124] 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;

[0125] R 4 It is hydrogen, -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(O)-(3- to 10-membered heterocyclyl), -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 4a The -C (3-10) The cycloalkyl group is optionally substituted with one to five R 4b The 3- to 10-membered heterocyclic group is optionally substituted by one to five R 4c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 4dThe -C(O)-(3- to 10-membered heterocyclic group) is optionally substituted by one to five R 4e The -C (6-10) The aryl group is optionally substituted by one to five R 4f and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 4g group substitution;

[0126] R 3a , R 3b , R 3c , R 3d , R 3e , R 3f and R 3g 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, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 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, 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 )(RN2 )、-CN、-C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radical substitution; and

[0127] R N1 and R N2 Each occurrence is independently H, -C (1-3) Alkyl or -C (1-3) Haloalkyl;

[0128] The prerequisite is that at least one of X, Y and Z is CH.

[0129] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein:

[0130] A is optionally replaced by one to three -C (1-4) 5- to 6-membered heteroaryl substituted with an alkyl group;

[0131] W is CH 2 or CF 2 ;

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

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

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

[0135] R X , R Y and R Z are independently halo, -CN, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0136] R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0137] R 2 is hydrogen, halo, -C (1-4) Alkyl or -C(1-4) Haloalkyl;

[0138] R 3 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0139] 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;

[0140] R 4 It is hydrogen, -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(O)-(3- to 10-membered heterocyclyl), -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 4a The -C (3-10) The cycloalkyl group is optionally substituted with one to five R 4b The 3- to 10-membered heterocyclic group is optionally substituted by one to five R 4c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 4d The -C(O)-(3- to 10-membered heterocyclic group) is optionally substituted by one to five R 4e The -C (6-10) The aryl group is optionally substituted by one to five R 4f and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 4g group substitution;

[0141] Each R 4a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-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, -C(O)N(R N1 )(R N2 )、-S(O)2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (6-10) aryl or 5 to 10 membered heteroaryl, wherein the -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 (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 (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radical substitution;

[0142] R 4b , R 4c , R 4d and R 4e 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(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 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, 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 (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radical substitution;

[0143] R 4f and R 4g 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, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 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, 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 (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radical substitution; and

[0144] R N1 and R N2 Each occurrence is independently H or -C (1-3) alkyl;

[0145] The prerequisite is that at least one of X, Y and Z is CH.

[0146] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein:

[0147] A is optionally replaced by one to three -C (1-4) 5- to 6-membered heteroaryl substituted with an alkyl group;

[0148] W is CH 2 or CF 2 ;

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

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

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

[0152] R X , R Y and RZ are independently halo, -CN, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0153] R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0154] R 2 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0155] R 3 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0156] 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;

[0157] R 4 Yes-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 4a The -C (3-10) The cycloalkyl group is optionally substituted with one to five R 4b The 3- to 10-membered heterocyclic group is optionally substituted by one to five R 4c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 4d and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 4g group substitution;

[0158] Each R 4a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-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, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (6-10) aryl or 5 to 10 membered heteroaryl, wherein the -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 (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 (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radical substitution;

[0159] R 4b , R 4c and R 4d 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(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 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, 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 (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radical substitution;

[0160] Each R 4g 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, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 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, 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 (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radical substitution; and

[0161] R N1 and R N2 Each occurrence is independently H or -C (1-3) alkyl;

[0162] The prerequisite is that at least one of X, Y and Z is CH.

[0163] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein:

[0164] A is optionally replaced by one to three -C (1-4) 5- to 6-membered heteroaryl substituted with an alkyl group;

[0165] W is CH 2 or CF 2 ;

[0166] X is N, CH or CR X ;

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

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

[0169] R X , R Y and R Z are independently halo, -CN, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0170] R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0171] R 2 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0172] R 3 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0173] 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;

[0174] R 4 It is hydrogen, -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(O)-(3- to 10-membered heterocyclyl), -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 4a The -C (3-10) The cycloalkyl group is optionally substituted with one to five R 4b The 3- to 10-membered heterocyclic group is optionally substituted by one to five R 4c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 4d The -C(O)-(3- to 10-membered heterocyclic group) is optionally substituted by one to five R 4e The -C (6-10) The aryl group is optionally substituted by one to five R 4f and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 4g group substitution;

[0175] Each R 4a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-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, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) alkyl or a 3- to 8-membered heterocyclic group, wherein the -C (1-6) Haloalkyl, -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 and -OC (1-4) Alkyl radical substitution;

[0176] R 4b , R 4c , R 4d and R 4e 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(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) 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 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 )、-CN、-C (1-4) Alkyl and -OC (1-4) Alkyl radical substitution;

[0177] R 4f and R 4g 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, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 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(1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radical substitution; and

[0178] R N1 and R N2 Each occurrence is independently H or -C (1-3) alkyl;

[0179] The prerequisite is that at least one of X, Y and Z is CH.

[0180] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein:

[0181] A is optionally replaced by a-C (1-4) 5- to 6-membered heteroaryl substituted with an alkyl group;

[0182] W is CH 2 or CF 2 ;

[0183] X is N, CH or CR X ;

[0184] Y is N, CH or CR Y ;

[0185] Z is N, CH or CR Z ;

[0186] R X , R Y and R Z are independently halo, -CN, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0187] R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0188] R 2 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0189] R 3 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0190] 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;

[0191] R 4 Yes-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 4a The -C (3-10) The cycloalkyl group is optionally substituted with one to five R 4b The 3- to 10-membered heterocyclic group is optionally substituted by one to five R 4c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 4d and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 4g Group substitution;

[0192] Each R 4a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-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, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) alkyl or a 3- to 8-membered heterocyclic group, wherein the -C (1-6) Haloalkyl, -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 )(RN2 )、-CN、-C (1-4) Alkyl and -OC (1-4) Alkyl radical substitution;

[0193] R 4b , R 4c and R 4d 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(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) 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 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 )、-CN、-C (1-4) Alkyl and -OC (1-4) Alkyl radical substitution;

[0194] Each R 4g 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, -C(O)N(R N1 )(R N2)、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 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 (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radical substitution; and

[0195] R N1 and R N2 Each occurrence is independently H or -C (1-3) alkyl;

[0196] The prerequisite is that at least one of X, Y and Z is CH.

[0197] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein:

[0198] A is optionally replaced by a-C (1-4) 5- to 6-membered heteroaryl substituted with an alkyl group;

[0199] W is CH 2 or CF 2 ;

[0200] X is N, CH or CR X;

[0201] Y is N, CH or CR Y ;

[0202] Z is N, CH or CR Z ;

[0203] R X , R Y and R Z are independently halo, -CN, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0204] R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0205] R 2 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0206] R 3 is hydrogen or -C (1-4) alkyl;

[0207] 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 with a -OC (1-3) Alkyl group substitution;

[0208] R 4 It is hydrogen, -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(O)-(3- to 10-membered heterocyclyl), -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 4a The -C (3-10) The cycloalkyl group is optionally substituted with one to five R 4b The 3- to 10-membered heterocyclic group is optionally substituted by one to five R 4c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 4d The -C(O)-(3- to 10-membered heterocyclic group) is optionally substituted by one to five R 4e The -C (6-10) The aryl group is optionally substituted by one to five R 4fand the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 4g group substitution;

[0209] Each R 4a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) alkyl or a 3- to 8-membered heterocyclic group, wherein the -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) The haloalkyl 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 and -OC (1-4) Alkyl radical substitution;

[0210] Each R 4b 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, 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;

[0211] R 4c and R 4d 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) 2 C (1-4) 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) 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 and -OC (1-4) Alkyl radical substitution;

[0212] Each R 4e 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;

[0213] Each R 4f 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(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl or -N(H)S(O) 2 C (1-4) Alkyl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl and -OC (3-8)The cycloalkyl 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 (1-6) haloalkyl radical substitution;

[0214] Each R 4g 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, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 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, -OC (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O)2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radical substitution; and

[0215] R N1 and R N2 Each occurrence is independently H or -C (1-3) alkyl;

[0216] The prerequisite is that at least one of X, Y and Z is CH.

[0217] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein:

[0218] A is optionally replaced by a-C (1-4) 5- to 6-membered heteroaryl substituted with an alkyl group;

[0219] W is CH 2 or CF 2 ;

[0220] X is N, CH or CR X ;

[0221] Y is N, CH or CR Y ;

[0222] Z is N, CH or CR Z ;

[0223] R X , R Y and R Z are independently halo, -CN, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0224] R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0225] R 2 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0226] R 3 is hydrogen or -C (1-4) alkyl;

[0227] 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 with a -OC(1-3) Alkyl group substitution;

[0228] R 4 Yes-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 4a The -C (3-10) The cycloalkyl group is optionally substituted with one to five R 4b The 3- to 10-membered heterocyclic group is optionally substituted by one to five R 4c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 4d and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 4g group substitution;

[0229] Each R 4a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) alkyl or a 3- to 8-membered heterocyclic group, wherein the -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) The haloalkyl 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 and -OC (1-4) Alkyl radical substitution;

[0230] Each R 4b 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, 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;

[0231] R 4c and R 4d 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) 2 C (1-4) 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) 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 and -OC (1-4) Alkyl radical substitution;

[0232] Each R 4g 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, -C(O)N(R N1 )(R N2 )、-S(O) 2 C(1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 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, -OC (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radical substitution; and

[0233] R N1 and R N2 Each occurrence is independently H or -C (1-3) alkyl;

[0234] The prerequisite is that at least one of X, Y and Z is CH.

[0235] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein:

[0236] A is a 5- to 6-membered heteroaryl group optionally substituted with one methyl group;

[0237] W is CH 2 or CF 2 ;

[0238] X is N, CH or CR X ;

[0239] Y is N, CH or CR Y ;

[0240] Z is N, CH or CR Z ;

[0241] R X , R Y and R Z are independently halo, -CN, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0242] R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0243] R 2 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0244] R 3 is hydrogen or -C (1-4) alkyl;

[0245] 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 with a -OC (1-3) Alkyl group substitution;

[0246] R 4 It is hydrogen, -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(O)-(3- to 10-membered heterocyclyl), -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 4a The -C (3-10) The cycloalkyl group is optionally substituted with one to five R 4b The 3- to 10-membered heterocyclic group is optionally substituted by one to five R 4c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 4d The -C(O)-(3 to 10 membered heterocyclic group) is optionally substituted by one to three -C (1-4) Alkyl group substituted, the -C (6-10) The aryl group is optionally substituted by one to five R 4f and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 4g Group substitution;

[0247] Each R 4a Each occurrence is independently halo, -OH, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) alkyl or a 3- to 8-membered heterocyclic group, wherein the -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) The haloalkyl and 3- to 8-membered heterocyclyl groups are optionally further substituted with one to five groups selected from halo and -OH;

[0248] Each R 4b Each occurrence is independently halo, -OH, -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -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 and -OH;

[0249] R 4c and R 4d Each occurrence is independently -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) 2 C (1-4) 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) 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 and -C (1-4) Alkyl radical substitution;

[0250] Each R4f Each occurrence is independently halo, -OH, -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 or -C(O)N(R N1 )(R N2 ), where -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl and -OC (3-8) The cycloalkyl group is optionally further substituted with one to five groups selected from halo and -OH;

[0251] Each R 4g Each occurrence is independently halo, -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)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, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-6)Haloalkyl and -C(O)N(R N1 )(R N2 ) is substituted with a group; and

[0252] R N1 and R N2 Each occurrence is independently H or -C (1-3) alkyl;

[0253] A prerequisite is that at least two of X, Y and Z are CH.

[0254] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein:

[0255] A is a 5- to 6-membered heteroaryl group optionally substituted with one methyl group;

[0256] W is CH 2 or CF 2 ;

[0257] X is N, CH or CR X ;

[0258] Y is N, CH or CR Y ;

[0259] Z is N, CH or CR Z ;

[0260] R X , R Y and R Z are independently halo, -CN, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0261] R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0262] R 2 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl;

[0263] R 3 is hydrogen or -C (1-4) alkyl;

[0264] 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 with a -OC (1-3) Alkyl group substitution;

[0265] R 4 Yes-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 4a The -C (3-10) The cycloalkyl group is optionally substituted with one to five R 4b The 3- to 10-membered heterocyclic group is optionally substituted by one to five R 4c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 4d and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 4g Group substitution;

[0266] Each R 4a Each occurrence is independently halo, -OH, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) alkyl or a 3- to 8-membered heterocyclic group, wherein the -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) The haloalkyl and 3- to 8-membered heterocyclyl groups are optionally further substituted with one to five groups selected from halo and -OH;

[0267] Each R 4b Each occurrence is independently halo, -OH, -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -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 and -OH;

[0268] R 4c and R 4d Each occurrence is independently -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) 2 C (1-4) 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) 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 and -C (1-4) Alkyl radical substitution;

[0269] Each R 4g Each occurrence is independently halo, -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)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, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-6) Haloalkyl and -C(O)N(R N1 )(R N2 ) is substituted with a group; and

[0270] R N1 and R N2 Each occurrence is independently H or -C (1-3) alkyl;

[0271] A prerequisite is that at least two of X, Y and Z are CH.

[0272] 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:

[0273]

[0274] 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:

[0275]

[0276] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is optionally substituted by one to three -C (1-4) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is a 5-membered heteroaryl optionally substituted with a methyl group. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is a 5-membered heteroaryl optionally substituted with a methyl group.

[0277] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is optionally substituted by one to three -C (1-4) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is a 6-membered heteroaryl optionally substituted with a methyl group. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is a 6-membered heteroaryl optionally substituted with a methyl group.

[0278] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is optionally substituted with a -C (1-4) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is a 5-membered heteroaryl or pyridyl, each of which is optionally substituted with a -C (1-4)In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is a 5-membered heteroaryl or pyridinyl, each of which is optionally substituted with a methyl group. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is a 5-membered heteroaryl or pyridinyl.

[0279] In some embodiments, disclosed herein are compounds of formula I or pharmaceutically acceptable salts thereof, wherein A is pyrazolyl, oxazolyl, thiazolyl or pyridinyl, each of which is optionally substituted with a methyl group. In some embodiments, disclosed herein are compounds of formula I or pharmaceutically acceptable salts thereof, wherein A is pyrazolyl, oxazolyl, thiazolyl or pyridinyl. In some embodiments, disclosed herein are compounds of formula I or pharmaceutically acceptable salts thereof, wherein A is pyrazolyl or thiazolyl. In some embodiments, disclosed herein are compounds of formula I or pharmaceutically acceptable salts thereof, wherein A is pyrazolyl. In some embodiments, disclosed herein are compounds of formula I or pharmaceutically acceptable salts thereof, wherein A is oxazolyl. In some embodiments, disclosed herein are compounds of formula I or pharmaceutically acceptable salts thereof, wherein A is thiazolyl. In some embodiments, disclosed herein are compounds of formula I or pharmaceutically acceptable salts thereof, wherein A is pyridinyl.

[0280] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is:

[0281]

[0282] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is

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

[0284] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is

[0285] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein A is

[0286] 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:

[0287]

[0288] 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:

[0289]

[0290] 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:

[0291]

[0292] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein W is CH 2 , CHD, CD 2 or CF 2 In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein W is CH 2 , CD 2 or CF 2 In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein W is CH 2 or CF 2 In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein W is CH 2 In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein W is CF 2 .

[0293] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein at least two of X, Y, and Z are CH. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein no more than one of X, Y, and Z is N.

[0294] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein X is CH or CR X In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein X is CH or CF. Disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein X is CH. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein X is CR X In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein X is CF.

[0295] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Y is N, CH, CF, or C-CN. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Y is N or CH. Disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Y is N. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Y is CH. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Y is CR Y In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Y is CF. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Y is C-CN.

[0296] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Z is N, CH or CF. Disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Z is N. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Z is CH. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Z is CR Z In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein Z is CF.

[0297] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R X , R Y and R Z are independently halo, -CN, -C (1-4) Alkyl or -C (1-4) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R X , R Y and R Z are each independently fluorine or -CN.

[0298] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein: X is CH or CF; Y is N, CH, CF, or C-CN; and Z is N, CH, or CF. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein: X is CH; Y is N, CH, or CF; and Z is N, CH, or CF. In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein: X is CH; Y is N or CH; and Z is N, CH, or CF.

[0299] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, which is a compound of any one of Formulas Ic-1 to Ic-4:

[0300]

[0301] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 1 is hydrogen or -C (1-4) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 1 is hydrogen or -CF 3 In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 1 In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 1 Yes - CF 3 .

[0302] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, which is a compound of any one of Formulas Id-1 to Id-5:

[0303]

[0304]

[0305] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 and R 3 are independently hydrogen, halo or -C (1-4) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 and R 3 Each is independently hydrogen, fluoro or methyl. In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 It's hydrogen.

[0306] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is hydrogen, halogen or -C (1-4) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is hydrogen, fluorine or methyl. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R2 It's hydrogen.

[0307] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 3 is hydrogen, halogen or -C (1-4) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 3 is hydrogen or -C (1-4) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 3 It's hydrogen.

[0308] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein L is absent, is -C (1-4) Alkylene or -C (3-6) Cycloalkylene, wherein the -C (1-4) The alkylene group is optionally substituted with a -OC (1-3) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein L is absent, is -C (1-4) Alkylene or cyclopropylene, wherein the -C (1-4) The alkylene group is optionally substituted with a -OC (1-3) Alkyl group substitution.

[0309] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein L is absent, is

[0310] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein L is absent or is

[0311] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein L is absent.

[0312] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein L is

[0313] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, which is a compound of any one of Formulas Ie-1 to Ie-8:

[0314]

[0315] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 Yes-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(O)-(3- to 10-membered heterocyclyl), -C (6-10) aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by one to five R 4x In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 Yes-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, each of which is optionally substituted by one to five R 4x Group substitution.

[0316] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4x 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, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 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 (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radicals are substituted.

[0317] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4x 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, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 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, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-6) Haloalkyl and -C(O)N(R N1 )(R N2 ) group substitution.

[0318] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4x Each occurrence is independently halo, -OH, -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, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) 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, -C (1-3) Alkyl C (3-10) Cycloalkyl and 3 to 8 membered heterocyclic groups 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, -OC (1-6) Haloalkyl and -C(O)N(R N1 )(R N2 ) group substitution.

[0319] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 Yes-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(O)-(3- to 10-membered heterocyclyl), -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 4a The -C (3-10) The cycloalkyl group is optionally substituted with one to five R 4b The 3- to 10-membered heterocyclic group is optionally substituted by one to five R 4c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 4d The -C(O)-(3- to 10-membered heterocyclic group) is optionally substituted by one to five R 4e The -C (6-10) The aryl group is optionally substituted by one to five R 4f and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 4g Group substitution.

[0320] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 Yes-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 4a The -C (3-10) The cycloalkyl group is optionally substituted with one to five R 4b The 3- to 10-membered heterocyclic group is optionally substituted by one to five R 4c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 4d and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 4g Group substitution.

[0321] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is optionally replaced by one to five R 3a -C (1-6) alkyl.

[0322] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-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, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (6-10) aryl or 5 to 10 membered heteroaryl, wherein the -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 (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 (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radicals are substituted.

[0323] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-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, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4)alkyl or a 3- to 8-membered heterocyclic group, wherein the -C (1-6) Haloalkyl, -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 and -OC (1-4) Alkyl radicals are substituted.

[0324] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) alkyl or a 3- to 8-membered heterocyclic group, wherein the -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) The haloalkyl 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 and -OC (1-4) Alkyl radicals are substituted.

[0325] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4a Each occurrence is independently halo, -OH, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4)alkyl or a 3- to 8-membered heterocyclic group, wherein the -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) The haloalkyl and 3- to 8-membered heterocyclyl are optionally further substituted with one to five groups selected from halo and -OH.

[0326] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0327]

[0328] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is optionally replaced by one to five R 4b -C (3-10) Cycloalkyl.

[0329] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl or spiro[3.3]heptyl, each of which is optionally substituted by one to three R 4b Group substitution.

[0330] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4b 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(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 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, 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 (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radicals are substituted.

[0331] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4b 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(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) 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 heterocyclyl and 5 to 10 membered heteroaryl are optionally further substituted by one to five groups selected from halo, -OH, -N(R N1 )(RN2 )、-CN、-C (1-4) Alkyl and -OC (1-4) Alkyl radicals are substituted.

[0332] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4b 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, 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 groups.

[0333] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4b Each occurrence is independently halo, -OH, -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -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 and -OH.

[0334] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4b Each occurrence is independently halo, -OH, -CN, -C (1-6) Alkyl or -OC (1-6) Alkyl, wherein the -C (1-6) The alkyl group is optionally further substituted with one -OH group.

[0335] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0336]

[0337] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is optionally replaced by one to five R 4c A 3- to 10-membered heterocyclic group substituted by a group.

[0338] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, pyrrolidin-2-onyl, piperidin-2-onyl, morpholinyl or piperazinyl, each of which is optionally substituted by one to three R 4c Group substitution.

[0339] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4c 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(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 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, 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(1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radicals are substituted.

[0340] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4c 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(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) 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 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 )、-CN、-C (1-4) Alkyl and -OC (1-4) Alkyl radicals are substituted.

[0341] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4c 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) 2 C (1-4) 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) 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 and -OC (1-4) Alkyl radicals are substituted.

[0342] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4c Each occurrence is independently -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) 2 C (1-4) 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) 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 and -C (1-4) Alkyl radicals are substituted.

[0343] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4c Each occurrence is independently -C (1-6) Alkyl, -C(O)C (1-4) Alkyl, -S(O) 2 C (1-4) alkyl, 3 to 8 membered heterocyclyl or 5 to 10 membered heteroaryl, wherein the -C (1-6) 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 and -C (1-4) Alkyl radicals are substituted.

[0344] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0345]

[0346] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is optionally replaced by one to five R 4d In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is optionally replaced by one to five R 4d A 5- to 12-membered bicyclic ring system containing one or more heteroatoms which is substituted by a radical.

[0347] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 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 4d In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is optionally replaced by one to five R 4d 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 3,5-fused ring system, a 5,6-fused ring system or a 6,6-fused ring system.

[0348] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 yes

[0349]

[0350] They are each optionally replaced by one to three R 4d Group substitution.

[0351] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4d 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(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 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, 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 (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radicals are substituted.

[0352] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4d 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(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C(1-4) Alkyl, -N(H)S(O) 2 C (1-4) 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 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 )、-CN、-C (1-4) Alkyl and -OC (1-4) Alkyl radicals are substituted.

[0353] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4d 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) 2 C (1-4) 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) 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 and -OC (1-4) Alkyl radicals are substituted.

[0354] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4d Each occurrence is independently -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) 2 C (1-4) 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) 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 and -C (1-4) Alkyl radicals are substituted.

[0355] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4d Each occurrence is independently -C (1-6) Alkyl, -OC (1-6) Alkyl or -C(O)C (1-4) Alkyl, 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 -OH.

[0356] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 yes

[0357]

[0358] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is optionally replaced by one to five R 4e In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is optionally replaced by one to three -C (1-4) -C(O)-(3- to 10-membered heterocyclyl) substituted with an alkyl group.

[0359] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4e 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(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 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, 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 (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radicals are substituted.

[0360] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4e 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(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2)、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) 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 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 )、-CN、-C (1-4) Alkyl and -OC (1-4) Alkyl radicals are substituted.

[0361] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4e 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.

[0362] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4e Each occurrence is independently -C (1-4) Alkyl group.

[0363] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 yes

[0364] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is optionally replaced by one to five R 4f -C (6-10) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is optionally replaced by one to five R 4f In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is optionally replaced by one to three R 4fA phenyl group substituted with a group.

[0365] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4f 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, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 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 (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radicals are substituted.

[0366] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4f 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(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl or -N(H)S(O) 2 C (1-4) Alkyl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl and -OC (3-8) The cycloalkyl 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 (1-6) The haloalkyl group is substituted.

[0367] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4f Each occurrence is independently halo, -OH, -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 or -C(O)N(R N1 )(R N2 ), where -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6)Haloalkyl and -OC (3-8) The cycloalkyl group is optionally further substituted with one to five groups selected from halo and -OH.

[0368] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4f Each occurrence is independently halo, -C (1-6) Alkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (3-8) Cycloalkyl or -C(O)N(R N1 )(R N2 ).

[0369] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0370]

[0371] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is optionally replaced by one to five R 4g In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is a 5- to 6-membered monocyclic heteroaryl or a 9- to 10-membered bicyclic heteroaryl, each of which is optionally substituted by one to three R 4g In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 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 4g Group substitution.

[0372] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridin-2-one, pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, benzimidazolyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyridinyl or pyrazolopyrimidinyl, each of which is optionally substituted by one to three R 4g In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is pyrazolyl, imidazolyl, oxazolyl, pyridinyl or pyrazolopyridinyl, each of which is optionally substituted by one to three R 4gIn some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is pyrazolyl or pyrazolopyridinyl, each of which is optionally substituted by one to three R 4g In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is optionally replaced by one to three R 4g In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is optionally replaced by one to three R 4g A pyrazolopyridinyl group substituted with a group.

[0373] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 yes

[0374]

[0375]

[0376] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 yes

[0377]

[0378] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 yes

[0379]

[0380] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0381]

[0382] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4g 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, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 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 (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radicals are substituted.

[0383] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4g 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, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl, -N(H)S(O) 2 C (1-4) Alkyl, 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, -OC (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O) 2 C (1-4) Alkyl and -N(H)S(O) 2 C (1-4) Alkyl radicals are substituted.

[0384] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4g Each occurrence is independently halo, -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)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, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-6) Haloalkyl and -C(O)N(R N1 )(R N2 ) group substitution.

[0385] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4g Each occurrence is independently halo, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl or 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) The cycloalkyl and 3 to 8 membered heterocyclyl are optionally further substituted with one to five groups selected from halo and -OH.

[0386] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4g Each occurrence is independently -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl or -OC (1-6) haloalkyl, each of which is optionally further substituted with one to five groups selected from halo and -OH. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R4g Each occurrence is independently -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl or -OC (1-6) haloalkyl, each of which is optionally further substituted with one to five groups selected from halo and -OH. 4g Each occurrence is independently -C (1-6) Alkyl or -OC (1-6) Alkyl groups, each of which is optionally further substituted with one to three groups selected from halo and -OH.

[0387] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4g Each occurrence independently is:

[0388]

[0389] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4g Each occurrence independently is:

[0390]

[0391] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4g Each occurrence independently is:

[0392]

[0393] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4g Each occurrence independently is:

[0394]

[0395] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4g Each occurrence independently is:

[0396]

[0397] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4g Each occurrence independently is:

[0398]

[0399]

[0400]

[0401] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4g Each occurrence independently is:

[0402]

[0403]

[0404]

[0405] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4g Each occurrence independently is:

[0406]

[0407]

[0408]

[0409] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4g Each occurrence independently is:

[0410]

[0411]

[0412] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4g Each occurrence independently is:

[0413]

[0414]

[0415] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4g Each occurrence independently is:

[0416]

[0417] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R N1 and R N2Each occurrence is independently H or -C (1-3) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R N1 and R N2 Each is hydrogen.

[0418] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ie-1:

[0419]

[0420] A is pyrazolyl or thiazolyl;

[0421] Y is N, CH or CF;

[0422] Z is N, CH or CF;

[0423] L does not exist or is -C (1-4) Alkylene;

[0424] R 4 is optionally replaced by one to five R 4g substituted 5- to 10-membered heteroaryl;

[0425] Each R 4g Each occurrence is independently -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl or -OC (1-6) haloalkyl, each of which is optionally further substituted with one to five groups selected from halo and -OH;

[0426] The prerequisite is that at least one of Y and Z is CH.

[0427] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, the compound having a structure as shown in any one of Tables 1A to 1M.

[0428] Table 1A

[0429]

[0430]

[0431]

[0432] Table 1B

[0433]

[0434]

[0435]

[0436] Table 1C

[0437]

[0438]

[0439]

[0440] Table 1D

[0441]

[0442]

[0443]

[0444] Table 1E

[0445]

[0446]

[0447]

[0448] Table 1F

[0449]

[0450]

[0451]

[0452] Table 1G

[0453]

[0454]

[0455]

[0456] Table 1H

[0457]

[0458]

[0459]

[0460] Table II

[0461]

[0462]

[0463]

[0464]

[0465] Table 1J

[0466]

[0467]

[0468]

[0469] Table 1K

[0470]

[0471]

[0472]

[0473] Table 1L

[0474]

[0475]

[0476] Table 1M

[0477]

[0478] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, the compound having a structure as shown in any one of Tables 2A to 2M.

[0479] Table 2A

[0480]

[0481]

[0482]

[0483]

[0484] Table 2B

[0485]

[0486]

[0487]

[0488] Table 2C

[0489]

[0490]

[0491]

[0492]

[0493] Table 2D

[0494]

[0495]

[0496]

[0497] Table 2E

[0498]

[0499]

[0500]

[0501] Table 2F

[0502]

[0503]

[0504]

[0505]

[0506] Table 2G

[0507]

[0508]

[0509]

[0510]

[0511] Table 2H

[0512]

[0513]

[0514]

[0515] Table 2I

[0516]

[0517]

[0518]

[0519] Table 2J

[0520]

[0521]

[0522]

[0523] Table 2K

[0524]

[0525]

[0526]

[0527]

[0528] Table 2L

[0529]

[0530]

[0531] Table 2M

[0532]

[0533] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof selected from the group consisting of:

[0534]

[0535]

[0536] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof selected from the group consisting of:

[0537]

[0538]

[0539] In some embodiments, disclosed herein are compounds of Formula I having the following formula:

[0540]

[0541] or a pharmaceutically acceptable salt thereof.

[0542] In some embodiments, disclosed herein are compounds of Formula I having the following formula:

[0543]

[0544] or a pharmaceutically acceptable salt thereof.

[0545] In some embodiments, disclosed herein are compounds of Formula I having the following formula:

[0546]

[0547] or a pharmaceutically acceptable salt thereof.

[0548] In some embodiments, disclosed herein are compounds of Formula I having the following formula:

[0549]

[0550] or a pharmaceutically acceptable salt thereof.

[0551] In some embodiments, disclosed herein are compounds of Formula I having the following formula:

[0552]

[0553] or a pharmaceutically acceptable salt thereof.

[0554] In some embodiments, disclosed herein are compounds of Formula I having the following formula:

[0555]

[0556] or a pharmaceutically acceptable salt thereof.

[0557] In some embodiments, disclosed herein are compounds of Formula I having the following formula:

[0558]

[0559] or a pharmaceutically acceptable salt thereof.

[0560] In some embodiments, disclosed herein are compounds of Formula I having the following formula:

[0561]

[0562] or a pharmaceutically acceptable salt thereof.

[0563] In some embodiments, disclosed herein are compounds of Formula I having the following formula:

[0564]

[0565] or a pharmaceutically acceptable salt thereof.

[0566] In some embodiments, disclosed herein are compounds of Formula I having the following formula:

[0567]

[0568] or a pharmaceutically acceptable salt thereof.

[0569] In some embodiments, disclosed herein are compounds of Formula I having the following formula:

[0570]

[0571] or a pharmaceutically acceptable salt thereof.

[0572] In some embodiments, disclosed herein are compounds of Formula I having the following formula:

[0573]

[0574] or a pharmaceutically acceptable salt thereof.

[0575] In some embodiments, disclosed herein are compounds of Formula I having the following formula:

[0576]

[0577] or a pharmaceutically acceptable salt thereof.

[0578] In some embodiments, disclosed herein are compounds of Formula I having the following formula:

[0579]

[0580] or a pharmaceutically acceptable salt thereof.

[0581] In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0582] Therapeutic Uses

[0583] 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.

[0584] 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.

[0585] The present disclosure also relates to a method for ameliorating or modifying the symptoms of a disease, disorder or medical condition mediated by NIK activity, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0586] In some embodiments of the therapeutic methods disclosed herein, the disease, disorder, or medical condition is selected from the group consisting of an inflammatory disorder and an autoimmune disorder.

[0587] 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.

[0588] 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.

[0589] In some embodiments of the methods of treatment disclosed herein, the disease, disorder or medical condition is an autoantibody-related disease. In some embodiments, the autoantibody-related 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").

[0590] 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.

[0591] 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, non-alcoholic steatohepatitis ("NASH"), and primary biliary cirrhosis.

[0592] 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.

[0593] 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.

[0594] 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.

[0595] In some embodiments of the treatment methods disclosed herein, the disease, disorder, or medical condition is osteoporosis.

[0596] In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is selected from the group consisting of RA, IBD, SLE, IgAN, metabolic syndrome, multiple sclerosis, immune thrombocytopenic purpura, primary biliary cirrhosis, transplantation, myasthenia gravis, osteoporosis, and bone resorption (periodontitis).

[0597] 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.

[0598] In some embodiments, disclosed herein is a method for preventing or controlling an excessive inflammatory response, 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.

[0599] In some embodiments of the methods disclosed herein, the subject is a human subject.

[0600] The present disclosure also provides a method for modulating NIK activity, the method comprising exposing NIK to an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0601] 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.

[0602] Dosage and Administration

[0603] In the methods disclosed herein, an effective amount of at least one compound according to the present disclosure is administered to a subject suffering from or diagnosed with such a disease, disorder or medical condition. An "effective amount" means an amount or dosage sufficient to produce a desired therapeutic or preventive beneficial effect in a patient who needs such treatment for a specified disease, disorder or medical condition as a whole. For a 70 kg person, an exemplary range of dosage is about 1 mg / day to 1000 mg / day in a single dose unit or multiple dose units.

[0604] 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

[0605] The dosage administered will be influenced by factors such as, but not limited to, the route of administration, the health, weight, and age of the recipient, the frequency of treatment, and the presence of concurrent and unrelated treatments.

[0606] It will also be apparent to those skilled in the art that the therapeutically effective dose of the compounds of the present disclosure or their pharmaceutical compositions will vary depending on the desired effect. Therefore, the optimal dose to be administered can be easily determined by those skilled in the art, and the optimal dose will vary with the specific compound used, the mode of administration, the strength of the formulation, and the progression of the disease condition. In addition, factors associated with the specific subject being treated, including the subject's 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 situations. Of course, there may be individual cases where a higher or lower dosage range should be used, and such cases are also within the scope of the present disclosure.

[0607] Once the patient's disease, disorder or condition improves, the dosage can be adjusted to preventive 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 preventive effect, depending on the symptoms. Of course, if the symptoms have been alleviated to an appropriate level, treatment can be stopped. However, the patient may require long-term intermittent treatment due to any recurrence of symptoms.

[0608] 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 nontoxic, biologically tolerable and in other words biologically suitable for application to a subject, such as inert substances, which are added to the pharmaceutical composition or in other words used as vehicles or diluents to facilitate the application of the agent 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 be used as formulation components include fillers, binders, disintegrants, and lubricants.

[0609] The delivery form of the pharmaceutical composition 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 methods of the present invention by a suitable delivery route, such as by oral, parenteral, rectal, topical or ocular routes, or by inhalation.

[0610] The preparations may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations or suppositories. These compositions may be formulated for any of a variety of routes of administration, such as but not limited to intravenous infusion, subcutaneous injection, topical administration or oral administration.

[0611] 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 dose unit or multiple dose units for a 70 kg person as an exemplary range.

[0612] Oral tablets may include compounds of the present disclosure mixed with compatible pharmaceutically acceptable excipients such as but not limited to diluents, disintegrants, binders, lubricants, sweeteners, flavoring agents, 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 may include starch and gelatin. Lubricants (when present) may be magnesium stearate, stearic acid or talc. If desired, tablets may be coated with materials such as but not limited to glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with enteric coatings. Available additional coatings include coatings designed to release compounds or active agents according to time, pH or bacterial content.

[0613] Capsules for oral administration include hard gelatin capsules and soft gelatin capsules or (hydroxypropyl) methylcellulose capsules. To prepare hard gelatin capsules, one or more active ingredients can be mixed with solid, semisolid or liquid diluents. Soft gelatin capsules can be prepared by mixing the active ingredient with the following substances: oils such as but not limited to peanut oil or olive oil, liquid paraffin, a mixture of monoglycerides and diglycerides of short-chain fatty acids, polyethylene glycol 400 or propylene glycol. The liquid for oral administration can be in the form of a suspension, solution, emulsion or syrup, 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 but not limited to 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., methyl or propyl paraben or sorbic acid); wetting agents, such as but not limited to lecithin; and, if desired, flavoring or coloring agents.

[0614] The compounds of the present disclosure may also be administered by non-oral routes. For example, the composition may be formulated into suppositories, enemas or foams for rectal administration. For parenteral use, including intravenous routes, intramuscular routes, intraperitoneal routes or subcutaneous routes, the compounds of the present disclosure may be provided in the form of sterile aqueous solutions or suspensions, which are buffered to appropriate pH and isotonicity or in parenterally acceptable oils. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit dosage forms (such as, but not limited to, ampoules or disposable injection devices), in multiple dose forms (such as vials) from which appropriate doses may be drawn, or in solid forms or pre-concentrates that may 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 for a period of several minutes to several days.

[0615] 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.

[0616] The compounds of the present disclosure may alternatively be administered in the methods of the present disclosure via the nasal or oral routes by inhalation, for example, in the form of a spray formulation also containing a suitable carrier.

[0617] 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, granted patents, or other cited references are incorporated by reference in their entirety.

[0618] Example

[0619] The following specific examples are provided to further illustrate embodiments within the scope of the present disclosure.

[0620] abbreviation

[0621] Herein and throughout this application, the following abbreviations may be used.

[0622]

[0623]

[0624]

[0625] 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.

[0626] By way of illustration and not limitation, the compounds of the present disclosure are prepared according to the following general preparation procedures given in schemes 1-5. It will be appreciated by those of ordinary skill in the art that, in order to obtain the various compounds herein, the raw materials may be appropriately selected so that, under protection or unprotection as required, the final desired substituents will be carried throughout the reaction scheme to obtain the desired product. Alternatively, the appropriate group replacing the final desired substituent may be subjected to the entire reaction scheme and replaced with the desired substituent where appropriate. Unless otherwise indicated, the variables in schemes 1-5 are all as defined above for formula I.

[0627] Solution 1

[0628]

[0629] 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 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 1 is a stannyl group and B in compound XII 2 When is a halogen, coupling under Stille conditions also yields compounds of Formula I. Typical Stille coupling conditions involve the use of a catalyst (usually palladium, but sometimes nickel), a suitable solvent, and other optional reagents including ligands, TEA or CuI. Examples of suitable catalysts include, but are not limited to, Pd(PPh 3 ) 4 、Pd(dppf)Cl 2 and Pd 2 (dba) 3 Suitable solvents include, but are not limited to, toluene, 1,4-dioxane, DMF, or mixtures thereof. The reaction may be heated to a temperature of about 80°C to about 130°C for a period of about 1 to 16 hours using microwave or conventional heating to provide a compound of Formula I.

[0630] Alternatively, when B 1 is a halogen such as but not limited to Cl, Br or I and when B 2When B is a boron-based coupling agent such as, but not limited to, boronic acid or a boronate ester, Suzuki coupling conditions can be used to couple compound XI to compound XII. Those skilled in the art will recognize that when B 1 is a boron-based coupling agent and when B 2 When is a halogen, coupling under Suzuki conditions also yields compounds of Formula I. Typical Suzuki coupling conditions involve the use of a palladium catalyst, a base, a suitable solvent, and other optional reagents, including a ligand (e.g., tricyclohexylphosphine). Examples of suitable palladium catalysts include, but are not limited to, Pd(dppf)Cl 2 , BrettPhos-Pd-G3 and Pd 2 (dba) 3 Suitable bases include, but are not limited to, K 2 CO 3 , Cs 2 CO 3 , KOAc and combinations thereof. Suitable solvents include, but are not limited to, 1,4-dioxane, 2-methyl-2-butanol, water or mixtures thereof. The reaction may be heated to a temperature of about 80°C to about 120°C for a period of about 0.5 to 16 hours using microwave or conventional heating to obtain a compound of Formula I.

[0631] Solution 2

[0632]

[0633] 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, but not limited to, TFA, TsOH or HCl in a solvent such as, but not limited to, isopropanol, DMSO, DMF or 1,4-dioxane. The reaction can be heated to a temperature of about 100° C. to about 160° C. for a period of about 1 to 16 hours using microwave or conventional heating to obtain a compound of Formula I.

[0634] Alternatively, compounds XIII and XIV may be combined with a suitable base such as, but not limited to, NaHMDS or DIPEA in a solvent such as, but not limited to, DMA or THF. The reaction mixture may be heated to a temperature of about 120° C. to about 160° C. for a period of about 1.5 to 3.5 hours using microwave or conventional heating to obtain a compound of Formula I. Alternatively, the reaction mixture may be cooled to about −72° C. for about 1 hour to obtain a compound of Formula I.

[0635] Solution 3

[0636]

[0637] The compounds of Formula I of the present disclosure can be prepared, for example, as shown in Scheme 3. Compounds XV and XIV can be mixed with a suitable acid such as, but not limited to, TFA, TsOH or HCl in a solvent such as, but not limited to, isopropanol, DMSO, DMF or 1,4-dioxane. The reaction can be heated to a temperature of about 100° C. to about 160° C. for a period of about 1 to 16 hours using microwave or conventional heating to obtain a compound of Formula I.

[0638] Alternatively, compounds XV and XIV can be combined with a suitable base such as, but not limited to, DIEA in a solvent such as, but not limited to, isopropanol, DMA or THF. The reaction mixture can be heated to a temperature of about 120° C. to about 160° C. for a period of about 1.5 to 3.5 hours using microwave or conventional heating to obtain a compound of Formula I.

[0639] Solution 4

[0640]

[0641] The compounds of Formula I of the present disclosure can be prepared, for example, as shown in Scheme 4. 3 When is a halogen (e.g., Cl, Br, or I), 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, but sometimes other metals; for example, Pd(OAc) 2 ), bases (e.g., Cs 2 CO 3 ) and a suitable solvent (e.g., 1,4-dioxane). A phosphate ligand may also be included, such as, but not limited to, Xantphos. The reaction may be heated to a temperature of about 90° C. to about 120° C. for a period of about 1 to 12 hours to obtain a compound of Formula I.

[0642] Solution 5

[0643]

[0644] The compounds of formula XIX disclosed herein can be prepared, for example, as shown in Scheme 5, wherein B 4 is a halogenated group, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl and -OC (1-4) haloalkyl, and wherein B 5 Compounds XVII and XVIII can be reacted with a suitable base (e.g., Cs 2 CO 3) are combined in a suitable solvent (eg, DMF). The reaction can be heated to a temperature of about 100° C. to about 120° C. for a period of about 0.5 to 2 hours to obtain a compound of Formula I.

[0645] In obtaining the compounds and corresponding analytical data described in the Examples below, the following experimental and analytical protocols were followed unless otherwise indicated.

[0646] Unless otherwise specified, the reaction solutions were kept at room temperature and N 2(g) or Ar (g) When solutions are "concentrated to dryness", they are concentrated under reduced pressure using a rotary evaporator. When solutions are dried, they are typically dried over a desiccant such as, but not limited to, MgSO 4 Or Na 2 SO 4 Unless otherwise specified, normal phase flash column chromatography (FCC) was performed using ethyl acetate (EtOAc) / hexane, CH 2 Cl 2 / MeOH or CH 2 Cl 2 / 10% 2N NH 3 MeOH solution as the eluent, using a pre-packed silica gel column such as but not limited to Performed on silica gel.

[0647] 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 specified, in the case of using reversed-phase HPLC to purify the compounds described in one of the following examples, the solvent used is an acetonitrile aqueous solution with a gradient of 10% to 80%. When purified in "acidic conditions" or "acidic medium", acetonitrile and water both contain 0.16% TFA. When carried out in "alkaline conditions" or "alkaline medium", the pH of acetonitrile and water has been adjusted to pH 10 with ammonium hydroxide. The following column abbreviations are also used throughout the examples:

[0648]

[0649]

[0650]

[0651] Thin layer chromatography uses silica gel plates, such as but not limited to Merck silica gel 60F 2542.5 cm × 7.5 cm 250 mm or 5.0 cm × 10.0 cm 250 μm pre-coated silica gel plates. Preparative thin layer chromatography uses silica gel plates such as, but not limited to, EMScience 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 zone. The microwave reaction was carried out in a microwave reactor such as but not limited to a CEM Biotage Initiator TM or Optimizer TM The microwave was used at the specified temperature. Unless otherwise indicated, mass spectra were obtained on a mass spectrometer such as, but not limited to, 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, but not limited to, Bruker model DPX400 (400 MHz), DPX500 (500 MHz), DRX600 (600 MHz) spectrometers. The following 1 The format of H NMR data is as follows: chemical shift (ppm) downfield from a tetramethylsilane reference (multiplicity, coupling constant J (Hz), integration).

[0652] 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 reagents given in the form of a percentage refers to the mass ratio. Whether or not explicitly indicated, the yields given in the following examples are calculated relative to the dry form of the compound for which any such yield is given.

[0653] Chemical names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye).

[0654] Intermediate 1: N-(1-methyl-1H-pyrazol-3-yl)-4-(trimethylstannyl)pyrimidin-2-amine

[0655]

[0656] A mixture of 4-chloro-N-(1-methylpyrazol-3-yl)pyrimidin-2-amine (7.50 g, 35.8 mmol), 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 (2 M, 150 mL) and stirred for 1 hour. The mixture was then extracted with ethyl acetate, washed with brine, and washed with Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave N-(1-methyl-1H-pyrazol-3-yl)-4-(trimethylstannyl)pyrimidin-2-amine (15.3 g, about 38% purity, 48%) as a brown powder, which was used without further purification. MS (ESI + ):m / z=339.5.

[0657] Intermediate 2: (R)-3-(3-(4-bromooxazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0658]

[0659] (R)-3-hydroxy-1-methyl-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-2-one (250 mg, 0.788 mmol), 2,4-dibromooxazole (358 mg, 1.58 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (58 mg, 0.079 mmol), K 2 CO 3 (1.58 mL, 1 M H 2 A mixture of 1,4-dioxane (6 mL) and 1,4-dioxane (10 mL) was heated at 100 °C for 2 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic extract was washed with MgSO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by FCC (gradient 30% to 100% EtOAc in hexanes) to give (R)-3-(3-(4-bromooxazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (225 mg, 84) as a sticky white solid. 1 HNMR (600 MHz, DMSO-d 6)δ8.49(s,1H),8.02(dt,J=2.4,1.0Hz,1H),7.86(ddd,J=6.1,3.0,1.8Hz,1H),7.55-7.47(m,2H),6.21(s,1H),3.47(ddd,J=9.9,8.0 ,5.2Hz,1H),3.36(ddd,J=9.9,7.8,5.3Hz,1H),2.85(s,3H),2.34(ddd,J=13.2,7.9,5.3Hz,1H),2.26(ddd,J=13.3,8.0,5.2Hz,1H). MS(ESI + ):m / z=337.1.

[0660] Intermediate 3: (R)-3-(3-(1H-pyrazol-3-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0661]

[0662] Step A: K 2 CO 3 (7.8 mL, 1 M H 2 A mixture of 1,4-dioxane (40 mL) and N 2 The mixture was aerated for 15 minutes and then added to a mixture of (R)-3-hydroxy-1-methyl-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-2-one (1.00 g, 3.15 mmol), 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (947 mg, 4.10 mmol) and bis(triphenylphosphine)palladium(II) dichloride (143 mg, 0.205 mmol) to give a reaction mixture. The reaction mixture was heated to 100°C for 1 hour, cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic extract was purified by MgSO 4 The residue was purified by FCC (100% EtOAc) to give (R)-3-hydroxy-1-methyl-3-(3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)phenyl)pyrrolidin-2-one (517 mg, 48%) as a white powder. MS (ESI + ):m / z=342.2.

[0663] Step B: A mixture of (R)-3-hydroxy-1-methyl-3-(3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)phenyl)pyrrolidin-2-one (517 mg, 1.514 mmol), TFA (1 mL) and DCM (5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated, then diluted with DCM and washed with K2 CO 3 Solution (1M H 2 O solution). The organic layer was washed with MgSO 4 Drying, filtration and concentration gave (R)-3-(3-(1H-pyrazol-3-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (533 mg). MS (ESI + ):m / z=258.15.

[0664] Intermediate 4: 4-(4-bromothiazol-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine

[0665]

[0666] A mixture of 2,4-dibromothiazole (151 mg, 0.621 mmol), N-(1-methyl-1H-pyrazol-3-yl)-4-(trimethylstannyl)pyrimidin-2-amine (Intermediate 1, 140 mg, 0.414 mmol), tetrakis(triphenylphosphine)palladium(0) (48 mg, 0.041 mmol) and 1,4-dioxane (3.5 mL) was heated at 95 °C overnight and then at 110 °C for 5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with MgSO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by FCC (30% to 100% EtOAc in hexanes) to give 4-(4-bromothiazol-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine (20 mg, 14%). MS (ESI + ):m / z=338.0.

[0667] Intermediate 5: 4-(4-bromooxazol-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine

[0668]

[0669] A mixture of N-(1-methyl-1H-pyrazol-3-yl)-4-(trimethylstannyl)pyrimidin-2-amine (Intermediate 1, 150 mg, 0.444 mmol), 2,4-dibromooxazole (201 mg, 0.888 mmol), tetrakis(triphenylphosphine)palladium(0) (77 mg, 0.067 mmol) and DMF (2 mL) was heated in a microwave reactor at 130 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic extract was washed with MgSO 4 The residue was purified by FCC (30% to 100% EtOAc in hexanes) to give 4-(4-bromooxazol-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine (10 mg, 7%) as a yellow powder. MS (ESI+ ):m / z=321.0.

[0670] Intermediate 6: 4-bromo-2-(2-(methylthio)pyrimidin-4-yl)thiazole

[0671]

[0672] A mixture of 2,4-dibromothiazole (7.0 g, 29 mmol), 2-(methylthio)-4-(tributylstannyl)pyrimidine (10 g, 24 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 g, 1.2 mmol) and DMF (200 mL) was heated to 140 °C for 5 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and washed with brine. The organic extract was washed with MgSO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by FCC (20% to 90% EtOAc in hexanes) to give 4-bromo-2-(2-(methylthio)pyrimidin-4-yl)thiazole (2.9 g, 41%) as a white powder. 1 H NMR (500MHz, DMSO) δ8.82 (d, J = 5.1 Hz, 1H), 8.20 (s, 1H), 7.75 (d, J = 5.1 Hz, 1H), 2.59 (s, 3H). MS(ESI + ):m / z=287.9.

[0673] Intermediate 7: (R)-3-(3-(4-bromothiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0674]

[0675] (R)-3-hydroxy-1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (16.0 g, 50.4 mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (4.12 g, 5.04 mmol), 2,4-dibromothiazole (12.3 g, 50.4 mmol), K 3 PO 4 A mixture of 1,4-dioxane (32.1 g, 151 mmol), water (50 mL) and anhydrous 1,4-dioxane (200 mL) was heated at 100 °C for 16 hours and then cooled to room temperature. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine and purified by anhydrous Na 2 SO 4Dried, filtered and concentrated. The residue was purified by FCC (gradient 5:1 to 0:1 petroleum ether:ethyl acetate) to give (R)-3-(3-(4-bromothiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (10 g, 43%) as a brown solid. 1 H NMR (400 MHz, CDCl 3 )δ8.13-7.96(m,1H),7.90-7.80(m,1H),7.42(br s,2H),7.26-7.21(m,1H),3.68-3.35(m,3H),3.02(s,3H),2.61-2.36(m,2H). MS(ESI + ):m / z=353.0.

[0676] Intermediate 8: (R)-3-Hydroxy-1-methyl-3-(3-(4-(2-(methylthio)pyrimidin-4-yl)thiazol-2-yl)benzene 1-(2-YL)pyrrolidin-2-one

[0677]

[0678] (R)-3-(3-(4-bromothiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 7, 500 mg, 0.142 mmol), Pd(PPh 3 ) 4 A mixture of 4-(176 mg, 0.142 mmol), 2-(methylthio)-4-(tributylstannyl)pyrimidine (647 mg, 1.56 mmol), TEA (0.395 mL, 1.13 mmol) and anhydrous toluene (10 mL) was heated at 120 ° C for 16 hours and then cooled to room temperature. The resulting mixture was poured into KF aqueous solution (10 mL). The resulting suspension was filtered through a celite pad and the pad was washed with EtOAc (20 mL). The filtrate was further extracted with EtOAc (20 mL×3), and the combined organic extracts were washed with brine and purified by anhydrous Na 2 SO 4 The mixture was dried, filtered and concentrated. The residue was purified by FCC (silica, gradient 5:1-0:1 petroleum ether-ethyl acetate) to give (R)-3-hydroxy-1-methyl-3-(3-(4-(2-(methylthio)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one (397 mg, 57%) as a brown oil. MS (ESI + ):m / z=399.0.

[0679] Intermediate 9: (R)-3-hydroxy-1-methyl-3-(3-(2-(2-(methylsulfonyl)pyrimidin-4-yl)thiazol-4-yl) Phenyl)pyrrolidin-2-one

[0680]

[0681] Step A: 4-bromo-2-(2-(methylthio)pyrimidin-4-yl)thiazole (Intermediate 6, 645 mg, 2.24 mmol), (R)-3-hydroxy-1-methyl-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-2-one (854 mg, 2.69 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (82 mg, 0.11 mmol), K 2 CO 3 (5.6 mL, 1 M H 2 A mixture of 1,4-dioxane (10 mL) and 1,4-dioxane (50 mL) was heated to 80 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic extract was washed with MgSO 4 The residue was purified by FCC (50% to 100% EtOAc in hexanes) to give (R)-3-hydroxy-1-methyl-3-(3-(2-(2-(methylthio)pyrimidin-4-yl)thiazol-4-yl)phenyl)pyrrolidin-2-one (715 mg, 80%) as a white powder. 1 H NMR (500MHz, DMSO) δ8.83(d,J=5.1Hz,1H),8.44(s,1H),8.12-8.06(m,1H),7.99-7.91(m,1H),7.89(d,J=5.0Hz,1H),7.49-7.41(m,1H) ,7.40-7.32(m,1H),6.10(s,1H),3.52-3.43(m,1H),3.43-3.33(m,1H),2.87(s,3H),2.61(s,3H),2.44-2.34(m,1H),2.33-2.21(m,1H). MS(ESI + ):m / z=399.0.

[0682] Step B: A mixture of (R)-3-hydroxy-1-methyl-3-(3-(2-(2-(methylthio)pyrimidin-4-yl)thiazol-4-yl)phenyl)pyrrolidin-2-one (715 mg, 1.79 mmol), potassium permonosulfate (2.4 g, 3.9 mmol), acetone (5 mL), water (5 mL) and THF (5 mL) was stirred at room temperature overnight. The mixture was diluted with ice water (30 mL) and stirred for 10 minutes. The resulting suspension was filtered and the precipitate was collected and washed with water and then dried under reduced pressure. The solid was washed with water and then dried under high vacuum to give (R)-3-hydroxy-1-methyl-3-(3-(2-(2-(methylsulfonyl)pyrimidin-4-yl)thiazol-4-yl)phenyl)pyrrolidin-2-one (642 mg, 83%) as a white solid. This material contained about 20% (R)-3-hydroxy-1-methyl-3-(3-(2-(2-(methylsulfinyl)pyrimidin-4-yl)thiazol-4-yl)phenyl)pyrrolidin-2-one. 1 HNMR (400 MHz, DMSO-d 6 )δ9.24(d,J=5.2Hz,1H),8.57(s,1H),8.46(d,J=5.1Hz,1H),8.12(q,J=2.0Hz,1H),8.08-7.92(m,1H),7.55-7.44(m,1H),7.44 -7.32(m,1H),6.12(d,J=1.0Hz,1H),3.56-3.44(m,4H),3.44-3.36(m,1H),2.87(s,4H),2.49-2.34(m,1H),2.33-2.20(m,1H). MS(ESI + ):m / z=432.0.

[0683] Intermediate 10: 4-bromo-2-(2-(methylsulfonyl)pyrimidin-4-yl)thiazole

[0684]

[0685] A mixture of 4-bromo-2-(2-(methylthio)pyrimidin-4-yl)thiazole (Intermediate 6, 500 mg, 1.74 mmol), potassium permonosulfate (2.35 g, 3.82 mmol), acetone (3.6 mL), water (3.6 mL) and MeOH (3.6 mL) was stirred at room temperature overnight. Potassium permonosulfate (2.35 g, 3.82 mmol) was added and the mixture was stirred at room temperature for another 24 hours. The reaction mixture was diluted with 20 mL of water and the resulting precipitate was collected by filtration, washed with water and dried under reduced pressure. The obtained solid was resuspended in water (20 mL) and stirred vigorously for 5 minutes. The resulting precipitate was collected by filtration, washed with water and dried under reduced pressure to give 4-bromo-2-(2-(methylsulfonyl)pyrimidin-4-yl)thiazole (383 mg, 69%) as a white powder. 1 H NMR (500 MHz, DMSO-d 6 )δ9.24(d,J=5.2Hz,1H),8.34(d,J=5.2Hz,1H),8.32(s,1H),3.49(s,3H). MS(ESI + ):m / z=320.1.

[0686] Intermediate 11: 4-(4-bromothiazol-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

[0687]

[0688] A mixture of 4-bromo-2-(2-(methylsulfonyl)pyrimidin-4-yl)thiazole (Intermediate 10, 150 mg, 0.468 mmol), 4-amino-1-methylpyrazole (91 mg, 0.94 mmol), TFA (0.090 mL, 1.2 mmol) and DMSO (0.75 mL) was heated to 150 °C in a microwave reactor for 1 hour. The reaction mixture was cooled to room temperature and then poured into K 2 CO 3 (0.5M H 2 The precipitate was collected by filtration, washed with water and dried under reduced pressure to give 4-(4-bromothiazol-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (111 mg, 70%) as a greenish yellow powder. 1 H NMR (500 MHz, DMSO-d 6 )δ9.81(s,1H),8.62(d,J=4.9Hz,1H),8.14(s,1H),7.90(s,1H),7.59(s,1H),7.31(d,J=4.9Hz,1H),3.84(s,3H). MS(ESI + ):m / z=336.9.

[0689] Intermediate 12: (R)-3-hydroxy-1-methyl-3-(3-(4-(2-(methylsulfonyl)pyrimidin-4-yl)thiazole-2- 1-(4-(4-(2-yl)phenyl)pyrrolidin-2-one

[0690]

[0691] A mixture of potassium permonosulfate (3.95 g, 6.43 mmol) in water (10 mL) was added to a mixture of (R)-3-hydroxy-1-methyl-3-(3-(4-(2-(methylthio)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one (intermediate 8, 1.28 g, 3.21 mmol) in THF (10 mL) and acetone (10 mL). The resulting mixture was stirred at room temperature for 16 hours, then EtOAc (30 mL) and water (25 mL) were added, and the mixture was stirred for 30 minutes. The precipitate was collected by filtration and rinsed with ethyl acetate (30 mL) to give (R)-3-hydroxy-1-methyl-3-(3-(4-(2-(methylsulfonyl)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one (1.10 g, 80% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ9.18(d,J=5.1Hz,1H),8.88(s,1H),8.39(d,J=5.1Hz,1H),8.14(t,J=1.6Hz,1H),8.01-7.97(m,1H),7.57-7.51(m,1H),7.50- 7.46(m,1H),6.27(s,1H),3.53(s,3H),3.51-3.46(m,1H),3.43-3.41(m,1H),2.87(s,3H),2.43-2.35(m,1H),2.34-2.25(m,1H). MS(ESI + ):m / z=453.0.

[0692] Intermediate 13: (R)-3-hydroxy-1-methyl-3-(3-(1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazole- 3-yl)phenyl)pyrrolidin-2-one

[0693]

[0694] A mixture of intermediate 21 (95.3 mg, 0.25 mmol), potassium permonosulfate (460.764 mg, 0.749 mmol), acetone (0.524 mL, 0.79 g / mL, 7.124 mmol), distilled water (0.524 mL, 29.071 mmol) and MeOH (0.524 mL, 0.791 g / mL, 12.929 mmol) was stirred at room temperature overnight. LCMS showed complete conversion of the starting material to the desired product. The reaction mixture was diluted with 50 mL of water and stirred for 5 minutes. The precipitate was collected by vacuum filtration and dried to give (R)-3-hydroxy-1-methyl-3-(3-(1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazol-3-yl)phenyl)pyrrolidin-2-one (38.8 mg, 38%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6 )δ9.16-9.09(m,1H),8.95-8.88(m,1H),8.27-8.20(m,1H),8.09-8.03(m,1H),7.95-7.89(m,1H),7.52-7.46(m,1H),7.45 -7.39(m,1H),7.33-7.27(m,1H),6.15-6.10(m,1H),3.54(s,3H),3.51-3.45(m,1H),3.45-3.37(m,2H),2.34-2.24(m,2H). MS(ESI + ):m / z=414.2.

[0695] Intermediate 14: 4-(4-bromothiazol-2-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine

[0696]

[0697] A mixture of 4-bromo-2-(2-(methylsulfonyl)pyrimidin-4-yl)thiazole (Intermediate 10, 500 mg, 1.562 mmol), 1-methyl-1h-pyrazol-5-amine (170.2 mg, 1.718 mmol), sodium bis(trimethylsilyl)amide (3.123 mL, 1 M, 3.123 mmol) and THF (10 mL) was heated at 50 °C under nitrogen for 1 hour. The mixture was cooled to room temperature, diluted with aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with MgSO 4 Drying, filtration and concentration gave a red solid, 4-(4-bromothiazol-2-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (350.5 mg, 67%). 1 H NMR (500 MHz, DMSO-d6 )δ9.76(s,1H),8.65(d,J=5.0Hz,1H),8.10(d,J=2.4Hz,1H),7.45(d,J=5.0Hz,1H),7.37(d,J=1.9Hz,1H),6.29(d,J=2.0Hz,1H),3.70(s,3H). MS(ESI + ):m / z=337.

[0698] Intermediate 15: 4-(3-bromo-1H-pyrazol-1-yl)-N-(3-cyclopropyloxy-1-(2,2-difluoroethyl)-1H-pyrazol-1-yl)- oxazol-4-yl)pyrimidin-2-amine

[0699]

[0700] To a 2-dram vial, 4-(3-bromo-1H-pyrazol-1-yl)-2-chloropyrimidine (Intermediate 18, 100 mg, 0.385 mmol), pyrazolo[1,5-a]pyridin-3-amine (66.707 mg, 0.501 mmol), TFA (0.0737 mL, 1.49 g / mL, 0.963 mmol), DMSO (1.2 mL, 1.092 g / mL, 16.771 mmol) were added under nitrogen to react at 150 °C in a microwave reactor for 1 hour. The mixture was washed with 100 mL of 1M K 2 CO 3 The aqueous solution was diluted and extracted with 3×100 mL EtOAc. The organic extracts were washed with MgSO 4 Dry, filter and concentrate. The product was then purified by FCC (12 g silica, 0-100% ethyl acetate in hexanes) to give 4-(3-bromo-1H-pyrazol-1-yl)-N-(3-cyclopropyloxy-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrimidin-2-amine (36.5 mg, 22%). 1 H NMR (400 MHz, DMSO-d 6 )δ8.83(s,1H),8.48(d,J=2.4Hz,1H),8.47(s,1H),7.90(s,1H),7.09(d,J=5.4Hz,1H),6.81(d,J=2.7Hz ,1H),6.47-6.15(m,2H),4.56-4.42(m,2H),4.13-4.05(m,1H),0.67(q,J=2.8Hz,2H),0.66-0.61(m,2H). MS(ESI + ):m / z=427.

[0701] Intermediate 16: N-(4-(3-bromo-1H-pyrazol-1-yl)pyrimidin-2-yl)pyrazolo[1,5-a]pyridin-3-amine

[0702]

[0703] To a 2 dram vial, 4-(3-bromo-1H-pyrazol-1-yl)-2-chloropyrimidine (Intermediate 18, 100 mg, 0.385 mmol), pyrazolo[1,5-a]pyridin-3-amine (113.396 mg, 0.852 mmol), TFA (0.0737 mL, 1.49 g / mL, 0.963 mmol) and DMSO (0.827 mL, 1.092 g / mL, 11.561 mmol) were added and stirred at 150 °C under nitrogen for 1 hour. The mixture was washed with 50 mL of 1 M K 2 CO 3 Dilute and extract with 3×50 mL EtOAc. The organic extracts were washed with MgSO 4 Dried, filtered and concentrated.The product was then purified by FCC (0-100% EtOAc in hexanes) to give N-(4-(3-bromo-1H-pyrazol-1-yl)pyrimidin-2-yl)pyrazolo[1,5-a]pyridin-3-amine (55.1 mg, 40%). 1 H NMR (400 MHz, DMSO-d 6 )δ8.83(s,1H),8.48(d,J=2.4Hz,1H),8.47(s,1H),7.90(s,1H),7.09(d,J=5.4Hz,1H),6.81(d,J=2.7Hz ,1H),6.47-6.15(m,2H),4.56-4.42(m,2H),4.13-4.05(m,1H),0.67(q,J=2.8Hz,2H),0.66-0.61(m,2H). MS(ESI + ):m / z=357.

[0704] Intermediate 17: 4-(3-Bromo-1H-pyrazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine

[0705]

[0706] 3-Bromopyrazole (40 mg, 0.272 mmol), 4-chloro-N-(1-methylpyrazol-3-yl)pyrimidin-2-amine (68.465 mg, 0.327 mmol), aqueous potassium carbonate solution (0.544 mL, 1 M, 0.544 mmol) and DMF (1.406 mL, 0.944 g / mL, 18.156 mmol) were added to a vial and heated at 60 °C for 1 hour. The temperature was raised to 100 °C and stirred for another hour. After cooling to room temperature, the reaction mixture was diluted in 5 mL of ethyl acetate and extracted with water (3×5 mL). The organic layer was washed with MgSO 4Dry, filter and concentrate. The residue was purified by silica gel chromatography (0-100% hexanes: 10% MeOH in ethyl acetate) to give 4-(3-bromo-1H-pyrazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine (44 mg, 50%). MS (ESI + ):m / z=321.

[0707] Intermediate 18: 4-(3-bromo-1H-pyrazol-1-yl)-2-chloropyrimidine

[0708]

[0709] In a 100 mL round-bottom flask, 3-bromopyrazole (500 mg, 3.402 mmol), 2,4-dichloropyrimidine (1013 mg, 6.804 mmol) and DMF (12 mL, 155 mmol) were added under nitrogen, followed by K 2 CO 3 Aqueous solution (8.505 mL, 1 M, 8.505 mmol). The reaction was then heated at 60 °C for 1 hour. The reaction mixture was diluted in ethyl acetate (30 mL) and washed with water (3 x 30 mL). The organic layer was washed with MgSO 4 The resulting mixture was filtered, dried, concentrated under reduced pressure and purified by FCC (silica, 0-60% hexanes:EtOAc) to give 4-(3-bromo-1H-pyrazol-1-yl)-2-chloropyrimidine (531.6 mg, 60%) as a white solid. 1 HNMR (600 MHz, DMSO-d 6 )δ8.84(d,J=5.6Hz,1H),8.68(d,J=2.8Hz,1H),7.89(d,J=5.5Hz,1H),6.89(d,J=2.8Hz,1H). MS(ESI + ):m / z=260.

[0710] Intermediate 19: N-(4-(3-bromo-1H-pyrazol-1-yl)pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-3-amine

[0711]

[0712] 4-(3-Bromo-1H-pyrazol-1-yl)-2-chloropyrimidine (Intermediate 18, 100 mg, 0.385 mmol), 3-aminopyrazolo[1,5-a]pyrimidine (103.387 mg, 0.771 mmol), TFA (0.0737 mL, 1.49 g / mL, 0.963 mmol) and DMSO (1.2 mL, 1.092 g / mL, 16.771 mmol) were added to a vial under nitrogen and subjected to microwave irradiation at 150 °C for 1 hour. The mixture was washed with 100 mL of 1M K 2CO 3 The aqueous solution was diluted and extracted with 3×100 mL EtOAc. The organic extracts were washed with MgSO 4 Dried, filtered and concentrated.The product was then purified by FCC (0-100% EtOAc in hexanes) to give N-(4-(3-bromo-1H-pyrazol-1-yl)pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-3-amine (26.7 mg, 19%). 1 H NMR (500 MHz, DMSO-d 6 )δ9.43(s,2H),9.06(d,J=1.7Hz,1H),9.04(d,J=1.7Hz,1H),8.50(d,J=1.7Hz,2H),8.49 (d,J=1.7Hz,1H),7.13(s,1H),7.12(s,1H),7.02(d,J=4.0Hz,1H),7.01(d,J=3.9Hz,1H). MS(ESI + ):m / z=358.

[0713] Intermediate 20: 4-(3-bromo-1H-pyrazol-1-yl)-N-(1-(2,2-difluoroethyl)-3-methoxy-1H-pyrazol- 4-yl)pyrimidin-2-amine

[0714]

[0715] 4-(3-Bromo-1H-pyrazol-1-yl)-2-chloropyrimidine (Intermediate 18, 100 mg, 0.385 mmol), 1-(2,2-difluoroethyl)-3-methoxy-1h-pyrazol-4-amine (136.539 mg, 0.771 mmol), TFA (0.0737 mL, 1.49 g / mL, 0.963 mmol) and DMSO (1.2 mL, 1.092 g / mL, 16.771 mmol) were combined under nitrogen and subjected to microwave irradiation at 150 °C for 1 hour. The mixture was washed with 100 mL of 1M K 2 CO 3 The aqueous solution was diluted and extracted with EtOAc (3×100 mL). The organic extracts were washed with MgSO 4 Dried, filtered and concentrated.The product was then purified by FCC (0-100% EtOAc in hexanes) to give 4-(3-bromo-1H-pyrazol-1-yl)-N-(1-(2,2-difluoroethyl)-3-methoxy-1H-pyrazol-4-yl)pyrimidin-2-amine (49.4 mg, 32%). 1 H NMR (500 MHz, DMSO-d 6)δ8.88(s,1H),8.48(s,1H),8.47(s,1H),7.88(s,1H),7.08(d,J=5.3Hz,1H),6.8 1(d,J=2.7Hz,1H),6.30(tt,J=55.2,3.9Hz,2H),4.51-4.41(m,2H),3.83(s,3H). MS(ESI + ):m / z=401.

[0716] Intermediate 21: (R)-3-Hydroxy-1-methyl-3-(3-(1-(2-(methylthio)pyrimidin-4-yl)-1H-pyrazole-3- 1-(4-(4-(2-yl)phenyl)pyrrolidin-2-one

[0717]

[0718] (R)-3-(3-(1H-pyrazol-3-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 3, 120 mg, 0.466 mmol), 4-chloro-2-(methylthio)pyrimidine (107.552 mg, 0.67 mmol), Cs 2 CO 3 A mixture of (759.803 mg, 2.332 mmol) and DMSO (0.747 mL, 1.092 g / mL, 10.435 mmol) was combined under a nitrogen atmosphere and heated in a microwave reactor at 150 ° C for 1 hour. LCMS showed conversion to the desired product. After cooling to room temperature, the reaction mixture was diluted with EtOAc (30 mL) and washed with water (3×50 mL). The extracted organic layer was purified by MgSO 4 Dried, filtered and concentrated then purified via FCC (12 g silica, 0-100% EtOAc in hexanes) to afford (R)-3-hydroxy-1-methyl-3-(3-(4-(2-(methylsulfonyl)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one (95.3 mg, 54%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6)δ8.79(d,J=2.8Hz,1H),8.73(d,J=5.5Hz,1H),8.02(t,J=1.8Hz,1H),7.88 (dt,J=7.7,1.4Hz,1H),7.69(d,J=5.5Hz,1H),7.46(t,J=7.7Hz,1H),7.40- 7.37(m,1H),7.18(d,J=2.8Hz,1H),6.11(s,1H),3.50-3.45(m,1H),3.41-3 .37(m,1H),2.87(s,3H),2.62(s,4H),2.42-2.36(m,2H),2.31-2.25(m,1H). MS(ESI + ):m / z=382.2.

[0719] Intermediate 22: (R)-3-(3-(4-(2-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)thiazol-2-yl) Phenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0720]

[0721] (R)-3-Hydroxy-1-methyl-3-(3-(4-(2-(methylsulfonyl)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one (Intermediate 12, 200 mg, 0.465 mmol), (2,4-dimethoxyphenyl)methanamine (0.42 mL, 2.3 mmol), DIPEA (1.44 mL, 8.36 mmol) and DMA (2.4 mL) were added to a 5 mL flask and the resulting mixture was heated at 150 °C for 16 hours. The reaction vessel was removed from the oil bath and allowed to gradually cool to room temperature. The reaction mixture was concentrated to dryness in vacuo to give a yellow solid. The yellow solid was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to give (R)-3-(3-(4-(2-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)thiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (400 mg, 95%) as a colorless oil. MS (ESI + ):m / z=518.1.

[0722] Intermediate 23: N-(2-methoxypyridin-3-yl)-4-(tributylstannyl)pyrimidin-2-amine

[0723]

[0724] Step A.4-chloro-N-(2-methoxypyridin-3-yl)pyrimidin-2-amine. 2-Methoxypyridin-3-amine (440 mg, 3.54 mmol) and THF (10 mL) were added to a dried and nitrogen-purged 50 mL three-necked round-bottom flask, which was then cooled to -72 ° C. and the resulting mixture was treated with LDA (2.0 mL, 2M in THF, 4.0 mmol) in batches over 3 minutes. After stirring at 78 ° C. for 30 minutes, the resulting mixture was treated with a THF solution (5 mL) of 4-chloro-2-(methylsulfonyl)pyrimidine (400 mg, 2.08 mmol). The mixture was stirred at room temperature for 1 hour. Thereafter, the mixture was poured into water (15 mL) and extracted with ethyl acetate (20 mL×3). The combined organic extracts were washed with brine (30 mL) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness in vacuo to give a yellow viscous oil. The oil was purified by silica gel chromatography (0-100% EtOAc / petroleum ether) to give 4-chloro-N-(2-methoxypyridin-3-yl)pyrimidin-2-amine (490 mg, 72%) as a white solid. MS (ESI + ):m / z=237.0.

[0725] Step B N-(2-methoxypyridin-3-yl)-4-(tributylstannyl)pyrimidin-2-amine. 4-Chloro-N-(2-methoxypyridin-3-yl)pyrimidin-2-amine (490 mg, 2.07 mmol), a stirring bar, 1,1,1,2,2,2-hexabutyldistanane (2.26 g, 3.90 mmol), LiCl (526 mg, 12.4 mmol) and 1,4-dioxane (30 mL) were added to a 100 mL round bottom flask, which was subsequently evacuated and refilled with argon (×3) and then heated with Pd 2 (dba) 3 (97 mg, 0.11 mmol) and tricyclohexylphosphine (62 mg, 0.22 mmol), and the resulting mixture was stirred at 120°C for 16 hours. The reaction mixture was then cooled to room temperature, quenched with saturated aqueous KF (40 mL), extracted with ethyl acetate (50 mL x 3), and the combined extracts were washed with brine (300 mL), and washed with anhydrous Na 2 SO 4 Drying, filtration and concentration to dryness in vacuo gave the product as a brown oil (2.5 g). MS (ESI + ):m / z=493.0.

[0726] Intermediate 24: 6-methyl-5-((4-(tributylstannyl)pyrimidin-2-yl)amino)nicotinonitrile

[0727]

[0728] Step A.5-((4-chloropyrimidin-2-yl)amino)-6-methylnicotinonitrile. 5-Amino-6-methylnicotinonitrile (249 mg, 1.87 mmol) and THF (1 mL) were added to a dried and nitrogen-purged 10 mL three-necked flask, which was then cooled to -72°C and LDA (1.04 mL, 2.08 mmol, 2M in hexane and THF) was added dropwise over 5 minutes. The resulting mixture was stirred at -72°C for 30 minutes. 4-Chloro-2-(methylsulfonyl)pyrimidine (200 mg, 1.04 mmol) was added dropwise to the mixture at -72°C. The resulting mixture was stirred for 1 hour while gradually warming to room temperature and then heated with H 2 O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic extracts were washed with brine (5 mL) and dried over anhydrous Na 2 SO 4 Drying, filtering and concentrating to dryness in vacuo gave a brown solid which was purified by silica gel chromatography (0-30% EtOAc / petroleum ether) to give 5-((4-chloropyrimidin-2-yl)amino)-6-methylnicotinonitrile (240 mg, 93%) as a yellow solid. MS (ESI + ):m / z=246.1[M+H + ].

[0729] Step B. 6-Methyl-5-((4-(tributylstannyl)pyrimidin-2-yl)amino)nicotinonitrile. 5-((4-chloropyrimidin-2-yl)amino)-6-methylnicotinonitrile (Intermediate 24, 240 mg, 0.977 mmol), a stirring bar, LiCl (248 mg, 5.86 mmol) and 1,4-dioxane (10 mL) were added to a 50 mL round bottom flask equipped with a reflux condenser and charged with 1,1,1,2,2,2-hexabutyldistanane (1.03 g, 1.78 mmol). The resulting mixture was aerated with Ar for 5 min and then heated with Pd 2 (dba) 3 (45mg, 0.049mmol) and tricyclohexylphosphine (27mg, 0.098mmol) were treated and stirred for 16 hours while heating at 120°C. The reaction vessel was removed from the oil bath and allowed to gradually cool to room temperature. The mixture was then quenched with saturated KF aqueous solution (30mL), extracted with EtOAc (20mL×3), and the combined extracts were washed with brine (20mL) and washed with anhydrous Na 2 SO 4Drying, filtering and concentrating to dryness in vacuo afforded a brown solid which was purified by silica gel chromatography (0-30% EtOAc / petroleum ether) to afford 6-methyl-5-((4-(tributylstannyl)pyrimidin-2-yl)amino)nicotinonitrile (76 mg, 15%) as a white solid. MS (ESI + ):m / z=500.7.

[0730] Intermediate 25: 3-Cyclopropyloxy-1-(2,2-difluoroethyl)-1H-pyrazol-4-amine

[0731]

[0732] Step A. 1,4-Dinitro-1H-pyrazole. KNO was added at 15 °C. 3 (0.89 g, 8.84 mmol), 4-nitro-1H-pyrazole (1.00 g, 8.84 mmol) and anhydrous CH 2 Cl 2 (5 mL) was added to a 50 mL single-necked round-bottom flask, followed by the addition of 2,2,2-trifluoroacetic anhydride (2.46 mL, 17.7 mmol) in anhydrous CH 2 Cl 2 The light yellow mixture was stirred at room temperature under N 2 The mixture was stirred for 5 hours at 4 °C, then poured into ice water and extracted with ethyl acetate (20 mL x 3). The combined organic extracts were washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 Drying, filtering and concentration to dryness in vacuo afforded a light yellow oil which was chromatographed on silica gel (0-20% EtOAc / petroleum ether) to afford 1,4-dinitro-1H-pyrazole (1.2 g, 86%) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ8.97(d,J=0.8Hz,1H),8.15-8.09(m,1H).

[0733] Step B.3-Cyclopropyloxy-4-nitro-1H-pyrazole. NaH (1.35 g, 33.7 mmol, 60 wt% in mineral oil) was added in portions to a 100 mL three-necked round-bottom flask containing cyclopropanol (1.96 g, 33.7 mmol) and 2-Me-THF (15 mL) at 0 °C. The mixture was stirred for 10 minutes while gradually warming to room temperature. The above suspension was added dropwise to a 100 mL three-necked round-bottom flask containing 1,4-dinitro-1H-pyrazole (Intermediate 25, 8.00 g, 50.6 mmol) and 2-Me-THF (15 mL) at -78 °C. The gray mixture was stirred at -78 °C for 1 hour, then allowed to warm to room temperature and stirred for 5 hours. Thereafter, the mixture was poured into water, treated with aqueous HCl (10 mL, 3N) and quenched with CH 2 Cl 2 The combined organic extracts were washed with brine (50 mL) and purified by anhydrous Na 2 SO 4 Drying, filtering and concentration to dryness in vacuo afforded a light yellow oil which was chromatographed on silica gel (0-30% EtOAC / petroleum ether) to afford 3-cyclopropyloxy-4-nitro-1H-pyrazole (1.1 g, 19%) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 )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).

[0734] Step C. 3-cyclopropyloxy-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole. 2 2- (tributylphosphoranylidene) acetonitrile (3.00g, 12.4mmol) is added to a 100mL three-necked round-bottom flask containing 3-cyclopropyloxy-4-nitro-1H-pyrazole (700mg, 4.14mmol), 2,2-difluoroethanol (1.02g, 12.4mmol) and anhydrous toluene (30mL). The mixture is heated at 60 ° C for 12 hours. The reaction vessel is taken out from the oil bath and allowed to gradually cool to room temperature. The mixture is then concentrated in vacuo to dryness to obtain a red oil, which is subjected to silica gel chromatography (20%-50% EtOAc / petroleum ether) to obtain 3-cyclopropyloxy-1- (2,2-difluoroethyl) -4-nitro-1H-pyrazole (500mg, 52%) as a red solid. 1 HNMR (400MHz, CDCl 3)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).

[0735] Step D. 3-cyclopropyloxy-1-(2,2-difluoroethyl)-1H-pyrazol-4-amine. Iron powder (838 mg, 15.0 mmol) was added to a mixture containing 3-cyclopropyloxy-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole (700 mg, 3.00 mmol, isomer mixture), NH 4 Cl (642 mg, 12.0 mmol), anhydrous EtOH (10 mL) and H 2 O (2mL) in a 50mL three-necked round-bottom flask. The mixture was heated at 70 ° C for 12 hours. The reaction vessel was taken out of the oil bath and allowed to gradually cool to room temperature. The mixture was filtered through a celite pad and the pad was washed with MeOH (30mL×3). The filtrate was concentrated in vacuo to dryness to give a black oil, which was subjected to silica gel chromatography (0-50% EtOAc / petroleum ether) to give 3-cyclopropoxy-1-(2,2-difluoroethyl)-1H-pyrazole-4-amine (300mg, 41%) as a black oil. MS (ESI + ):m / z=203.6.

[0736] Intermediate 26: 3-amino-N,4-dimethylbenzamide

[0737]

[0738] Step A: 4-Dimethyl-3-nitrobenzamide. DIPEA (2.74 mL, 16.6 mmol), 4-methyl-3-nitrobenzoic acid (1.00 g, 5.52 mmol), methylamine hydrochloride (0.69 g, 6.63 mmol), HATU (3.15 g, 8.28 mmol) and anhydrous DMF (20 mL) were added to a 100 mL flask. The resulting mixture was stirred at room temperature under N 2 Thereafter, the mixture was stirred for 12 hours. 2 O (50 mL) and diluted with CH 2 Cl 2 The combined organic extracts were washed with brine (50 mL x 2) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The residue was chromatographed on silica gel (0-100% EtOAc / petroleum ether) to give N,4-dimethyl-3-nitrobenzamide (1 g, 92%) as a white solid. MS (ESI+ ):m / z=194.6[M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ8.35(d,J=1.6Hz,1H),7.97-7.94(m,1H),7.44(d,J=7.6Hz,1H),6.26(s,1H),3.05(d,J=4.8Hz,3H),2.66(s,3H).

[0739] Step B: 3-amino-N,4-dimethylbenzamide. A mixture of N,4-dimethyl-3-nitrobenzamide (1.70 g, 8.75 mmol), wet Pd / C (500 mg, 10 wt%, 0.46 mmol) and EtOH (30 mL) was stirred at room temperature under H 2 (50psi) for 12 hours. Thereafter, the mixture was filtered through a pad of celite and the pad was washed with EtOAc (20mL×3). The filtrate was concentrated to dryness in vacuo to give a liquid, which was subjected to silica gel chromatography (0-50% EtOAc / petroleum ether) to obtain 3-amino-N,4-dimethylbenzamide (790mg, 55%) as a white solid. MS (ESI + ):m / z=164.7. 1 H NMR (400 MHz, CDCl 3 )δ7.15(d,J=1.2Hz,1H),7.08(d,J=7.6Hz,1H),7.00-6.98(m,1H),6.07(s,1H),3.73(s,2H),3.00(d,J=4.8Hz,3H),2.20(s,3H).

[0740] Intermediate 27: 1-(2,2-difluoroethyl)-3-(2-methoxyethoxy)-1H-pyrazol-4-amine

[0741]

[0742] Step A. 1-(3-(2-methoxyethoxy)-1H-pyrazol-1-yl)ethanone. 1-Acetyl-1H-pyrazol-3(2H)-one (5.5 g, 43.6 mmol), 1-bromo-2-methoxyethane (6.37 g, 45.79 mmol), K 2 CO 3 (9.04 g, 65.42 mmol) and anhydrous DMF (45 mL) were added to a 100 mL three-necked round-bottom flask dried and purged with nitrogen and the resulting mixture was heated at 80° C. for 2 hours. The reaction mixture was then diluted with EtOAc (200 mL), washed with brine (100 mL), and washed with anhydrous Na 2 SO4 Drying, filtering and concentrating to dryness in vacuo gave a brown solid which was chromatographed on silica gel (0-50% EtOAc / petroleum ether) to give 1-(3-(2-methoxyethoxy)-1H-pyrazol-1-yl)ethanone (6.7 g, 83%) as a colorless liquid.

[0743] Step B. 3-(2-methoxyethoxy)-1H-pyrazole. 1-(3-(2-methoxyethoxy)-1H-pyrazol-1-yl)ethanone (6.7 g, 36.4 mmol), NaOH (4.37 g, 109 mmol), MeOH (40 mL) and H 2 O (12 mL) was added to a 100 mL round-bottom flask equipped with a reflux condenser and the resulting mixture was heated at 50 ° C for 1 hour. The resulting white suspension was concentrated to dryness in vacuo to give a white solid, which was acidified to pH = 3-4 with aqueous HCl (2N, 40 mL) and extracted with EtOAc (40 mL×4). The combined extracts were washed with brine (30 mL) and purified by anhydrous Na 2 SO 4 Drying, filtering and concentration to dryness in vacuo gave a colorless oil which was chromatographed on silica gel (0-50% EtOAc / petroleum ether) to give 3-(2-methoxyethoxy)-1H-pyrazole (5 g, 97%) as a colorless liquid.

[0744] Step C. 3-(2-methoxyethoxy)-4-nitro-1H-pyrazole. 3-(2-methoxyethoxy)-1H-pyrazole (2 g, 14.1 mmol) and concentrated H 2 SO 4 (8 mL) was added to a 50 mL round-bottom flask and the resulting mixture was carefully treated dropwise with fuming HNO over 10 min at room temperature. 3 (2.31 g, 36.6 mmol) and then heated at 50°C for 12 hours. The yellow solution was carefully added dropwise to ice water (20 mL) and then extracted with EtOAc (30 mL×3). The combined extracts were washed with brine (10 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate the filtrate to dryness in vacuo to give a white solid. The white solid was chromatographed on silica gel (30%-50% EtOAc / petroleum ether) to give 3-(2-methoxyethoxy)-4-nitro-1H-pyrazole (1.3 g, 49%) as a white solid.

[0745] Step D. 1-(2,2-difluoroethyl)-3-(2-methoxyethoxy)-4-nitro-1H-pyrazole. 2-(tributylphosphoranylidene)acetonitrile (5.03 g, 20.8 mmol), 3-(2-methoxyethoxy)-4-nitro-1H-pyrazole (1.3 g, 6.95 mmol), 2,2-difluoroethanol (1.71 g, 20.8 mmol) and anhydrous toluene (25 mL) were added to a 100 mL three-necked round bottom flask equipped with a reflux condenser and nitrogen purged and the resulting 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 reaction mixture was concentrated to dryness in vacuo to give a red oil, which was chromatographed on silica gel (20%-50% EtOAc / petroleum ether) to give 1-(2,2-difluoroethyl)-3-(2-methoxyethoxy)-4-nitro-1H-pyrazole (1.1 g, 63%) as a red oil.

[0746] Step E. 1-(2,2-difluoroethyl)-3-(2-methoxyethoxy)-1H-pyrazol-4-amine. Iron powder (1.11 g, 19.9 mmol), 1-(2,2-difluoroethyl)-3-(2-methoxyethoxy)-4-nitro-1H-pyrazole (1 g, 3.98 mmol), NH 4 Cl (852 mg, 15.9 mmol), anhydrous EtOH (50 mL) and H 2 The mixture was stirred for 12 hours at 70 ℃ for 12 hours. The reaction vessel was removed from the oil bath and allowed to gradually cool to room temperature. The black suspension was filtered through a diatomaceous earth pad and the pad was washed with MeOH (50 mL × 3). The filtrate was concentrated in vacuo to dryness to give a black oil, which was distributed between EtOAc (60 mL) and brine (20 mL). The aqueous phase was then extracted with EtOAc (20 mL × 2) and the combined organic extracts were washed with brine (20 mL). The mixture was stirred for 2 hours at 70 ℃ for 12 hours. The mixture was stirred for 3 hours at 70 ℃ for 12 hours. The reaction vessel was removed from the oil bath and allowed to gradually cool to room temperature. The black suspension was filtered through a diatomaceous earth pad and the pad was washed with MeOH (50 mL × 3). The filtrate was concentrated in vacuo to dryness to give a black oil, which was distributed between EtOAc (60 mL) and brine (20 mL). The aqueous phase was then extracted with EtOAc (20 mL × 2) and the combined organic extracts were washed with brine (20 mL). 2 SO 4 Dry, filter and concentrate the filtrate to dryness in vacuo to give a brown solid. The brown solid was chromatographed on silica gel (30%-50% EtOAc / petroleum ether) to give 1-(2,2-difluoroethyl)-3-(2-methoxyethoxy)-1H-pyrazol-4-amine (490 mg, 56%) as a brown oil. 1 H NMR (400 MHz, CDCl 3)δ7.00-6.85(m,1H),6.13-5.79(m,1H),4.34-4.32(m,2H),4.15-4.14(m,2H),3.77-3.69(m,2H),3.44(s,3H).

[0747] Intermediate 28: 2,4-Difluoro-N-methyl-5-nitrobenzamide

[0748]

[0749] SOCl 2 4-Difluoro-5-nitrobenzoic acid (5.00 g, 24.6 mmol) was added to a 100 mL single-necked round-bottom flask. The resulting brown suspension was heated to reflux for 3 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 yellow solid, which was dissolved in anhydrous CH 2 Cl 2 (50 mL), cooled to -40 °C and stirred with CH 3 NH 2 HCl (1.66 g, 24.6 mmol) and Et 3 N (9.97 g, 98.5 mmol). The resulting white suspension was stirred at -40 ° C for 1 hour and allowed to warm to 0 ° C and stirred for 10 minutes. The mixture was concentrated to dryness in vacuo to give a yellow solid. The yellow solid was dissolved in EtOAc (60 mL) and saturated NaHCO 3 The aqueous phase was then extracted with EtOAc (30 mL x 2) and the combined organic extracts were washed with brine (20 mL) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate the filtrate to dryness in vacuo to give a yellow solid. The yellow solid was chromatographed on silica gel (20%-50% EtOAc / petroleum ether) to give 2,4-difluoro-N-methyl-5-nitrobenzamide (3 g, 56%) as a yellow solid.

[0750] Intermediate 29 and Intermediate 30: 4-cyclopropyloxy-2-fluoro-N-methyl-5-nitrobenzamide and 2-cyclopropyloxy- 4-Fluoro-N-methyl-5-nitrobenzamide

[0751]

[0752] At room temperature, Cs 2 CO 34-difluoro-N-methyl-5-nitrobenzamide (intermediate 28, 2.70 g, 12.5 mmol), cyclopropanol (726 mg, 12.49 mmol), a stirring bar and anhydrous 1,4-dioxane (55 mL) were added to a 100 mL three-necked round-bottom flask. The resulting yellow suspension was stirred at 80 ° C for 1 hour. The reaction vessel was removed from the oil bath and allowed to gradually cool to room temperature. The reaction mixture was concentrated in vacuo to dryness to obtain a yellow solid. The yellow solid was dissolved in EtOAc (100 mL) and H 2 O (40 mL). The aqueous phase was then extracted with EtOAc (30 mL x 2) and the combined organic extracts were washed with brine (30 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried, filtered and the filtrate was concentrated to dryness in vacuo to give a yellow solid. The yellow solid was chromatographed on silica gel (20%-50% EtOAc / petroleum ether) to give a mixture of 4-cyclopropyloxy-2-fluoro-N-methyl-5-nitrobenzamide and 2-cyclopropyloxy-4-fluoro-N-methyl-5-nitrobenzamide as a yellow solid (2200 mg, 69%).

[0753] Intermediate 31 and Intermediate 32: 5-amino-4-cyclopropyloxy-2-fluoro-N-methylbenzamide and 5-amino-2-cyclopropyloxy Propoxy-4-fluoro-N-methylbenzamide

[0754]

[0755] Iron powder (2.42 g, 43.3 mmol) was added to a mixture containing 4-cyclopropyloxy-2-fluoro-N-methyl-5-nitrobenzamide (2.20 g, 8.65 mmol, isomer mixture, intermediate 29 and intermediate 30), NH 4 Cl (1.85 g, 34.6 mmol), a stirring bar, anhydrous EtOH (50 mL) and H 2 O (10mL) in a 100mL three-necked round-bottom flask. The resulting black suspension was heated at 70°C for 1 hour. The reaction vessel was removed from the oil bath and allowed to gradually cool to room temperature. The reaction mixture was filtered through a celite pad and the pad was washed with MeOH (50mL×3). The filtrate was concentrated to dryness in vacuo to give a black oil, which was distributed between EtOAc (60mL) and brine (20mL). The aqueous phase was then extracted with EtOAc (20mL×2) and the combined organic extracts were washed with brine (20mL) and filtered through anhydrous Na 2 SO 4The mixture was dried, filtered and the filtrate was concentrated to dryness in vacuo to give a brown solid. The brown solid was subjected to silica gel chromatography (25%-50% EtOAc / petroleum ether) to give a mixture of 5-amino-4-cyclopropyloxy-2-fluoro-N-methylbenzamide and 5-amino-2-cyclopropyloxy-4-fluoro-N-methylbenzamide as a yellow solid (1600 mg, 82%). MS (ESI + ):m / z=224.9.

[0756] Intermediate 33: 5-amino-4-cyclopropyloxy-2-fluoro-N-methylbenzamide

[0757]

[0758] 5-Amino-4-cyclopropyloxy-2-fluoro-N-methylbenzamide (1.6 g, 7.14 mmol, mixture of isomers, intermediate 31 and intermediate 32) was purified by HPLC (Boston Uni C18 column, 5 μm, 40×150 mm, 8%-38% (v / v) CH 3 CN / H 2 D, containing 0.225% HCOOH) and lyophilized to give 5-amino-4-cyclopropyloxy-2-fluoro-N-methylbenzamide (390 mg, 24%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ7.41(d,J=8.0Hz,1H),6.92-6.89(m,1H),6.79-6.59(m,1H),3.83-3.73(m,1H),3.67-3.07(m,2H),3.01(d,J=4.8Hz,3H),0.89-0.80(m,4H).

[0759] Intermediate 34: 5-amino-1-isobutyl-N-methyl-1H-pyrazole-3-carboxamide

[0760]

[0761] Step A.5-amino-1-isobutyl-1H-pyrazole-3-carboxylic acid ethyl ester. Concentration HCl (7.01mL, 83.90mmol, 1.18g / mL, 37 wt%) was added to a 250mL three-necked round-bottom flask containing ethyl 3-cyano-2-oxopropanoate (4g, 28.3mmol), isobutylhydrazine hydrochloride (3.53g, 28.3mmol) and anhydrous EtOH (150mL) at room temperature. The resulting brown suspension was heated at 80°C for 12 hours. The reaction vessel was taken out from the oil bath and allowed to gradually cool to room temperature. The mixture was concentrated in vacuo to dryness to obtain a yellow solid. The yellow solid was cooled with ice water, and the pH was then adjusted with saturated NaHCO 3The aqueous solution (30 mL) was adjusted to pH = 9-10. The resulting brown suspension was extracted with EtOAc (60 mL x 3). The combined organic extracts were washed with brine (30 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to give a brown solid. The brown solid was chromatographed on silica gel (50%-100% EtOAc / petroleum ether) to give ethyl 5-amino-1-isobutyl-1H-pyrazole-3-carboxylate (2.5 g, 42%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ6.14(s,1H),4.41-4.35(m,2H),3.95-3.93(m,2H),3.58(s,2H),2.36-2.26(m,1H),1.42-1.33(m,3H),0.95-0.93(m,6H).

[0762] Step B. 5-amino-1-isobutyl-1H-pyrazole-3-carboxylic acid. LiOH·H 2 O (2.68 g, 63.9 mmol) was added to a mixture containing ethyl 5-amino-1-isobutyl-1H-pyrazole-3-carboxylate (2.70 g, 12.8 mmol), THF (75 mL) and H 2 O (15mL) in a 250mL three-necked round-bottom flask. The resulting yellow suspension was heated at 70°C for 3 hours. The reaction vessel was removed from the oil bath and allowed to gradually cool to room temperature. The reaction mixture was concentrated to dryness in vacuo to obtain a yellow solid. The yellow solid was treated with aqueous HCl (3N, 20mL) and the resulting mixture was extracted with EtOAc (30mL×5). The combined organic extracts were washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to give 5-amino-1-isobutyl-1H-pyrazole-3-carboxylic acid (2.3 g, 94%) as a yellow solid. MS (ESI + ):m / z=183.9.

[0763] Step C. 5-amino-1-isobutyl-N-methyl-1H-pyrazole-3-carboxamide. HATU (4.11 g, 10.8 mmol) was added to a mixture containing 5-amino-1-isobutyl-1H-pyrazole-3-carboxylic acid (1.8 g, 9.83 mmol), CH 3 NH 2HCl (1.00 g, 14.7 mmol), DIPEA (3.81 g, 29.5 mmol), a stirring bar and anhydrous DMF (65 mL) were placed in a 100 mL single-necked round-bottom flask. The resulting brown solution was stirred at room temperature for 12 h. Thereafter, the mixture was heated with H 2 O (60 mL) and extracted with EtOAc (50 mL×5). The combined organic extracts were washed with H 2 O (30 mL × 2) and brine (30 mL), and washed with anhydrous Na 2 SO 4 The mixture was dried, filtered and the filtrate was concentrated to dryness in vacuo to give a yellow oil. The yellow oil was combined with another batch of this material (500 mg) and subjected to silica gel chromatography (50%-100% EtOAc / petroleum ether) to give 5-amino-1-isobutyl-N-methyl-1H-pyrazole-3-carboxamide (1.8 g, 73%) as a brown oil. MS (ESI + ):m / z=196.9.

[0764] Intermediate 35: (R)-3-(3-(4-(2-chloropyrimidin-4-yl)thiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrole Alkane-2-one

[0765]

[0766] (R)-3-(3-(4-bromothiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 7, 600 mg, 1.70 mmol), 2-chloro-4-(tributylstannyl)pyrimidine (754 mg, 1.868 mmol), Et 3 N (0.47 mL, 3.40 mmol) and anhydrous toluene (15 mL) were added to an oven-dried and nitrogen-purged 50 mL round-bottom flask equipped with a reflux condenser and Pd(PPh 3 ) 4 (294 mg, 0.255 mmol). The mixture was washed with N 2 The mixture was stirred for 5 minutes and heated at 120 ° C for 12 hours to obtain a brown suspension. The reaction vessel was taken out from the oil bath and allowed to gradually cool to room temperature. The suspension was concentrated in vacuo to dryness to obtain a brown solid. The brown solid was subjected to silica gel chromatography (0-100% EtOAc / petroleum ether) to obtain (R) -3- (3- (4- (2- chloropyrimidine -4- bases) thiazol-2-yl) phenyl) -3- hydroxy -1- methylpyrrolidin-2-one (350 mg, 53%) as a yellow solid.

[0767] Intermediate 36: 3-amino-1,5-dimethylpyridin-2(1H)-one

[0768]

[0769] Step A. 1,5-dimethyl-3-nitropyridin-2(1H)-one. 2 Next CH 3 I (1.38 g, 9.73 mmol) was added dropwise to a mixture containing 5-methyl-3-nitropyridin-2(1H)-one (1 g, 6.49 mmol), K 2 CO 3 (1.79 g, 12.98 mmol) and anhydrous DMF (10 mL) were placed in a 100 mL three-necked round-bottom flask at 0 °C. The resulting mixture was stirred for 12 hours while gradually warming to room temperature. Thereafter, the mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL×3). The combined organic extracts were washed with brine (10 mL) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate the filtrate to dryness in vacuo to give a yellow oil. The yellow oil was chromatographed on silica gel (50%-100% EtOAc / petroleum ether) to give 1,5-dimethyl-3-nitropyridin-2(1H)-one (690 mg, 63%) as a yellow solid. MS (ESI + ):m / z=168.8. 1 H NMR (400 MHz, CDCl 3 )δ8.20(d,J=2.4Hz,1H),7.52(d,J=1.8Hz,1H),3.71-3.58(m,3H),2.20(s,3H).

[0770] Step B. 3-amino-1,5-dimethylpyridin-2(1H)-one. Pd / C (wet, 500 mg, 50% H 2 0) was added to a 50 mL single-necked round-bottom flask containing a mixture of 1,5-dimethyl-3-nitropyridin-2(1H)-one (Intermediate 36, 850 mg, 5.06 mmol), anhydrous MeOH (15 mL) and THF (15 mL). The resulting black suspension was stirred under H 2 (15psi) and stirred at room temperature for 12 hours. The suspension was then filtered through a celite pad and the pad was washed with MeOH (15mL×5). The filtrate combined with the material from the additional batch was concentrated to dryness in vacuo to give a brown solid. The brown solid was subjected to silica gel chromatography (2%-5% MeOH / DCM) to give 3-amino-1,5-dimethylpyridin-2(1H)-one (850mg) as a yellow solid. MS (ESI + ):m / z=138.8. 1 H NMR (400 MHz, CDCl 3)δ6.49-6.48(m,1H),6.41-6.40(m,1H),4.77-3.56(m,2H),3.53(s,3H),2.01(s,3H).

[0771] Intermediate 37: (R)-3-Hydroxy-1-methyl-3-(3-(4-(2-(methylthio)pyrimidin-4-yl)thiazol-2-yl)benzene 1-(2-YL)pyrrolidin-2-one

[0772]

[0773] ((R)-3-(3-(4-bromothiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 7, 1.00 g, 2.83 mmol), Pd(PPh 3 ) 4 (351 mg, 0.283 mmol), 2-(methylthio)-4-(tributylstannyl)pyrimidine (1.29 g, 3.11 mmol), Et 3 N (0.789 mL, 5.66 mmol) and anhydrous toluene (30 mL) were added to a 100 mL three-necked round-bottom flask equipped with a reflux condenser. The resulting mixture was heated at 120 °C under N 2 The reaction mixture was poured into aqueous KF solution (20 mL), filtered through a celite pad and the pad was washed with EtOAc (50 mL). The filtrate was extracted with EtOAc (40 mL × 3). The combined organic extracts were washed with brine (50 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried, filtered and the filtrate was concentrated to dryness in vacuo to give a brown oil. The brown oil was chromatographed on silica gel (20%-100% EtOAc / petroleum ether) to give (R)-3-hydroxy-1-methyl-3-(3-(4-(2-(methylthio)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one (810 mg, 66%) as a brown oil. MS (ESI + ):m / z=399.0[M+H] + .

[0774] Intermediate 38: (R)-3-Hydroxy-1-methyl-3-(3-(4-(2-(methylsulfinyl)pyrimidin-4-yl)thiazole-2- 1-(4-(4-(2-yl)phenyl)pyrrolidin-2-one

[0775]

[0776] (R)-3-Hydroxy-1-methyl-3-(3-(4-(2-(methylthio)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one (Intermediate 37, 134 mg, 0.336 mmol), hydrogen peroxide (68.7 μL, 0.673 mmol) and hexafluoro-2-propanol (4 mL) were added to a 10 mL round bottom flask. The resulting mixture was stirred at room temperature for 16 hours. Thereafter, the mixture was washed with saturated Na 2 O 3 S 2 The solution was quenched with aqueous solution (5 mL) and extracted with EtOAc (20 mL×3). The combined organic extracts were purified by anhydrous Na 2 SO 4 The mixture was dried, filtered and the filtrate was concentrated to dryness in vacuo to give a brown oil. The brown oil was subjected to silica gel chromatography (20%-100% EtOAc / petroleum ether) to give (R)-3-hydroxy-1-methyl-3-(3-(4-(2-(methylsulfinyl)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one (110 mg, 74%) as a yellow solid. MS (ESI + ):m / z=415.0.

[0777] Intermediate 39: 5-amino-1-cyclopentyl-N-methyl-1H-pyrazole-3-carboxamide

[0778]

[0779] Step A.5-amino-1-cyclopentyl-1H-pyrazole-3-carboxylic acid ethyl ester. Concentration HCl (5.26mL, 62.92mmol, 1.18g / mL, 37 wt%) was added to a 250mL three-necked round-bottom flask containing a mixture of ethyl 3-cyano-2-oxopropanoate (3g, 21.26mmol), cyclopentylhydrazine hydrochloride (2.90g, 21.26mmol) and anhydrous EtOH (120mL) at room temperature. The resulting brown suspension was heated at 80°C for 12 hours. The reaction vessel was taken out from the oil bath and allowed to gradually cool to room temperature. The reaction mixture was then concentrated in vacuo to dryness to obtain a yellow solid. The yellow solid was cooled to 0°C and then washed with saturated NaHCO 3 The pH was adjusted to pH = 9-10 with aqueous solution (30 mL). The resulting suspension was extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine (30 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to give a yellow solid. The yellow solid was chromatographed on silica gel (50%-100% EtOAc / petroleum ether) to give ethyl 5-amino-1-cyclopentyl-1H-pyrazole-3-carboxylate (1.5 g, 32%) as a yellow solid. 1H NMR (400 MHz, CDCl 3 )δ6.09(s,1H),4.56-4.48(m,1H),4.36(q,J=7.2Hz,2H),2.19-2.04(m,4H),1.99-1.89(m,2H),1.73-1.60(m,2H),1.37(t,J=7.2Hz,3H).

[0780] Step B. 5-amino-1-cyclopentyl-1H-pyrazole-3-carboxylic acid. LiOH·H 2 O (1.28 g, 30.5 mmol) was added to a solution containing ethyl 5-amino-1-cyclopentyl-1H-pyrazole-3-carboxylate (1.70 g, 7.61 mmol), THF (50 mL) and H 2 O (10mL) in a 100mL three-necked round-bottom flask. The resulting yellow suspension was heated at 70°C for 3 hours. The reaction vessel was removed from the oil bath and allowed to gradually cool to room temperature. The solution was concentrated to dryness in vacuo to obtain a yellow solid. The yellow solid was treated with aqueous HCl (3N, 10mL) and the resulting mixture was extracted with EtOAc (30mL×5). The combined organic extracts were washed with brine (10mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to give 5-amino-1-cyclopentyl-1H-pyrazole-3-carboxylic acid (1.2 g, 81%) as a yellow solid. MS (ESI + ):m / z=195.9. 1 H NMR (400 MHz, DMSO-d 6 )δ12.17(br s,1H),5.66(s,1H),5.32(br s,2H),4.64-4.47(m,1H),2.02-1.93(m,2H),1.88-1.74(m,4H),1.64-1.52(m,2H).

[0781] Step C. 5-amino-1-cyclopentyl-N-methyl-1H-pyrazole-3-carboxamide. HATU (2.57 g, 6.76 mmol) was added to a mixture containing 5-amino-1-cyclopentyl-1H-pyrazole-3-carboxylic acid (1.2 g, 6.1 mmol), CH 3 NH 2 HCl (0.623 g, 9.22 mmol), DIPEA (2.38 g, 18.4 mmol) and anhydrous DMF (40 mL) were placed in a 100 mL single-necked round-bottom flask. The resulting brown solution was stirred at room temperature under N 2Afterwards, the mixture was extracted with EtOAc (40 mL x 2) and the combined extracts were washed with H 2 O (20 mL × 2) and brine (30 mL), and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate the filtrate to dryness in vacuo to give a yellow solid. The yellow solid was chromatographed on silica gel (50%-100% EtOAc / petroleum ether) to give 5-amino-1-cyclopentyl-N-methyl-1H-pyrazole-3-carboxamide (1.1 g, 86%) as a brown oil. MS (ESI + ):m / z=208.9.

[0782] Intermediate 40: 4-Chloro-5-methyl-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine

[0783]

[0784] 1-Methyl-1H-pyrazole-3-amine (592 mg, 6.10 mmol) and anhydrous THF (20 mL) were added to a 100 mL three-necked round-bottom flask dried and purged with nitrogen, which was then cooled to -70 ° C. LDA (3.39 mL, 6.78 mmol, 2M hexane and THF solution) was added dropwise over 5 minutes. The resulting mixture was stirred at -70 ° C for 30 minutes. 4-Chloro-5-methyl-2-(methylsulfonyl)pyrimidine (700 mg, 3.39 mmol, in 5 mL anhydrous THF) was added dropwise to the mixture at -70 ° C. and the resulting mixture was stirred for 1 hour while gradually warming to room temperature. The reaction mixture was heated to 40 ° C. with H 2 O (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic extracts were washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 Drying, filtering and concentrating to dryness in vacuo afforded a brown solid which was then subjected to silica gel chromatography (25%-50% EtOAc / petroleum ether) to afford 4-chloro-5-methyl-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine (260 mg, 34%) as a yellow solid.

[0785] Intermediate 41: (R)-3-Hydroxy-1-methyl-3-(3-(4-(trimethylstannyl)thiazol-2-yl)phenyl)pyrrolidone Pyrrolidone-2-one

[0786]

[0787] Pd(PPh 3 ) 4(327 mg, 0.283 mmol), 1,1,1,2,2,2-hexamethyldistanane (1.39 g, 4.25 mmol), (R)-3-(3-(4-bromothiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 7, 1.00 g, 2.83 mmol) and anhydrous toluene (10 mL) were added to a 100 mL three-necked round-bottom flask equipped with a reflux condenser. The resulting mixture was heated at 110 ° C for 16 hours and then cooled to room temperature. The mixture was treated with KF aqueous solution (100 mL, 2N) and stirred at room temperature for 2 hours. The mixture was then extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with brine (50 mL) and purified by anhydrous Na 2 SO 4 The product was dried, filtered and concentrated to dryness in vacuo to give the product, which was chromatographed on silica gel (0-100% EtOAc / petroleum ether) to give a yellow oil. The yellow oil was purified by HPLC (Boston Prime C18 column, 5 μM, 150×30 mm; 55%-85% (v / v) CH 3 CN / H 2 O, containing 0.05% NH 3 ·H 2 O + 10 mM NH 4 HCO 3 ) was further purified and lyophilized to give (R)-3-hydroxy-1-methyl-3-(3-(4-(trimethylstannyl)thiazol-2-yl)phenyl)pyrrolidin-2-one (100 mg, 8%) as a yellow oil. MS (ESI + ):m / z=439.0[M+H] + .

[0788] Intermediate 42: N-(1-methyl-1H-pyrazol-3-yl)-4-(tributylstannyl)pyrimidin-2-amine

[0789]

[0790] 4-Chloro-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine (300 mg, 1.43 mmol), LiCl (364 mg, 8.59 mmol), 1,1,1,2,2,2-hexabutyldistanane (1.79 g, 3.09 mmol) and 1,4-dioxane (10 mL) were added to a 50 mL flask equipped with a reflux condenser. 2 Purge three times and then use Pd 2 (dba) 3 (66 mg, 0.072 mmol) and tricyclohexylphosphine (40 mg, 0.14 mmol). The resulting mixture was treated with N 2The mixture was purged 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 aqueous KF solution (30 mL), stirred for 1 hour and extracted with EtOAc (20 mL×3). The combined organic extracts were washed with brine (20 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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.

[0791] Intermediate 43: (R)-3-(3-(4-bromo-5-methylthiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidine-2-yl ketone

[0792]

[0793] (R)-3-hydroxy-1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (200 mg, 0.631 mmol), 2,4-dibromo-5-methylthiazole (162 mg, 0.631 mmol), K 3 PO 4 (402 mg, 1.89 mmol) and 1,4-dioxane / H 2 O (3 mL, v / v = 4:1) was added to a 20 mL microwave tube. The mixture was heated with N 2 Aeration for 5 minutes, with Pd(dtbpf)Cl 2 (41 mg, 0.063 mmol) and heated at 80 °C via microwave irradiation for 1 hour. Thereafter, the reaction vessel was taken out of the microwave reactor and allowed to gradually cool to room temperature. The reaction mixture was then washed with H 2 O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with brine (10 mL) and dried over anhydrous Na 2 SO 4 The mixture was dried, filtered and concentrated to dryness in vacuo to give a brown oil. The oil was purified by silica gel chromatography (0-100% EtOAc / petroleum ether) to give (R)-3-(3-(4-bromo-5-methylthiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (190 mg, 78%) as a yellow oil. MS (ESI + ):m / z=369.0[M+H] + .

[0794] Intermediate 44: (R)-3-(3-(2-bromothiazol-4-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0795]

[0796] Step A. (R)-3-Hydroxy-1-methyl-3-(3-(thiazol-4-yl)phenyl)pyrrolidin-2-one. 1,4-Dioxane (8 mL), water (2 mL), (R)-3-hydroxy-1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (2.0 g, 6.3 mmol), 4-bromothiazole (562 μL, 6.31 mmol), K 3 PO 4 (4.0 g, 19 mmol) and Pd(dtbpf)Cl 2 A mixture of (411 mg, 0.631 mmol) was heated to 90 °C in a microwave reactor for 1 hour. The mixture was then cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, Na 2 SO 4 Dry, filter and concentrate. The residue was purified by FCC (silica, gradient 0-100% EtOAc-petroleum ether) to give (R)-3-hydroxy-1-methyl-3-(3-(thiazol-4-yl)phenyl)pyrrolidin-2-one (1.4 g, 80%) as a brown oil. MS (ESI + ):m / z / =274.6.

[0797] Step B. (R)-3-(3-(2-bromothiazol-4-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one. To a stirred mixture of THF (30 mL) and (R)-3-hydroxy-1-methyl-3-(3-(thiazol-4-yl)phenyl)pyrrolidin-2-one (1.4 g, 5.1 mmol) was added LDA (9 mL, 1 M solution in THF, 18 mmol) at -72°C. After 30 minutes, the resulting mixture was treated with bromine (471 μL, 9.19 mmol). After another 30 minutes, water (50 mL) was added and the resulting mixture was extracted with EtOAc. The organic extracts were washed with Na 2 SO 4 Dry, filter and concentrate. The residue was purified by FCC (silica gel, gradient 0-100% EtOAc / petroleum ether) to give (R)-3-(3-(2-bromothiazol-4-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (1 g, 49%) as a brown oil. MS (ESI + ):m / z=353.0.

[0798] Intermediate 45: (R,S)-7-(3-(4-bromothiazol-2-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole Oxazolin-7-ol

[0799]

[0800] Step A. (R,S)-7-(3-bromophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol. 1,3-Dibromobenzene (2.32 g, 9.83 mmol) and anhydrous THF (10 mL) were added to a 100 mL three-necked round-bottom flask, which was then cooled to -72 °C and treated with n-butyllithium (2.5 M in hexane, 4.3 mL, 11 mmol). The resulting light yellow mixture was stirred at -72 °C for 30 minutes, treated with anhydrous THF solution (5 mL) of 5H-pyrrolo[1,2-a]imidazol-7(6H)-one (1.00 g, 8.19 mmol) and stirred at about -72 °C for 30 minutes. Thereafter, the brown mixture was quenched with water (40 mL), warmed to room temperature and extracted with EtOAc (50 mL x 2). The combined organic extracts were purified by anhydrous Na 2 SO 4 Dry, filter and concentrate the filtrate to dryness in vacuo to obtain a yellow solid. The yellow solid was purified by silica gel chromatography (0-50% EtOAc / petroleum ether) to obtain a yellow solid. The yellow solid was purified by HPLC (Xtimate C18 column, 10 mm, 150×40 mm; 21%-51% (v / v) CH 3 CN / water, containing 0.05% NH 3 ·H 2 O + 10 mM NH 4 HCO 3 ) was further purified and freeze-dried to give (R,S)-7-(3-bromophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (600 mg, 26%) as a white solid. MS (ESI + ):m / z=279.0.

[0801] Step B. (R,S)-7-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol. (R,S)-7-(3-bromophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (700 mg, 2.51 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolan) (1.15 g, 4.51 mmol), Pd(dppf)Cl were added under nitrogen atmosphere. 2 ·CH 2 Cl 2(367 mg, 0.502 mmol), KOAc (738 mg, 7.52 mmol) and 1,4-dioxane (7 mL) were added to a 50 mL round-bottom flask equipped with a reflux condenser. The resulting mixture was heated at 100 °C for 16 hours and turned black. Thereafter, the reaction mixture was cooled to room temperature and poured into H 2 O (50 mL) and extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with brine (200 mL) and dried over anhydrous Na 2 SO 4 The mixture was dried, filtered and the filtrate was concentrated to dryness in vacuo to give a black solid. The black solid was chromatographed on silica gel (10%-100% EtOAc / petroleum ether) to give (R,S)-7-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (300 mg, 37%) as a solid.

[0802] Step C. (R,S)-7-(3-(4-bromothiazol-2-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol. 2,4-Dibromothiazole (232 mg, 0.956 mmol), (R,S)-7-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (260 mg, 0.797 mmol), K 2 CO 3 (330 mg 2.39 mmol) and 1,4-dioxane / H 2 O(4:1) (1 mL) was added to a 5 mL microwave tube purged with nitrogen, and then Pd(dppf)Cl 2 (58 mg, 0.080 mmol). The resulting mixture was treated with N 2 Purging for 5 minutes and heating via microwave irradiation at 90°C for 1 hour gave a black solution. Afterwards, the mixture was cooled to room temperature and poured into H 2 O (50 mL) and extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with brine (200 mL) and dried over anhydrous Na 2 SO 4 The mixture was dried, filtered and the filtrate was concentrated to dryness in vacuo to give a black solid. The black solid was chromatographed on silica gel (0-10% MeOH / DCM) to give (R,S)-7-(3-(4-bromothiazol-2-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (160 mg, 55%) as a yellow solid.

[0803] Intermediate 46: (R)-3-(3-(6-bromopyridin-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0804]

[0805] 2,6-dibromopyridine (934 mg, 3.94 mmol), (R)-3-hydroxy-1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (500 mg, 1.58 mmol), K 2 CO 3 (654 mg, 4.73 mmol) and anhydrous 1,4-dioxane / H 2 O (4:1) (15 mL) was added to a 30 mL microwave tube purged with nitrogen, and then Pd(dppf)Cl 2 (115 mg, 0.158 mmol). The resulting mixture was treated with N 2 Purging for 5 minutes, followed by heating at 110 °C for 1 hour via microwave irradiation, afforded a black solution. The solution was cooled to room temperature and poured into H 2 O (50 mL) and extracted with ethyl acetate (20 mL×3). The combined organic extracts were washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate the filtrate to dryness in vacuo to give a black solid. The black solid was subjected to silica gel chromatography (0-100% EtOAc / petroleum ether) to give (R)-3-(3-(6-bromopyridin-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (340 mg, 62%) as a yellow solid. MS (ESI + ):m / z=347.0.

[0806] Intermediate 47: (R)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylsulfinyl)pyrimidin-4-yl)pyridine-2- 1-(4-(4-(2-yl)phenyl)pyrrolidin-2-one

[0807]

[0808] Step A. (R)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)phenyl)pyrrolidin-2-one. (R)-3-(3-(6-bromopyridin-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 46, 190 mg, 0.55 mmol), Pd(PPh 3 ) 4The mixture was heated at 120 ° C for 16 hours and turned brown. The reaction mixture was concentrated in vacuo to give a brown oil. The brown oil was purified by silica gel chromatography (50%-100% EtOAc / petroleum ether) to give (R)-3-hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidine-4-yl)pyridin-2-yl)phenyl)pyrrolidin-2-one (200 mg, 93%).

[0809] Step B. (R)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylsulfinyl)pyrimidin-4-yl)pyridin-2-yl)phenyl)pyrrolidin-2-one. ((R)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)phenyl)pyrrolidin-2-one (200 mg, 0.510 mmol), hydrogen peroxide (0.625 mL, 6.12 mmol) and 1,1,1,3,3,3-hexafluoro-2-propanol (12 mL) were added to a 50 mL round bottom flask. The resulting mixture was then stirred at room temperature for 16 hours and turned yellow. The reaction mixture was washed with Na 2 O 3 S 2 The mixture was quenched with aqueous solution (50 mL, 2N) and extracted with EtOAc (50 mL×3). The combined organic extracts were purified by anhydrous Na 2 SO 4 Dry, filter and concentrate the filtrate to dryness in vacuo to give (R)-3-hydroxy-1-methyl-3-(3-(6-(2-(methylsulfinyl)pyrimidin-4-yl)pyridin-2-yl)phenyl)pyrrolidin-2-one (200 mg) as a yellow solid. MS (ESI + ):m / z=409.0.

[0810] Intermediate 48: (R,S)-3-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene 1-Methylpyrrolidin-2-one

[0811]

[0812] Step A. (R,S)-3-(5-bromo-2-fluorophenyl)-3-hydroxy-1-methylpyrrolidin-2-one. 4-Bromo-1-fluoro-2-iodobenzene (3.46 g, 11.5 mmol) and anhydrous THF (20 mL) were added to a oven dried 100 mL three-necked round bottom flask, which was then cooled to -70 °C and the resulting mixture was treated with n-BuLi (2.5 M in hexanes, 4.60 mL, 11.5 mmol) in batches over 10 minutes. The reaction mixture was stirred at this temperature for 30 minutes and then treated with a second solution of 1-methylpyrrolidine-2,3-dione (1.00 g, 8.84 mmol) and anhydrous THF (3 mL) in batches over 10 minutes. The final mixture was stirred for an additional 30 minutes. The reaction mixture was washed with NH 4 Aqueous Cl solution (10 mL, 2N) and H 2 O (10 mL), then removed from the dry ice / EtOH bath, then allowed to warm to room temperature, extracted with EtOAc (20 mL×3), and the combined extracts were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness in vacuo to give an off-white solid. The solid was chromatographed on silica gel (0-60% ethyl acetate / petroleum ether) followed by HPLC (Welch Xtimate C18 column, 5 μm, 150×30 mm; eluent: 20%-50% (v / v) CH 3 CN and H 2 O, containing 0.225% HCOOH), and lyophilized to give (R,S)-3-(5-bromo-2-fluorophenyl)-3-hydroxy-1-methylpyrrolidin-2-one (670 mg, 34%) as a white solid. MS (ESI + ):m / z=287.5. 1 H NMR (400MHz, CD 3 OD)δ7.84-7.81(m,1H),7.49-7.45(m,1H),7.04-7.00(m,1H),3.67-3.57(m ,1H),3.50-3.45(m,1H),2.94(s,3H),2.48-2.40(m,1H),2.29-2.22(m,1H).

[0813] Step B. (R,S)-3-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one. (R,S)-3-(5-bromo-2-fluorophenyl)-3-hydroxy-1-methylpyrrolidin-2-one (100 mg, 346 μmol) and B 2 pin 2(176mg, 692μmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (28.3 mg, 34.6 μmol), KOAc (102 mg, 1.04 mmol), a stirring bar and anhydrous 1,4-dioxane (6 mL) were added to an oven-dried and N 2 The resulting mixture was heated to 100°C for 16 hours and turned black. The reaction vessel was removed from the oil bath and allowed to cool to room temperature and then passed through a celite pad (e.g., ) was filtered and the filter cake was rinsed with EtOAc (10 mL×3). The filtrate was concentrated to dryness in vacuo to give a brown solid, which was subjected to silica gel chromatography (0-60% ethyl acetate / petroleum ether) to give (R,S)-3-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (100 mg, 69%) as a white solid. MS (ESI + ):m / z=335.7. 1 H NMR (400 MHz, CDCl 3 )δ8.09-8.06(m,1H),7.77-7.73(m,1H),7.05-7.01(m,1H),3.57-3.41(m,2H),2.99(s,3H),2.51-2.35(m,2H),1.34(s,12H).

[0814] Intermediate 49: (R,S)-3-(3-chloro-5-fluorophenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0815]

[0816] Step A. (3-Chloro-5-fluorophenyl)magnesium bromide. Mg (790 mg, 30.0 mmol), iodine (61 mg, 0.24 mmol) and anhydrous THF (3 mL) were added to a 100 mL three-necked round bottom flask at room temperature and then heated at 60° C. for 5 minutes. A solution of 1-bromo-3-chloro-5-fluorobenzene (5.0 g, 24 mmol) in anhydrous THF (7 mL) was added over about 5 minutes, and the mixture was heated at 65° C. for 30 minutes. The mixture was cooled to room temperature and used in the next step without purification.

[0817] Step B. (R,S)-3-(3-chloro-5-fluorophenyl)-3-hydroxy-1-methylpyrrolidin-2-one. 1-Methylpyrrolidine-2,3-dione (1.00 g, 8.84 mmol) and anhydrous THF (3 mL) were combined and then cooled to -78 °C and charged with (3-chloro-5-fluorophenyl)magnesium bromide (5.17 mL, 8.84 mmol). The mixture was stirred at -78 °C for 2 hours. The mixture was added to saturated NH 4 The product was dissolved in aqueous Cl solution (5 mL) and extracted with EtOAc (10 mL×3). The combined organic extracts were washed with brine (10 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate the filtrate to dryness in vacuo to give a yellow oil. The yellow oil was chromatographed on silica gel (0-100% EtOAc / petroleum ether) to give (R,S)-3-(3-chloro-5-fluorophenyl)-3-hydroxy-1-methylpyrrolidin-2-one (200 mg, 9%) as a yellow solid.

[0818] Intermediate 50: (R,S)-3-(3-chloro-4-fluorophenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0819]

[0820] Step A. (3-Chloro-4-fluorophenyl)magnesium bromide. Mg (754 mg, 28.6 mmol), iodine (61 mg, 0.24 mmol) and anhydrous THF (3 mL) were added to a three-necked round-bottom flask at room temperature and heated at 60° C. for 5 minutes. A solution of 4-bromo-2-chloro-1-fluorobenzene (5.0 g, 24 mmol) in anhydrous THF (7 mL) was added over about 5 minutes, and the mixture was heated at 65° C. for 30 minutes. The mixture was cooled to room temperature and used in the next step without purification.

[0821] Step B. (R,S)-3-(3-chloro-4-fluorophenyl)-3-hydroxy-1-methylpyrrolidin-2-one. 1-Methylpyrrolidine-2,3-dione (1.5 g, 13 mmol) and anhydrous THF (5 mL) were combined and then cooled to -78°C. (3-chloro-4-fluorophenyl)magnesium bromide (6.20 mL, 13.3 mmol) was then charged to the mixture and the resulting mixture was stirred at -78°C for 2 hours. The mixture was added to saturated NH 4 The solution was added with aqueous Cl (15 mL) and extracted with EtOAc (10 mL×3). The combined organic extracts were washed with brine (10 mL) and washed with anhydrous Na 2 SO 4Dry, filter and concentrate the filtrate to dryness in vacuo to give a yellow oil. The yellow oil was chromatographed on silica gel (eluent: 50%-100% EtOAc / petroleum ether) to give (R,S)-3-(3-chloro-4-fluorophenyl)-3-hydroxy-1-methylpyrrolidin-2-one (480 mg, 15%) as a yellow solid.

[0822] Intermediate 51: (R,S)-3-(2-bromopyridin-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one

[0823]

[0824] Isopropylmagnesium chloride lithium chloride complex (1.30M THF solution, 244mL, 1.00 equivalent) was added dropwise to a solution of 2-bromo-4-iodopyridine (90.0g, 317mmol, 1.00 equivalent) in THF (100mL) at 0°C. The reaction mixture was stirred at this temperature for 30 minutes. 1-Methylpyrrolidine-2,3-dione (35.9g, 317mmol, 1.00 equivalent) was added as a solid at one time and the resulting mixture was stirred at 0°C for 1 hour. The temperature was then raised to 25°C and the reaction mixture was stirred for 12 hours. The reaction mixture was stirred by adding saturated NH 4 The mixture was diluted with aqueous Cl (200 mL), then further diluted with water (300 mL), and extracted with 1500 mL EtOAc (300 mL×5). The combined organic layers were washed with brine (300 mL×1) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give a residue. The residue was purified by FCC (silica, 0-100% ethyl acetate / petroleum ether) to give (R,S)-3-(2-bromopyridin-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (37.0 g, 121.05 mmol, 38%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.35(d,J=4.75Hz,1H),7.59(d,J=1.00Hz,1H),7.38(dd,J=5.19,1.56Hz,1H),6.43(s,1H ),3.35-3.51(m,2H),2.83(s,3H),2.29-2.40(m,1H),2.22(ddd,J=13.38,8.13,5.00Hz,1H). MS(ESI + ):m / z=273.1.

[0825] Intermediate 52 and Intermediate 53: (R)-3-(2-bromopyridin-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one and (S)-3-(2-Bromopyridin-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one

[0826]

[0827] The (R) and (S) enantiomers of (R,S)-3-(2-bromopyridin-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 51, 37.0 g, 121.05 mmol) were subjected to chiral SFC using a CHIRALPAK-AD column, 250×50 mm ID, 10 μm column (mobile phase: A is CO 2 and B is methanol (0.1% NH 3 ·H 2 O); gradient: B 25%; flow rate: 140 mL / min; back pressure: 100 bar; column temperature: 40°C; wavelength: 220 nM) to give: the first eluting peak, which was designated as enantiomer 1 of 3-(2-bromopyridin-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (intermediate 52) (10.0 g, 27%). The enantiomeric excess (retention time = 1.324 minutes [first eluting peak], ee% = 100%) was determined by analytical SFC using a Waters UPC2 analytical SFC (SFC-E) instrument equipped with a CHIRALPAK AD, 50×4.6 mm ID, 3 μm column (mobile phase: A is CO 2 and B was methanol (0.05% DEA); gradient: 5% to 40% B in 2.5 min and hold at 40% for 0.5 min, then 5% B for 1 min; flow rate: 4 mL / min; back pressure: 100 bar; column temperature: 35° C.; wavelength: 220 nM). 1 H NMR (400 MHz, DMSO-d 6 )δ8.34(d,J=5.25Hz,1H),7.59(d,J=0.88Hz,1H),7.38(dd,J=5.19,1.44Hz, 1H),6.43(s,1H),3.35-3.50(m,2H),2.83(s,3H),2.30-2.39(m,1H),2.23(br dd,J=8.07,5.07Hz,1H). MS(ESI + ):m / z=273.2. [α] 20 D = -32 (c = 0.1 in MeOH).

[0828] The second eluting peak was assigned as Enantiomer 2 of 3-(2-bromopyridin-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 53) (10.0 g, 27%, ee% = 100%). 1 H NMR (400 MHz, DMSO-d 6)δ8.34(d,J=5.13Hz,1H),7.59(d,J=0.88Hz,1H),7.38(dd,J=5.19,1.44Hz,1H),6 .43(s,1H),3.35-3.51(m,2H),2.83(s,3H),2.30-2.39(m,1H),2.17-2.26(m,1H). MS(ESI + ):m / z=271.2. [α] 20 D =+21 (c=0.1 in MeOH). SFC Rt=1.217 min.

[0829] Intermediate 54: (R,S)-3-(5-bromopyridin-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one

[0830]

[0831] To a solution of 3,5-dibromopyridine (100 g, 422 mmol) in THF (1000 mL) was added isopropylmagnesium chloride lithium chloride complex (1.30 M in THF, 357 mL) at 0°C. The reaction mixture was stirred at this temperature for 30 minutes. 1-Methylpyrrolidine-2,3-dione (43.0 g, 380 mmol) was added as a solid at one time and the resulting mixture was stirred at 0°C for 1 hour. The reaction mixture was washed with saturated NH at 0°C. 4 The solution was diluted with aqueous Cl solution (200 mL), then further diluted with water (300 mL) and extracted with ethyl acetate (1500 mL, 300 mL×5). The combined organic layers were washed with brine (300 mL×1) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give a residue. The residue was purified by FCC (silica, 0-100% ethyl acetate / petroleum ether) to give (R,S)-3-(5-bromopyridin-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (28.9 g, 99.0 mmol, 23%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.63(d,J=2.13Hz,1H),8.55(d,J=1.88Hz,1H),8.00(t,J=2.13Hz,1H),6.38(s,1H),3.35-3.50( m,2H),2.83(s,3H),2.43(ddd,J=13.35,7.91,5.38Hz,1H),2.24(ddd,J=13.35,8.04,5.13Hz,1H). MS(ESI + ):m / z=273.1.

[0832] Intermediate 55 and Intermediate 56: (R)-3-(5-bromopyridin-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one and (S)-3-(5-bromopyridin-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one

[0833]

[0834] The (R) and (S) enantiomers of (R,S)-3-(5-bromopyridin-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 54, 28.9 g, 99.0 mmol) were subjected to chiral SFC using a CHIRALPAK-AD column, 300×50 mm ID, 10 μm column (mobile phase: A is CO 2 and B is methanol; gradient: B 40%; flow rate: 200 mL / min; back pressure: 100 bar; column temperature: 38°C; wavelength: 220 nM) to give the first eluting peak, which was designated as enantiomer 1 of 3-(5-bromopyridin-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 55) (10.0 g, 35%). The enantiomeric excess (retention time = 1.763 minutes [second eluting peak], ee% = 99.7%) was determined by analytical SFC using a Waters UPC2 analytical SFC (SFC-H) instrument equipped with a CHIRALPAK AD, 150×4.6 mm ID, 3 μm column (mobile phase: A is CO 2 and B is methanol (0.05% DEA); gradient: B 40%; flow rate: 2.5 mL / min; back pressure: 100 bar; column temperature: 35° C.; wavelength: 220 nM). 1 H NMR (400 MHz, DMSO-d 6): δ8.63(d,J=2.13Hz,1H),8.55(d,J=1.88Hz,1H),8.00(t,J=2.06Hz,1H),6.38(s,1H),3.37-3.49( m,2H),2.83(s,3H),2.43(ddd,J=13.41,7.91,5.32Hz,1H),2.24(ddd,J=13.35,8.04,5.13Hz,1H). MS(ESI + ):m / z=271.2. [α] 20 D = -36 (c = 0.1 in MeOH).

[0835] The second eluting peak was assigned as Enantiomer 2 of 3-(5-bromopyridin-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 56) (10.0 g, 35%, ee% = 100%). 1 H NMR (400 MHz, DMSO-d 6): δ8.62(d,J=2.13Hz,1H),8.54(d,J=1.88Hz,1H),8.00(t,J=2.13Hz,1H),6.38(s,1H),3 .37-3.49(m,2H),2.82(s,3H),2.42(ddd,J=13.35,7.91,5.38Hz,1H),2.19-2.28(m,1H). MS(ESI + ):m / z=271.2. [α] 20 D =+26 (c=0.1 in MeOH). SFC Rt=1.473 min.

[0836] Intermediate 57: (R,S)-3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)pyridin-2-yl)-1H-pyrrolidone Tert-Butyl oxadiazole-1-carboxylate

[0837]

[0838] (R,S)-3-(2-bromopyridin-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 51, 0.2 g, 0.738 mmol), 1-tert-butyloxycarbonyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (282.1 mg, 0.959 mmol), bis(triphenylphosphine)palladium(II) dichloride (51.78 mg, 0.0738 mmol), K 2 CO 3 (1M H 2 A mixture of 1,4-dioxane (8 mL) and 1,4-dioxane (10 mL) was heated at 70 °C for 2 h and then at 40 °C for 16 h. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic extract was washed with anhydrous MgSO 4 The residue was purified by FCC (gradient 0->15% MeOH in DCM) to give (R,S)-tert-butyl 3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)pyridin-2-yl)-1H-pyrazole-1-carboxylate (22 mg, 8%) as a colorless oil. MS (ESI + ):m / z=359.1.

[0839] Intermediate 58: (R,S)-3-(6'-chloro-[2,2'-bipyridinyl]-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one

[0840]

[0841] A mixture of (R,S)-3-(2-bromopyridin-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 51, 250 mg, 0.922 mmol), 6-chloro-2-(tributylstannyl)pyridine (408.4 mg, 1.014 mmol), tetrakis(triphenylphosphine)palladium(0) (213 mg, 0.184 mmol) and toluene (2 mL, 0.867 g / mL, 18.819 mmol) was heated in a microwave reactor at 130 °C for 1 hour and then at 160 °C for another hour. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic extract was washed with anhydrous MgSO 4 The residue was purified by FCC (silica, gradient 50%-100% EtOAc in hexanes) to give (R,S)-3-(6'-chloro-[2,2'-bipyridyl]-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (90 mg, 32%) as a white powder. MS (ESI + ):m / z=304.0.

[0842] Intermediate 59: (R,S)-3-(2-(4-bromothiazol-2-yl)pyridin-4-yl)-3-hydroxy-1-methylpyrrolidine-2-yl ketone

[0843]

[0844] Step A: (R,S)-3-Hydroxy-1-methyl-3-(2-(trimethylstannyl)pyridin-4-yl)pyrrolidin-2-one. A mixture of (R,S)-3-(2-bromopyridin-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 51, 350 mg, 1.291 mmol), hexamethylditin (423 mg, 1.29 mmol), tetrakis(triphenylphosphine)palladium(0) (149.183 mg, 0.129 mmol) and 1,4-dioxane (2.5 mL) was heated at 110 °C for 2 h. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic extract was washed with anhydrous MgSO 4 Drying, filtration and concentration gave (R,S)-3-hydroxy-1-methyl-3-(2-(trimethylstannyl)pyridin-4-yl)pyrrolidin-2-one (262.2 mg, 57%) as a beige powder. MS (ESI + ):m / z=357.0.

[0845] Step B: (R,S)-3-(2-(4-bromothiazol-2-yl)pyridin-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one. A mixture of (R,S)-3-hydroxy-1-methyl-3-(2-(trimethylstannyl)pyridin-4-yl)pyrrolidin-2-one (100 mg, 0.282 mmol), 2,4-dibromothiazole (205 mg, 0.845 mmol), tetrakis(triphenylphosphine)palladium(0) (48.8 mg, 0.0423 mmol) and DMF (2.8 mL) was heated in a microwave reactor at 120 °C for 1 hour and then at 140 °C for another hour. The mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with anhydrous MgSO 4 Dry, filter and concentrate. The residue was purified by chromatography (silica, gradient 50->100% in hexanes and 10% MeOH-EtOAc) to give (R,S)-3-(2-(4-bromothiazol-2-yl)pyridin-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (17.2 mg, 17%).

[0846] Intermediate 60: 4,4-difluoro-3,3-dihydroxy-1-methylpyrrolidin-2-one

[0847]

[0848] Step A. (E)-1-methyl-3-((1-phenylethyl)imino)pyrrolidin-2-one. To a 20 L 4-necked round-bottom flask was added 1-methylpyrrolidine-2,3-dione (346 g, 3058.80 mmol), MgSO 4 (368.16g, 3058.80mmol) and DCM (7L). (+ / -)-α-methylbenzylamine (389.21g, 3211.74mmol) and TFA (0.2mL) were added thereto at room temperature. The resulting mixture was stirred overnight at 40 °C under a nitrogen atmosphere. The mixture was cooled to room temperature. The solid was filtered out and washed with DCM (1×1L). The filtrate was collected and concentrated under reduced pressure. The product was slurried with ether (1.5L). The solid was collected by filtration. This produced (3E)-1-methyl-3-[(1-phenylethyl)imino]pyrrolidin-2-one (540g) as a purple solid. 1 HNMR (300 MHz, DMSO-d 6 )δ7.39-7.08(m,5H),5.41(d,J=7.0Hz,1H),4.88(t,J=2.4Hz,1H),4.30-4.13(m,1H),3.76-3.52(m,2H),2.89(s,3H),1.40(d,J=6.8Hz,3H).

[0849] Step B. 4,4-difluoro-3,3-dihydroxy-1-methylpyrrolidin-2-one. In a 10 L 4-necked round-bottom flask, (3E)-1-methyl-3-[(1-phenylethyl)imino]pyrrolidin-2-one (540 g, 2496.71 mmol), Na 2 SO 4 (510.5 g, 3595.26 mmol) and acetonitrile (5.4 L). Select-F (1945.87 g, 5492.77 mmol) was added portionwise thereto at 0 °C. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with acetonitrile (5.4 L). HCl / 1,4-dioxane (4N, 936 mL) was added dropwise to the mixture at 0 °C. The resulting mixture was stirred at room temperature for another hour. The resulting precipitate was filtered off 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: CH 3 CN / H 2 O (0.1% NH 4 HCO 3 ) = 1% to 15% purification to afford 4,4-difluoro-3,3-dihydroxy-1-methylpyrrolidin-2-one (122 g, 23.9% for two steps) as an off-white solid. 1 H NMR (300 MHz, DMSO-d 6 )δ7.29(s,2H),3.65(t,J=12.0Hz,2H),2.80(s,3H).

[0850] Intermediate 61: 1-Methyl-5-(trifluoromethyl)pyrrolidine-2,3-dione

[0851]

[0852] Step A. Ethyl 4,4,4-trifluoro-3-(methylamino)butanoate To a solution of ethyl (E)-4,4,4-trifluorobut-2-enoate (4400 g, 26.17 mol, 3.89 L) in THF (18.0 L) was added MeNH 2 (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 without further purification. 1 H 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).

[0853] Step B. 4-Hydroxy-1-methyl-5-oxo-2-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester. At 25 °C under N 2 To a solution of ethyl 4,4,4-trifluoro-3-(methylamino)butanoate (2400 g, 12.05 mol) in 2-MeTHF (24000 mL) was added t-BuOK (1.35 kg, 12.05 mol) and diethyl oxalate (1.76 kg, 12.05 mol, 1.65 L) under N atmosphere. 2 The reaction mixture was heated at 60°C for 3 hours under a C atmosphere. The reaction mixture was heated by adding NH 4 Cl (saturated aqueous solution, 10.0 L), the pH of the mixture was adjusted to pH = 2-3 with 1M HCl aqueous solution (9.00 L), and the resulting mixture was extracted twice with EtOAc (5.00 L). The combined organic extracts were washed with brine (15.0 L), and the mixture was purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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, 69%) 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).

[0854] Step C. 1-methyl-5-(trifluoromethyl)pyrrolidine-2,3-dione. A mixture of 4-hydroxy-1-methyl-5-oxo-2-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester (2000 g, 7.90 mol) in HCl (10.96 kg, 10.75 L, 36% aqueous solution) was heated at 110°C for 16 hours. The reaction mixture was cooled to 20°C and extracted with isopropyl acetate (5000 mL×8). The combined organic extracts were washed with brine (10000 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give a residue. The residue was triturated with MTBE (5000 mL) at 25°C for 3 hours. The solid was filtered, washed with MTBE (1000 mL) and dried under reduced pressure 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).

[0855] Intermediate 62: (R,S)-3-(3-(4-bromothiazol-2-yl)phenyl)-4,4-difluoro-3-hydroxy-1-methylpyrrole Alkane-2-one

[0856]

[0857] Step A: (3-bromophenyl)lithium. n-BuLi (2.016 mL, 2.5 M in hexanes) was added to a solution of dibromobenzene (0.581 mL, 1 eq.) in THF (4 mL, 1.2 M) at -78°C over 5 min. The resulting solution was stirred for 30 min and then used in the next step.

[0858] Step B: (R,S)-3-(3-bromophenyl)-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one. 4,4-difluoro-3,3-dihydroxy-1-methylpyrrolidin-2-one (Intermediate 60, 500 mg, 2.992 mmol) was dissolved in TFAA (7.48 mL, 2.992 mmol) and heated at 40 ° C for 1 hour. The resulting mixture was cooled to room temperature and concentrated. THF was then added and the solution was cooled to -78 ° C. (3-bromophenyl) lithium (5.3 mL, 1.3 equiv) from step A was added dropwise to the solution at -78 ° C and the resulting mixture was stirred for 1 hour. The resulting mixture was diluted with MeOH, filtered and concentrated. The residue was purified by FCC to give (R,S)-3-(3-bromophenyl)-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one (321.6 mg, 35%) as a white solid. MS (ESI + ):m / z=308.0.

[0859] Step C: (R,S)-4,4-difluoro-3-hydroxy-1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one. A mixture of (R,S)-3-(3-bromophenyl)-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one (213 mg, 0.696 mmol), bis(pinacolato)diboron (247 mg, 0.974 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (55 mg, 0.0696 mmol), potassium acetate (273 mg, 2.783 mmol) and 1,4-dioxane (3.5 mL) was heated at 110° C. for 2 hours. The mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated and purified by FCC (100% hexanes) to give (R,S)-4,4-difluoro-3-hydroxy-1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (240 mg, 98%) as a yellow oil.

[0860] Step D: (R,S)-3-(3-(4-bromothiazol-2-yl)phenyl)-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one. (R,S)-4,4-difluoro-3-hydroxy-1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (240 mg, 0.68 mmol), 2,4-dibromothiazole (214 mg, 0.883 mmol), PdCl 2 (dppf) (50 mg, 0.068 mmol), K 2 CO 3 (2M H 2 O solution, 1.359 mL, 2.718 mmol) and 1,4-dioxane (4.5 mL) were heated at 110 °C for 4 hours. The mixture was cooled to room temperature, filtered through celite and purified by FCC (0-100% EtOAc in hexanes) to give (R,S)-3-(3-(4-bromothiazol-2-yl)phenyl)-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one. MS (ESI + ):m / z=388.9.

[0861] Intermediate 63: 4-(4-bromothiazol-2-yl)-N-(1-(1-methyl-1H-pyrazol-3-yl)ethyl)pyrimidin-2-amine

[0862]

[0863] 4-Bromo-2-(2-(methylsulfonyl)pyrimidin-4-yl)thiazole (Intermediate 10, 250 mg, 0.781 mmol), 1-(1-methyl-1H-pyrazol-3-yl)ethanamine (195.467 mg, 1.562 mmol), TFA (0.149 mL, 1.49 g / mL, 1.952 mmol) and DMSO (2 mL, 1.092 g / mL, 27.952 mmol) were combined and heated in a microwave reactor at 150 °C for 1 hour. After cooling to room temperature, the reaction mixture was washed with ethyl acetate (100 mL) and water (3 x 100 mL). The organic extract was washed with anhydrous MgSO 4 Dry, filter and concentrate under reduced pressure. The material was purified by chromatography (gradient 0-100% EtOAc in hexanes) to give a beige solid, 4-(4-bromothiazol-2-yl)-N-(1-(1-methyl-1H-pyrazol-3-yl)ethyl)pyrimidin-2-amine (111.3 mg, 39%). 1 H NMR (500 MHz, CDCl 3 )δ8.43(d,J=5.0Hz,1H),7.37(s,1H),7.31(dd,J=5.0,0.7Hz,1H),7.27(d,J=2.2Hz,1H),6.19 (d,J=2.2Hz,1H),5.77(d,J=7.6Hz,1H),5.34-5.26(m,1H),3.88(s,3H),1.62(d,J=6.8Hz,4H). MS(ESI + ):m / z=366.

[0864] Intermediate 64: 4-(4-bromothiazol-2-yl)-N-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)pyrimidin-2-amine

[0865]

[0866] 4-Bromo-2-(2-(methylsulfonyl)pyrimidin-4-yl)thiazole (Intermediate 10, 250 mg, 0.781 mmol), 1-(1-methyl-1h-pyrazol-4-yl)ethanamine (195.467 mg, 1.562 mmol), DIPEA (0.149 mL, 0.75 g / mL, 0.867 mmol) and DMA (2 mL, 0.941 g / mL, 21.602 mmol) were combined and heated in a microwave reactor at 150 °C for 1 hour. After cooling to room temperature, the reaction mixture was washed with ethyl acetate (100 mL) and water (3 x 100 mL). The organic extract was washed with anhydrous MgSO 4Dry, filter and concentrate under reduced pressure.The material was then purified by chromatography (gradient 0-100% EtOAc in hexanes) to give a solid, 4-(4-bromothiazol-2-yl)-N-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)pyrimidin-2-amine (191.9 mg, 67%). 1 H NMR (500 MHz, DMSO-d 6 )δ8.51-8.45(m,1H),8.08(s,1H),7.77-7.70(m,1H),7.58(s,1H),7.40-7.36(m, 1H), 7.16 (d, J = 4.9Hz, 1H), 5.20-5.06 (m, 2H), 3.76 (s, 3H), 1.47 (d, J = 6.9Hz, 3H). MS(ESI + ):m / z=365.1.

[0867] Intermediate 65: N-(1-(1H-pyrazol-3-yl)ethyl)-4-(4-bromothiazol-2-yl)pyrimidin-2-amine

[0868]

[0869] 4-Bromo-2-(2-(methylsulfonyl)pyrimidin-4-yl)thiazole (Intermediate 10, 144.04 mg, 0.45 mmol), 1-(1H-pyrazol-3-yl)ethan-1-amine (100 mg, 0.9 mmol), DIPEA (0.31 mL, 0.75 g / mL, 1.799 mmol) and DMA (1 mL, 1.092 g / mL, 13.976 mmol) were combined and heated in a microwave reactor at 150 °C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and extracted with water (3 x 100 mL). The organic extract was washed with anhydrous MgSO 4 Drying, filtration and concentration followed by purification by chromatography (gradient 0-100% EtOAc in hexanes) gave N-(1-(1H-pyrazol-3-yl)ethyl)-4-(4-bromothiazol-2-yl)pyrimidin-2-amine (91 mg, 57% yield) as a yellow solid. 1 HNMR (500 MHz, DMSO-d 6 )δ12.65-12.38(m,1H),8.49(d,J=4.9Hz,1H),8.08(s,1H),7.92-7.63(m,1H),7.63- 7.35(m,1H),7.18(d,J=4.9Hz,1H),6.20(s,1H),5.28(s,1H),1.50(d,J=6.9Hz,3H). MS(ESI + ):m / z=352.1.

[0870] Example 1: (R)-3-hydroxy-1-methyl-3-(3-(4-(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidine- 4-yl)oxazol-2-yl)phenyl)pyrrolidin-2-one

[0871]

[0872] A mixture of N-(1-methyl-1H-pyrazol-3-yl)-4-(trimethylstannyl)pyrimidin-2-amine (Intermediate 1, 150 mg), (R)-3-(3-(4-bromooxazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 2, 100 mg, 0.297 mmol), tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.030 mmol), cuprous iodide (11 mg, 0.059 mmol) and DMF (1.3 mL) was heated to 80 °C for 2 hours and then at 100 °C overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with anhydrous MgSO 4 The mixture was dried, filtered and concentrated under reduced pressure. (R)-3-hydroxy-1-methyl-3-(3-(4-(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)oxazol-2-yl)phenyl)pyrrolidin-2-one was purified by FCC (0% to 15% MeOH in DCM) followed by RP HPLC (acidic conditions, column C1) to give (R)-3-hydroxy-1-methyl-3-(3-(4-(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)oxazol-2-yl)phenyl)pyrrolidin-2-one as a yellow powder as its trifluoroacetate salt (28 mg, 22%). 1 H NMR (500 MHz, DMSO-d 6 )δ9.90(s,1H),8.86(s,1H),8.55(d,J=5.0Hz,1H),8.15(t,J=1.8Hz,1H),7.97(dt,J=7.5,1.5Hz,1H),7.61-7.48(m,3H),7. 30(d,J=5.0Hz,1H),6.69(d,J=2.2Hz,1H),3.77(s,3H),2.87(s,3H),2.36(ddd,J=13.1,7.8,5.2Hz,1H),2.32-2.24(m,1H). 19 F NMR (471 MHz, DMSO-d 6 )δ-74.65. MS (ESI + ):m / z=432.3.

[0873] Example 2: (R)-3-hydroxy-1-methyl-3-(3-(1-(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidine- 4-yl)-1H-pyrazol-3-yl)phenyl)pyrrolidin-2-one

[0874]

[0875] (R)-3-(3-(1H-pyrazol-3-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 3, 100 mg, 0.389 mmol), 4-chloro-N-(1-methylpyrazol-3-yl)pyrimidin-2-amine (122 mg, 0.583 mmol), Cs 2 CO 3 A mixture of (253 mg, 0.777 mmol) and DMF (2 mL) was heated at 100 °C for 30 min and then at 115 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic extract was washed with anhydrous MgSO 4 The mixture was dried, filtered and concentrated under reduced pressure. The residue was purified by RP HPLC (basic, column C2) to give (R)-3-hydroxy-1-methyl-3-(3-(1-(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)-1H-pyrazol-3-yl)phenyl)pyrrolidin-2-one (61.5 mg, 36%) as a white powder. 1 H NMR (400 MHz, DMSO-d 6 )δ9.97(s,1H),8.60(d,J=2.7Hz,1H),8.54(d,J=5.4Hz,1H),8.08-7.95(m,1H),7.91-7.80(m,1H),7.60(d ,J=2.2Hz,1H),7.45(t,J=7.7Hz,1H),7.36(ddd,J=7.8,1.9,1.2Hz,1H),7.29(d,J=5.4Hz,1H),7.13(d,J=2 .7Hz,1H),6.63(d,J=2.2Hz,1H),6.10(s,1H),3.77(s,3H),3.47(ddd,J=9.9,8.1,4.9Hz,1H),3.38(ddd,J =9.9,7.7,6.2Hz,1H),2.86(s,3H),2.38(ddd,J=12.7,7.6,4.9Hz,1H),2.27(ddd,J=13.4,8.1,5.7Hz,1H). MS(ESI + ):m / z=431.1.

[0876] Example 3: (R)-3-Hydroxy-1-methyl-3-(3-(2-(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidine- 4-yl)thiazol-4-yl)phenyl)pyrrolidin-2-one

[0877]

[0878] 4-(4-bromothiazol-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine (Intermediate 4, 20 mg, 0.059 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4.4 mg, 0.0059 mmol), K 2 CO 3 (0.15 mL, 1 M H 2 O solution, 0.15 mmol), 1,4-dioxane (0.5 mL) and (R)-3-hydroxy-1-methyl-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-2-one (22.6 mg, 0.0712 mmol) were heated at 80 ° C for 1 hour and then cooled to room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with anhydrous MgSO 4 The mixture was dried, filtered and concentrated under reduced pressure. The residue was purified by RP HPLC (acidic conditions, column C1) and then filtered through a carbonate cartridge to give (R)-3-hydroxy-1-methyl-3-(3-(2-(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)thiazol-4-yl)phenyl)pyrrolidin-2-one (9.3 mg, 35%) as a yellow powder. 1 H NMR (600 MHz, DMSO-d 6 )δ10.04(s,1H),8.63(d,J=4.9Hz,1H),8.35(s,1H),8.09(t,J=1.8Hz,1H),7.95(ddd, J=7.7,1.8,1.1Hz,1H),7.63(d,J=2.2Hz,1H),7.51(d,J=4.9Hz,1H),7.45(t,J=7.7Hz, 1H),7.36(ddd,J=7.8,1.8,1.1Hz,1H),6.80-6.64(m,2H),6.10(s,1H),3.78(s,3H),3. 51-3.43(m,1H),3.42-3.35(m,1H),2.87(s,3H),2.43-2.36(m,1H),2.32-2.24(m,1H). MS(ESI + ):m / z=448.1.

[0879] Example 4: (R)-3-hydroxy-1-methyl-3-(3-(2-(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidine- 4-yl)oxazol-4-yl)phenyl)pyrrolidin-2-one

[0880]

[0881] 4-(4-bromooxazol-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine (Intermediate 5, 10 mg, 0.031 mmol), (R)-3-hydroxy-1-methyl-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-2-one (12.8 mg, 0.0405 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.3 mg, 0.0031 mmol), K 2 CO 3 (0.080 mL, 1 M H 2 A mixture of 1,4-dioxane (0.3 mL) and 1,4-dioxane (0.080 mmol) was heated at 80 °C for 4 h. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic extract was washed with anhydrous MgSO 4 The mixture was dried, filtered and concentrated under reduced pressure. The residue was purified by RP HPLC (basic, column C2) to give (R)-3-hydroxy-1-methyl-3-(3-(2-(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)oxazol-4-yl)phenyl)pyrrolidin-2-one (6.9 mg, 51%) as a yellow solid. 1 H NMR (600 MHz, DMSO-d 6 )δ10.09(s,1H),8.89(s,1H),8.63(d,J=4.9Hz,1H),7.96-7.89(m,1H),7.81-7.74(m,1H),7.62-7.55(m,1H),7.49-7.39(m,2H),7.37-7.2 9(m,1H),6.77(s,1H),6.10(s,1H),3.76(s,2H),3.51-3.43(m,1H),3 .41-3.35(m,1H),2.87(s,2H),2.39-2.31(m,1H),2.31-2.23(m,1H). MS(ESI + ):m / z=432.4.

[0882] Example 5: (R)-3-hydroxy-1-methyl-3-(3-(2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidine- 4-yl)thiazol-4-yl)phenyl)pyrrolidin-2-one

[0883]

[0884] 4-(4-bromothiazol-2-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (Intermediate 14, 21 mg, 0.0623 mmol), (R)-3-hydroxy-1-methyl-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-2-one (39.508 mg, 0.125 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.294 mg, 0.00311 mmol), K 2 CO 3 A mixture of (0.156 mL, 1 M, 0.156 mmol) and 1,4-dioxane (0.4 mL, 1.033 g / mL, 4.69 mmol) was heated at 80 °C for 1 hour. Then, the reaction mixture was diluted with ethyl acetate (15 mL) and extracted with (3 × 15 mL) water. The organic layer was washed with anhydrous MgSO 4 Dry, filter and concentrate. The residue was purified by RP HPLC (basic, column C8) to give (R)-3-hydroxy-1-methyl-3-(3-(2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)thiazol-4-yl)phenyl)pyrrolidin-2-one (26.8 mg, 25%). 1 H NMR (500 MHz, DMSO-d 6 )δ9.73(s,1H),8.67(d,J=5.0Hz,1H),8.35(s,1H),8.08(t,J=1.8Hz,1H),7.94(dt,J= 7.7,1.8,1.1Hz,1H),7.60(d,J=5.0Hz,1H),7.45(t,J=7.7Hz,1H),7.39(d,J=1.9Hz,1 H),7.36(dt,J=7.8,1.9,1.1Hz,1H),6.36-6.31(m,1H),6.10(s,1H),3.73(s,3H),3.5 1-3.44(m,1H),3.42-3.37(m,1H),2.87(s,3H),2.43-2.35(m,1H),2.32-2.24(m,1H). MS(ESI + ):m / z=448.

[0885] Example 6: (R)-3-(3-(4-(2-aminopyrimidin-4-yl)thiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidone Pyrrolidone-2-one

[0886]

[0887] (R)-3-(3-(4-(2-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)thiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 22, 400 mg, 0.773 mmol) and DCM (4 mL) were added to a 25 mL round-bottom flask and charged with TFA (4 mL). The resulting mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to pH = 9 with aqueous NaOH (2 M) and extracted with DCM (30 mL x 3). The combined extracts were washed with brine (15 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried, filtered and concentrated to dryness in vacuo to give a colorless oil. The colorless oil was then purified by HPLC (Xtimate C18, 5 μm, 150×40 mm column (isocratic: 18%-48% ACN (v / v) / water (0.05% NH 3 H 2 O))) to give (R)-3-(3-(4-(2-aminopyrimidin-4-yl)thiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (78.9 mg, 28%) as a colorless solid. MS (ESI + ):m / z=368.1. 1 H NMR (400 MHz, DMSO-d 6 ): δ8.43-8.38(m,1H),8.33(s,1H),8.12-8.08(m,1H),7.95-7.90(m,1H),7.54 -7.48(m,1H),7.46-7.41(m,1H),7.32-7.28(m,1H),6.76-6.69(m,2H),6.27(br s,1H),3.53-3.43(m,2H),2.87(s,3H),2.43-2.33(m,1H),2.33-2.22(m,1H).

[0888] Example 7: (R)-3-hydroxy-3-(3-(4-(2-((2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)thiol oxazol-2-yl)phenyl)-1-methylpyrrolidin-2-one

[0889]

[0890] (R)-3-(3-(4-bromothiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 7, 200 mg, 0.566 mmol), N-(2-methoxypyridin-3-yl)-4-(tributylstannyl)pyrimidin-2-amine (Intermediate 23, 1.0 g, 2.0 mmol), TEA (170 μL, 1.22 mmol) and toluene (13 mL) were added to a 100 mL round-bottom flask, which was subsequently evacuated and refilled with argon (×3), and then heated with Pd(PPh 3 ) 4 (66 mg, 0.057 mmol) was treated. The resulting mixture was heated at 120 ° C for 16 hours. After the reaction mixture was cooled to room temperature, the resulting mixture was stirred for 2 hours and then treated with saturated KF aqueous solution (40 mL) over a 5-minute process. The mixture was then extracted with ethyl acetate (50 mL × 3), and the combined extracts were washed with brine (300 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried, filtered and concentrated to dryness in vacuo to obtain a nearly black viscous oil. The oil was then purified by HPLC (Xtimate C18 column, 5 μm, 150×40 mm; (40%-70% (v / v) ACN / H 2 O(NH 3 ·H 2 O))) was lyophilized to give (R)-3-hydroxy-3-(3-(4-(2-((2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)thiazol-2-yl)phenyl)-1-methylpyrrolidin-2-one (51.9 mg, 19%) as a white solid. MS (ESI + ):m / z=475.2. 1 H NMR (400 MHz, DMSO-d 6 ): δ8.66(d,J=5.0Hz,1H),8.63-8.58(m,1H),8.57(s,1H),8.28(s,1H), 8.13(s,1H),7.96(d,J=7.6Hz,1H),7.88-7.82(m,1H),7.61(d,J=5.1Hz, 1H),7.55-7.50(m,1H),7.47-7.43(m,1H),7.11-7.04(m,1H),3.97(s,3H ),3.47-3.46(m,2H),2.87(s,3H),2.40-2.35(m,1H),2.32-2.26(m,1H).

[0891] Example 8: (R)-5-((4-(2-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)phenyl)thiazole-4- 2-Methyl-2-pyrimidin-2-yl)amino)-6-methylnicotinonitrile

[0892]

[0893] (R)-3-(3-(4-bromothiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 7, 50 mg, 0.14 mmol), 6-methyl-5-((4-(tributylstannyl)pyrimidin-2-yl)amino)nicotinonitrile (Intermediate 24, 71 mg, 0.14 mmol), TEA (39 μL, 0.28 mmol) and toluene (1 mL) were added to an 8 mL glass vial, which was subsequently evacuated and refilled with argon (×3) and then heated with Pd(PPh 3 ) 4 (16 mg, 0.014 mmol). The resulting mixture was heated at 120 ° C for 16 hours. The reaction vessel was removed from the oil bath and allowed to gradually cool to room temperature. The mixture was then quenched with saturated aqueous KF solution (5 mL), extracted with EtOAc (5 mL × 3) and the combined extracts were washed with brine (5 mL) and washed with anhydrous Na 2 SO 4 The solid was dried, filtered and concentrated to dryness in vacuo to give a brown solid, which was then purified by HPLC (Boston Prime C18 column, 5 μm, 150×30 mm; 40%-70% (v / v) ACN (v / v) / H 2 O(0.05% NH 3 H 2 O + 10 mM NH 4 HCO 3 )) was purified and lyophilized to give (R)-5-((4-(2-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)phenyl)thiazol-4-yl)pyrimidin-2-yl)amino)-6-methylnicotinonitrile (46.6 mg, 68%) as a colorless solid. MS (ESI + ):m / z=484.2. 1 H NMR (400 MHz, DMSO-d 6 )δ9.38(s,1H),8.68-8.61(m,2H),8.57(d,J=1.9Hz,1H),8.37(s,1H),8.13-8.08(m,1H),7.99-7.93(m,1H),7.61(d,J=5.0 Hz,1H),7.55-7.49(m,1H),7.47-7.43(m,1H),6.26(s,1H),3.49-3.47(m,2H),2.87(s,3H),2.60(s,3H),2.43-2.24(m,2H).

[0894] Example 9: (R)-3-(3-(4-(2-((3-cyclopropyloxy-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino 4-yl)pyrimidin-4-yl)thiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0895]

[0896] (R)-3-Hydroxy-1-methyl-3-(3-(4-(2-(methylsulfonyl)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one (Intermediate 12, 70.6 mg, 0.16 mmol), 3-cyclopropyloxy-1-(2,2-difluoroethyl)-1H-pyrazol-4-amine (Intermediate 25, 100 mg, 0.49 mmol), 4-methylbenzenesulfonic anhydride (28.3 mg, 0.16 mmol) and 1,4-dioxane (3 mL) were added to a 10 mL round-bottom flask equipped with a reflux condenser, and the yellow mixture was heated at 115 °C under N 2 The reaction vessel was removed from the oil bath and allowed to gradually cool to room temperature. The reaction mixture was combined with another batch (made from 100 mg of 3-cyclopropyloxy-1-(2,2-difluoroethyl)-1H-pyrazole-4-amine). The yellow mixture was washed with H 2 O (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic extracts were washed with brine (30 mL x 2) and dried over anhydrous Na 2 SO 4 Drying, filtration and concentration in vacuo gave a yellow oil which was subjected to silica gel chromatography (0-100% EtOAC / petroleum ether). The product was purified by HPLC (Boston Green ODS column, 5 μm, 150×30 mm; 35%-65% (v / v) CH 3 CN / H 2 D, containing 0.225% HCOOH) was further purified and lyophilized to give (R)-3-(3-(4-(2-((3-cyclopropyloxy-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (41.1 mg) as a white solid. MS (ESI + ):m / z=554.3. 1 H NMR (400 MHz, DMSO-d 6)δ8.54(d,J=4.8Hz,2H),8.46(s,1H),8.12(s,1H),8.01(s,1H),7.96-7. 94(m,1H),7.56-7.49(m,1H),7.45(d,J=5.2Hz,2H),6.49-6.15(m,2H),4 .55-4.48(m,2H),4.12-4.11(m,1H),3.54-3.43(m,2H),2.87(s,3H),2.4 3-2.34(m,1H),2.33-2.24(m,1H),0.76-0.69(m,2H),0.67-0.61(m,2H).

[0897] Example 10: (R)-3-((4-(2-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)phenyl)thiazole- 4-yl)pyrimidin-2-yl)amino)-N,4-dimethylbenzamide

[0898]

[0899] (R)-3-Hydroxy-1-methyl-3-(3-(4-(2-(methylsulfonyl)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one (Intermediate 12, 168 mg, 0.41 mmol), 3-amino-N,4-dimethylbenzamide (Intermediate 26, 200 mg, 1.22 mmol), 4-methylbenzenesulfonic anhydride (116 mg, 0.61 mmol) and isopropanol (3 mL) were added to a 10 mL microwave tube. The yellow mixture was heated at 120 ° C for 2 hours via microwave irradiation. The reaction vessel was taken out of the microwave reactor and allowed to gradually cool to room temperature. The yellow mixture was washed with H 2 O (10 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine (50 mL×2) and dried over anhydrous Na 2 SO 4 Drying, filtration and concentration in vacuo gave a yellow oil which was purified initially by silica gel chromatography (0-100% EtOAc / petroleum ether) and subsequently by HPLC (Boston Green ODS column, 5 μm, 150×30 mm; 27%-57% (v / v) CH 3 CN / H 2 D, containing 0.225% HCOOH) was further purified and lyophilized to give (R)-3-((4-(2-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)phenyl)thiazol-4-yl)pyrimidin-2-yl)amino)-N,4-dimethylbenzamide (47.1 mg, 31%) as a light yellow solid. MS (ESI + ):m / z=515.3. 1 HNMR (400 MHz, DMSO-d6 )δ9.01(s,1H),8.56(d,J=4.8Hz,1H),8.40-8.32(m,2H),8.19(s,1H),8.11(s,1H),7.94(d,J=8.0Hz,1H),7.58-7.48(m,3H),7.47-7.43 (m,1H),7.31(d,J=8.0Hz,1H),6.28-6.20(s,1H),3.51-3.45(m,2H),2.87(s,3H),2.78(d,J=4.8Hz,3H),2.40-2.35(m,2H),2.31(s,3H).

[0900] Example 11: (R)-3-(3-(4-(2-((1-(2,2-difluoroethyl)-3-(2-methoxyethoxy)-1H-pyrrolidone oxazol-4-yl)amino)pyrimidin-4-yl)thiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0901]

[0902] TsOH (150 mg, 0.871 mmol), (R)-3-hydroxy-1-methyl-3-(3-(4-(2-(methylsulfonyl)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one (Intermediate 12, 250 mg, 0.581 mmol), 1-(2,2-difluoroethyl)-3-(2-methoxyethoxy)-1H-pyrazol-4-amine (Intermediate 27, 488 mg, 2.21 mmol) and anhydrous 1,4-dioxane (15 mL) were added to a oven-dried and nitrogen-purged 50 mL single-necked round bottom flask equipped with a reflux condenser and the resulting mixture was heated at 115 °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 to dryness in vacuo to give a green semisolid which was initially purified by silica gel chromatography (0-8% MeOH / CH 2 Cl 2 ) and then purified by HPLC (C18 column, 5 μm, 150×25 mm; 30%-60% (v / v) CH 3 CN / H 2 D, containing 0.225% HCOOH) was further purified and lyophilized to give (R)-3-(3-(4-(2-((1-(2,2-difluoroethyl)-3-(2-methoxyethoxy)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (57.1 mg, 17%) as a yellow solid. MS (ESI + ):m / z=572.3. 1 H NMR (400 MHz, DMSO-d 6)δ8.55-8.54(m,2H),8.48(s,1H),8.12(s,1H),8.08-7.85(m,2H),7.5 6-7.48(m,1H),7.48-7.40(m,2H),6.49-6.16(m,2H),4.55-4.49(m,2H) ,4.32-4.20(m,2H),3.70-3.61(m,2H),3.52-3.44(m,1H),3.44-3.39( m,1H),3.29(s,3H),2.87(s,3H),2.42-2.33(m,1H),2.33-2.25(m,1H).

[0903] Example 12: (R)-4-cyclopropyloxy-2-fluoro-5-((4-(2-(3-(3-hydroxy-1-methyl-2-oxopyrrolidine- 3-yl)phenyl)thiazol-4-yl)pyrimidin-2-yl)amino)-N-methylbenzamide

[0904]

[0905] (R)-3-Hydroxy-1-methyl-3-(3-(4-(2-(methylsulfonyl)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one (Intermediate 12, 200 mg, 0.483 mmol), 5-amino-4-cyclopropyloxy-2-fluoro-N-methylbenzamide (Intermediate 33, 216.4 mg, 0.965 mmol) and TsOH (99.7 mg, 0.579 mmol) were added to a 20 mL microwave tube and the resulting mixture was dissolved in IPA (2.5 mL). The resulting mixture was heated at 120 °C via microwave irradiation for 3 hours. The reaction vessel was removed from the microwave reactor and allowed to gradually cool to room temperature. The mixture was concentrated in vacuo to dryness to give a green semi-solid which was initially purified by silica gel chromatography (0-8% MeOH / CH 2 Cl 2 ) and then purified by HPLC (Welch Xtimate C18 column, 5 μm, 150×25 mm; 44%-74% (v / v) CH 3 CN / H 2 D, containing 0.225% HCOOH) was further purified and lyophilized to give (R)-4-cyclopropyloxy-2-fluoro-5-((4-(2-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)phenyl)thiazol-4-yl)pyrimidin-2-yl)amino)-N-methylbenzamide as a gray solid (107.7 mg, 38%). MS (ESI + ):m / z=575.3. 1 H NMR (400 MHz, DMSO-d 6)δ8.65-8.64(m,1H),8.61-8.60(m,1H),8.56(s,1H),8.30(s,1H),8.13(s,1H),8.07-8.01 (m,1H),7.96-7.95(m,1H),7.57-7.50(m,1H),7.52(d,J=7.6Hz,1H),7.49-7.44(m,1H),7.2 6-7.25(m,1H),6.27(s,1H),4.09-4.02(m,1H),3.53-3.47(m,1H),3.54-3.43(m,1H),2.88( s,3H),2.84(d,J=4.0Hz,3H),2.43-2.35(m,1H),2.34-2.26(m,1H),0.88-0.81(m,2H),0.81 -0.73(m,2H).

[0906] Example 13: (R)-5-((4-(2-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)phenyl)thiazole- 4-yl)pyrimidin-2-yl)amino)-1-isobutyl-N-methyl-1H-pyrazole-3-carboxamide

[0907]

[0908] (R)-3-(3-(4-(2-chloropyrimidin-4-yl)thiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 35, 150 mg, 0.388 mmol), 5-amino-1-isobutyl-N-methyl-1H-pyrazole-3-carboxamide (Intermediate 34, 98.9 mg, 0.504 mmol), Cs 2 CO 3 (253 mg, 0.775 mmol), Xantphos (22.4 mg, 0.039 mmol) and 1,4-dioxane (15 mL) were added to an oven-dried and nitrogen-purged 50 mL round-bottom flask, which was treated with Pd(OAc) 2 (17.4 mg, 0.078 mmol), then evacuated and heated to 40 °C. 2 The resulting mixture was heated at 90°C for 12 hours. The reaction vessel was removed from the oil bath and allowed to gradually cool to room temperature. The reaction mixture was then diluted with EtOAc (60 mL) and washed with H 2 O (20 mL) and brine (20 mL), and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness in vacuo to give a brown solid. The brown solid was purified initially by silica gel chromatography (0-100% EtOAc / petroleum ether) and then by HPLC (Welch Xtimate C18 column, 5 μm, 150×25 mm; 35%-65% (v / v) CH 3CN / H 2 D, containing 0.225% HCOOH) was further purified and lyophilized to give (R)-5-((4-(2-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)phenyl)thiazol-4-yl)pyrimidin-2-yl)amino)-1-isobutyl-N-methyl-1H-pyrazole-3-carboxamide (11.8 mg, 38%) as a white solid. MS (ESI + ):m / z=547.3. 1 HNMR (400 MHz, MeOH-d 4 )δ8.53(d,J=5.2Hz,1H),8.38(s,1H),8.19(s,1H),7.98-7.97(m,1H), 7.67(d,J=4.8Hz,1H),7.52-7.51(m,2H),6.85(s,1H),3.97-3.96(m,2H ),3.63-3.55(m,1H),3.54-3.46(m,1H),3.00(s,3H),2.92(s,3H),2.57 -2.48(m,1H),2.47-2.38(m,1H),2.35-2.24(m,1H),0.91-0.89(m,6H).

[0909] Example 14: (R)-3-((4-(2-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)phenyl)thiazole- 4-yl)pyrimidin-2-yl)amino)-1,5-dimethylpyridin-2(1H)-one

[0910]

[0911] (R)-3-Hydroxy-1-methyl-3-(3-(4-(2-(methylsulfinyl)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one (Intermediate 38, 200 mg, 0.483 mmol), 3-amino-1,5-dimethylpyridin-2(1H)-one (Intermediate 36, 200 mg, 1.448 mmol) and TsOH (99.7 mg, 0.579 mmol) were added to a 20 mL microwave tube and the resulting mixture was dissolved in IPA (3 mL). The resulting mixture was heated at 120 °C via microwave irradiation for 3 hours and then cooled to room temperature. The reaction mixture was then concentrated in vacuo to dryness to give a brown semi-solid which was purified by silica gel chromatography (0-10% MeOH / CH 2 Cl 2 ) and then purified by preparative HPLC (Welch Xtimate C18 column, 5 μm, 150×25 mm; 36%-66% (v / v) CH 3 CN / H 2O, containing 0.225% HCOOH) was further purified and lyophilized to give (R)-3-((4-(2-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)phenyl)thiazol-4-yl)pyrimidin-2-yl)amino)-1,5-dimethylpyridin-2(1H)-one (58.1 mg, 24%) as a brown solid. MS (ESI + ):m / z=489.1. 1 H NMR (400 MHz, DMSO-d 6 )δ8.71(d,J=4.8Hz,1H),8.60(s,1H),8.36(d,J=1.6Hz,1H),8.33(s,1H) ,8.12(s,1H),7.96(d,J=7.6Hz,1H),7.63(d,J=4.8Hz,1H),7.55-7.49(m, 1H),7.48-7.43(m,1H),7.13(s,1H),6.26(s,1H),3.52(s,3H),3.50-3.4 2(m,2H),2.88(s,3H),2.43-2.35(m,1H),2.34-2.26(m,1H),2.15(s,3H).

[0912] Example 15: (R)-1-cyclopentyl-5-((4-(2-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)benzene 1-(4-yl)thiazol-4-yl)pyrimidin-2-yl)amino)-N-methyl-1H-pyrazole-3-carboxamide

[0913]

[0914] (R)-3-(3-(4-(2-chloropyrimidin-4-yl)thiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 35, 80 mg, 0.207 mmol), 5-amino-1-cyclopentyl-N-methyl-1H-pyrazole-3-carboxamide (Intermediate 39, 64.6 mg, 0.310 mmol), Cs 2 CO 3 (134.8 mg, 0.414 mmol), Xantphos (12 mg, 0.021 mmol) and 1,4-dioxane (5 mL) were added to a 10 mL round bottom flask that was oven dried and purged with nitrogen. The mixture was treated with Pd(OAc) 2 (9.28 mg, 0.041 mmol), then evacuated and heated to 40 °C. 2(×3) refill. The resulting mixture was heated at 90°C for 12 hours. The reaction vessel was removed from the oil bath and allowed to gradually cool to room temperature. The reaction mixture was then concentrated to dryness in vacuo to give a yellow viscous solid. The solid was purified by silica gel chromatography (0-100% EtOAc / petroleum ether) and then by HPLC (Welch Xtimate C18 column, 5μm, 150×25mm; 35%-65% (v / v) CH 3 CN / H 2 D, containing 0.225% HCOOH) was further purified and lyophilized to give (R)-1-cyclopentyl-5-((4-(2-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)phenyl)thiazol-4-yl)pyrimidin-2-yl)amino)-N-methyl-1H-pyrazole-3-carboxamide (8.5 mg, 20%) as a yellow solid. MS (ESI + ):m / z=559.3. 1 H NMR (400 MHz, DMSO-d 6 )δ9.58(s,1H),8.60(d,J=4.8Hz,1H),8.31(s,1H),8.10(s,1H),7.99-7.83(m,2H),7.5 8(d,J=4.8Hz,1H),7.55-7.48(m,1H),7.47-7.41(m,1H),6.61(s,1H),6.25(s,1H),4.82 -4.78(m,1H),3.51-3.48(m,1H),2.87(s,3H),2.76(d,J=4.8Hz,3H),2.4 1-2.25(m,2H),2.07-1.90(m,5H),1.90-1.82(m,2H),1.63-1.54(m,2H).

[0915] Example 16: (R)-3-hydroxy-1-methyl-3-(3-(4-(5-methyl-2-((1-methyl-1H-pyrazol-3-yl)amino 4-YL)Pyrimidin-4-yl)Thiazol-2-yl)Phenyl)Pyrrolidin-2-one

[0916]

[0917] In N 2 Pd(PPh 3 ) 44-(1-(trimethylstannyl)thiazol-2-yl)phenyl)pyrrolidin-2-one (Intermediate 41, 45 mg, 0.10 mmol), TEA (31.3 mg, 0.309 mmol) and anhydrous toluene (1 mL) were added to an 8 mL sealed tube. The resulting mixture was heated at 110 °C for 16 hours and then cooled to room temperature to give a black solution. The mixture was filtered through a pad of celite and the pad was washed with ethyl acetate (10 mL) and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was purified by preparative HPLC using a Boston Prime C18 150×30 mm×5 μm column (eluent: 25%-55% (v / v) CH 3 CN and H 2 O, containing 0.05% NH 3 ) was purified to give the pure product. The product was suspended in water (10 mL), the mixture was frozen using dry ice / EtOH, and then frozen to dryness to give (R)-3-hydroxy-1-methyl-3-(3-(4-(5-methyl-2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one (30 mg, 63%) as a white solid. MS (ESI + ):m / z=462.2[M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ9.61(s,1H),8.42-8.38(m,2H),8.10-8.05(m,1H),7.95-7.88(m,1H),7.61-7.43(m,3H),6.72-7. 68(m,1H),6.24(s,1H),3.75(s,3H),3.52-3.45(m,2H),2.87(s,3H),2.55(s,3H),2.40-2.25(m,2H).

[0918] Example 17: (R)-3-Hydroxy-1-methyl-3-(3-(5-methyl-4-(2-((1-methyl-1H-pyrazol-3-yl)amino 4-YL)Pyrimidin-4-yl)Thiazol-2-yl)Phenyl)Pyrrolidin-2-one

[0919]

[0920] Toluene (3 mL), (R)-3-(3-(4-bromo-5-methylthiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 43, 150 mg, 0.408 mmol) / N-(1-methyl-1H-pyrazol-3-yl)-4-(tributylstannyl)pyrimidin-2-amine (Intermediate 42, 190 mg, 0.408 mmol) and Et 3 N (114 μL, 0.817 mmol) was added to the dried and N 2 A 10 mL round bottom flask was purged and charged with Pd(PPh 3 ) 4 (47 mg, 0.041 mmol). 2 Aeration was performed for 5 minutes, followed by heating 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 then quenched with saturated aqueous KF solution (20 mL), stirred at room temperature for 1 hour and extracted with EtOAc (20 mL×3). The combined organic extracts were washed with brine (20 mL) and purified by anhydrous Na 2 SO 4 The oil was purified by HPLC (Welch Xtimate C18 column, 5 μm, 150×30 mm; 33%-63% MeCN / water, containing 0.05% NH 3 ·H 2 O + 10 mM NH 4 HCO 3 ) was purified and lyophilized to give (R)-3-hydroxy-1-methyl-3-(3-(5-methyl-4-(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one (44.6 mg, 23%) as a colorless solid. MS (ESI + ):m / z=462.2. 1 H NMR (400 MHz, DMSO-d 6 )δ9.67(s,1H),8.54(d,J=5.1Hz,1H),8.06-8.01(m,1H),7.85(d,J=7.7Hz,1H),7.58-7.56(m,1H),7.52-7.45(m,2H),7.43-7.39(m, 1H),6.56-6.50(m,1H),6.23(s,1H),3.76(s,3H),3.52-3.48(m,2H),2.93(s,3H),2.86(s,3H),2.40-2.34(m,1H),2.32-2.24(m,1H).

[0921] Example 18 and Example 19: (R)-3-hydroxy-1-methyl-3-(3-(4-(2-((1-((R)-tetrahydrofuran-3- (R)-3-hydroxy-1-methyl- 3-(3-(4-(2-((1-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)

[0922] Thiazol-2-yl)phenyl)pyrrolidin-2-one

[0923]

[0924] (R)-3-Hydroxy-1-methyl-3-(3-(4-(2-(methylsulfonyl)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one (Intermediate 12, 93.7 mg, 0.261 mmol), (R,S)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-amine (100 mg, 0.653 mmol), TsOH (45.0 mg, 0.261 mmol) and anhydrous 1,4-dioxane (5 mL) were added to a 40 mL reaction vial oven-dried and nitrogen-purged, and the resulting mixture was heated at 110 °C for 12 hours to give a brown solution. The reaction mixture was purified by HPLC (Welch Xtimate C18 column, 5 μm, 150×25 mm; 34%-64% (v / v) CH 3 CN / H 2 The (R) and (S) enantiomers of (R)-3-hydroxy-1-methyl-3-(3-(4-(2-((1-((R,S)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one were purified by SFC (DAICEL CHIRALPAK IC column, 10 μm, 250×30 mm; 50% IPA (containing 0.1% 25% NH 3 Aqueous solution) / supercritical CO 2 ) was separated. The first eluting product was designated as diastereomer 1 of (R)-3-hydroxy-1-methyl-3-(3-(4-(2-((1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one (Example 18) (18.0 mg, yellow solid, 16%). MS (ESI + ):m / z=504.2. 1 H NMR (400 MHz, DMSO-d 6)δ9.63(s,1H),8.63-8.45(m,2H),8.17-8.07(m,2H),7.98-7.92(m,1H),7.63(s,1H),7 .55-7.48(m,1H),7.47-7.42(m,2H),6.26(s,1H),5.08(s,1H),4.07-3.96(m,2H),3.93 -3.77(m,2H),3.56-3.41(m,2H),2.87(s,3H),2.44-2.21(m,4H).

[0925] The second eluting product was designated as Diastereomer 2 of (R)-3-hydroxy-1-methyl-3-(3-(4-(2-((1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one (Example 19) (yellow solid, 17.9 mg, 16%). MS (ESI + ):m / z=504.2.

[0926] 1 H NMR (400 MHz, DMSO-d 6 )δ9.63(s,1H),8.65 -8.45(m,2H),8.16-8.06(m,2H),7.99-7.93(m,1H),7.63(s,1H),7.57-7.49 (m,1H),7.47-7.41(m,2H),6.26(s,1H),5.08(s,1H),4.04-3.80(m,4H),3.52 -3.40(m,2H),2.87(s,3H),2.43-2.24(m,4H).

[0927] Example 20: (R)-3-(3-(2-(2-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl) Thiazol-4-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0928]

[0929] The title compound was prepared using conditions similar to those described in Example 49 using 1-(cyclopropylmethyl)-1H-pyrazole-4-amine instead of 1,5-dimethyl-1H-pyrazole-3-amine. The compound was purified via FCC (100% DCM increased to 5% MeOH-DCM). The resulting compound was then further purified using column C9 under basic conditions to give the title compound (89% yield). 1 HNMR (400 MHz, methanol-d 4)δ8.51(d,J=5.0Hz,1H),8.19-8.09(m,2H),8.03(s,1H),7.97-7.86(m,1H),7.63(s,1H),7.55-7.35(m,3H),4.00(d,J= 7.0Hz,2H),3.65-3.44(m,2H),3.00(s,3H),2.61-2.37(m,2H),1.29-1.36(m,1H),0.71-0.60(m,2H),0.42-0.44(m,2H). MS(ESI + ):m / z=488.20.

[0930] Example 21: (R)-3-hydroxy-3-(3-(4-(2-(imidazo[1,2-a]pyridin-3-ylamino)pyrimidin-4-yl) Thiazol-2-yl)phenyl)-1-methylpyrrolidin-2-one

[0931]

[0932] The title compound was prepared using conditions similar to those described in Example 49 using imidazo[1,2-a]pyridin-3-amine instead of 1,5-dimethyl-1H-pyrazol-3-amine. The compound was purified by RP HPLC (Xtimate C18 150×25 mm×5 μm column; eluent: 29% to 69% (v / v) ACN and H 2 O, containing 0.05% ammonium hydroxide and 10 mM NH 4 HCO 3 ) to afford the title compound (1%). 1 H NMR (400 MHz, DMSO-d 6 ): δ8.82-8.77(m,1H),8.61(s,1H),8.53

[0933] -8.47(m,1H),8.14-8.11(m,1H),8.05-8.01(m,1H),7.99-7.95(m,1H),7.93

[0934] -7.87(m,1H),7.80 -7.75(m,1H),7.56-7.42(m,2H),7.28-7.22(m,1H),6.25(s,1H),5.38-5.31(m,2H),3. 54-3.45(m,1H),3.43-3.38(m,1H),2.87(s,3H),2.43-2.35(m,1H),2.34-2.25(m,1H). MS(ESI + ):m / z=484.2.

[0935] Example 22: (R)-3-Hydroxy-1-methyl-3-(3-(6-(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidine pyridin-4-yl)pyridin-2-yl)phenyl)pyrrolidin-2-one

[0936]

[0937] In N 2 Pd(PPh 3 ) 4 (33 mg, 0.029 mmol), N-(1-methyl-1H-pyrazol-3-yl)-4-(trimethylstannyl)pyrimidin-2-amine (Intermediate 1, 214 mg, 0.634 mmol), (R)-3-(3-(6-bromopyridin-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 46, 100 mg, 0.288 mmol), TEA (0.118 mL, 0.864 mmol), anhydrous toluene (1 mL) and anhydrous 1,4-dioxane (1 mL) were added to an 8 mL vial. The resulting mixture was heated at 100 °C for 16 hours and then cooled to room temperature. The mixture was concentrated to dryness in vacuo to give a yellow oil. The oil was purified by HPLC (Phenomenex C18 column, 3 μm, 75×30 mm; 29%-59% (v / v) CH 3 CN / H 2 O, containing 0.05% NH 3 ) was purified and then subjected to SFC (DAICEL CHIRALCEL OD-H column, 10 μm, 250×30 mm; 50% EtOH (containing 0.1% 25% NH 3 Aqueous solution) / supercritical CO 2 ), and lyophilized to give (R)-3-hydroxy-1-methyl-3-(3-(6-(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)pyridin-2-yl)phenyl)pyrrolidin-2-one (60 mg, 47%) as a white solid. MS (ESI + ):m / z=442.2. 1 H NMR (400 MHz, DMSO-d 6 )δ9.87(s,1H),8.65(d,J=4.8Hz,1H),8.36-8.30(m,1H),8.25(s,1H),8.18-8.08(m,3H),7.83(d,J=5.2Hz,1H),7.66-7.59(m ,1H),7.55-7.42(m,2H),6.73(d,J=2.0Hz,1H),6.17(s,1H),3.78(s,3H),3.54-3.41(m,2H),2.88(s,3H),2.46-2.24(m,2H).

[0938] Example 23: (R)-3-Hydroxy-3-(3-(6-(2-((3-hydroxypropyl)amino)pyrimidin-4-yl)pyridin-2-yl)benzene 1-Methylpyrrolidin-2-one

[0939]

[0940] (R)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylsulfinyl)pyrimidin-4-yl)pyridin-2-yl)phenyl)pyrrolidin-2-one (Intermediate 47, 210 mg, 0.514 mmol), 3-aminopropan-1-ol (232 mg, 3.09 mmol) and DIEA (0.548 mL, 3.09 mmol) were added to a 20 mL microwave tube and the resulting mixture was dissolved in IPA (5 mL). The resulting mixture was heated at 120 ° C for 2 hours via microwave irradiation to give a yellow solution. Thereafter, the mixture was cooled to room temperature and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was purified by HPLC (Boston Prime C18 column, 5 μm, 150×30 mm; 19%-39% (v / v) CH 3 CN / H 2 D (0.05% HCOOH) to give (R)-3-hydroxy-3-(3-(6-(2-((3-hydroxypropyl)amino)pyrimidin-4-yl)pyridin-2-yl)phenyl)-1-methylpyrrolidin-2-one (31.3 mg, 14%) as a white solid. MS (ESI + ):m / z=420.2. 1 H NMR (400 MHz, DMSO-d 6 )δ8.51-8.46(m,1H),8.32(s,1H),8.23(s,1H),8.12-8.06(m,3H),7.64-7.61(m,1H),7.55-7.47(m,1H),7.46-7.39(m,1H), 7.29-7.24(m,1H),6.16(s,1H),4.51(t,J=5.2Hz,1H),3.58-3.41(m,6H),2.88(s,3H),2.41-2.25(m,2H),1.82-1.69(m,2H).

[0941] Example 24 and Example 25: (R)-3-(2-fluoro-5-(2-(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidine (S)-3-(2-fluoro-5-(2-(2-((1-methylpyrrolidin-4-yl)thiazol-4-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one 1-Methylpyrrolidin-2-one

[0942]

[0943] 4-(4-bromothiazol-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine (Intermediate 4, 357 mg, 212 μmol), (R,S)-3-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 48, 100 mg, 240 μmol), Pd(dppf)Cl 2 (17.6...

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: A is optionally replaced by one to three -C (1-4) 5- to 6-membered heteroaryl substituted with an alkyl group; W is CH2, CHF or CF2; X is N, CH or CR X ; Y is N, CH or CR Y ; Z is N, CH or CR Z ; R X , R Y and R Z are independently halo, -CN, -C (1-4) Alkyl or -C (1-4) Haloalkyl; R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl; R 2 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl; R 3 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl; 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 4 It is hydrogen, -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(O)-(3- to 10-membered heterocyclyl), -C (6-10) aryl or 5 to 10 membered heteroaryl, wherein the -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(O)-(3- to 10-membered heterocyclyl), -C (6-10) Aryl and 5- to 10-membered heteroaryl are each optionally substituted by one to five R 4x Group substitution; Each R 4x 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, -C(O)N(R N1 )(R N2 )、-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 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, 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 (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O)2C (1-4) Alkyl and -N(H)S(O)2C (1-4) Alkyl radical substitution; and R N1 and R N2 Each occurrence is independently H, -C (1-3) Alkyl or -C (1-3) Haloalkyl; The prerequisite is that at least one of X, Y and Z is CH.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: A is optionally replaced by one to three -C (1-4) 5- to 6-membered heteroaryl substituted with an alkyl group; W is CH2 or CF2; X is N, CH or CR X ; Y is N, CH or CR Y ; Z is N, CH or CR Z ; R X , R Y and R Z are independently halo, -CN, -C (1-4) Alkyl or -C (1-4) Haloalkyl; R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl; R 2 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl; R 3 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl; 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 4 It is hydrogen, -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(O)-(3- to 10-membered heterocyclyl), -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 4a The -C (3-10) The cycloalkyl group is optionally substituted with one to five R 4b The 3- to 10-membered heterocyclic group is optionally substituted by one to five R 4c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 4d The -C(O)-(3 to 10 membered heterocyclyl) is optionally substituted by one to five R 4e The -C (6-10) The aryl group is optionally substituted by one to five R 4f and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 4g Group substitution; Each R 4a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-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, -C(O)N(R N1 )(R N2 )、-S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) Alkyl, 3 to 8 membered heterocyclic group, -C (6-10) aryl or 5 to 10 membered heteroaryl, wherein the -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 (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 (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O)2C (1-4) Alkyl and -N(H)S(O)2C (1-4) Alkyl radical substitution; R 4b , R 4c , R 4d and R 4e 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(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-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 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 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 (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O)2C (1-4) Alkyl and -N(H)S(O)2C (1-4) Alkyl radical substitution; R 4f and R 4g 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, -C(O)N(R N1 )(R N2 )、-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 or 5 to 10 membered heteroaryl, wherein the -C (1-6) Alkyl, -C (1-6) Halogenated alkyl, -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, 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 (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O)2C (1-4) Alkyl and -N(H)S(O)2C (1-4) Alkyl radical substitution; and R N1 and R N2 Each occurrence is independently H or -C (1-3) alkyl; The prerequisite is that at least one of X, Y and Z is CH.

3. 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- to 6-membered heteroaryl substituted with an alkyl group; W is CH2 or CF2; X is N, CH or CR X ; Y is N, CH or CR Y ; Z is N, CH or CR Z ; R X , R Y and R Z are independently halo, -CN, -C (1-4) Alkyl or -C (1-4) Haloalkyl; R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl; R 2 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl; R 3 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl; 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 4 It is hydrogen, -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(O)-(3- to 10-membered heterocyclyl), -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 4a The -C (3-10) The cycloalkyl group is optionally substituted with one to five R 4b The 3- to 10-membered heterocyclic group is optionally substituted by one to five R 4c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 4d The -C(O)-(3 to 10 membered heterocyclyl) is optionally substituted by one to five R 4e The -C (6-10) The aryl group is optionally substituted by one to five R 4f and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 4g Group substitution; Each R 4a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-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, -C(O)N(R N1 )(R N2 )、-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 (1-6) Haloalkyl, -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 and -OC (1-4) Alkyl radical substitution; R 4b , R 4c , R 4d and R 4e 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(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O)2C (1-4) Alkyl, -N(H)S(O)2C (1-4) 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 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 )、-CN、-C (1-4) Alkyl and -OC (1-4) Alkyl radical substitution; R 4f and R 4g 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, -C(O)N(R N1 )(R N2 )、-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 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 (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O)2C (1-4) Alkyl and -N(H)S(O)2C (1-4) Alkyl radical substitution; and R N1 and R N2 Each occurrence is independently H or -C (1-3) alkyl; The prerequisite is that at least one of X, Y and Z is CH.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein: A is optionally replaced by a-C (1-4) 5- to 6-membered heteroaryl substituted with an alkyl group; W is CH2 or CF2; X is N, CH or CR X ; Y is N, CH or CR Y ; Z is N, CH or CR Z ; R X , R Y and R Z are independently halo, -CN, -C (1-4) Alkyl or -C (1-4) Haloalkyl; R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl; R 2 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl; R 3 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) The alkylene group is optionally substituted with a -OC (1-3) Alkyl group substitution; R 4 It is hydrogen, -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(O)-(3- to 10-membered heterocyclyl), -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 4a The -C (3-10) The cycloalkyl group is optionally substituted with one to five R 4b The 3- to 10-membered heterocyclic group is optionally substituted by one to five R 4c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 4d The -C(O)-(3 to 10 membered heterocyclyl) is optionally substituted by one to five R 4e The -C (6-10) The aryl group is optionally substituted by one to five R 4f and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 4g Group substitution; Each R 4a Each occurrence is independently halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -C(O)N(R N1 )(R N2 )、-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 (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) The haloalkyl 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 and -OC (1-4) Alkyl radical substitution; Each R 4b 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, 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; R 4c and R 4d 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, 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 with one to five radicals selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1-4) Alkyl and -OC (1-4) Alkyl radical substitution; Each R 4e 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 4f 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(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O)2C (1-4) Alkyl or -N(H)S(O)2C (1-4) Alkyl, wherein the -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl and -OC (3-8) The cycloalkyl 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 (1-6) haloalkyl radical substitution; Each R 4g 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, -C(O)N(R N1 )(R N2 )、-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) 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, -OC (1-6) Haloalkyl, -C(O)C (1-4) Alkyl, -C(O)N(R N1 )(R N2 )、-S(O)2C (1-4) Alkyl and -N(H)S(O)2C (1-4) Alkyl radical substitution; and R N1 and R N2 Each occurrence is independently H or -C (1-3) alkyl; The prerequisite is that at least one of X, Y and Z is CH.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein: A is a 5- to 6-membered heteroaryl group optionally substituted with one methyl group; W is CH2 or CF2; X is N, CH or CR X ; Y is N, CH or CR Y ; Z is N, CH or CR Z ; R X , R Y and R Z are independently halo, -CN, -C (1-4) Alkyl or -C (1-4) Haloalkyl; R 1 It is hydrogen, -C (1-4) Alkyl or -C (1-4) Haloalkyl; R 2 is hydrogen, halo, -C (1-4) Alkyl or -C (1-4) Haloalkyl; R 3 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) The alkylene group is optionally substituted with a -OC (1-3) Alkyl group substitution; R 4 It is hydrogen, -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(O)-(3- to 10-membered heterocyclyl), -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 4a The -C (3-10) The cycloalkyl group is optionally substituted with one to five R 4b The 3- to 10-membered heterocyclic group is optionally substituted by one to five R 4c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 4d The -C(O)-(3 to 10 membered heterocyclic group) is optionally substituted by one to three -C (1-4) Alkyl group substituted, the -C (6-10) The aryl group is optionally substituted by one to five R 4f and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 4g Group substitution; Each R 4a Each occurrence is independently halo, -OH, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -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 (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) The haloalkyl and 3- to 8-membered heterocyclyl groups are optionally further substituted with one to five groups selected from halo and -OH; Each R 4b Each occurrence is independently halo, -OH, -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -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 and -OH; R 4c and R 4d Each occurrence is independently -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, 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 with one to five radicals selected from halo, -OH and -C (1-4) Alkyl radical substitution; Each R 4f Each occurrence is independently halo, -OH, -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 or -C(O)N(R N1 )(R N2 ), wherein said -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl and -OC (3-8) The cycloalkyl group is optionally further substituted with one to five groups selected from halo and -OH; Each R 4g Each occurrence is independently halo, -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)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, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-6) Haloalkyl and -C(O)N(R N1 )(R N2 ) is substituted with a group; and R N1 and R N2 Each occurrence is independently H or -C (1-3) alkyl; A prerequisite is that at least two of X, Y and Z are CH.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl or pyridyl, each of which is optionally substituted by a -C (1-4) Alkyl group substitution.

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

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

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

12. A compound according to any one of claims 1 to 4 or 6 to 10, or a pharmaceutically acceptable salt thereof, wherein two of X, Y and Z are CH.

13. A compound according to any one of claims 1 to 4 or 6 to 10, or a pharmaceutically acceptable salt thereof, wherein no more than one of X, Y and Z is N.

14. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein R X , R Y and R Z are each independently fluorine or -CN.

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

16. A compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein R 1 It is hydrogen or -CF3.

17. A compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula Id-1 to Id-5:

18. A compound according to any one of claims 1, 2 or 6 to 17, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each independently hydrogen, fluorine or methyl.

19. A compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 It's hydrogen.

20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein L is absent, -C (1-4) Alkylene or cyclopropylene, wherein the -C (1-4) The alkylene group is optionally substituted with a -OC (1-3) Alkyl group substitution.

21. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein L is absent, 22. A compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of any one of formulas If-1 to If-8:

23. A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R 4 Yes-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(O)-(3- to 10-membered heterocyclyl), -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 4a The -C (3-10) The cycloalkyl group is optionally substituted with one to five R 4b The 3- to 10-membered heterocyclic group is optionally substituted by one to five R 4c The 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted by one to five R 4d The -C(O)-(3 to 10 membered heterocyclyl) is optionally substituted by one to five R 4e The -C (6-10) The aryl group is optionally substituted by one to five R 4f and the 5- to 10-membered heteroaryl group is optionally substituted by one to five R 4g Group substitution.

24. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R 4 is optionally replaced by one to five R 4a -C (1-6) alkyl.

25. The compound according to claim 24 or a pharmaceutically acceptable salt thereof, wherein each R 4a Each occurrence is independently halo, -OH, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -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 (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) The haloalkyl and 3- to 8-membered heterocyclyl are optionally further substituted with one to five groups selected from halo and -OH.

26. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R 4 yes:

27. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R 4 is optionally replaced by one to five R 4b -C (3-10) Cycloalkyl.

28. The compound according to claim 27 or a pharmaceutically acceptable salt thereof, wherein R 4 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl or spiro[3.3]heptyl, each of which is optionally substituted by one to three R 4b Group substitution.

29. The compound according to claim 28 or a pharmaceutically acceptable salt thereof, wherein each R 4b Each occurrence is independently halo, -OH, -CN, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl, -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 and -OH.

30. The compound according to claim 28 or a pharmaceutically acceptable salt thereof, wherein each R 4b Each occurrence is independently halo, -OH, -CN, -C (1-6) Alkyl or -OC (1-6) Alkyl, wherein the -C (1-6) The alkyl group is optionally further substituted with one -OH group.

31. A compound according to any one of claims 1 to 23 or 27 to 30, or a pharmaceutically acceptable salt thereof, wherein R 4 yes:

32. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R 4 is optionally replaced by one to five R 4c A 3- to 10-membered heterocyclic group substituted by a group.

33. The compound according to claim 32 or a pharmaceutically acceptable salt thereof, wherein R 4 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, pyrrolidin-2-onyl, piperidin-2-onyl, morpholinyl or piperazinyl, each of which is optionally substituted by one to three R 4c Group substitution.

34. The compound according to claim 33 or a pharmaceutically acceptable salt thereof, wherein each R 4c Each occurrence is independently -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, 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 with one to five radicals selected from halo, -OH and -C (1-4) Alkyl radicals are substituted.

35. The compound according to claim 33 or a pharmaceutically acceptable salt thereof, wherein each R 4c Each occurrence is independently -C (1-6) Alkyl, -C(O)C (1-4) Alkyl, -S(O)2C (1-4) alkyl, 3 to 8 membered heterocyclyl or 5 to 10 membered heteroaryl, wherein the -C (1-6) 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 and -C (1-4) Alkyl radicals are substituted.

36. A compound according to any one of claims 1 to 23 or 32 to 35, or a pharmaceutically acceptable salt thereof, wherein R 4 yes:

37. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R 4 is optionally replaced by one to five R 4d A 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms which is substituted by a radical.

38. The compound according to claim 37 or a pharmaceutically acceptable salt thereof, wherein R 4 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 4d Group substitution.

39. The compound according to claim 37 or a pharmaceutically acceptable salt thereof, wherein R 4 is optionally replaced by one to five R 4d 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 3,5-fused ring system, a 5,6-fused ring system or a 6,6-fused ring system.

40. A compound according to any one of claims 37 to 39, or a pharmaceutically acceptable salt thereof, wherein each R 4d Each occurrence is independently -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, 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 with one to five radicals selected from halo, -OH and -C (1-4) Alkyl radicals are substituted.

41. A compound according to any one of claims 37 to 39, or a pharmaceutically acceptable salt thereof, wherein each R 4d Each occurrence is independently -C (1-6) Alkyl, -OC (1-6) Alkyl or -C(O)C (1-4) Alkyl, 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 -OH.

42. A compound according to any one of claims 1 to 23 or 37 to 41, or a pharmaceutically acceptable salt thereof, wherein R 4 yes:

43. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R 4 is optionally replaced by one to five R 4e -C(O)-(3- to 10-membered heterocyclyl) substituted with a group.

44. The compound according to claim 43 or a pharmaceutically acceptable salt thereof, wherein R 4 is optionally replaced by one to three -C (1-4) -C(O)-(3- to 10-membered heterocyclyl) substituted with an alkyl group.

45. The compound according to claim 43 or a pharmaceutically acceptable salt thereof, wherein R 4 yes 46. ​​A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R 4 is optionally replaced by one to five R 4f -C (6-10) Aryl.

47. The compound according to claim 46 or a pharmaceutically acceptable salt thereof, wherein R 4 is optionally replaced by one to five R 4f A phenyl group substituted with a group.

48. The compound according to claim 47 or a pharmaceutically acceptable salt thereof, wherein each R 4f Each occurrence is independently halo, -OH, -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 or -C(O)N(R N1 )(R N2 ), wherein said -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl and -OC (3-8) The cycloalkyl group is optionally further substituted with one to five groups selected from halo and -OH.

49. The compound according to claim 47 or a pharmaceutically acceptable salt thereof, wherein each R 4f Each occurrence is independently halo, -C (1-6) Alkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (3-8) Cycloalkyl or -C(O)N(R N1 )(R N2 ).

50. A compound according to any one of claims 1 to 23 or 46 to 49, or a pharmaceutically acceptable salt thereof, wherein R 4 yes:

51. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R 4 is optionally replaced by one to five R 4g A 5- to 10-membered heteroaryl group is substituted with a moiety.

52. The compound according to claim 51 or a pharmaceutically acceptable salt thereof, wherein R 4 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 4g Group substitution.

53. The compound according to claim 52 or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridin-2-one, pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, benzimidazolyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyridinyl or pyrazolopyrimidinyl, each of which is optionally substituted by one to three R 4g Group substitution.

54. A compound according to any one of claims 1 to 23 or 51 to 53, or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrazolyl or pyrazolopyridinyl, each of which is optionally substituted by one to three R 4g Group substitution.

55. A compound according to any one of claims 1 to 23 or 51 to 53, or a pharmaceutically acceptable salt thereof, wherein R 4 yes:

56. A compound according to any one of claims 1 to 23 or 51 to 55, or a pharmaceutically acceptable salt thereof, wherein R 4 yes:

57. A compound according to any one of claims 1 to 4, 6 to 23 or 51 to 56, or a pharmaceutically acceptable salt thereof, wherein each R 4g Each occurrence is independently halo, -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)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, -C (1-4) Alkyl, -C (1-4) Haloalkyl, -OC (1-4) Alkyl, -OC (1-6) Haloalkyl and -C(O)N(R N1 )(R N2 ) group substitution.

58. The compound according to claim 57 or a pharmaceutically acceptable salt thereof, wherein each R 4g Each occurrence is independently halo, -C (1-6) Alkyl, -C (1-6) Haloalkyl, -C (3-8) Cycloalkyl, -OC (1-6) Alkyl, -OC (1-6) Haloalkyl, -OC (3-8) Cycloalkyl or 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) The cycloalkyl and 3 to 8 membered heterocyclyl are optionally further substituted with one to five groups selected from halo and -OH.

59. The compound according to claim 57 or a pharmaceutically acceptable salt thereof, wherein each R 4g Each occurrence is independently -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl or -OC (1-6) haloalkyl, each of which is optionally further substituted with one to five groups selected from halo and -OH.

60. A compound according to any one of claims 1 to 23 or 51 to 57, or a pharmaceutically acceptable salt thereof, wherein each R 4g independently at each occurrence is:

61. A compound according to any one of claims 1 to 23 or 51 to 57, or a pharmaceutically acceptable salt thereof, wherein each R 4g independently at each occurrence is:

62. A compound according to any one of claims 1 to 23 or 51 to 57, or a pharmaceutically acceptable salt thereof, wherein each R 4g independently at each occurrence is:

63. A compound according to any one of claims 1 to 23 or 51 to 53, 55, 57 or 60, or a pharmaceutically acceptable salt thereof, wherein R 4 yes:

64. A compound according to any one of claims 1 to 23 or 51 to 53, 55, 57 or 60, or a pharmaceutically acceptable salt thereof, wherein each R 4 yes:

65. A compound according to any one of claims 1 to 23 or 51 to 61 or 63 to 64, or a pharmaceutically acceptable salt thereof, wherein each R 4 yes:

66. A compound according to any one of claims 1 to 23 or 51 to 55 or 57 to 63 or 65, or a pharmaceutically acceptable salt thereof, wherein each R 4 yes:

67. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula If-1: A is pyrazolyl or thiazolyl; Y is N, CH or CF; Z is N, CH or CF; L does not exist or is -C (1-4) Alkylene; R 4 is optionally replaced by one to five R 4g substituted 5- to 10-membered heteroaryl; Each R 4g Each occurrence is independently -C (1-6) Alkyl, -C (1-6) Haloalkyl, -OC (1-6) Alkyl or -OC (1-6) haloalkyl, each of which is optionally further substituted with one to five groups selected from halo and -OH; The prerequisite is that at least one of Y and Z is CH.

68. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having a structure selected from the group consisting of those in any one of Tables 2A to 2M.

69. The compound of claim 68, or a pharmaceutically acceptable salt thereof, having a structure selected from the group consisting of:

70. The compound of claim 69 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula:

71. The compound of claim 69 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula:

72. The compound of claim 69 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula:

73. The compound of claim 69 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula:

74. The compound of claim 69 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula:

75. The compound of claim 69 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula:

76. The compound of claim 69 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula:

77. The compound of claim 69 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula:

78. The compound of claim 69 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula:

79. The compound of claim 68 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula:

80. The compound of claim 68, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula:

81. The compound of claim 69 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula:

82. The compound of claim 69 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula:

83. The compound of claim 69 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula:

84. A pharmaceutical composition comprising a compound according to any one of claims 1 to 83 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

85. A method of treating a disease, disorder or medical condition mediated by NIK activity, the method comprising administering to a subject in need of such treatment an effective amount of (i) a compound according to any one of claims 1 to 83 or a pharmaceutically acceptable carrier thereof, or (ii) a pharmaceutical composition according to claim 84.

86. The method of claim 85, 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.

87. The method of claim 86, 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.

88. The method of claim 85, 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.

89. The method of claim 88, wherein the disease, disorder or medical condition mediated by NIK activity is selected from the group consisting of systemic lupus erythematosus ("SLE"), rheumatoid arthritis ("RA"), Sjögren's syndrome, lupus nephritis, inflammatory bowel disease ("IBD"), ANCA-associated vasculitis, myositis, IgG4-associated disease, bullous pemphigoid, neuromyelitis optica spectrum disorder ("NMOSD"), atopic dermatitis ("AD"), hidradenitis suppurativa ( "HS"), steatosis, nonalcoholic steatohepatitis ("NASH"), primary biliary cirrhosis, leukemia, lymphoma, pancreatic cancer, breast cancer, melanoma, obesity, diabetes, acute kidney injury, IgAN, autosomal dominant polycystic kidney disease ("ADCKD"), membranous nephropathy, osteoporosis, bone resorption (periodontitis), multiple sclerosis ("MS"), immune thrombocytopenic purpura, transplantation, myasthenia gravis, scleroderma, myositis, IgG4-related disease, and bullous pemphigoid.

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