Pyrrolidione derivatives as inhibitors of NF-kappa B-inducing kinase

Abstract

The present disclosure relates to compounds of formula (I) that inhibit NIK, pharmaceutical compositions containing such compounds, and methods of using the same. These compounds and pharmaceutical compositions are useful for preventing or treating diseases such as, but not limited to, inflammatory and autoimmune disorders. 【Chemical 1】 TIFF2025516559000386.tif31128

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the priority and benefit of U.S. Provisional Patent Application No. 63 / 364,550, filed on May 11, 2022, which is incorporated herein by reference in its entirety.

[0002] (Field of the Invention) The present disclosure relates to the fields of chemistry and medicine. More particularly, the present disclosure relates to NF - κB - inducing kinase inhibitors and their use in medicine.

Background Art

[0003] 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 role in immune system regulation, inhibition of NIK blocks several downstream pathways that produce inflammatory molecules. Clinical validation with biologics has confirmed the important role of several NIK - dependent pathways in autoimmune diseases. See, for example, S. V. Navarra, et al., The Lancet, 2011; 377(9767):721 - 31. One way to reduce or eliminate the adverse effects associated with NIK activity is to increase NIK inhibition.

[0004] Therefore, there is a need to develop effective NIK inhibitors that can be used to treat various diseases.

Summary of the Invention

[0005] This application relates to a compound of formula I:

[0006]

Chemical Formula

[0007] This application also discloses a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0008] This 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"), Sjögren's syndrome, lupus nephritis, inflammatory bowel disease ("IBD"), ANCA (antineutrophil cytoplasmic antibody)-associated vasculitis, myositis, IgG4-related diseases, bullous pemphigoid, neuromyelitis optica spectrum disorder ("NMOSD"), atopic dermatitis ("AD"), hidradenitis suppurativa ("HS"), lipodystrophy, non-alcoholic 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 diseases, and bullous pemphigoid. DETAILED DESCRIPTION OF THE INVENTION

[0009] The discussions of documents, operations, materials, devices, articles, etc. included in this specification are for the purpose of providing the context of the present disclosure. Such discussions do not admit that any or all of these things constitute a part of the prior art with respect to any of the present disclosure content disclosed or claimed.

[0010] (NF-κB-inducing kinase, referred to as NIK and also well-known as MAP3K14) is a regulator and driver of non-canonical NIK cascades and thus represents an attractive target for therapeutic intervention. Embodiments described herein relate to compounds that inhibit NIK and pharmaceutical compositions containing such compounds. The compounds and pharmaceutical compositions described herein are useful for preventing or treating diseases such as, but not limited to, inflammatory disorders and autoimmune disorders.

[0011] NIK-dependent transcriptional activation is a tightly regulated signaling pathway through sequential events including phosphorylation and proteolysis. In the NIK activation pathway, which is well-known as a non-canonical pathway, activation is achieved by phosphorylating the catalytic complex subunit IKKα, resulting in partial proteolysis of the gene product p100 and 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-canonical pathway is activated by ligands including, but not limited to, CD40 ligand, B cell activating factor (BAFF), lymphotoxin β receptor ligand, TNF-related apoptosis-inducing ligand (TWEAK) cytokine, and receptor activator of nuclear factor kappa-B ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11). NIK has been shown to be required for activation of the pathway by these ligands (S.-C. Sun, Nat Rev Immunol. 2017, 17(9), 545-558). For its role, NIK expression is tightly regulated. Under normal unstimulated conditions, NIK protein levels are very low. This is due to its interaction with baculoviral IAP-repeat-containing-3 (BIRC3, also known as CIAP2) and a range of TNF receptor-associated factors (TRAF2 and TRAF3), which are ubiquitin ligases and result in the degradation of NIK. When the non-canonical pathway is stimulated by a ligand under pathological / abnormal conditions, the activated receptor is thought to compete here for TRAF (TNF receptor-associated factor), dissociating the TRAF-BIRC3-NIK complex, thereby increasing the level of NIK (for a more detailed analysis of this background, see, for example, S.-C. Sun (cited above) and Thu and Richmond, Cytokine Growth F. R. 2010, 21, 213-226). Since NIK plays a role in promoting immune response disorders, an increase in NIK levels is undesirable, and one way to reduce or eliminate the adverse effects associated with such an increase is NIK inhibition.

[0012] BAFF / BAFF-R is a clinically validated therapeutic target whose inhibition is thought to be beneficial for the treatment of systemic lupus erythematosus (SLE). Belimumab (anti-BAFF antibody) is approved for treating seropositive SLE patients (S. V. Navarra, et al., The Lancet, 2011; 377(9767):721-31). The CD40L / CD40 pathway plays an important role in T cell-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 demonstrated promising efficacy in phase 2 clinical trials in SLE patients (P.I.Sidiropoulos and D.T. Boumpas, Lupus 2004 May; 13(5):391-7). Mice lacking NIK (R. Shinkura, et al., Nature Genetics 1999; 22(1):74-7, H. D. Brightbill, et al., J Immunol.2015; 195(3):953-64), or conditional knockout of NIK (H. D. Brightbill, et al., J Immunol.2015; 195(3):953-64), or human patients carrying NIK gene mutations (K. L. Willmann, et al., Nature Comm.2014; 5:5360) have shown deficiencies in non-canonical activation pathways of NIK such as the BAFF and CD40L pathways, a decrease in B lymphocytes in peripheral blood, and a decrease in lymphoid organs, as well as a decrease in T cell-dependent antibody responses carrying NIK as a therapeutic target for SLE, among others.

[0013] NIK has been characterized 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, are deficient in B and T cells, and have impaired receptor activator of NIK ligand-stimulated osteoclast formation. K. Aya et al. (J. Clin. Invest. 2005, 115, 1848-1854) used NIK- / - mice to investigate the role of NIK in a murine model of inflammatory arthritis. The serum transfer arthritis model was initiated by preformed antibody and required only intact neutrophils and complement system in the recipient. NIK- / - mice had inflammation equivalent to that of NIK+ / + controls, but Ada et al., (cited above) showed significantly less periarticular osteoclast formation and less bone erosion. In contrast, NIK- / - mice were completely resistant to antigen-induced arthritis (AIA), which requires intact antigen presentation and lymphocyte function but not lymph nodes. Furthermore, transfer of NIK+ / + splenocytes or T cells into Rag2- / - mice conferred sensitivity to AIA, but transfer of NIK- / - cells did not. NIK- / - mice were also resistant to a genetically generated form of spontaneous arthritis in mice expressing both the KRN T cell receptor and H-2g7. Using transgenic mice with OC-lineage expression of NIK lacking the TRAF3-binding domain (NT3), it was demonstrated that constitutive activation of NIK drives enhancement of osteoclast formation and bone resorption in both the basal state and in response to inflammatory stimuli. See Aya et al. cited above. Furthermore, constitutive activation of NIK drives enhancement of osteoclast formation and bone resorption in both the basal state and in response to inflammatory stimuli.(C.Yang, et al., PLoS ONE 2010, 5(11): e15383, doi:10.1371 / journal.pone.0015383).

[0014] NIK is also a therapeutic target for other BAFF, CD40L, or lymphotoxin β receptor ligand-driven autoimmune disorders such as Sjögren's syndrome (J. Groom, et al., J. Clin. Invest. 2002; 109(1):59-68) and proliferative lupus glomerulonephritis (D.T. Boumpas, et al., Arthritis & Rheumatism 2003; 48(3):719-27).

[0015] Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the case of otherwise, the specific terms used herein have the meaning as described herein.

[0016] To assist the reader of this application, the description is divided into various paragraphs or sections or directed to various embodiments of this application. These separations should not be considered to sever the substance of a paragraph or section or embodiment from the substance of another paragraph or section or embodiment. On the contrary, one of ordinary skill in the art will understand that this description has broad applications and encompasses all combinations of the various sections, paragraphs, and passages that can be contemplated. The consideration of any embodiment is intended to be merely exemplary and is not intended to suggest that the scope of the disclosure, including the claims, is limited to these examples.

[0017] It should be noted that, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0018] As used herein, the terms "including", "containing", and "comprising" are used in a broad, non-limiting sense.

[0019] For the sake of providing a more concise description, some of the quantitative expressions presented herein are not modified by the term "about". Whether or not the term "about" is explicitly used, all of the amounts presented herein are meant to refer to the actual given value, and also to refer to approximations of such given values that can be reasonably inferred based on ordinary skill in the art, including equivalent values and approximations due to experimental conditions and / or measurement conditions for such given values.

[0020] With respect to the methods of the present disclosure, the term "administering" means a method for prophylactically, therapeutically, or prophylactically treating, preventing, or ameliorating a syndrome, disorder, or disease described herein by using a compound of the present disclosure or a pharmaceutically acceptable salt thereof, a composition thereof, or a pharmaceutical 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 pharmaceutical thereof at different times during the course of treatment, or simultaneously or sequentially as combination therapy.

[0021] The term "subject" refers to a patient who may be or is being treated by a method according to an embodiment of the present application, preferably a mammal, most preferably a human. Examples of mammals include, but are not limited to, non-human primates (NHPs) such as cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys or apes, and humans, more preferably humans.

[0022] The terms "therapeutically effective amount" or "effective amount" mean the amount of an active compound or pharmaceutical agent that elicits a biological or medical response in a tissue system, animal, or human that is sought by a researcher, veterinarian, physician, or other clinician and that includes preventing, treating, or ameliorating the symptoms of a syndrome, disorder, or disease being treated.

[0023] As used herein, the terms "treatment" or "treating" are defined as the application or administration of a therapeutic agent (i.e., a compound of the disclosure, alone or in combination with another pharmaceutical agent) to a patient having a disorder or disease, or symptoms thereof, as described herein, or the application or administration of a therapeutic agent to an excised tissue or cell line derived from a patient (e.g., for diagnostic or ex vivo (in vitro) applications), or, with respect to the potential for developing a disorder or disease, where the purpose of the application or administration is to cure, heal, alleviate, relieve, alter, treat, remit, improve, or affect a disorder or disease, or symptoms thereof, or the potential for developing a disorder or disease. Such treatment may be specifically adjusted or modified based on knowledge obtained from the field of pharmacogenomics.

[0024] As used herein, the terms "prevent" or "prevention" mean the absence of the development of a disorder or disease when the development has not occurred, or the absence of further development of a disorder or disease when the development has already occurred. Also considered is an individual's ability to prevent some or all of the symptoms associated with a disorder or disease.

[0025] The term "C (a~b)"(wherein, a and b are integers indicating the number of carbon atoms shown) refers to, for example, an alkyl, alkenyl, alkynyl, alkoxy, or cycloalkyl radical, or an alkyl moiety of a radical that exists as a prefix root containing a to b (including boundary values) carbon atoms. For example, C (1-4) represents a radical containing 1, 2, 3, or 4 carbon atoms.

[0026] The term "alkyl" is a straight-chain 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 )alkyl). Examples of alkyl groups include methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 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(CH3 ) CH 2 CH 2 CH 3 ) Neo-pentyl (-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 (-(CH2) 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 ) 10 CH 3 ) And dodecyl (-(CH 2 ) 11 CH 3 ) are mentioned, but not limited thereto. In one embodiment, the alkyl is C (1~6) alkyl. In another embodiment, the alkyl is C (1~4) alkyl. In another embodiment, the alkyl is C (1-3) alkyl.

[0027] The term "alkylene" refers to 1 to 12 carbon atoms (i.e., (C 1 ~C 12 ) alkylene), 1 to 6 carbon atoms (i.e., (C 1 ~C6 ) 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), and refers to a linear or branched saturated divalent hydrocarbon moiety derived from an alkane. Examples of alkylene groups include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), -C(CH 3 )H-, propylene (-CH 2 CH 2 CH 2 -), isopropylene (-CH(CH 3 )CH 2 -), and -CH 2 CH(CH 3 ), but are not limited thereto. In one embodiment, alkylene refers to C (1~4) alkylene. In another embodiment, alkylene refers to C (1-2) alkylene.

[0028] The term "halo" or "halogen" refers to bromo (-Br), chloro (-Cl), fluoro (-F), or iodo (-I). In one embodiment, halo refers to fluoro.

[0029] The term "haloalkyl" refers to a linear or branched 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, and optionally having one or more H atoms substituted with halo. 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 2F), trifluoroethyl (CH 2 CF 3 ), tetrafluorotrifluoromethyl ethyl (CF(CF 3 )) 2 ), and based on ordinary skill in the art and the teachings provided herein, groups that are considered equivalent to any one of the foregoing examples. In one embodiment, the haloalkyl is C (1~6) referring to haloalkyl. In another embodiment, the haloalkyl is C (1~4) referring to haloalkyl. In another embodiment, the alkyl is C (1~3) referring to haloalkyl.

[0030] The term "cycloalkyl" refers to, for example, a saturated or partially unsaturated all-carbon ring system having 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) cycloalkyl), where the cycloalkyl ring system has a monocyclic or polycyclic structure that is fused, spirocyclic, or bridged (bridged configuration). Exemplary cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Some cycloalkyl groups may exist as spirocycloalkyls, where two cycloalkyl rings are fused through a single carbon atom, and by way of example and not limitation, an example of a spiropentyl group is

[0031]

Chemical formula

[0032]

Chemical formula

[0033]

Chemical formula

[0034]

Chemical formula

[0035] The term "cycloalkylene" refers to, for example, a divalent saturated or partially unsaturated all-carbon cyclic system (i.e., C (3~10) cycloalkylene) derived from a cycloalkane having 3 to 10 carbon atoms, a divalent saturated or partially unsaturated all-carbon cyclic system (i.e., C (3~8) cycloalkylene) derived from a cycloalkane having 3 to 8 carbon atoms, or a divalent saturated or partially unsaturated all-carbon cyclic system (i.e., C (3~6) cycloalkylene) derived from a cycloalkane having 3 to 6 carbon atoms, where the cycloalkyl ring system has a monocyclic or polycyclic structure of fused, spiro, or bridged rings. Examples of alkylene groups include

[0036]

Chemical formula

[0037] Unless otherwise specified, the term "aryl" refers to a polyunsaturated, typically aromatic hydrocarbon group, which can be monocyclic or polycyclic (up to 3 rings) that are fused or covalently bonded to each other. The term aromatic is well known to those skilled in the art and refers to a cyclic conjugated system of 4n + 2 electrons, such as 6, 10, 14, etc. π - electrons (Hückel method). Examples of aryl groups include phenyl, naphthyl, anthracenyl. In one embodiment, aryl is C (6-10) Refers to aryl. In another embodiment, aryl refers to phenyl.

[0038] 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, which contains carbon atoms and at least one atom other than carbon in the ring, and the atoms are 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, oxetanyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, and thiomorpholinyl. Unless otherwise described, the heterocyclyl group is bonded to its pendant group through any heteroatom or carbon atom that results in a stable structure. In one embodiment, heterocyclyl refers to a 3 - 10 membered heterocyclyl. In another embodiment, heterocyclyl refers to a 3 - 8 membered heterocyclyl. In another embodiment, heterocyclyl refers to a 3 - 6 membered heterocyclyl.

[0039] As used herein, the term "5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms" refers to a 5- to 12-membered (or 7- to 12-membered or 7- to 10-membered) ring system that contains carbon atoms and 1 to 7 heteroatoms, 1 to 5 heteroatoms, 1 to 4 heteroatoms, or 1 to 3 heteroatoms, where the heteroatoms are independently selected from the group consisting of N, O, and S, and that is a saturated or partially saturated bridged polycyclic, fused polycyclic, or spiro polycyclic ring system. The ring system may include a fully 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 of the rings 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 bi- 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 specified, the bicyclic or tricyclic ring system is attached by its pendant group to any heteroatom or carbon atom that results in a stable structure. In one embodiment, the 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, the 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, the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms refers to a 7- to 10-membered bicyclic ring system containing one or more heteroatoms.

[0040] The term "heteroaryl" refers to a monocyclic aryl ring system or a bicyclic aryl ring system having 5 to 12 ring members, 5 to 10 ring members, or 5 to 6 ring members, which contains carbon atoms and 1 to 5 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms, and the heteroatoms are independently selected from the group consisting of N, O, and S. Included within the term heteroaryl are 5- or 6-membered aromatic rings where the ring consists of carbon atoms and has at least 1 heteroatomic member. Suitable heteroatoms include nitrogen, oxygen, and sulfur. In the case of a 5-membered ring, in some embodiments, the heteroaryl ring contains 1 member of nitrogen, oxygen, or sulfur and up to an additional 3 members of nitrogen. In the case of a 6-membered ring, in some embodiments, the heteroaryl ring contains 1 to 3 nitrogen atoms. When the 6-membered ring has 3 nitrogen atoms, at most 2 nitrogen atoms are adjacent. Examples of heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzoisoxazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinazolinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. One of ordinary skill in the art will recognize that the recited species of heteroaryl groups are not inclusive and that additional species within the scope of these defined terms may be selected. Unless otherwise described, heteroaryl is bonded through its pendant group to any heteroatom or carbon atom that results in a stable structure. In one embodiment, heteroaryl refers to 5- to 10-membered 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.

[0041] The term "substituted" means that the specified group or moiety has one or more substituents. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that the specified group is either unsubstituted or substituted with one or more substituents. When the term "substituted" is used to describe a structural moiety, the substitution is meant to occur at any position where the valence is permitted in the moiety.

[0042] When the compounds disclosed herein have at least one stereocenter, these compounds may accordingly exist as enantiomers (optical isomers) or diastereomers (diastereoisomers). It is understood that all such isomers and mixtures thereof are included within the scope of the present disclosure.

[0043] A "diastereoisomer" is a stereoisomer that has at least two asymmetric atoms but is not a mirror image of each other.

[0044] An "enantiomer" is 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 "scalemic" mixture of enantiomers is a mixture of enantiomers in a ratio other than 1:1.

[0045] When a mixture of stereoisomers results from a process for preparing a compound according to the present disclosure, these isomers may be separated by conventional techniques such as, but not limited to, preparative chromatography. These compounds may be prepared in racemic form, and the scalemic mixture or individual enantiomers may be prepared by either enantioselective synthesis or resolution. The compounds may form diastereomeric pairs, for example, by forming salts with optically active acids such as, but not limited to, (−)-di-p-toluoyl-D-tartaric acid and / or (+)-di-p-toluoyl-L-tartaric acid, and may then be resolved into their component enantiomers by standard methods such as fractional crystallization and regeneration of the free base. These compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, these compounds may be resolved using chiral column HPLC or SFC. In some cases, 1 result in complex multiplets and peak integrations in the 1H NMR spectrum 1 rotational isomers of the compounds may be observable by 1H NMR.

[0046] Absolute stereochemistry is assigned according to the Cahn-Ingold-Prelog R-S system. Chiral centers with known absolute configuration are designated with the prefixes R and S assigned by standard sequence rule procedures, and where appropriate, the appropriate locant precedes (Pure & Appl. Chem. 45, 1976, 11-30). Certain pairs of enantiomers and diastereomers are presented together in the examples. These enantiomers / diastereomers may be designated and characterized as enantiomer 1 or enantiomer 2 (or diastereomer 1 or diastereomer 2) by the following synthetic methods. The presentation of stereoisomers in this manner conveys the separate preparation or isolation of the compound as a pure single enantiomer or diastereomer at the specified stereocenter. However, unless otherwise specified, when a pure single enantiomer (or diastereomer) is presented together with the corresponding pure single enantiomer (or diastereomer) in the examples of the present disclosure, the order in which the chemical structure / IUPAC name is presented does not necessarily correspond to the order in which the example numbers are listed. As an example, if the R enantiomer and S enantiomer of a compound are presented side by side under the heading "Example X and Example Y", in the following methods and characterizations, unless otherwise specified, regardless of the order in which the IUPAC name or chemical structure of the compound is presented, Example X may be either the R enantiomer or the S enantiomer, and Example Y is the opposite enantiomer.

[0047] Pseudoasymmetric stereocenters are treated in the same manner as chiral centers, but are given the lowercase symbols r or s (Angew. Chem. Int. Ed. Engl. 1982, 21, 567-583).

[0048] During any of the processes for preparing the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups in any of the relevant molecules. This can be achieved by conventional protecting groups such as, but not limited to, those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973, and T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient later stage using methods well known in the art.

[0049] Furthermore, within the scope of this disclosure, particularly when referring to the compounds of this disclosure or pharmaceutically acceptable salts thereof, any element is intended to include all isotopes and mixtures of isotopes of that element, whether occurring naturally or produced synthetically, in any natural abundance or in isotopically enriched form. For example, reference to hydrogen or "H" is intended, within its scope, to 1 include H, 2 H (i.e., deuterium or D), and 3 H (i.e., tritium or T). In some embodiments, the compounds described herein include 2 H (i.e., deuterium) isotopes. By way of example, a group denoted as -C (1-6) alkyl includes not only -C 1 H 3 but also C 1 HD 2 C 1 H 2 D, CD 3 and other isotopic forms, and a group denoted as C 1 H 2 C 1 H 3 includes not only C 1 HDC 1 HD 2 C 1 HDC 1 H 2D, C 1 H 2 C 1 H 3 , CD 2 CD 3 also includes other tautomeric forms such as. Similarly, when nonexplicit hydrogen atoms are present in the chemical structure, those hydrogen atoms may be 1 H, 2 H (i.e., deuterium or D), or 3 H (i.e., tritium or T). By way of example, the group

[0050]

Chem.

[0051]

Chem.

[0052] References to the compounds described herein refer to either (a) the actually recited forms of such compounds, and (b) the forms of such compounds in media in which such compounds are believed to exist at the time of specification. For example, without limitation in this specification, a reference to a compound such as R-COOH refers to, for example, R-COOH (s) , R-COOH (sol) , and R-COO - (sol) , including a reference to any one of them. In this example, R-COOH (s) refers to a solid compound, for example, when it may be present in a pharmaceutical composition or preparation such as a tablet or some other solid, and R-COOH (sol) refers to the undissociated form of the compound in a solvent, and 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, regardless of whether such a dissociated form is derived from R-COOH, its salt, or any other entity that gives rise to R-COO - upon dissociation in the medium under consideration. In another example, an expression such as "exposing an entity to compound of formula R-COOH" refers to exposing such an entity to the form of the compound R-COOH that exists in the medium in which such exposure occurs. In yet another example, an expression such as "reacting an entity with a compound of formula R-COOH" means that (a) the entity in the chemically relevant form of such entity that exists in the medium in which such reaction occurs, (b) reacts with the chemically relevant form of the compound R-COOH that exists in the medium in which such reaction occurs. In this regard, when such an entity exists, for example, in an aqueous environment, since the compound R-COOH exists in such the same medium, the entity is not limited to these but includes R-COOH (aq) and / or R-COO - (aq)It is understood to be exposed to species such as, in which case, in accordance with its customary meaning in chemistry and biochemistry, the subscript “(aq)” means “aqueous”. In these examples of nomenclature, a carboxylic acid functional group was chosen, but this choice is not intended to be limiting and is merely illustrative. Similar examples can be provided for other functional groups including, but not limited to, hydroxyl, basic nitrogen members such as the nitrogen member in an amine, and any other group that interacts or converts in a well-known manner in a medium containing the compound. Such interactions and conversions include, but are not limited to, dissociation, association, tautomerism, solvolysis (including hydrolysis), solvation (including hydration), protonation, and deprotonation. Although no further examples are provided herein in this regard, the reason is that these interactions and conversions occurring in a given medium are well known to those skilled in the art.

[0053] The term “pharmaceutically acceptable” means approved or approvable by the regulatory authorities of the federal or state governments of the United States or the corresponding agencies in countries outside the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopeias for use in animals, more specifically humans.

[0054] "Pharmaceutically acceptable salt" is intended to mean a salt of the free acid or base of a compound disclosed herein that is non-toxic, biologically acceptable, or otherwise biologically suitable for administration to a subject. It should possess the desired pharmacological activity of the parent compound. Generally, see G.S. 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, S.M. Berge, et al., “Pharmaceutical Salts”, J Pharm Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of a patient without undue toxicity, irritation, or allergic response. Since the compounds of the present disclosure can have sufficiently acidic groups, sufficiently basic groups, or both types of functional groups, they can react with a number of inorganic or organic bases, as well as inorganic and organic acids, to form pharmaceutically acceptable salts.

[0055] The compounds of the present disclosure This application relates to a compound of formula I:

[0056]

Chemical formula

[0057] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: A is a 5- to 6-membered heteroaryl optionally substituted with one -C (1~4) alkyl group, W is CH 2 , or CF 2 . X is N, C-H, or C-R X . Y is N, C-H, or C-R Y . Z is N, C-H, or C-R Z . R X , R Y , and R Z are each independently halo, -CN, -C (1~4) alkyl, or -C (1~4) haloalkyl, R 1 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, -C (1~4) alkyl, or -C (1~4) haloalkyl, L is absent or -C (1~4) alkylene, or -C (3~6) cycloalkylene, where -C (1~4) alkylene and -C (3~6) cycloalkylene are optionally substituted with one to three groups selected from halo, -C (1~3) alkyl, and -OC (1~3) alkyl, R 4 is -C (1~6) alkyl, -C (3~10) cycloalkyl, a 3- to 10-membered heterocyclyl, a 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 a 5- to 10-membered heteroaryl, each of which is optionally substituted with one to five R 4x groups, each R 4x is, independently at each occurrence, 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) alkylC (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, a 3- to 8-membered heterocyclyl, -C(1~3) alkyl(3- to 8-membered heterocyclyl), -C (6~10) aryl, or 5- to 10-membered heteroaryl, where -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 heterocyclyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), -C (6~10) aryl, and 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 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, and is optionally further substituted, R N1 and R N2 are each, independently at each occurrence, H, or -C (1~3) alkyl, provided that at least one of X, Y, and Z is C-H.

[0058] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: A is 5- to 6-membered heteroaryl optionally substituted with one methyl group, W is CH 2 , or CF 2 and, X is N, C-H, or C-R Xand Y is N, C-H, or C-R Y and Z is N, C-H, or C-R Z and R X R Y and R Z are each independently halo, -CN, -C (1~4) alkyl, or -C (1~4) haloalkyl, R 1 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 is absent or -C (1~4) alkylene, or -C (3~6) cycloalkylene, where -C (1~4) alkylene is optionally substituted with one -OC (1~3) alkyl group, R 4 is -C (1~6) alkyl, -C (3~10) cycloalkyl, a 3- to 10-membered heterocyclyl, a 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 a 5- to 10-membered heteroaryl, each of which is optionally substituted with 1 to 5 R 4x groups, each R 4x is, each time it appears, 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 heterocyclyl, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), -C (6~10) Aryl, or 5- to 10-membered heteroaryl, where -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 heterocyclyl, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), -C (6~10) Aryl, and 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 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 )), and R N1 and R N2 are each, independently at each occurrence, H, or -C (1~3) alkyl, provided that at least one of X, Y, and Z is C-H.

[0059] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: A is a 5- to 6-membered heteroaryl optionally substituted with one methyl group, W is CH 2 or CF 2 and X is N, C-H, or C-R X and Y is N, C-H, or C-R Y and Z is N, C-H, or C-R Z and R X R Y and R Z are each independently halo, -CN, -C (1~4) alkyl, or -C (1~4) haloalkyl R 1 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 is absent or -C (1~4) alkylene, or -C (3~6) cycloalkylene, where -C (1~4) alkylene is optionally substituted with one -OC (1~3) alkyl group R 4 is -C (1~6) alkyl, -C (3~10) cycloalkyl, a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with 1 to 5 R 4x groups Each R 4x is, each time it appears, 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, a 3- to 8-membered heterocyclyl, where (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 the 3- to 8-membered heterocyclyl are optionally further substituted with 1 to 5 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 ) and are optionally further substituted, and R N1 and R N2 are each, independently at each occurrence, H, or -C (1~3) Alkyl, provided that at least one of X, Y, and Z is C-H.

[0060] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: A is a 5- to 6-membered heteroaryl optionally substituted with 1 to 3 -C (1~4) Alkyl groups, W is CH 2 , CHF, or CF 2 , X is N, C-H, or C-R X , Y is N, C-H, or C-R Y , Z is N, C-H, or C-RZ and R X , R Y , and R Z are each independently halo, -CN, -C (1~4) alkyl, or -C (1~4) haloalkyl, R 1 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 is absent or -C (1~4) alkylene, or -C (3~6) cycloalkylene, where -C (1~4) alkylene and -C (3~6) cycloalkylene are optionally substituted with 1 to 3 groups selected from halo, -C (1~3) alkyl, and -OC (1~3) alkyl, R 4 is hydrogen, -C (1~6) alkyl, -C (3~10) cycloalkyl, 3- to 10-membered heterocyclyl, a 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, where: -C (1~6) alkyl is optionally substituted with 1 to 5 R 4a groups, -C (3~10) cycloalkyl is optionally substituted with 1 to 5 R 4b groups, 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R 4c groups, and a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R 4doptionally substituted with a group, and -C(O)-(3- to 10-membered heterocyclyl) is 1 to 5 R 4e optionally substituted with a group, -C (6~10) aryl is 1 to 5 R 4f optionally substituted with a group, 5- to 10-membered heteroaryl is 1 to 5 R 4g optionally substituted with a group, R 3a R 3b R 3c R 3d R 3e R 3f and R 3g are each, independently at each occurrence, 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) alkylC (3~10) cycloalkyl, -C (3~10) cycloalkylC (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 heterocyclyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), -C (6~10) aryl, or 5- to 10-membered heteroaryl, where -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) alkylC (3~10) cycloalkyl, -C (3~10)Cycloalkyl C (1~3) alkyl, 3- to 8-membered heterocyclyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), -C (6~10) aryl, and 5- to 10-membered heteroaryl are each independently optionally further substituted with 1 to 5 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, R N1 and R N2 are each independently, each occurrence, H, -C (1~3) alkyl, or -C (1~3) haloalkyl, provided that at least one of X, Y, and Z is C-H.

[0061] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: A is a 5- to 6-membered heteroaryl optionally substituted with 1 to 3 -C (1~4) alkyl groups, W is CH 2 or CF 2 , X is N, C-H, or C-R X , Y is N, C-H, or C-R Y , Z is N, C-H, or C-R Z , R X , R Y , and R Z are each independently halo, -CN, -C(1~4) alkyl, or -C (1~4) is haloalkyl, R 1 is hydrogen, -C (1~4) alkyl, or -C (1~4) is haloalkyl, R 2 is hydrogen, halo, -C (1~4) alkyl, or -C (1~4) is haloalkyl, R 3 is hydrogen, halo, -C (1~4) alkyl, or -C (1~4) is haloalkyl, L is absent or -C (1~4) alkylene, or -C (3~6) is cycloalkylene, where -C (1~4) alkylene and -C (3~6) cycloalkylene are optionally substituted with one to three groups selected from halo, -C (1~3) alkyl, and -OC (1~3) alkyl, R 4 is hydrogen, -C (1~6) alkyl, -C (3~10) cycloalkyl, 3- to 10-membered heterocyclyl, a 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, where: -C (1~6) alkyl is optionally substituted with one to five R 4a groups, -C (3~10) cycloalkyl is optionally substituted with one to five R 4b groups, 3- to 10-membered heterocyclyl is optionally substituted with one to five R 4c groups, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with one to five R 4d groups, -C(O)-(3- to 10-membered heterocyclyl) is optionally substituted with one to five R 4e groups, -C (6~10) aryl is optionally substituted with one to five R4f is optionally substituted on the basis, and the 5- to 10-membered heteroaryl is 1 to 5 R 4g is optionally substituted on the basis, each R 4a is, each time it appears, 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 heterocyclyl, -C (6~10) aryl, or 5- to 10-membered heteroaryl, where -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, -C (6~10) aryl, and 5- to 10-membered heteroaryl are optionally further substituted by 1 to 5 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, R 4b 、R 4c 、R 4d 、and R4e is, for each occurrence, independently of one another, 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, a 3- to 8-membered heterocyclyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), -C (6~10) aryl, or a 5- to 10-membered heteroaryl, where -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~8) cycloalkyl, a 3- to 8-membered heterocyclyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), -C (6~10) aryl, and a 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 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, R 4f and R 4gFor each occurrence, independently of one another, 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) alkylC (3~10) cycloalkyl, -C (3~10) cycloalkylC (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 heterocyclyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), -C (6~10) aryl, or 5- to 10-membered heteroaryl, where -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) alkylC (3~10) cycloalkyl, -C (3~10) cycloalkylC (1~3) alkyl, 3- to 8-membered heterocyclyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), -C (6~10) aryl, and 5- to 10-membered heteroaryl are 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) optionally further substituted with 1 to 5 groups selected from alkyl, R N1 and R N2 is, each occurrence, independently, H, or -C (1~3) alkyl, provided that at least one of X, Y, and Z is C-H.

[0062] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: A is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 -C (1~4) alkyl groups, W is CH 2 , or CF 2 and X is N, C-H, or C-R X and Y is N, C-H, or C-R Y and Z is N, C-H, or C-R Z and R X , R Y , and R Z are each independently halo, -CN, -C (1~4) alkyl, or -C (1~4) haloalkyl, R 1 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 is absent or -C (1~4)an alkylene, or -C (3~6) is a cycloalkylene, where -C (1~4) the alkylene and -C (3~6) the cycloalkylene are optionally substituted with 1 to 3 groups selected from halo, -C (1~3) alkyl, and -OC (1~3) alkyl, R 4 is -C (1~6) alkyl, -C (3~10) cycloalkyl, a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, where: -C (1~6) the alkyl is optionally substituted with 1 to 5 R 4a groups, -C (3~10) the cycloalkyl is optionally substituted with 1 to 5 R 4b groups, the 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R 4c groups, the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R 4d groups, and the 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R 4g groups, each R 4a , each occurrence independently, is 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, a 3- to 8-membered heterocyclyl, -C (6~10) aryl, or a 5- to 10-membered heteroaryl, where -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, -C (6~10) Aryl, and 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 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 and are optionally further substituted, R 4b , R 4c , and R 4d are each, independently at each occurrence, 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, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), -C (6~10) Aryl, or 5- to 10-membered heteroaryl, where -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, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), -C (6~10) Aryl, and 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 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 and are optionally further substituted, Each R 4g is, each time it appears, 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) AlkylC (3~10) Cycloalkyl, -C (3~10) CycloalkylC (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) Cycloalkyl, 3- to 8-membered heterocyclyl, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), -C (6~10) Aryl, or 5- to 10-membered heteroaryl, where -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 heterocyclyl, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), -C (6~10) Aryl, and 5- to 10-membered heteroaryl are each independently 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 and are optionally further substituted with 1 to 5 groups independently selected from R N1 and R N2 are each independently, for each occurrence, H, or -C (1~3) Alkyl, provided that at least one of X, Y, and Z is C-H.

[0063] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: A is a 5- to 6-membered heteroaryl optionally substituted with 1 to 3 -C (1~4) Alkyl groups, W is CH 2 , or CF 2 , X is N, C-H, or C-R X , Y is N, C-H, or C-R Y and Z is N, C-H, or C-R Z and R X , R Y , and R Z are each independently halo, -CN, -C (1~4) alkyl, or -C (1~4) haloalkyl R 1 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, -C (1~4) alkyl, or -C (1~4) haloalkyl L is absent or -C (1~4) alkylene or -C (3~6) cycloalkylene, where -C (1~4) alkylene and -C (3~6) cycloalkylene are optionally substituted with 1 to 3 groups selected from halo, -C (1~3) alkyl, and -OC (1~3) alkyl R 4 is hydrogen, -C (1~6) alkyl, -C (3~10) cycloalkyl, a 3- to 10-membered heterocyclyl, a 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 a 5- to 10-membered heteroaryl, where:-C (1~6) alkyl is optionally substituted with 1 to 5 R 4a groups, -C (3~10) cycloalkyl is optionally substituted with 1 to 5 R 4b groups, and a 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R 4cOptionally substituted with a group, the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is substituted with 1 to 5 R 4d Optionally substituted with a group, -C(O)-(3- to 10-membered heterocyclyl) is substituted with 1 to 5 R 4e Optionally substituted with a group, -C (6~10) Aryl is substituted with 1 to 5 R 4f Optionally substituted with a group, 5- to 10-membered heteroaryl is substituted with 1 to 5 R 4g Optionally substituted with a group, Each R 4a Is, each time it appears, 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 heterocyclyl, where C (1~6) Haloalkyl, -C (3~8) Cycloalkyl, -OC (1~6) Alkyl, -OC (1~6) Haloalkyl, -OC (3~8) Cycloalkyl, and 3- to 8-membered heterocyclyl are optionally further substituted with 1 to 5 groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1~4) Alkyl, and -OC (1~4) Alkyl, R 4b 、R 4c 、R 4d 、and R 4e Are, each time they appear, each 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, where -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 with 1 to 5 groups selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1~4) Alkyl, and -OC (1~4) Alkyl, R 4f and R 4g are, each time they appear, independently of one another, 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 heterocyclyl, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), -C (6~10) Aryl, or 5- to 10-membered heteroaryl, wherein, -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 heterocyclyl, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), -C (6~10) Aryl, and 5- to 10-membered heteroaryl are each independently optionally further substituted with 1 to 5 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, and is optionally further substituted with 1 to 5 groups selected therefrom, R N1 And R N2 Are each independently, each occurrence, H, or -C (1~3) Alkyl, Provided that at least one of X, Y, and Z is C-H.

[0064] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: A is 5- to 6-membered heteroaryl optionally substituted with one -C (1~4) Alkyl group, W is CH 2 , or CF 2 Thereby, X is N, C-H, or C-R X and Y is N, C-H, or C-R Y and Z is N, C-H, or C-R Z and R X R Y and Z R (1~4) are each independently halo, -CN, -C (1~4) alkyl, or -C R 1 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, -C (1~4) alkyl, or -C (1~4) haloalkyl, L is absent or -C (1~4) alkylene, or -C (3~6) cycloalkylene, where -C (1~4) alkylene and -C (3~6) cycloalkylene are optionally substituted with 1 to 3 groups selected from halo, -C (1~3) alkyl, and -OC (1~3) alkyl, R 4 is -C (1~6) alkyl, -C (3~10) cycloalkyl, a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, where:-C (1~6) alkyl is optionally substituted with 1 to 5 R 4a groups, -C (3~10) cycloalkyl is optionally substituted with 1 to 5 R 4b groups, a 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R 4coptionally substituted with a group R, and a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms 4d optionally substituted with a group R, and a 5- to 10-membered heteroaryl 4g optionally substituted with a group R each R 4a is, independently for each occurrence, 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 heterocyclyl, where C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~8) cycloalkyl, and the 3- to 8-membered heterocyclyl are optionally further substituted with 1 to 5 groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1~4) alkyl, and -OC (1~4) alkyl R 4b , R 4c , and R 4d are, independently for each occurrence, each 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) Is cycloalkyl, 3- to 8-membered heterocyclyl, or 5- to 10-membered heteroaryl, where -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 with 1 to 5 groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1~4) Alkyl, and -OC (1~4) Alkyl, Each R 4g Is, each time it appears, 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) AlkylC (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) Is cycloalkyl, 3- to 8-membered heterocyclyl, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), -C (6~10) Aryl, or 5- to 10-membered heteroaryl, where -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 heterocyclyl, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), -C (6~10) Aryl, and 5- to 10-membered heteroaryl are each independently optionally further substituted with 1 to 5 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 and are optionally further substituted with 1 to 5 groups so selected, R N1 and R N2 are each independently, each occurrence, H, or -C (1~3) Alkyl, provided that at least one of X, Y, and Z is C-H.

[0065] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: A is a 5- to 6-membered heteroaryl optionally substituted with one -C (1~4) Alkyl group, W is CH 2 , or CF 2 . X is N, C-H, or C-R X . Y is N, C-H, or C-R Y . Z is N, C-H, or C-R Z . R X 、R Y 、and R Z are each independently halo, -CN, -C (1~4) alkyl, or -C (1~4) haloalkyl, R 1 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 is absent or -C (1~4) alkylene, or -C (3~6) cycloalkylene, where -C (1~4) alkylene is optionally substituted with one -OC (1~3) alkyl group, R 4 is hydrogen, -C (1~6) alkyl, -C (3~10) cycloalkyl, a 3- to 10-membered heterocyclyl, a 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 a 5- to 10-membered heteroaryl, where: -C (1~6) alkyl is optionally substituted with 1 to 5 R 4a groups, -C (3~10) cycloalkyl is optionally substituted with 1 to 5 R 4b groups, a 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R 4c groups, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R 4d groups, -C(O)-(3- to 10-membered heterocyclyl) is optionally substituted with 1 to 5 R 4e groups, -C (6~10) aryl is optionally substituted with 1 to 5 R 4fis optionally substituted on the basis, and the 5- to 10-membered heteroaryl is 1 to 5 R 4g is optionally substituted on the basis, each R 4a is, each time it appears, 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 heterocyclyl, where -C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, and the 3- to 8-membered heterocyclyl are optionally further substituted with 1 to 5 groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1~4) alkyl, and -OC (1~4) alkyl, each R 4b is, each time it appears, 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, where -C (1~6) alkyl, -C (1~6) haloalkyl, -OC (1~6) alkyl, and -OC (1~6) haloalkyl are optionally further substituted with 1 to 5 groups selected from halo, -OH, -N(R N1 )(R N2 ), and -CN, R 4c and R 4dFor each occurrence, 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, a 3- to 8-membered heterocyclyl, or a 5- to 10-membered heteroaryl, where -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, a 3- to 8-membered heterocyclyl, and a 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1~4) alkyl, and -OC (1~4) alkyl, each R 4e is, for each occurrence, 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 is, for each occurrence, 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) 2 C (1~4) is alkyl, 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) cycloalkyl are optionally further substituted with 1 to 5 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, each R 4g is, independently at each occurrence, 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) alkylC (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 heterocyclyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), or -C (6~10) aryl, where -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) alkylC(3~10) Cycloalkyl, 3- to 8-membered heterocyclyl, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), and -C (6~10) Aryl is optionally further substituted with 1 to 5 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 and is optionally further substituted with 1 to 5 groups selected therefrom, R N1 and R N2 are each, independently at each occurrence, H, or -C (1~3) Alkyl, provided that at least one of X, Y, and Z is C-H.

[0066] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: A is a 5- to 6-membered heteroaryl optionally substituted with one -C (1~4) Alkyl group, W is CH 2 , or CF 2 , X is N, C-H, or C-R X , Y is N, C-H, or C-R Y , Z is N, C-H, or C-R Z , R X , R Y , and R Z are each independently halo, -CN, -C (1~4) Alkyl, or -C (1~4) Haloalkyl, R 1 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 is absent or -C (1~4) alkylene, or -C (3~6) cycloalkylene, where -C (1~4) alkylene is optionally substituted with one -OC (1~3) alkyl group, R 4 is -C (1~6) alkyl, -C (3~10) cycloalkyl, a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, where: -C (1~6) alkyl is optionally substituted with 1 to 5 R 4a groups, -C (3~10) cycloalkyl is optionally substituted with 1 to 5 R 4b groups, a 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R 4c groups, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R 4d groups, and a 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R 4g groups, each R 4a is, independently at each occurrence, 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 heterocyclyl, where -C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, and the 3- to 8-membered heterocyclyl are optionally further substituted with 1 to 5 groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1~4) alkyl, and -OC (1~4) alkyl, each R 4b is, each occurrence 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, where -C (1~6) alkyl, -C (1~6) haloalkyl, -OC (1~6) alkyl, and -OC (1~6) haloalkyl are optionally further substituted with 1 to 5 groups selected from halo, -OH, -N(R N1 )(R N2 ), and -CN, R 4c and R 4d are, each occurrence, independently of each other, 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, a 3- to 8-membered heterocyclyl, or a 5- to 10-membered heteroaryl, where -C (1~6)Alkyl, -C (1~6) Haloalkyl, -C (3~8) Cycloalkyl, -OC (1~6) Alkyl, -OC (1~6) Haloalkyl, 3- to 8-membered heterocyclyl, and 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1~4) Alkyl, and -OC (1~4) Alkyl, and each R 4g is, independently at each occurrence, 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) AlkylC (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 heterocyclyl, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), or -C (6~10) Aryl, where -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) AlkylC (3~10) Cycloalkyl, 3- to 8-membered heterocyclyl, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), and -C (6~10) Aryl are 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) optionally further substituted with 1 to 5 groups selected from alkyl, R N1 and R N2 are each independently, in each occurrence, H, or -C (1~3) alkyl, provided that at least one of X, Y, and Z is C-H.

[0067] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: A is a 5- to 6-membered heteroaryl optionally substituted with one methyl group, W is CH 2 , or CF 2 and X is N, C-H, or C-R X and Y is N, C-H, or C-R Y and Z is N, C-H, or C-R Z and R X , R Y , and R Z are each independently halo, -CN, -C (1~4) alkyl, or -C (1~4) haloalkyl, R 1 is hydrogen, -C (1~4) alkyl, or -C (1~4) haloalkyl, R 2 is hydrogen, halo, -C (1~4) alkyl, or -C (1~4)is a haloalkyl, R 3 is hydrogen, or -C (1~4) alkyl, L is absent or -C (1~4) alkylene, or -C (3~6) cycloalkylene, where -C (1~4) alkylene is optionally substituted with one -OC (1~3) alkyl group, R 4 is hydrogen, -C (1~6) alkyl, -C (3~10) cycloalkyl, a 3- to 10-membered heterocyclyl, a 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 a 5- to 10-membered heteroaryl, where: -C (1~6) alkyl is optionally substituted with 1 to 5 R 4a groups, -C (3~10) cycloalkyl is optionally substituted with 1 to 5 R 4b groups, a 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R 4c groups, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R 4d groups, -C(O)-(3- to 10-membered heterocyclyl) is optionally substituted with 1 to 3 -C (1~4) alkyl groups, -C (6~10) aryl is optionally substituted with 1 to 5 R 4f groups, a 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R 4g groups, each R 4a is, independently at each occurrence, 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) is alkyl, or a 3- to 8-membered heterocyclyl, where -C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, and the 3- to 8-membered heterocyclyl are each optionally further substituted with 1 to 5 groups selected from halo and -OH, each R 4b is, each occurrence independently, halo, -OH, -CN, -C (1~6) alkyl, -C (1~6) haloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, where -C (1~6) alkyl, -C (1~6) haloalkyl, -OC (1~6) alkyl, and -OC (1~6) haloalkyl are each optionally further substituted with 1 to 5 groups selected from halo and -OH, R 4c and R 4d are, each occurrence, independently of each other, -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, a 3- to 8-membered heterocyclyl, or a 5- to 10-membered heteroaryl, where -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, the 3- to 8-membered heterocyclyl, and the 5- to 10-membered heteroaryl are each optionally further substituted with 1 to 5 groups selected from halo, -OH, and -C (1~4) alkyl, each R 4f is, each occurrence 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 ) and wherein -C (1~6) Alkyl, -C (1~6) Haloalkyl, -C (3~8) Cycloalkyl, -OC (1~6) Alkyl, -OC (1~6) Haloalkyl, and -OC (3~8) Cycloalkyl are each optionally further substituted with from 1 to 5 groups selected from halo and -OH, each R 4g is, each occurrence, 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) AlkylC (3~10) Cycloalkyl, -C(O)N(R N1 )(R N2 ), a 3- to 8-membered heterocyclyl, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), or -C (6~10) Aryl and wherein -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) AlkylC (3~10) Cycloalkyl, a 3- to 8-membered heterocyclyl, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), and -C (6~10) Aryl are each 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 ) and is optionally further substituted with 1 to 5 groups selected from, and R N1 and R N2 are, each occurrence, independently, H, or -C (1~3) Alkyl, and provided that at least two of X, Y, and Z are C-H.

[0068] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: A is a 5- to 6-membered heteroaryl optionally substituted with one methyl group; W is CH 2 , or CF 2 ; X is N, C-H, or C-R X ; Y is N, C-H, or C-R Y ; Z is N, C-H, or C-R Z ; R X , R Y , and R Z are each independently halo, -CN, -C (1~4) Alkyl, or -C (1~4) Haloalkyl; R 1 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 is absent, -C (1~4) Alkylene, or -C (3~6)is a cycloalkylene, where -C (1~4) alkylene is optionally substituted with one -OC (1~3) alkyl group, R 4 is -C (1~6) alkyl, -C (3~10) cycloalkyl, a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, where: -C (1~6) alkyl is optionally substituted with 1 to 5 R 4a groups, -C (3~10) cycloalkyl is optionally substituted with 1 to 5 R 4b groups, a 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R 4c groups, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R 4d groups, and a 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R 4g groups, each R 4a is, independently at each occurrence, 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 heterocyclyl, where: -C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, and a 3- to 8-membered heterocyclyl are optionally further substituted with 1 to 5 groups selected from halo and -OH, each R 4b is, independently at each occurrence, halo, -OH, -CN, -C (1~6) alkyl, -C (1~6) haloalkyl, -OC (1~6)Alkyl, -OC (1~6) is haloalkyl, where -C (1~6) alkyl, -C (1~6) haloalkyl, -OC (1~6) alkyl, and -OC (1~6) haloalkyl is optionally further substituted with 1 to 5 groups selected from halo and -OH, R 4c and R 4d are, each occurrence, 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, where -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, 3- to 8-membered heterocyclyl, and 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -OH, and -C (1~4) alkyl, each R 4g is, each occurrence, 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) alkylC (3~10) cycloalkyl, -C(O)N(R N1 )(R N2 ), 3- to 8-membered heterocyclyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), or -C (6~10) aryl, where -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 heterocyclyl, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), and -C (6~10) Aryl is optionally further substituted with 1 to 5 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 ) and is optionally further substituted with 1 to 5 groups selected therefrom, and R N1 and R N2 are each, independently at each occurrence, H, or -C (1~3) alkyl, provided that at least two of X, Y, and Z are C-H.

[0069] 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:

[0070]

Chemical formula

[0071] 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:

[0072]

Chemical formula

[0073] In some embodiments, disclosed herein is that A is a 5-membered heteroaryl optionally substituted with 1 to 3 -C (1~4) alkyl groups, a compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is that A is a 5-membered heteroaryl optionally substituted with 1 methyl group, a compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is that A is a 5-membered heteroaryl, a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0074] In some embodiments, disclosed herein is that A is a 6-membered heteroaryl optionally substituted with 1 to 3 -C (1~4) alkyl groups, a compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is that A is a 6-membered heteroaryl optionally substituted with 1 methyl group, a compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is that A is a 6-membered heteroaryl, a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, disclosed herein is that A is a 5- to 6-membered heteroaryl optionally substituted with 1 -C (1~4) alkyl group, a compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is that A is a 5-membered heteroaryl or pyridinyl, each of which is 1 -C (1~4)A compound of formula I, or a pharmaceutically acceptable salt thereof, optionally substituted with an alkyl group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl or pyridinyl, each of which is optionally substituted with one methyl group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl or pyridinyl.

[0076] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is pyrazolyl, oxazolyl, thiazolyl, or pyridinyl, each of which is optionally substituted with one methyl group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is pyrazolyl, oxazolyl, thiazolyl, or pyridinyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is pyrazolyl or thiazolyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is pyrazolyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is oxazolyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is thiazolyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is pyridinyl.

[0077] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is:

[0078]

Chemical formula

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

[0080]

Chemical formula

[0081] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is

[0082]

Chemical formula

[0083] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is

[0084]

Chemical formula

[0085] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is

[0086]

Chemical formula

[0087] 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:

[0088]

Chemical formula

[0089]

Chem.

[0090] 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:

[0091]

Chem.

[0092] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is CH 2 , CHD, CD 2 , or CF 2 . In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is CH 2 , CD 2 , or CF 2 . In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is CH 2 or CF 2 . In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is CH 2 . In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is CF 2 .

[0093] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein at least two of X, Y, and Z are C-H. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein one or fewer of X, Y, and Z is N.

[0094] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is C-H or C-R X In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is C-H or C-F. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is C-H. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is C-R X In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is C-F.

[0095] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Y is N, C-H, C-F, or C-CN. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Y is N or C-H. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Y is N. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-H. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-R Y In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-F. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-CN.

[0096] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Z is N, C-H, or C-F. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Z is N. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Z is C-H. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Z is C-R Z and is a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Z is C-F.

[0097] In some embodiments, disclosed herein is R X R Y and R Z each independently is halo, -CN, -C (1~4) alkyl, or -C (1~4) haloalkyl, and is a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is R X R Y and R Z each independently is fluoro or -CN, and is a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is C-H or C-F, Y is N, C-H, C-F, or C-CN, and Z is N, C-H, or C-F. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is C-H, Y is N, C-H, or C-F, and Z is N, C-H, or C-F. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is C-H, Y is N or C-H, and Z is N, C-H, or C-F.

[0099] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is any one compound of Formulae Ic-1 to Ic-4:

[0100]

Chemical formula

[0101] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or -C (1~4) haloalkyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or -CF 3 . In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is -CF 3 .

[0102] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is any one compound of Formulae Id-1 to Id-5:

[0103]

Chemical formula

[0104] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each independently hydrogen, halo, or -C (1~4) alkyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3is, independently of each other, hydrogen, fluoro, or methyl, a compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is R 2 and R 3 are hydrogen, a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments, disclosed herein is R 2 is hydrogen, halo, or -C (1~4) alkyl, a compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is R 2 is hydrogen, fluoro, or methyl, a compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is R 2 is hydrogen, a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, disclosed herein is R 3 is hydrogen, halo, or -C (1~4) alkyl, a compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is R 3 is hydrogen or -C (1~4) alkyl, a compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is R 3 is hydrogen, a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, disclosed herein is that L is absent, -C (1~4) alkylene, or -C (3~6) cycloalkylene, wherein -C (1~4) alkylene is optionally substituted with one -OC (1~3) alkyl group, a compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is that L is absent, -C (1~4)is alkylene or cyclopropylene, where -C (1~4) alkylene is optionally substituted with one -OC (1~3) a compound of formula I, or a pharmaceutically acceptable salt thereof, which is optionally substituted with an alkyl group.

[0108] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein L is absent or

[0109]

Chemical formula

[0110] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein L is absent or

[0111]

Chemical formula

[0112] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein L is absent.

[0113] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein L is

[0114]

Chemical formula

[0115] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, which is one of the compounds of formula Ie-1 to formula Ie-8:

[0116]

Chemical formula

[0117] In some embodiments, disclosed herein is R 4 is -C (1~6) alkyl, -C (3~10) cycloalkyl, 3- to 10-membered heterocyclyl, a 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 with 1 to 5 R 4x groups, a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is R 4 is -C (1~6) alkyl, -C (3~10) cycloalkyl, 3- to 10-membered heterocyclyl, a 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 with 1 to 5 R 4x groups, a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4x is, independently at each occurrence, 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) alkylC (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 heterocyclyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), -C (6~10) aryl, or 5- to 10-membered heteroaryl, where -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 heterocyclyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), -C (6~10) aryl, and 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 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.

[0119] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4x is, independently at each occurrence, 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 heterocyclyl, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), -C (6~10) Aryl, or 5- to 10-membered heteroaryl, where -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) AlkylC (3~10) Cycloalkyl, 3- to 8-membered heterocyclyl, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), -C (6~10) Aryl, and 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 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 )).

[0120] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4x is, independently at each occurrence, 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) AlkylC (3~10) Cycloalkyl, -C(O)C (1~4) Alkyl, -C(O)N(RN1 )(R N2 )、 -S(O) 2 C (1~4) alkyl, 3 - to 8 - membered heterocyclyl, where -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) alkylC (3~10) cycloalkyl, and 3 - to 8 - membered heterocyclyl are optionally further substituted with 1 to 5 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 ).

[0121] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is -C (1~6) alkyl, -C (3~10) cycloalkyl, 3 - to 10 - membered heterocyclyl, a 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, where: -C (1~6) alkyl is optionally substituted with 1 to 5 R 4a groups, -C (3~10) cycloalkyl is optionally substituted with 1 to 5 R 4b groups, 3 - to 10 - membered heterocyclyl is optionally substituted with 1 to 5 R 4c groups, a 5 - to 12 - membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R 4d groups, -C(O)-(3 - to 10 - membered heterocyclyl) is optionally substituted with 1 to 5 R 4eis optionally substituted on the basis of -C (6~10) Aryl is optionally substituted with 1 to 5 R 4f is optionally substituted with 1 to 5 R, and 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R 4g is optionally substituted with a group.

[0122] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is -C (1~6) alkyl, -C (3~10) cycloalkyl, 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or 5- to 10-membered heteroaryl, where: -C (1~6) alkyl is optionally substituted with 1 to 5 R 4a groups, -C (3~10) cycloalkyl is optionally substituted with 1 to 5 R 4b groups, 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R 4c groups, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R 4d groups, and 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R 4g groups.

[0123] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is -C (1~6) alkyl, which is optionally substituted with 1 to 5 R 3a groups.

[0124] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4a is, each time it appears, 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 heterocyclyl, -C (6~10) Aryl, or 5- to 10-membered heteroaryl, wherein, (1~6) Haloalkyl, -C (3~8) Cycloalkyl, -OC (1~6) Alkyl, -OC (1~6) Haloalkyl, -OC (3~8) Cycloalkyl, 3- to 8-membered heterocyclyl, -C (6~10) Aryl, and 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 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.

[0125] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4a is, independently at each occurrence, 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 heterocyclyl, where -C (1~6) Haloalkyl, -C (3~8) Cycloalkyl, -OC (1~6) Alkyl, -OC (1~6) Haloalkyl, -OC (3~8) Cycloalkyl, and the 3- to 8-membered heterocyclyl are optionally further substituted with 1 to 5 groups selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1~4) Alkyl, and -OC (1~4) Alkyl.

[0126] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4a is, each occurrence 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 heterocyclyl, where -C (1~6) Haloalkyl, -C (3~8) Cycloalkyl, -OC (1~6) Alkyl, -OC (1~6) Haloalkyl, and the 3- to 8-membered heterocyclyl are halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1~4)Alkyl, and -OC (1~4) Optionally further substituted with 1 to 5 groups selected from alkyl.

[0127] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4a is, independently at each occurrence, 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 heterocyclyl, where -C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, and the 3- to 8-membered heterocyclyl are optionally further substituted with 1 to 5 groups selected from halo and -OH.

[0128] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is:

[0129]

Chemical formula

[0130] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is -C (3~10) cycloalkyl, which is optionally substituted with 1 to 5 R 4b groups.

[0131] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, or spirocyclo[3.3]heptyl, each of which is optionally substituted with from 1 to 3 R 4b groups.

[0132] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4b is, independently at each occurrence, 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, a 3- to 8-membered heterocyclyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), -C (6~10) aryl, or a 5- to 10-membered heteroaryl, where -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~8) cycloalkyl, a 3- to 8-membered heterocyclyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), -C (6~10) aryl, and a 5- to 10-membered heteroaryl are optionally substituted with 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 and is optionally further substituted with 1 to 5 groups selected from

[0133] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4b is, independently at each occurrence, 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, a 3- to 8-membered heterocyclyl, or a 5- to 10-membered heteroaryl, wherein -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~8) cycloalkyl, a 3- to 8-membered heterocyclyl, and a 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1~4) alkyl, and -OC (1~4) alkyl.

[0134] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4b is, independently at each occurrence, 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 -C (1~6) alkyl, -C (1~6) haloalkyl, -OC (1~6) alkyl, and -OC (1~6) haloalkyl are optionally further substituted with 1 to 5 groups selected from halo, -OH, -N(R N1 )(R N2 ), and -CN.

[0135] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4b is, independently at each occurrence, halo, -OH, -CN, -C (1~6) alkyl, -C (1~6) haloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, wherein -C (1~6) alkyl, -C (1~6) haloalkyl, -OC (1~6) alkyl, and -OC (1~6) haloalkyl are optionally further substituted with 1 to 5 groups selected from halo and -OH.

[0136] In some embodiments, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein each R 4b is, independently at each occurrence, halo, -OH, -CN, -C (1~6) alkyl, or -OC (1~6) alkyl, wherein -C (1~6) alkyl is optionally further substituted with one -OH group.

[0137] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is:

[0138]

Chemical formula

[0139] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is a 3- to 10-membered heterocyclyl, which is optionally substituted with 1 to 5 R 4c groups.

[0140] In some embodiments, disclosed herein is a compound of formula I, 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 with 1 to 3 R 4c groups.

[0141] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4c , each occurrence independently, is 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, -C (1~3) alkyl(3- to 8-membered heterocyclyl), -C (6~10) aryl, or 5- to 10-membered heteroaryl, wherein, -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, -C (1~3) alkyl(3- to 8-membered heterocyclyl), -C (6~10) aryl, and 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 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.

[0142] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4c is, independently at each occurrence, 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 -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 with 1 to 5 groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1~4) alkyl, and -OC (1~4) alkyl.

[0143] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4c is, independently at each occurrence, 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 -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, 3- to 8-membered heterocyclyl, and 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1~4) alkyl, and -OC (1~4)Optionally further substituted with 1 to 5 groups selected from alkyl.

[0144] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4c is, independently at each occurrence, -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, a 3- to 8-membered heterocyclyl, or a 5- to 10-membered heteroaryl, wherein -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, a 3- to 8-membered heterocyclyl, and a 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -OH, and -C (1~4) alkyl.

[0145] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4c is, independently at each occurrence, -C (1~6) alkyl, -C(O)C (1~4) alkyl, -S(O) 2 C (1~4) alkyl, a 3- to 8-membered heterocyclyl, or a 5- to 10-membered heteroaryl, wherein -C (1~6) alkyl, a 3- to 8-membered heterocyclyl, and a 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -OH, and -C (1~4) alkyl.

[0146] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R4 is:

[0147] [Chem.] as follows.

[0148] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, which is optionally substituted with 1 to 5 R 4d groups. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, which is optionally substituted with 1 to 5 R 4d groups.

[0149] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is a 5- to 12-membered bicyclic ring system containing 1 to 5 heteroatoms selected from O, N, and S, wherein the 5- to 12-membered bicyclic ring system is optionally substituted with 1 to 5 R 4d groups. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, which is optionally substituted with 1 to 5 R 4d groups, wherein the 5- to 12-membered bicyclic ring system is a 3,5-fused ring system, 5,6-fused ring system, or 6,6-fused ring system.

[0150] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is:

[0151] [Chem.] and each of these is optionally substituted with 1 to 3 R groups. 4d In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R

[0152] is, independently at each occurrence, halo, -OH, -N(R 4d )(R N1 ), -CN, -C N2 alkyl, -C (1~6) haloalkyl, -C (1~6) cycloalkyl, -OC (3~8) alkyl, -OC (1~6) haloalkyl, -OC (1~6) cycloalkyl, -C(O)C (3~8) alkyl, -C(O)N(R (1~4) )(R N1 ), -S(O) N2 C 2 alkyl, -N(H)S(O) (1~4) C 2 alkyl, a 3- to 8-membered heterocyclyl, -C (1~4) alkyl(3- to 8-membered heterocyclyl), -C (1~3) aryl, or a 5- to 10-membered heteroaryl, where -C (6~10) alkyl, -C (1~6) haloalkyl, -C (1~6) cycloalkyl, -OC (3~8) alkyl, -OC (1~6) haloalkyl, -OC (1~6) cycloalkyl, a 3- to 8-membered heterocyclyl, -C (3~8) alkyl(3- to 8-membered heterocyclyl), -C (1~3) aryl, and a 5- to 10-membered heteroaryl are optionally substituted with halo, -OH, -N(R (6~10) )(R N1 ), -CN, -C N2 alkyl, -C (1~4) haloalkyl, -OC (1~4) alkyl, -OC (1~4) haloalkyl, -C(O)C (1~6) alkyl, -C(O)N(R (1~4) )(RN1 )(R N2 )、-S(O) 2 C (1~4) alkyl, and -N(H)S(O) 2 C (1~4) alkyl and is optionally further substituted with 1 to 5 groups selected from

[0153] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4d is, independently at each occurrence, 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, a 3- to 8-membered heterocyclyl, or a 5- to 10-membered heteroaryl, where -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~8) cycloalkyl, a 3- to 8-membered heterocyclyl, and a 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1~4) alkyl, and -OC (1~4) alkyl.

[0154] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4dis, independently at each occurrence, 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、a 3- to 8-membered heterocyclyl、or a 5- to 10-membered heteroaryl, where -C (1~6) alkyl、-C (1~6) haloalkyl、-C (3~8) cycloalkyl、-OC (1~6) alkyl、-OC (1~6) haloalkyl、a 3- to 8-membered heterocyclyl、and a 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -OH, -N(R N1 )(R N2 )、-CN、-C (1~4) alkyl、and -OC (1~4) alkyl.

[0155] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4d is, independently at each occurrence, -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、a 3- to 8-membered heterocyclyl、or a 5- to 10-membered heteroaryl, where -C (1~6) alkyl、-C (1~6) haloalkyl、-C (3~8) cycloalkyl、-OC (1~6) alkyl、-OC (1~6) haloalkyl、a 3- to 8-membered heterocyclyl、and a 5- to 10-membered heteroaryl are halo, -OH, and -C(1~4) Optionally further substituted with 1 to 5 groups selected from alkyl.

[0156] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4d is, each occurrence, independently, -C (1~6) alkyl, -OC (1~6) alkyl, or -C(O)C (1~4) alkyl, wherein -C (1~6) alkyl and -OC (1~6) alkyl are optionally further substituted with 1 to 5 groups selected from halo and -OH.

[0157] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is:

[0158]

Chemical formula

[0159] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is -C(O)-(3- to 10-membered heterocyclyl), which is optionally substituted with 1 to 5 R 4e groups. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is -C(O)-(3- to 10-membered heterocyclyl), which is optionally substituted with 1 to 3 -C (1~4) alkyl groups.

[0160] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4e is, each occurrence, 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, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), -C (6~10) Aryl, or 5- to 10-membered heteroaryl, wherein, -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, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), -C (6~10) Aryl, and 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 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 and are optionally further substituted with 1 to 5 groups selected therefrom.

[0161] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4eis, for each occurrence, 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, a 3- to 8-membered heterocyclyl, or a 5- to 10-membered heteroaryl, where -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~8) cycloalkyl, a 3- to 8-membered heterocyclyl, and a 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1~4) alkyl, and -OC (1~4) alkyl.

[0162] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4e is, for each occurrence, 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.

[0163] In some embodiments, disclosed herein is each R 4e is, for each occurrence, independently, -C(1~4) A compound of formula I that is an alkyl group, or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, disclosed herein is R 4 is

[0165] [Chemical formula] A compound of formula I that is, or a pharmaceutically acceptable salt thereof.

[0166] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is -C (6~10) aryl, which is optionally substituted with 1 to 5 R 4f groups. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl, which is optionally substituted with 1 to 5 R 4f groups. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl, which is optionally substituted with 1 to 3 R 4f groups.

[0167] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4f is, each occurrence 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) alkylC (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, a 3- to 8-membered heterocyclyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), -C (6~10) aryl, or a 5- to 10-membered heteroaryl, where -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) alkylC (3~10) cycloalkyl, a 3- to 8-membered heterocyclyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), -C (6~10) aryl, and a 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 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.

[0168] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4f is, independently at each occurrence, 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, 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) Cycloalkyl is optionally further substituted with 1 to 5 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.

[0169] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4f is, each occurrence 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 is optionally further substituted with 1 to 5 groups selected from halo and -OH.

[0170] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4f is, independently at each occurrence, 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 ).

[0171] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is:

[0172]

Chemical formula

[0173] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is a 5- to 10-membered heteroaryl, which is optionally substituted with 1 to 5 R 4g groups. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt 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 with 1 to 3 R 4g groups. In some embodiments, disclosed herein is a compound of formula I, 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 with 1 to 3 R 4g groups.

[0174] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridin-2-onyl, pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, benzimidazolyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyridinyl, or pyrazolopyrimidinyl, each of which is optionally substituted with 1 to 3 R 4g groups. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrazolyl, imidazolyl, oxazolyl, pyridinyl, or pyrazolopyridinyl, each of which is optionally substituted with 1 to 3 R 4g groups. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrazolyl or pyrazolopyridinyl, each of which is optionally substituted with 1 to 3 R 4g groups. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrazolyl, which is optionally substituted with 1 to 3 R 4g groups. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrazolopyridinyl, which is optionally substituted with 1 to 3 R 4g groups.

[0175] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is:

[0176]

Chemical formula

[0177] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is:

[0178]

Chemical formula

[0179] is as follows.

[0180] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is:

[0181]

Chemical formula

[0182] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is:

[0183]

Chemical formula

[0184] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt 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) alkylC (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, a 3- to 8-membered heterocyclyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), -C (6~10) aryl, or a 5- to 10-membered heteroaryl, where -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) alkylC (3~10) cycloalkyl, a 3- to 8-membered heterocyclyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), -C (6~10) aryl, and a 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 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.

[0185] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4g is, independently at each occurrence, 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 heterocyclyl, -C (1~3) Alkyl(3 - to 8 - membered heterocyclyl), or -C (6~10) Aryl, where, -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 heterocyclyl, -C (1~3) Alkyl(3 - to 8 - membered heterocyclyl), and -C (6~10) Aryl is optionally further substituted with 1 to 5 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.

[0186] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4gis, independently at each occurrence, 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) alkylC (3~10) cycloalkyl, -C(O)N(R N1 )(R N2 ), 3- to 8-membered heterocyclyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), or -C (6~10) aryl, where -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) alkylC (3~10) cycloalkyl, 3- to 8-membered heterocyclyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), and -C (6~10) aryl are optionally further substituted with 1 to 5 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 ).

[0187] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4g is, independently at each occurrence, 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 a 3- to 8-membered heterocyclyl, where -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~8) cycloalkyl, and the 3- to 8-membered heterocyclyl are optionally further substituted with 1 to 5 groups selected from halo and -OH.

[0188] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4g is, each occurrence 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 1 to 5 groups selected from halo and -OH. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4g is, each occurrence 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 1 to 5 groups selected from halo and -OH. In some embodiments, each R 4g is, each occurrence independently, -C (1~6) alkyl, or -OC (1~6) alkyl, each of which is optionally further substituted with 1 to 3 groups selected from halo and -OH.

[0189] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4g is, each occurrence independently:

[0190]

Chemical formula

[0191] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4g is, independently at each occurrence:

[0192]

Chemical formula

[0193] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4g is, independently at each occurrence:

[0194]

Chemical formula

[0195] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4g is, independently at each occurrence:

[0196]

Chemical formula

[0197] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4g is, independently at each occurrence:

[0198]

Chemical formula

[0199] In some embodiments, disclosed herein are compounds of formula I, or a pharma- ceutically acceptable salt thereof, wherein each R 4g is, for each occurrence independently:

[0200] [ka]

[0201] [ka]

[0202] [ka] It is.

[0203] In some embodiments, disclosed herein are compounds of formula I, or a pharma- ceutically acceptable salt thereof, wherein each R 4g is, for each occurrence independently:

[0204] [ka]

[0205] [ka] It is.

[0206] In some embodiments, disclosed herein are compounds of formula I, or a pharma- ceutically acceptable salt thereof, wherein each R 4g is, for each occurrence independently:

[0207] [ka]

[0208] [ka] It is.

[0209] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4g is, independently at each occurrence:

[0210]

Chemical formula

[0211] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4g is, independently at each occurrence:

[0212]

Chemical formula

[0213] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 4g is, independently at each occurrence:

[0214]

Chemical formula

[0215] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R N1 and R N2 are, independently at each occurrence, each H or -C (1~3) alkyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R N1 and R N2 are each hydrogen.

[0216] 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:

[0217]

Chem.

[0218] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, having a structure as shown in any one of Tables 1A to 1M.

[0219]

Table 1-1

[0220]

Table 1-2

[0221]

Table 1-3

[0222]

Table 2-1

[0223]

Table 2-2

[0224]

Table 3-1

[0225]

Table 3-2

[0226]

Table 4-1

[0227]

Table 4-2

[0228]

Table 4-3

[0229]

Table 5-1

[0230]

Table 5-2

[0231]

Table 5-3

[0232]

Table 6-1

[0233]

Table 6-2

[0234]

Table 7-1

[0235]

Table 7-2

[0236]

Table 7-3

[0237]

Table 8-1

[0238]

Table 8-2

[0239]

Table 8-3

[0240]

Table 9-1

[0241]

Table 9-2

[0242]

Table 9-3

[0243]

Table 10-1

[0244]

Table 10-2

[0245]

Table 10-3

[0246]

Table 11-1

[0247]

Table 11-2

[0248]

Table 11-3

[0249]

Table 12-1

[0250]

Table 12-2

[0251]

Table 13

[0252] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, having a structure as shown in any one of Tables 2A - 2M.

[0253]

Table 14-1

[0254]

Table 14-2

[0255]

Table 14-3

[0256]

Table 15-1

[0257]

Table 15-2

[0258]

Table 15-3

[0259]

Table 16-1

[0260]

Table 16-2

[0261]

Table 16-3

[0262]

Table 17-1

[0263]

Table 17-2

[0264]

Table 17-3

[0265]

Table 18-1

[0266]

Table 18-2

[0267]

Table 18-3

[0268]

Table 19-1

[0269]

Table 19-2

[0270]

Table 19-3

[0271]

Table 20-1

[0272]

Table 20-2

[0273]

Table 20-3

[0274]

Table 20-4

[0275]

Table 21-1

[0276]

Table 21-2

[0277]

Table 21-3

[0278]

Table 22-1

[0279]

Table 22-2

[0280]

Table 22-3

[0281]

Table 23-1

[0282]

Table 23-2

[0283]

Table 23-3

[0284]

Table 24-1

[0285]

Table 24-2

[0286]

Table 24-3

[0287]

Table 25-1

[0288]

Table 25-2

[0289]

Table 26

[0290]

Chemical Formula

[0291]

Chemical Formula

[0292] a compound of Formula I, or a pharmaceutically acceptable salt thereof, selected from the group consisting of. In some embodiments, what is disclosed herein is

[0293]

Chemical Formula

[0294]

Chem.

[0295] In some embodiments, disclosed herein is the following formula:

[0296]

Chem.

[0297] In some embodiments, disclosed herein is the following formula:

[0298]

Chem.

[0299] In some embodiments, disclosed herein is the following formula:

[0300]

Chem.

[0301] In some embodiments, disclosed herein is the following formula:

[0302]

Chem.

[0303] In some embodiments, what is disclosed herein is the following formula:

[0304]

Chemical formula

[0305] In some embodiments, what is disclosed herein is the following formula:

[0306]

Chemical formula

[0307] In some embodiments, what is disclosed herein is the following formula:

[0308]

Chemical formula

[0309] In some embodiments, what is disclosed herein is the following formula:

[0310]

Chemical formula

[0311] In some embodiments, what is disclosed herein is the following formula:

[0312]

Chemical formula

[0313] In some embodiments, what is disclosed herein is the following formula:

[0314] [Chem.] A compound of formula I having the following, or a pharmaceutically acceptable salt thereof.

[0315] In some embodiments, disclosed herein is the following formula:

[0316] [Chem.] A compound of formula I having the following, or a pharmaceutically acceptable salt thereof.

[0317] In some embodiments, disclosed herein is the following formula:

[0318] [Chem.] A compound of formula I having the following, or a pharmaceutically acceptable salt thereof.

[0319] In some embodiments, disclosed herein is the following formula:

[0320] [Chem.] A compound of formula I having the following, or a pharmaceutically acceptable salt thereof.

[0321] In some embodiments, disclosed herein is the following formula:

[0322] [Chem.] A compound of formula I having the following, or a pharmaceutically acceptable salt thereof.

[0323] 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.

[0324] Therapeutic use The present disclosure also relates to 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 a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0325] 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 can be used in combination with another therapeutic agent.

[0326] The present disclosure also relates to a method for ameliorating or alleviating 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.

[0327] In some embodiments of the treatment methods disclosed herein, the disease, disorder, or medical condition is selected from the group consisting of inflammatory disorders and autoimmune disorders.

[0328] 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.

[0329] In some embodiments of the treatment methods disclosed herein, the disease, disorder, or medical condition is selected from the group consisting of inflammatory disorders, autoimmune disorders, cancer, metabolic disorders, and osteoporosis.

[0330] In some embodiments of the treatment methods disclosed herein, the disease, disorder, or medical condition is an autoimmune-related disease. In some embodiments, the autoimmune-related disease is selected from the group consisting of antineutrophil cytoplasmic antibody ("ANCA")-associated vasculitis, scleroderma, Sjogren's disease, myositis, IgG4-related disease, bullous pemphigoid, and neuromyelitis optica spectrum disorder ("NMOSD").

[0331] In some embodiments of the treatment methods 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.

[0332] In some embodiments of the treatment methods disclosed herein, the disease, disorder, or medical condition is hepatitis or liver injury. In some embodiments, the hepatitis or liver injury is selected from the group consisting of steatosis, non-alcoholic steatohepatitis ("NASH"), and primary biliary cirrhosis.

[0333] In some embodiments of the treatment methods 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.

[0334] In some embodiments of the treatment methods 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.

[0335] In some embodiments of the treatment methods 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, Berger's disease (IgA nephropathy (IgAN)), autosomal dominant polycystic kidney disease ("ADCKD"), and membranous nephropathy.

[0336] In some embodiments of the treatment methods disclosed herein, the disease, disorder, or medical condition is osteoporosis.

[0337] In some embodiments of the treatment methods disclosed herein, the disease, disorder, or medical condition is selected from the group consisting of RA, IBD, SLE, IgAN, metabolic syndrome (visceral adiposity syndrome), multiple sclerosis, immune thrombocytopenic purpura, primary biliary cirrhosis, transplantation, myasthenia gravis, osteoporosis, and bone resorption (periodontitis).

[0338] In some embodiments of the treatment methods 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 (antineutrophil cytoplasmic antibody)-associated vasculitis, myositis, IgG4-related disease, bullous pemphigoid, neuromyelitis optica spectrum disorder ("NMOSD"), atopic dermatitis ("AD"), hidradenitis suppurativa ("HS"), adiposis, non-alcoholic steatohepatitis ("NASH"), primary biliary cirrhosis, leukemia, lymphoma, pancreatic cancer, breast cancer, melanoma (malignant 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.

[0339] In some embodiments, 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.

[0340] In some embodiments of the methods of the present disclosure, the subject is a human subject.

[0341] The present disclosure also provides a method of 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.

[0342] In some embodiments, the present disclosure provides a method of 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.

[0343] Dosage and Administration In the methods disclosed herein, an effective amount of at least one compound according to the present disclosure is administered to a subject having or diagnosed as having such a disease, disorder, or medical condition. "Effective amount" means an amount or dosage sufficient to generally produce the desired therapeutic or prophylactic effect in a patient in need of such treatment for a specified disease, disorder, or medical condition. In a 70 kg human, an exemplary range of dosage is from about 1 to 1000 mg / day, in single or multiple dosage units.

[0344] 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, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300 mg of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 300, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 mg of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 mg of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0345] The dosage is affected by factors such as, but not limited to, the route of administration, the health status, weight, and age of the recipient, the frequency of treatment, and the presence of concurrent unrelated treatments.

[0346] It is also obvious to those skilled in the art that the therapeutically effective amount of the compounds of the present disclosure or their pharmaceutical compositions may vary depending on the desired effect. Therefore, the optimal dosage may be easily determined by those skilled in the art and will vary depending on the specific compound used, the method of administration, the strength of the preparation, and the progression of the disease state. It should be noted that it is necessary to adjust the dosage to an appropriate therapeutic level according to factors related to the specific subject being treated, including the age, weight, diet, and administration time of the subject. Therefore, the above dosages are illustrative of average cases. Of course, there may be individual cases where larger or smaller dosage ranges are effective, and such cases are also within the scope of the present disclosure.

[0347] Once improvement in the patient's disease, disorder, or condition has occurred, the dosage may be adjusted for prophylactic or maintenance treatment. For example, the dosage or dosing frequency, or both, may be reduced as a function of the symptoms to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, when the symptoms have been alleviated to an appropriate level, treatment may be discontinued. However, in the event that any symptoms recur, the patient may require long-term intermittent treatment.

[0348] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be formulated in a pharmaceutical composition comprising any well-known pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers commonly used in pharmaceutical compositions are substances that are added to the pharmacological composition or, alternatively, used as vehicles or diluents to facilitate the administration of the drug and are compatible with the drug, non-toxic, biologically tolerable, and biologically suitable for administration to the subject for other reasons, such as inert substances. Exemplary carriers include, but are not limited to, any suitable solvent, dispersion medium, coating, antibacterial and antifungal agents, and isotonic agents. Exemplary excipients that can also be components of the formulation include fillers, binders, disintegrants, and lubricants.

[0349] Delivery forms of pharmaceutical compositions containing one or more compounds of the present disclosure may be prepared using pharmaceutically acceptable excipients and formulation techniques well known or available to those skilled in the art. The composition may be administered by a suitable delivery route, such as, for example, orally, parenterally, rectally, topically, or ophthalmically, or by inhalation, in the methods of the present invention.

[0350] The preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, reconstitutable powders, liquid preparations, or suppositories. The composition may be formulated for any one of a plurality of administration routes, for example, but not limited to, intravenous injection, subcutaneous injection, topical administration, or oral administration.

[0351] In the case of oral administration, the compounds of the present disclosure may be provided as tablets, capsules, or beads, or as solutions, emulsions, or suspensions. To prepare an oral composition, the active agent may be formulated, by way of illustrative range, in single dosage units or more than single dosage units to provide a dosage of, for example, about 1 to 1000 mg / day for a 70 kg human.

[0352] The oral tablets may contain the compounds of the present disclosure mixed with compatible pharmaceutically acceptable excipients, such as, but not limited to, diluents, disintegrants, binders, lubricants, sweeteners, flavoring agents, coloring agents, 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, and the like. Exemplary examples of liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are examples of disintegrants. Starches and gelatin may be mentioned as binders. The lubricant, if present, may be magnesium stearate, stearic acid, or talc. Optionally, the tablets may be coated with substances such as, but not limited to, glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be enteric-coated. Additional coatings that may be used include coatings designed to release the compound or active agent as a function of time, pH, or bacterial content.

[0353] Examples of oral capsules include hard gelatin and soft gelatin, or (hydroxypropyl) methylcellulose capsules. To prepare hard gelatin capsules, the active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with an oil 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. Oral liquids may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized for reconstitution with water or another suitable vehicle before use, or presented as a dry product. 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, ethyl alcohol or water, preservatives (e.g., methyl p-hydroxybenzoate or propyl p-hydroxybenzoate, or sorbic acid), wetting agents such as, but not limited to, lecithin, and, optionally, flavoring or coloring agents.

[0354] The compounds of the present disclosure may also be administered by parenteral routes. For example, the composition may be formulated as a suppository, enema, or foam for the purpose of rectal administration. In the case of parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of the present disclosure may be provided in a sterile aqueous solution or suspension buffered to an appropriate pH and isotonicity, or in a parenterally acceptable oil. 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, multi-dose forms such as vials from which appropriate doses can be withdrawn, or solid forms or pre-concentrates that can be used to prepare injectable formulations. Exemplary infusion doses are such that the drug admixed with the pharmaceutical carrier ranges from about 1 to 1000 μg / kg / min over a period ranging from several minutes to several days.

[0355] In the case of topical administration, the compounds of the present disclosure may be mixed with a pharmaceutical carrier. Another method of administering the compounds of the present disclosure may utilize a patch formulation for transdermal delivery.

[0356] Alternatively, the compounds of the present disclosure may be included in, for example, a spray formulation that also contains a suitable carrier and administered by the methods of the present disclosure by inhalation via the nasal or oral route.

[0357] Embodiments of the present invention are described in connection with certain specific embodiments for purposes of illustration, but the embodiments of the present invention are not limited thereto. Accordingly, various modifications, adaptations, and combinations of the various features of the described embodiments may be practiced without departing from the scope of the present invention as set forth in the claims. Further, the following examples are illustrative of the compounds, compositions, and methods described herein, but are not limited thereto. Other suitable modifications and adaptations known to those skilled in the art are within the scope of the following embodiments. Any and all academic papers, patent applications, issued patents, or other cited references are hereby incorporated herein by reference in their entirety.

Examples

[0358] The following specific examples are provided to further illustrate embodiments within the scope of the present disclosure.

[0359] Abbreviations Throughout this specification and this application, the following abbreviations may be used.

[0360] [Table 27-1]

[0361] [Table 27-2]

[0362] In some embodiments, provided herein are the processes and intermediates disclosed herein that are useful for preparing the compounds of the present disclosure or pharmaceutically acceptable salts thereof.

[0363] By way of illustration and not limitation, the compounds of the present disclosure are prepared according to the following general procedures given by Schemes 1-5. Those skilled in the art will understand that, to obtain the various compounds herein, the starting materials can be suitably selected so that the ultimately desired substituents are carried through the reaction schemes, either protected or unprotected as appropriate, to give the desired product. Alternatively, instead of the ultimately desired substituents, appropriate groups are used that are carried throughout the reaction scheme and can be replaced by the desired substituents as appropriate. Unless otherwise specified, the variables in Schemes 1-5 are as defined above with reference to Formula I.

[0364] [Chemical formula]

[0365] The compounds of Formula I of the present disclosure can be prepared, for example, as shown in Scheme 1. Substituent B in Compound XI 1is a halide (e.g., Cl, Br, or I), and the substituent B in compound XII 2 is a stannyl group (e.g., Sn(Me) 3 or Sn(n-Bu) 3 ), this coupling is achieved by reaction under Stille conditions. Those skilled in the art will also recognize that coupling under Stille conditions also provides a compound of formula I when B 1 in compound XI is a stannyl group and B 2 in compound XII is a halide. Typical Stille coupling conditions include the use of a catalyst (usually palladium, but sometimes nickel), a suitable solvent, and other optional reagents including a ligand, TEA, or CuI. Examples of suitable catalysts include, but are not limited to, Pd(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 about 1 to 16 hours using microwave or conventional heating to obtain the compound of formula I.

[0366] Alternatively, B 1 is a halide such as, but not limited to, Cl, Br, or I, and B 2 is a boron-based coupling agent such as, but not limited to, a boronic acid or boronic ester, the compound XI can be coupled to compound XII using Suzuki coupling conditions. Those skilled in the art will also recognize that coupling under Suzuki conditions also provides a compound of formula I when B 1 is a boron-based coupling agent and B 2It will be appreciated that when it is a halide, a compound of formula I is provided. 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 Pd(dppf)Cl 2 , BrettPhos-Pd-G3, and Pd 2 (dba) 3 , but are not limited thereto. Suitable bases include K 2 CO 3 , Cs 2 CO 3 , KOAc, and combinations thereof, but are not limited thereto. Suitable solvents include 1,4-dioxane, 2-methyl-2-butanol, water, or mixtures thereof, but are not limited thereto. Using microwave or conventional heating, the reactants may be heated to a temperature of about 80 °C to about 120 °C for about 0.5 to 16 hours to obtain a compound of formula I.

[0367] [Chemical formula]

[0368] The compounds of formula I of the present disclosure can be prepared, for example, as shown in Scheme 2. Compounds XIII and XIV may be combined 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. Using microwave or conventional heating, the reactants may be heated to a temperature of about 100 °C to about 160 °C for about 1 to 16 hours to obtain a compound of formula I.

[0369] 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. Using microwave or conventional heating, the reaction mixture may be heated to a temperature of about 120 °C to about 160 °C for about 1.5 to 3.5 hours to obtain the compound of Formula I. Alternatively, the reaction mixture may be cooled to about -72 °C for about 1 hour to obtain the compound of Formula I.

[0370]

Chem.

[0371] The compound of Formula I of the present disclosure can be prepared, for example, as shown in Scheme 3. Compounds XV and XIV may be combined 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. Using microwave or conventional heating, the reactants may be heated to a temperature of about 100 °C to about 160 °C for about 1 to 16 hours to obtain the compound of Formula I.

[0372] Alternatively, Compounds XV and XIV may 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. Using microwave or conventional heating, the reaction mixture may be heated to a temperature of about 120 °C to about 160 °C for about 1.5 to 3.5 hours to obtain the compound of Formula I.

[0373]

Chem.

[0374] The compound of Formula I of the present disclosure can be prepared, for example, as shown in Scheme 4. Substituent B in Compound XVI 3When it is a halide (e.g., Cl, Br, or I), the preparation of the compound of formula I can be achieved under Buchwald-Hartwig amination conditions. A typical Buchwald-Hartwig reaction involves the use of a catalyst (usually palladium, but sometimes other metals such as Pd(OAc) 2 ), a base (e.g., Cs 2 CO 3 ), and a suitable solvent (e.g., 1,4-dioxane). Phosphine ligands such as xantphos may also be included, but are not limited thereto. The reactants may be heated to a temperature of about 90 °C to about 120 °C for about 1 to 12 hours to obtain the compound of formula I.

[0375]

Chemical formula

[0376] The compound of formula XIX of the present disclosure can be prepared, for example, as shown in Scheme 5, where B 4 is halo, -C (1~4) alkyl, -C (1~4) haloalkyl, -OC (1~4) alkyl, and -OC (1~4) haloalkyl, and B 5 is a halide (e.g., F or Cl). Compounds XVII and XVIII may be combined with a suitable base (e.g., Cs 2 CO 3 ) in a suitable solvent (e.g., DMF). The reactants may be heated to a temperature of about 100 °C to about 120 °C for about 0.5 to 2 hours to obtain the compound of formula I.

[0377] When obtaining the compounds and corresponding analytical data described in the following examples, unless otherwise indicated, the following experimental and analytical protocols were followed.

[0378] Unless otherwise specified, the reaction solution was N 2(g) or Ar (g)The reaction was stirred at room temperature under the atmosphere. When the solution was "concentrated to dryness", they were concentrated under reduced pressure using a rotary evaporator. When the solution was dried, typically but not limited to these, it was dried over a desiccant such as MgSO 4 or Na 2 SO 4 etc. Column chromatography (FCC) was carried out on silica gel using a pre-packed silica gel column such as RediSep (registered trademark) as the eluent with ethyl acetate (EtOAc) / hexane, CH 2 Cl 2 / MeOH, or CH 2 Cl 2 / MeOH containing 10% 2N NH 3 in 10% 2N NH

[0379] The compounds described in the examples can also be purified by preparative reverse-phase HPLC. Typical HPLC chromatographic separations are in the time range of about 10 to about 20 minutes. Suitable solvent gradients and conditions for purification may be determined by those skilled in the art. Unless otherwise specified, when reverse-phase HPLC is used to purify the compounds described in one of the following examples, the solvents used are a gradient of 10% to 80% acetonitrile in water. When the purification is carried out under "acidic conditions" or in an "acidic medium", both acetonitrile and water contain 0.16% TFA. When carried out under "basic conditions" or in a "basic medium", the pH of acetonitrile and water is adjusted to pH 10 with ammonium hydroxide. The following abbreviations in the columns are also used throughout the examples:

[0380]

Table 28

[0381]

Table 29

[0382] Thin layer chromatography was carried out using silica gel plates such as Merck silica gel 60 F 254 (2.5 cm × 7.5 cm, 250 mm, or 5.0 cm × 10.0 cm, 250 μm) pre-coated silica gel plates. Preparative thin layer chromatography was carried out using silica gel plates such as EM Science silica gel 60 F 254 (20 cm x 20 cm, 0.5 mm) pre-coated plates, using a plate with a concentration zone of 20 cm x 4 cm. The microwave reaction was carried out in a microwave reactor, for example, but not limited to, CEM Discover a , Biotage Initiator (trademark) or Optimizer (trademark) microwave at a specific temperature. The mass spectrum was obtained using electrospray ionization (ESI) in positive mode, for example, but not limited to, a mass spectrometer such as Agilent series 1100 MSD, unless otherwise specified. The calculated mass corresponds to the exact mass. The NMR spectrum was obtained using 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 the following 1H NMR data is as follows: chemical shift (ppm) on the low magnetic field side with tetramethylsilane as the reference substance (multiplicity, coupling constant J (Hz), integral value).

[0383] Whenever the yield is expressed as a percentage, such a yield refers to the mass of the entity whose yield is shown relative to the maximum amount of the same entity that can be obtained under specific stoichiometric conditions. The reagent concentration expressed as a percentage refers to the mass ratio, unless otherwise specified. Whether or not it is clearly indicated, the yields given in the following examples are calculated with respect to the dry form of any compound for which such a yield is obtained.

[0384] The compound names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye).

[0385] Intermediate 1: N-(1-Methyl-1H-pyrazol-3-yl)-4-(trimethylstannyl)pyrimidin-2-amine

[0386] [Chemical formula] 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 h. The mixture was cooled to room temperature, diluted with an aqueous KF solution (2 M, 150 mL) and stirred for 1 h. The mixture was then extracted with ethyl acetate, washed with brine, dried over Na 2 SO 4 and filtered, concentrated under reduced pressure to give N-(1-methyl-1H-pyrazol-3-yl)-4-(trimethylstannyl)pyrimidin-2-amine (15.3 g, purity about 38%, 48%) as a brown powder, which was used without further purification. MS (ESI + ): m / z = 339.5.

[0387] Intermediate 2: (R)-3-(3-(4-Bromooxazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0388]

Chem.

[0389] Intermediate 3: (R)-3-(3-(1H-Pyrazol-3-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0390]

Chemical formula

[0391] 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 K 2 CO 3 solution (1 M in H 2 O). The organic layer was dried over MgSO 4It was dried, filtered, and concentrated to obtain (R)-3-(3-(1H-pyrazol-3-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one (533 mg). MS (ESI + ): m / z = 258.15.

[0392] Intermediate 4: 4-(4-Bromothiazol-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine

[0393]

Chemical formula

[0394] Intermediate 5: 4-(4-Bromooxazol-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine

[0395]

Chemical formula

[0396] Intermediate 6: 4-Bromo-2-(2-(methylthio)pyrimidin-4-yl)thiazole

[0397]

Chemical formula

[0398] Intermediate 7: (R)-3-(3-(4-Bromothiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0399]

Chem.

[0400] Intermediate 8: (R)-3-Hydroxy-1-methyl-3-(3-(4-(2-(methylthio)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one

[0401] [Chem.] (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 (176 mg, 0.142 mmol), 2-(Methylthio)-4-(tributylstannyl)pyrimidine (647 mg, 1.56 mmol), TEA (0.395 mL, 1.13 mmol), and a mixture of anhydrous toluene (10 mL) were heated at 120 °C for 16 h and then cooled to room temperature. The resulting mixture was poured into aqueous KF (10 mL). The resulting suspension was filtered through a pad of diatomaceous earth and the pad was washed with EtOAc (20 mL). The filtrate was further extracted with EtOAc (20 mL × 3), the combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 and filtered and concentrated. The residue was purified by FCC (silica, gradient of 5:1 to 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 as a brown oil (397 mg, 57%). MS (ESI + ): m / z = 399.0.

[0402] Intermediate 9: (R)-3-Hydroxy-1-methyl-3-(3-(2-(2-(methylsulfonyl)pyrimidin-4-yl)thiazol-4-yl)phenyl)pyrrolidin-2-one

[0403] [Chem.] Project 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, H 2 O in 1 M, 5.6 mmol), and a mixture of 1,4-dioxane (10 mL) were heated to 80 °C over 1 hour. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic extract was dried over MgSO 4 and filtered, and concentrated under reduced pressure. The residue was purified by FCC (50% - 100% EtOAc in hexane) 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 (500 MHz, DMSO) δ 8.83 (d, J = 5.1 Hz, 1H), 8.44 (s, 1H), 8.12 - 8.06 (m, 1H), 7.99 - 7.91 (m, 1H), 7.89 (d, J = 5.0 Hz, 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.

[0404] Project 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 peroxymonosulfate (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, the precipitate was collected, washed with water and then dried under reduced pressure. The solid was washed with water and then dried under high vacuum to obtain (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 substance contained approximately 20% of (R)-3-hydroxy-1-methyl-3-(3-(2-(2-(methylsulfinyl)pyrimidin-4-yl)thiazol-4-yl)phenyl)pyrrolidin-2-one. 1 H NMR(400MHz,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.

[0405] Intermediate 10: 4-Bromo-2-(2-(methylsulfonyl)pyrimidin-4-yl)thiazole

[0406]

Chemical Structure

[0407] Intermediate 11: 4-(4-bromothiazol-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

[0408]

Chemical Structure

[0409] Intermediate 12: (R)-3-Hydroxy-1-methyl-3-(3-(4-(2-(methylsulfonyl)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one

[0410]

Chemical formula

[0411] Intermediate 13: (R)-3-Hydroxy-1-methyl-3-(3-(1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazol-3-yl)phenyl)pyrrolidin-2-one

[0412]

Chem.

[0413] Intermediate 14: 4-(4-Bromothiazol-2-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine

[0414]

Chemical Structure

[0415] Intermediate 15: 4-(3-Bromo-1H-pyrazol-1-yl)-N-(3-cyclopropoxy-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrimidin-2-amine

[0416]

Chemical Structure

[0417] Intermediate 16: N-(4-(3-Bromo-1H-pyrazol-1-yl)pyrimidin-2-yl)pyrazolo[1,5-a]pyridin-3-amine

[0418]

Chem.

[0419] Intermediate 17: 4-(3-bromo-1H-pyrazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine

[0420]

Chem.

[0421] Intermediate 18: 4-(3-bromo-1H-pyrazol-1-yl)-2-chloropyrimidine

[0422]

Chemical formula

[0423] Intermediate 19: N-(4-(3-Bromo-1H-pyrazol-1-yl)pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-3-amine

[0424]

Chemical Structure

[0425] Intermediate 20: 4-(3-Bromo-1H-pyrazol-1-yl)-N-(1-(2,2-difluoroethyl)-3-methoxy-1H-pyrazol-4-yl)pyrimidin-2-amine

[0426]

Chemical Structure

[0427] Intermediate 21: (R)-3-Hydroxy-1-methyl-3-(3-(1-(2-(methylthio)pyrimidin-4-yl)-1H-pyrazol-3-yl)phenyl)pyrrolidin-2-one

[0428] [Chemical formula] (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 (759.803 mg, 2.332 mmol), and DMSO (0.747 mL, 1.092 g / mL, 10.435 mmol) were combined under a nitrogen atmosphere and heated in a microwave reactor at 150 °C for 1 hour. Conversion to the desired product was revealed by LCMS. 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 dried over MgSO 4 and filtered, concentrated, and then purified by FCC (12 g of silica, 0 - 100% EtOAc in hexane) to obtain (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 1H NMR (500 MHz, DMSO-d 6 ) δ 8.79 (d, J = 2.8 Hz, 1H), 8.73 (d, J = 5.5 Hz, 1H), 8.02 (t, J = 1.8 Hz, 1H), 7.88 (dt, J = 7.7, 1.4 Hz, 1H), 7.69 (d, J = 5.5 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.40 - 7.37 (m, 1H), 7.18 (d, J = 2.8 Hz, 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.

[0429] Intermediate 22: (R)-3-(3-(4-(2-((2,4-Dimethoxybenzyl)amino)pyrimidin-4-yl)thiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0430]

Chem.

[0431] Intermediate 23: N-(2-Methoxypyridin-3-yl)-4-(tributylstannyl)pyrimidin-2-amine

[0432]

Chem.

[0433] Procedure 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 stir bar, 1,1,1,2,2,2-hexabutyldistannane (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 then evacuated and refilled with argon (×3), then Pd 2 (dba) 3(97 mg, 0.11 mmol) and tricyclohexylphosphine (62 mg, 0.22 mmol) were treated, and the resulting mixture was stirred at 120 °C for 16 h. Next, the reaction mixture was cooled to room temperature, quenched with saturated aqueous KF (40 mL), extracted with ethyl acetate (50 mL × 3), and the combined extracts were washed with brine (300 mL) and dried over anhydrous Na 2 SO 4 , filtered, and concentrated to dryness in vacuo to give the product as a brown oil (2.5 g). MS (ESI + ): m / z = 493.0.

[0434] Intermediate 24: 6-Methyl-5-((4-(tributylstannyl)pyrimidin-2-yl)amino)nicotinonitrile

[0435]

Chemical Structure

[0436] 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 stir 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-hexabutyldistannane (1.03 g, 1.78 mmol). The resulting mixture was sparged with Ar for 5 minutes and then treated with Pd 2 (dba) 3 (45 mg, 0.049 mmol) and tricyclohexylphosphine (27 mg, 0.098 mmol), and stirred while heating at 120 °C for 16 hours. The reaction vessel was removed from the oil bath and cooled gradually to room temperature. Next, the mixture was quenched with saturated aqueous KF (30 mL), extracted with EtOAc (20 mL × 3), the combined extracts were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to dryness in vacuo to give a brown solid, which was purified by silica gel chromatography (0 - 30% EtOAc / petroleum ether) to give 6-methyl-5-((4-(tributylstannyl)pyrimidin-2-yl)amino)nicotinonitrile as a white solid (76 mg, 15%). MS (ESI + ): m / z = 500.7.

[0437] Intermediate 25: 3-Cyclopropoxy-1-(2,2-difluoroethyl)-1H-pyrazol-4-amine

[0438]

Chemical Structure

[0439] Step B. 3-Cyclopropoxy-4-nitro-1H-pyrazole. NaH (1.35 g, 33.7 mmol, 60 wt% in mineral oil) was added portionwise to a 100 mL three-neck 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 min while gradually warming to room temperature. The above suspension was added dropwise to a 100 mL three-neck 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 grey mixture was stirred at -78 °C for 1 h, then warmed to room temperature and stirred for 5 h. Thereafter, the mixture was poured into water and treated with aqueous HCl (10 mL, 3 N), and extracted with CH 2 Cl 2 (20 mL × 3). The combined organic extracts were washed with brine (50 mL) and dried over anhydrous Na 2 SO 4It was dried, filtered, concentrated to dryness in vacuo to obtain a pale yellow oil, which was subjected to silica gel chromatography (0 - 30% EtOAC / petroleum ether) to give 3 - cyclopropoxy - 4 - nitro - 1H - pyrazole as a yellow oil (1.1 g, 19%). 1 H NMR(400MHz,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).

[0440] Step C. 3 - Cyclopropoxy - 1 - (2,2 - difluoroethyl) - 4 - nitro - 1H - pyrazole. 2 - (Tributylphosphoranylidene)acetonitrile (3.00 g, 12.4 mmol) was added at room temperature under N 2 to a 100 mL three - necked round - bottom flask containing 3 - cyclopropoxy - 4 - nitro - 1H - pyrazole (700 mg, 4.14 mmol), 2,2 - difluoroethanol (1.02 g, 12.4 mmol), and anhydrous toluene (30 mL). The mixture was heated at 60 °C for 12 h. The reaction vessel was removed from the oil bath and gradually cooled to room temperature. Then the mixture was concentrated to dryness in vacuo to obtain a red oil, which was subjected to silica gel chromatography (20 - 50% EtOAc / petroleum ether) to give 3 - cyclopropoxy - 1 - (2,2 - difluoroethyl) - 4 - nitro - 1H - pyrazole (500 mg, 52%) as a red solid. 1 H NMR(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).

[0441] Step D. 3 - Cyclopropoxy - 1 - (2,2 - difluoroethyl) - 1H - pyrazol - 4 - amine. Iron powder (838 mg, 15.0 mmol) was added to 3 - cyclopropoxy - 1 - (2,2 - difluoroethyl) - 4 - nitro - 1H - pyrazole (700 mg, 3.00 mmol, isomer mixture), NH4 Cl (642 mg, 12.0 mmol), anhydrous EtOH (10 mL) and H 2 O (2 mL) were added at room temperature to a 50 mL three-necked round-bottom flask. The mixture was heated at 70 °C for 12 hours. The reaction vessel was removed from the oil bath and gradually cooled to room temperature. The mixture was filtered through a pad of diatomaceous earth, and the pad was washed with MeOH (30 mL × 3). The filtrate was concentrated to dryness in vacuo to obtain a black oil, which was subjected to silica gel chromatography (0 - 50% EtOAc / petroleum ether) to give 3-cyclopropoxy-1-(2,2-difluoroethyl)-1H-pyrazol-4-amine (300 mg, 41%) as a black oil. MS (ESI + ): m / z = 203.6.

[0442] Intermediate 26: 3-Amino-N,4-dimethylbenzamide.

[0443]

Chemical Structure

[0444] Process 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 (50 psi) for 12 h. Then, the mixture was filtered through a pad of diatomaceous earth and the pad was washed with EtOAc (20 mL × 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 afford 3 - amino - N,4 - dimethylbenzamide as a white solid (790 mg, 55%). MS (ESI + ): m / z = 164.7. 1 1H NMR (400 MHz, CDCl 3 ) δ 7.15 (d, J = 1.2 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.00 - 6.98 (m, 1H), 6.07 (s, 1H), 3.73 (s, 2H), 3.00 (d, J = 4.8 Hz, 3H), 2.20 (s, 3H).

[0445] Intermediate 27: 1 - (2,2 - Difluoroethyl) - 3 - (2 - methoxyethoxy) - 1H - pyrazol - 4 - amine

[0446]

Chemical Structure

[0447] 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) were added to a 100 mL round-bottom flask equipped with a reflux condenser, and the resulting mixture was heated at 50 °C for 1 h. The resulting white suspension was concentrated to dryness in vacuo to obtain a white solid, which was acidified to pH = 3 - 4 with aqueous HCl (2 N, 40 mL) and extracted with EtOAc (40 mL × 4). The combined extracts were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to dryness in vacuo to obtain a colorless oil, which was subjected to silica gel chromatography (0 - 50% EtOAc / petroleum ether) to give 3-(2-methoxyethoxy)-1H-pyrazole as a colorless liquid (5 g, 97%).

[0448] 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) were added to a 50 mL round-bottom flask, and the resulting mixture was treated with fuming HNO 3(2.31 g, 36.6 mmol) was carefully treated and added dropwise over 10 minutes at room temperature, 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 and filtered, and the filtrate was concentrated to dryness in vacuo to obtain a white solid. The white solid was subjected to silica gel chromatography (30 - 50% EtOAc / petroleum ether) to obtain 3-(2-methoxyethoxy)-4-nitro-1H-pyrazole as a white solid (1.3 g, 49%).

[0449] 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 that had been oven-dried and purged with nitrogen and equipped with a reflux condenser, and the resulting mixture was heated at 60 °C for 12 hours. The reaction vessel was removed from the oil bath and gradually cooled to room temperature. The reaction mixture was concentrated to dryness in vacuo to obtain a red oil, which was subjected to silica gel chromatography (20 - 50% EtOAc / petroleum ether) to obtain 1-(2,2-difluoroethyl)-3-(2-methoxyethoxy)-4-nitro-1H-pyrazole as a red oil (1.1 g, 63%).

[0450] Step E. 1-(2,2-Difluoroethyl)-3-(2-methoxyethoxy)-1H-pyrazol-4-amine. Fe 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 2O (10 mL) was added to a 100 mL three-necked round-bottom flask equipped with a reflux condenser and dried under nitrogen purge, and the resulting mixture was heated at 70 °C for 12 h. The reaction vessel was taken out of the oil bath and gradually cooled 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 to dryness in vacuo to give a black oil, which was partitioned between EtOAc (60 mL) and brine (20 mL). Subsequently, the aqueous phase was extracted with EtOAc (20 mL × 2), the combined organic extracts were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and filtered, and the filtrate was concentrated to dryness in vacuo to give a brown solid. The brown solid was subjected to silica gel chromatography (30 - 50% EtOAc / petroleum ether) to give 1-(2,2-difluoroethyl)-3-(2-methoxyethoxy)-1H-pyrazol-4-amine as a brown oil (490 mg, 56%). 1 1H NMR (400 MHz, CDCl 3 ) δ 7.00 - 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).

[0451] Intermediate 28: 2,4-Difluoro-N-methyl-5-nitrobenzamide

[0452]

Chemical Structure

[0453] Intermediates 29 and 30: 4-cyclopropoxy-2-fluoro-N-methyl-5-nitrobenzamide and 2-cyclopropoxy-4-fluoro-N-methyl-5-nitrobenzamide

[0454]

Chemical formula

[0455] Intermediates 31 and 32: 5 - Amino - 4 - cyclopropoxy - 2 - fluoro - N - methylbenzamide and 5 - Amino - 2 - cyclopropoxy - 4 - fluoro - N - methylbenzamide

[0456]

Chemical formula

[0457] Intermediate 33: 5 - Amino - 4 - cyclopropoxy - 2 - fluorobenzamide

[0458]

Chem.

[0459] Intermediate 34: 5 - Amino - 1 - isobutyl - N - methyl - 1H - pyrazole - 3 - carboxamide

[0460]

Chem.

[0461] Process B. 5-Amino-1-isobutyl-1H-pyrazole-3-carboxylic acid. LiOH·H 2 2O (2.68 g, 63.9 mmol) was added to ethyl 5-amino-1-isobutyl-1H-pyrazole-3-carboxylate (2.70 g, 12.8 mmol), THF (75 mL), and H 2O (15 mL) was added to a 250 mL three-necked round-bottom flask at room temperature. The resulting yellow suspension was heated at 70 °C for 3 hours. The reaction vessel was removed from the oil bath and gradually cooled 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 (3 N, 20 mL), and the resulting mixture was extracted with EtOAc (30 mL × 5). The combined organic extracts were washed with brine and dried over anhydrous Na 2 SO 4 and filtered, and concentrated in vacuo to obtain 5-amino-1-isobutyl-1H-pyrazole-3-carboxylic acid as a yellow solid (2.3 g, 94%). MS (ESI + ): m / z = 183.9.

[0462] Step C. 5-Amino-1-isobutyl-N-methyl-1H-pyrazole-3-carboxamide. HATU (4.11 g, 10.8 mmol) was added at room temperature to a 100 mL single-necked round-bottom flask containing 5-amino-1-isobutyl-1H-pyrazole-3-carboxylic acid (1.8 g, 9.83 mmol), CH 3 NH 2 ·HCl (1.00 g, 14.7 mmol), DIPEA (3.81 g, 29.5 mmol), a stir bar, and anhydrous DMF (65 mL). The resulting brown solution was stirred at room temperature for 12 hours. Thereafter, the mixture was diluted 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), dried over anhydrous Na 2 SO 4 and filtered, and the filtrate was concentrated to dryness in vacuo to obtain a yellow oil. The yellow oil was combined with another batch of this substance (500 mg) and subjected to silica gel chromatography (50 - 100% EtOAc / petroleum ether) to obtain 5-amino-1-isobutyl-N-methyl-1H-pyrazole-3-carboxamide as a brown oil (1.8 g, 73%). MS (ESI + ): m / z = 196.9.

[0463] Intermediate 35: (R)-3-(3-(4-(2-Chloropyrimidin-4-yl)thiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0464]

Chem.

[0465] Intermediate 36: 3-Amino-1,5-dimethylpyridin-2(1H)-one

[0466]

Chem.

[0467] Step B. 3-Amino-1,5-dimethylpyridin-2(1H)-one. Pd / C (wet, 500 mg, 50% H 2 O) was added at room temperature 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 at room temperature for 12 hours under H 2 (15 psi). The suspension was then filtered through a pad of diatomaceous earth and the pad was washed with MeOH (15 mL × 5). The filtrate combined with an additional batch of this material 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 as a yellow solid (850 mg). MS (ESI + ): m / z = 138.8. 1 H NMR (400 MHz, CDCl 3)δ 6.49 - 6.48 (m, 1H), 6.41 - 6.40 (m, 1H), 4.77 - 3.56 (m, 2H), 3.53 (s, 3H), 2.01 (s, 3H).

[0468] Intermediate 37: (R)-3-Hydroxy-1-methyl-3-(3-(4-(2-(methylthio)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one

[0469]

Chemical Structure

[0470] Intermediate 38: (R)-3-Hydroxy-1-methyl-3-(3-(4-(2-(methylsulfinyl)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one

[0471]

Chem.

[0472] Intermediate 39: 5-Amino-1-cyclopentyl-N-methyl-1H-pyrazole-3-carboxamide

[0473]

Chem.

[0474] Project B. 5-Amino-1-cyclopentyl-1H-pyrazole-3-carboxylic acid. LiOH·H 2 2O (1.28 g, 30.5 mmol) was added to ethyl 5-amino-1-cyclopentyl-1H-pyrazole-3-carboxylate (1.70 g, 7.61 mmol), THF (50 mL) and H 2A solution consisting of O(10 mL) was added to a 100 mL three-necked round-bottom flask at room temperature. The resulting yellow suspension was heated at 70 °C for 3 hours. The reaction vessel was taken out of the oil bath and gradually cooled to room temperature. The solution was concentrated to dryness in vacuo to obtain a yellow solid. The yellow solid was treated with aqueous HCl (3 N, 10 mL), and the resulting mixture was extracted with EtOAc (30 mL × 5). The combined organic extracts were washed with brine (10 mL) and dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to obtain 5-amino-1-cyclopentyl-1H-pyrazole-3-carboxylic acid as a yellow solid (1.2 g, 81%). MS (ESI + ): m / z = 195.9. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.17 (brs, 1H), 5.66 (s, 1H), 5.32 (brs, 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).

[0475] Step C. 5-Amino-1-cyclopentyl-N-methyl-1H-pyrazole-3-carboxamide. HATU (2.57 g, 6.76 mmol) was added to a 100 mL single-necked round-bottom flask 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) at room temperature. The resulting brown solution was stirred at room temperature for 12 hours under N 2 . Thereafter, the mixture was extracted with EtOAc (40 mL × 2), and the combined extracts were washed with H 2 O (20 mL × 2) and brine (30 mL), and dried over anhydrous Na 2 SO 4It was dried, filtered, and the filtrate was concentrated to dryness in vacuo to obtain a yellow solid. The yellow solid was subjected to silica gel chromatography (50 - 100% EtOAc / petroleum ether) to obtain 5 - amino - 1 - cyclopentyl - N - methyl - 1H - pyrazole - 3 - carboxamide as a brown oil (1.1 g, 86%). MS (ESI + ): m / z = 208.9.

[0476] Intermediate 40: 4 - chloro - 5 - methyl - N - (1 - methyl - 1H - pyrazol - 3 - yl) pyrimidin - 2 - amine

[0477]

Chemical formula

[0478] Intermediate 41: (R)-3-Hydroxy-1-methyl-3-(3-(4-(trimethylstannyl)thiazol-2-yl)phenyl)pyrrolidin-2-one

[0479] [Chemical Structure] Pd(PPh 3 ) 4 (327 mg, 0.283 mmol), 1,1,1,2,2,2-Hexamethyldistannane (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 under a nitrogen atmosphere. The resulting mixture was heated at 110 °C for 16 hours and then cooled to room temperature. The mixture was treated with aqueous KF (100 mL, 2 N) 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 dried over anhydrous Na 2 SO 4 , filtered, and concentrated to dryness in vacuo to obtain the product, which was subjected to silica gel chromatography (0 - 100% EtOAc / petroleum ether) to obtain a yellow oil. The yellow oil was further purified by HPLC (Boston Prime C18 column, 5 μM, 150 × 30 mm, 55 - 85% (v / v) CH 3 CN / H 2 O with 0.05% NH 3 ·H 2 O + 10 mM NH 4 HCO 3 ) and freeze-dried to obtain (R)-3-Hydroxy-1-methyl-3-(3-(4-(trimethylstannyl)thiazol-2-yl)phenyl)pyrrolidin-2-one as a yellow oil (100 mg, 8%). MS (ESI + ): m / z = 439.0 [M + H] + .

[0480] Intermediate 42: N-(1-Methyl-1H-pyrazol-3-yl)-4-(tributylstannyl)pyrimidin-2-amine

[0481]

Chem.

[0482] Intermediate 43: (R)-3-(3-(4-Bromo-5-methylthiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0483]

Chem.

[0484] Intermediate 44: (R)-3-(3-(2-bromothiazol-4-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0485]

Chemical Structure

[0486] Project 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) at -72 °C was added LDA (9 mL, 1 M solution in THF, 18 mmol). After 30 minutes, the resulting mixture was treated with bromine (471 μL, 9.19 mmol). After an additional 30 minutes, water (50 mL) was added and the resulting mixture was extracted with EtOAc. The organic extract was dried over Na 2 SO 4It was dried, filtered, and concentrated. The residue was purified by FCC (silica gel, gradient of 0 - 100% EtOAc / petroleum ether) to obtain (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.

[0487] Intermediate 45: (R,S)-7-(3-(4-bromothiazol-2-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol

[0488]

Chemical formula

[0489] 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’-bi(1,3,2-dioxaborolane) (1.15 g, 4.51 mmol), Pd(dppf)Cl 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 under a nitrogen atmosphere. The resulting mixture was heated at 100 °C for 16 h, and it turned black. Then, the reaction mixture was cooled to room temperature, 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 filtered, and the filtrate was concentrated to dryness in vacuo to obtain a black solid. The black solid was subjected to silica gel chromatography (10 - 100% EtOAc / petroleum ether) to obtain (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 as a solid (300 mg, 37%).

[0490] Project 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) were added to a nitrogen-purged 5 mL microwave tube, and then treated with Pd(dppf)Cl 2 (58 mg, 0.080 mmol). The resulting mixture was purged with N 2 for 5 minutes and heated at 90 °C for 1 hour by microwave irradiation to obtain a black solution. Thereafter, the mixture was cooled to room temperature, 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), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated to dryness in vacuo to obtain a black solid. The black solid was subjected to silica gel chromatography (0 - 10% MeOH / DCM) to obtain (R,S)-7-(3-(4-bromothiazol-2-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol as a yellow solid (160 mg, 55%).

[0491] Intermediate 46: (R)-3-(3-(6-Bromopyridin-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0492]

Chemical Structure

[0493] Intermediate 47: (R)-3-hydroxy-1-methyl-3-(3-(6-(2-(methylsulfinyl)pyrimidin-4-yl)pyridin-2-yl)phenyl)pyrrolidin-2-one

[0494]

Chemical Structure

[0495] Project 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. Then, the resulting mixture was heated at room temperature for 16 h, whereupon it changed to yellow. The reaction mixture was quenched with aqueous Na 2 O 3 S 2 (50 mL, 2 N) and extracted with EtOAc (50 mL × 3). The combined organic extracts were dried over anhydrous Na 2 SO 4It was dried, filtered, and the filtrate was concentrated to dryness in vacuo to obtain (R)-3-hydroxy-1-methyl-3-(3-(6-(2-(methylsulfinyl)pyrimidin-4-yl)pyridin-2-yl)phenyl)pyrrolidin-2-one as a yellow solid (200 mg). MS (ESI + ): m / z = 409.0.

[0496] Intermediate 48: (R,S)-3-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0497]

Chem.

[0498] 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), B 2 pin 2 (176 mg, 692 μmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (28.3 mg, 34.6 μmol), KOAc (102 mg, 1.04 mmol), a stir bar, and anhydrous 1,4-dioxane (6 mL) were oven-dried and N 2It was added to a purged 10 mL one-neck round-bottom flask. When the resulting mixture was heated to 100 °C over 16 hours, it changed to black. The reaction vessel was taken out of the oil bath, cooled to room temperature, then filtered through a pad of diatomaceous earth (e.g., Celite®), 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 as a white solid (100 mg, 69%). MS(ESI + ): m / z = 335.7. 1 H NMR (400 MHz, CDCl 3 ) δ 8.09 - 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).

[0499] Intermediate 49: (R,S)-3-(3-chloro-5-fluorophenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0500]

Chemical Structure

[0501] Process 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 subsequently 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 aqueous NH 4 Cl (5 mL) and extracted with EtOAc (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated to dryness in vacuo to afford a yellow oil. The yellow oil was subjected to silica gel chromatography (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.

[0502] Intermediate 50: (R,S)-3-(3-chloro-4-fluorophenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0503]

Chemical formula

[0504] Process 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 subsequently cooled to -78 °C. Then, the mixture was charged with (3-chloro-4-fluorophenyl)magnesium bromide (6.20 mL, 13.3 mmol), and the resulting mixture was stirred at -78 °C for 2 hours. The mixture was added to saturated aqueous NH 4 Cl (15 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 and filtered, and the filtrate was concentrated to dryness in vacuo to give a yellow oil. The yellow oil was subjected to silica gel chromatography (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.

[0505] Intermediate 51: (R,S)-3-(2-Bromopyridin-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one

[0506]

Chemical Structure

[0507] Intermediates 52 and 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

[0508]

Chemical Structure

[0509] The second elution peak was designated 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)δ 8.34 (d, J = 5.13 Hz, 1H), 7.59 (d, J = 0.88 Hz, 1H), 7.38 (dd, J = 5.19, 1.44 Hz, 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.

[0510] Intermediate 54: (R,S)-3-(5-Bromopyridin-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one

[0511]

Chem.

[0512] Intermediates 55 and 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

[0513]

Chemical Structure

[0514] The second elution peak was designated as the 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 ): δ 8.62 (d, J = 2.13 Hz, 1H), 8.54 (d, J = 1.88 Hz, 1H), 8.00 (t, J = 2.13 Hz, 1H), 6.38 (s, 1H), 3.37 - 3.49 (m, 2H), 2.82 (s, 3H), 2.42 (ddd, J = 13.35, 7.91, 5.38 Hz, 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.

[0515] Intermediate 57: (R,S)-tert-butyl 3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)pyridin-2-yl)-1H-pyrazole-1-carboxylate

[0516]

Chemical Structure

[0517] Intermediate 58: (R,S)-3-(6’-Chloro-[2,2’-bipyridin]-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one

[0518]

Chemical Structure

[0519] Intermediate 59: (R,S)-3-(2-(4-bromothiazol-2-yl)pyridin-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one

[0520]

Chemical formula

[0521] 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 h and then at 140 °C for an additional 1 h. The mixture was diluted with water and extracted with ethyl acetate. The organic extract was dried over anhydrous MgSO 4 and filtered and concentrated. The residue was purified by chromatography (silica, gradient 50→100% hexane and 10% MeOH-EtOAc) to obtain (R,S)-3-(2-(4-bromothiazol-2-yl)pyridin-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (17.2 mg, 17%).

[0522] Intermediate 60: 4,4-Difluoro-3,3-dihydroxy-1-methylpyrrolidin-2-one

[0523]

Chemical Structure

[0524] Step B. 4,4-Difluoro-3,3-dihydroxy-1-methylpyrrolidin-2-one. In a 10 L four-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) were added at room temperature. To this, Select-F (1945.87 g, 5492.77 mmol) was added portionwise at 0 °C. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with acetonitrile (5.4 L). To the mixture, HCl / 1,4-dioxane (4N, 936 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 1 hour. The resulting precipitate was filtered off and washed with acetonitrile (1 x 2 L). The filtrate was concentrated in vacuo. This filtration and concentration were repeated two more times. The residue was purified by DAC:CH 3 CN / H 2 O (0.1% of NH 4 HCO 3)= Purified by 1% - 15% over 17 minutes to obtain 4,4-difluoro-3,3-dihydroxy-1-methylpyrrolidin-2-one (122 g, 23.9% in two steps) as an off-white solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.29 (s, 2H), 3.65 (t, J = 12.0 Hz, 2H), 2.80 (s, 3H).

[0525] Intermediate 61: 1-Methyl-5-(trifluoromethyl)pyrrolidine-2,3-dione

[0526]

Chemical formula

[0527] Step B. Ethyl 4-hydroxy-1-methyl-5-oxo-2-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylate. To a solution of ethyl 4,4,4-trifluoro-3-(methylamino)butanoate (2400 g, 12.05 mol) in 2-MeTHF (24000 mL) were added t-BuOK (1.35 kg, 12.05 mol) and diethyl oxalate (1.76 kg, 12.05 mol, 1.65 L) under N 2 atmosphere at 25 °C. The reaction mixture was under N 2It was heated at 60 °C for 3 hours under an atmosphere. The reaction mixture was quenched at 25 °C by the addition of NH 4 Cl (saturated aqueous solution, 10.0 L), the pH of the mixture was adjusted to pH = 2 - 3 with 1 M aqueous HCl (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), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (DCM / MeOH 0% - 3%) to obtain the title compound as a brown oil (4.20 kg, 69%). 1 1H 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).

[0528] Step C. 1 - Methyl - 5 - (trifluoromethyl)pyrrolidine - 2,3 - dione. A mixture of ethyl 4 - hydroxy - 1 - methyl - 5 - oxo - 2 - (trifluoromethyl)-2,5 - dihydro - 1H - pyrrole - 3 - carboxylate (2000 g, 7.90 mol) in HCl (10.96 kg, 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), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a residue. The residue was triturated with MTBE (5000 mL) at 25 °C for 3 hours. The solid was filtered, washed with MTBE (1000 mL), and dried under reduced pressure to obtain the title compound as a yellow solid (1.15 kg, 6.35 mol, 40.2%). 1 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).

[0529] Intermediate 62: (R,S)-3-(3-(4-bromothiazol-2-yl)phenyl)-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one

[0530]

Chem.

[0531] 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. Then, THF was 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.

[0532] Process 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 diatomaceous earth. The filtrate was concentrated and purified by FCC (100% hexane) 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 as a yellow oil (240 mg, 98%).

[0533] Process 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 (H 2A mixture of O₂M (1.359 mL, 2.718 mmol), and 1,4-dioxane (4.5 mL) was heated at 110 °C for 4 h. The mixture was cooled to room temperature, filtered through diatomaceous earth, and purified by FCC (0 - 100% EtOAc in hexane) to obtain (R,S)-3-(3-(4-bromothiazol-2-yl)phenyl)-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one. MS (ESI + ): m / z = 388.9.

[0534] Intermediate 63: 4-(4-Bromothiazol-2-yl)-N-(1-(1-methyl-1H-pyrazol-3-yl)ethyl)pyrimidin-2-amine

[0535]

Chemical formula

[0536] Intermediate 64: 4-(4-Bromothiazol-2-yl)-N-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)pyrimidin-2-amine

[0537]

Chemical Structure

[0538] Intermediate 65: N-(1-(1H-pyrazol-3-yl)ethyl)-4-(4-bromothiazol-2-yl)pyrimidin-2-amine

[0539]

Chem.

[0540] Example 1: (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

[0541] [Chemical formula] 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 at 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 dried over anhydrous MgSO 4 and 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% - 15% MeOH in DCM), followed by reverse-phase 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 its trifluoroacetate salt (28 mg, 22%) as a yellow powder. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.86 (s, 1H), 8.55 (d, J = 5.0 Hz, 1H), 8.15 (t, J = 1.8 Hz, 1H), 7.97 (dt, J = 7.5, 1.5 Hz, 1H), 7.61 - 7.48 (m, 3H), 7.30 (d, J = 5.0 Hz, 1H), 6.69 (d, J = 2.2 Hz, 1H), 3.77 (s, 3H), 2.87 (s, 3H), 2.36 (ddd, J = 13.1, 7.8, 5.2 Hz, 1H), 2.32 - 2.24 (m, 1H). 19 F NMR (471 MHz, DMSO-d 6 ) δ -74.65. MS (ESI + ): m / z = 432.3.

[0542] Example 2: (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

[0543]

Chemical formula

[0544] Example 3: (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

[0545]

Chemical Structure

[0546] Example 4: (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

[0547]

Chem.

[0548] Example 5: (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

[0549]

Chem.

[0550] Example 6: (R)-3-(3-(4-(2-Aminopyrimidin-4-yl)thiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0551]

Chem.

[0552] Example 7: (R)-3-Hydroxy-3-(3-(4-(2-((2-Methoxypyrimidin-3-yl)amino)pyrimidin-4-yl)thiazol-2-yl)phenyl)-1-methylpyrrolidin-2-one

[0553]

Chemical formula

[0554] Example 8: (R)-5-((4-(2-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)phenyl)thiazol-4-yl)pyrimidin-2-yl)amino)-6-methylnicotinonitrile

[0555]

Chemical Structure

[0556] Example 9: (R)-3-(3-(4-(2-((3-cyclopropoxy-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0557]

Chemical Structure

[0558] Example 10: (R)-3-((4-(2-(3-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)phenyl)thiazol-4-yl)pyrimidin-2-yl)amino)-N,4-dimethylbenzamide

[0559]

Chem.

[0560] Example 11: (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

[0561]

Chemical formula

[0562] Example 12: (R)-4-Cyclopropoxy-2-fluoro-5-((4-(2-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)phenyl)thiazol-4-yl)pyrimidin-2-yl)amino)-N-methylbenzamide

[0563]

Chemical Structure

[0564] Example 13: (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

[0565]

Chem.

[0566] Example 14: (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

[0567] [Chemical] (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 for 3 hours by microwave irradiation and then cooled to room temperature. Subsequently, the reaction mixture was concentrated to dryness in vacuo to obtain a brown semi-solid, which was purified by silica gel chromatography (0 - 10% MeOH / CH 2 Cl 2 ), and then further purified by preparative HPLC (Welch Xtimate C18 column, 5 μm, 150×25 mm, 36 - 66% (v / v) CH 3 CN / H 2 O and 0.225% HCOOH). After lyophilization, (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 was obtained as a brown solid (58.1 mg, 24%). MS (ESI + ): m / z = 489.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.71 (d, J = 4.8 Hz, 1H), 8.60 (s, 1H), 8.36 (d, J = 1.6 Hz, 1H), 8.33 (s, 1H), 8.12 (s, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 4.8 Hz, 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 - 3.42 (m, 2H), 2.88 (s, 3H), 2.43 - 2.35 (m, 1H), 2.34 - 2.26 (m, 1H), 2.15 (s, 3H).

[0568] Example 15: (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

[0569]

Chemical formula

[0570] Example 16: (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

[0571]

Chemical Structure

[0572] Example 17: (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

[0573]

Chemical formula

[0574] Example 18 and Example 19: (R)-3-Hydroxy-1-methyl-3-(3-(4-(2-((1-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one (R)-3-Hydroxy-1-methyl-3-(3-(4-(2-((1-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-2-yl)phenyl)pyrrolidin-2-one

[0575]

Chemical formula

[0576] The second eluted 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. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.63 (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).

[0577] 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

[0578]

Chemical formula

[0579] Example 21: (R)-3-Hydroxy-3-(3-(4-(2-(Imidazo[1,2-a]pyridin-3-ylamino)py...

Claims

1. A compound of formula I: 【Chemical Formula 1】 or a pharmaceutically acceptable salt thereof, wherein A is a 5- to 6-membered heteroaryl optionally substituted with 1 to 3 -C （１～４） alkyl groups, W is CH ２ , CHF, or CF ２ and X is N, C-H, or C-R Ｘ wherein Y is N, C-H, or C-R Ｙ wherein Z is N, C-H, or C-R Ｚ wherein R Ｘ 、 R Ｙ 、 and R Ｚ are each independently halo, -CN, -C （１～４） alkyl, or -C （１～４） haloalkyl, and R １ is hydrogen, -C （１～４） alkyl, or -C （１～４） haloalkyl, and R ２ is hydrogen, halo, -C （１～４） alkyl, or -C （１～４） haloalkyl, and R ３ is hydrogen, halo, -C （１～４） alkyl, or -C （１～４） haloalkyl, and L is absent or is -C （１～４） alkylene, or -C （３～６） cycloalkylene, where the -C （１～４） alkylene and -C （３～６） cycloalkylene are optionally substituted with 1 to 3 groups selected from halo, -C （１～３） alkyl, and -OC （１～３） alkyl, and is optionally substituted with 1 to 3 groups selected from halo, -C R ４ is hydrogen, -C （１～６） alkyl, -C （３～１０） cycloalkyl, 3- to 10-membered heterocyclyl, a 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 said -C （１～６） alkyl, -C （３～１０） cycloalkyl, 3- to 10-membered heterocyclyl, a 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 with 1 to 5 R ４ｘ groups, Each R ４ｘ is, each time it appears, 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） alkylC （３～１０） cycloalkyl, -C （３～１０） cycloalkylC （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 heterocyclyl, -C （１～３） alkyl(3- to 8-membered heterocyclyl), -C （６～１０） aryl, or 5- to 10-membered heteroaryl, where 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） alkylC （３～１０） cycloalkyl, -C （３～１０） cycloalkylC （１～３） alkyl, 3- to 8-membered heterocyclyl, -C （１～３） alkyl(3- to 8-membered heterocyclyl), -C （６～１０） aryl, and 5- to 10-membered heteroaryl are 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） optionally further substituted with 1 to 5 groups selected from R Ｎ１ and R Ｎ２ each independently, at each occurrence, is H, -C （１～３） alkyl, or -C （１～３） haloalkyl, provided that at least one of X, Y, and Z is C—H).

2. A is a 5- to 6-membered heteroaryl optionally substituted with 1 to 3 -C （１～４） alkyl groups, W is CH ２ or CF ２ and X is N, C-H, or C-R Ｘ wherein Y is N, C-H, or C-R Ｙ wherein Z is N, C-H, or C-R Ｚ wherein R Ｘ 、R Ｙ 、and R Ｚ are each independently halo, -CN, -C （１～４） alkyl, or -C （１～４） haloalkyl, R １ is hydrogen, -C （１～４） alkyl, or -C （１～４） haloalkyl, and R ２ is hydrogen, halo, -C （１～４） alkyl, or -C （１～４） haloalkyl, and R ３ is hydrogen, halo, -C （１～４） alkyl, or -C （１～４） haloalkyl, and L is absent or -C （１～４） alkylene, or -C （３～６） cycloalkylene, where the -C （１～４） alkylene and -C （３～６） cycloalkylene are optionally substituted with 1 to 3 groups selected from halo, -C （１～３） alkyl, and -OC （１～３） alkyl, and is optionally substituted with 1 to 3 groups selected from halo, -C R ４ is hydrogen, -C （１～６） alkyl, -C （３～１０） cycloalkyl, 3- to 10-membered heterocyclyl, a 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, where: said -C （１～６） alkyl is optionally substituted with 1 to 5 R ４ａ groups, said -C （３～１０） cycloalkyl is optionally substituted with 1 to 5 R ４ｂ groups, said 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R ４ｃ groups, said 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R ４ｄ groups, said -C(O)-(3- to 10-membered heterocyclyl) is optionally substituted with 1 to 5 R ４ｅ groups, said -C （６～１０） aryl is optionally substituted with 1 to 5 R ４ｆ groups, said 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R ４ｇ groups, Each R ４ａ is, each time it appears, 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, a 3- to 8-membered heterocyclyl, -C （６～１０） aryl, or a 5- to 10-membered heteroaryl, where the -C （１～６） haloalkyl, -C （３～８） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, -OC （３～８） cycloalkyl, a 3- to 8-membered heterocyclyl, -C （６～１０） aryl, and a 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 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, R ４ｂ 、R ４ｃ 、R ４ｄ 、and R ４ｅ each independently represents, upon each occurrence, 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, a 3- to 8-membered heterocyclyl, -C （１～３） alkyl(3- to 8-membered heterocyclyl), -C （６～１０） aryl, or a 5- to 10-membered heteroaryl, where 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, a 3- to 8-membered heterocyclyl, -C （１～３） alkyl(3- to 8-membered heterocyclyl), -C （６～１０） aryl, and a 5- to 10-membered heteroaryl are each independently 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） Optionally further substituted with 1 to 5 groups selected from alkyl, R ４ｆ and R ４ｇ each independently represents, upon each occurrence, 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） alkylC （３～１０） cycloalkyl, -C （３～１０） cycloalkylC （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, a 3- to 8-membered heterocyclyl, -C （１～３） alkyl(3- to 8-membered heterocyclyl), -C （６～１０） aryl, or a 5- to 10-membered heteroaryl, where 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） alkylC （３～１０） cycloalkyl, -C （３～１０） cycloalkylC （１～３） alkyl, a 3- to 8-membered heterocyclyl, -C （１～３） alkyl(3- to 8-membered heterocyclyl), -C （６～１０） aryl, and the 5- to 10-membered heteroaryl are each independently 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, and is optionally further substituted with 1 to 5 groups selected from R Ｎ１ and R Ｎ２ each independently represents H or -C （１～３） alkyl each time it appears, The compound according to claim 1, or a pharmaceutically acceptable salt thereof, provided that at least one of X, Y, and Z is C—H).

3. A is a 5- to 6-membered heteroaryl optionally substituted with one -C （１～４） alkyl group, W is CH ２ or CF ２ and X is N, C-H, or C-R Ｘ wherein Y is N, C-H, or C-R Ｙ wherein Z is N, C-H, or C-R Ｚ wherein R Ｘ 、 R Ｙ 、 and R Ｚ are each independently halo, -CN, -C （１～４） alkyl, or -C （１～４） haloalkyl, R １ is hydrogen, -C （１～４） alkyl, or -C （１～４） haloalkyl, and R ２ is hydrogen, halo, -C （１～４） alkyl, or -C （１～４） haloalkyl, and R ３ is hydrogen, -C （１～４） alkyl, or -C （１～４） haloalkyl, and L is absent or -C （１～４） alkylene, or -C （３～６） cycloalkylene, where the -C （１～４） alkylene and -C （３～６） cycloalkylene are optionally substituted with one to three groups selected from halo, -C （１～３） alkyl, and -OC （１～３） alkyl, and is optionally substituted with one to three groups selected from halo, -C R ４ is hydrogen, -C （１～６） alkyl, -C （３～１０） cycloalkyl, 3- to 10-membered heterocyclyl, a 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, where: said -C （１～６） alkyl is optionally substituted with 1 to 5 R ４ａ groups, said -C （３～１０） cycloalkyl is optionally substituted with 1 to 5 R ４ｂ groups, said 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R ４ｃ groups, said 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R ４ｄ groups, said -C(O)-(3- to 10-membered heterocyclyl) is optionally substituted with 1 to 5 R ４ｅ groups, said -C （６～１０） aryl is optionally substituted with 1 to 5 R ４ｆ groups, said 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R ４ｇ groups, Each R ４ａ is, each time it appears, 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 heterocyclyl, where the C （１～６） haloalkyl, -C （３～８） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, -OC （３～８） cycloalkyl, and the 3- to 8-membered heterocyclyl are optionally further substituted with 1 to 5 groups selected from halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -CN, -C （１～４） alkyl, and -OC （１～４） alkyl, R ４ｂ 、 R ４ｃ 、 R ４ｄ 、 and R ４ｅ each independently represents, at each occurrence, 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, a 3- to 8-membered heterocyclyl, or a 5- to 10-membered heteroaryl, wherein said -C （１～６） alkyl, -C （１～６） haloalkyl, -C （３～８） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, -OC （３～８） cycloalkyl, a 3- to 8-membered heterocyclyl, and a 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -CN, -C （１～４） alkyl, and -OC （１～４） alkyl), R ４ｆ and R ４ｇ each independently represents, at each occurrence, 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） alkylC （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 heterocyclyl, -C （１～３） alkyl(3- to 8-membered heterocyclyl), -C （６～１０） aryl, or 5- to 10-membered heteroaryl, where 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） alkylC （３～１０） cycloalkyl, 3- to 8-membered heterocyclyl, -C （１～３） alkyl(3- to 8-membered heterocyclyl), -C （６～１０） aryl, and 5- to 10-membered heteroaryl are 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） Optionally further substituted with 1 to 5 groups selected from alkyl R Ｎ１ and R Ｎ２ each independently represents H or -C （１～３） alkyl each time it appears, The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, provided that at least one of X, Y, and Z is C—H).

4. A is a 5- or 6-membered heteroaryl optionally substituted with one -C （１～４） alkyl group, W is CH ２ or CF ２ and X is N, C-H, or C-R Ｘ wherein Y is N, C-H, or C-R Ｙ wherein Z is N, C-H, or C-R Ｚ wherein R Ｘ , R Ｙ , and R Ｚ are each independently halo, -CN, -C （１～４） alkyl, or -C （１～４） haloalkyl, and R １ is hydrogen, -C （１～４） alkyl, or -C （１～４） haloalkyl, and R ２ is hydrogen, halo, -C （１～４） alkyl, or -C （１～４） haloalkyl, and R ３ is hydrogen or -C （１～４） alkyl, and L is absent or -C （１～４） alkylene, or -C （３～６） cycloalkylene, where the -C （１～４） alkylene is optionally substituted with one -OC （１～３） alkyl group, R ４ is hydrogen, -C （１～６） alkyl, -C （３～１０） cycloalkyl, 3- to 10-membered heterocyclyl, a 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, where: said -C （１～６） alkyl is optionally substituted with 1 to 5 R ４ａ groups, said -C （３～１０） cycloalkyl is optionally substituted with 1 to 5 R ４ｂ groups, said 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R ４ｃ groups, said 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R ４ｄ groups, said -C(O)-(3- to 10-membered heterocyclyl) is optionally substituted with 1 to 5 R ４ｅ groups, said -C （６～１０） aryl is optionally substituted with 1 to 5 R ４ｆ groups, said 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R ４ｇ groups, Each R ４ａ is, each time it appears, 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 3- to 8-membered heterocyclyl, where the -C （１～６） haloalkyl, -C （３～８） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, and 3- to 8-membered heterocyclyl are optionally further substituted with 1 to 5 groups selected from halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -CN, -C （１～４） alkyl, and -OC （１～４） alkyl, Each R ４ｂ is, independently for each occurrence, halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -CN, -C （１～６） alkyl, -C （１～６） haloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, where the -C （１～６） alkyl, -C （１～６） haloalkyl, -OC （１～６） alkyl, and -OC （１～６） haloalkyl are optionally further substituted with 1 to 5 groups selected from halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), and -CN, R ４ｃ and R ４ｄ each independently, at each occurrence, is 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, a 3- to 8-membered heterocyclyl, or a 5- to 10-membered heteroaryl, where the -C （１～６） alkyl, -C （１～６） haloalkyl, -C （３～８） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, a 3- to 8-membered heterocyclyl, and a 5- to 10-membered heteroaryl are each optionally further substituted with 1 to 5 groups selected from halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -CN, -C （１～４） alkyl, and -OC （１～４） alkyl, Each R ４ｅ is, each time it appears, 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, and Each R ４ｆ is, each time it appears, 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, where 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） cycloalkyl are optionally further substituted with 1 to 5 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, each R ４ｇ is, independently for each occurrence, 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） alkylC （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, a 3- to 8-membered heterocyclyl, -C （１～３） alkyl(3- to 8-membered heterocyclyl), or -C （６～１０） aryl, where 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） alkylC （３～１０） cycloalkyl, a 3- to 8-membered heterocyclyl, -C （１～３） alkyl(3- to 8-membered heterocyclyl), and -C （６～１０） aryl are 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） Optionally further substituted with 1 to 5 groups selected from alkyl, R Ｎ１ and R Ｎ２ each independently represents H or -C （１～３） alkyl at each occurrence, The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, provided that at least one of X, Y, and Z is C—H).

5. A is a 5- to 6-membered heteroaryl optionally substituted with one methyl group, W is CH ２ or CF ２ and X is N, C-H, or C-R Ｘ wherein Y is N, C-H, or C-R Ｙ wherein Z is N, C—H, or C—R Ｚ wherein R Ｘ , R Ｙ , and R Ｚ are each independently halo, -CN, -C （１～４） alkyl, or -C （１～４） haloalkyl, R １ is hydrogen, -C （１～４） alkyl, or -C （１～４） haloalkyl, and R ２ is hydrogen, halo, -C （１～４） alkyl, or -C （１～４） haloalkyl, and R ３ is hydrogen or -C （１～４） alkyl, and L is absent or -C （１～４） alkylene, or -C （３～６） cycloalkylene, where the -C （１～４） alkylene is optionally substituted with one -OC （１～３） alkyl group R ４ is hydrogen, -C （１～６） alkyl, -C （３～１０） cycloalkyl, 3- to 10-membered heterocyclyl, a 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, where: said -C （１～６） alkyl is optionally substituted with 1 to 5 R ４ａ groups, said -C （３～１０） cycloalkyl is optionally substituted with 1 to 5 R ４ｂ groups, said 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R ４ｃ groups, said 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R ４ｄ groups, said -C(O)-(3- to 10-membered heterocyclyl) is optionally substituted with 1 to 3 -C （１～４） alkyl groups, said -C （６～１０） aryl is optionally substituted with 1 to 5 R ４ｆ groups, said 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R ４ｇ groups, Each R ４ａ is, independently for each occurrence, 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 3- to 8-membered heterocyclyl, where the -C （１～６） haloalkyl, -C （３～８） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, and 3- to 8-membered heterocyclyl are optionally further substituted with 1 to 5 groups selected from halo and -OH, Each R ４ｂ is, each time it appears, independently, halo, -OH, -CN, -C （１～６） alkyl, -C （１～６） haloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, where the -C （１～６） alkyl, -C （１～６） haloalkyl, -OC （１～６） alkyl, and -OC （１～６） haloalkyl are optionally further substituted with 1 to 5 groups selected from halo and -OH, R ４ｃ and R ４ｄ is, each time it appears, independently of the others, -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, a 3- to 8-membered heterocyclyl, or a 5- to 10-membered heteroaryl, where the -C （１～６） alkyl, -C （１～６） haloalkyl, -C （３～８） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, a 3- to 8-membered heterocyclyl, and a 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -OH, and -C （１～４） alkyl, Each R ４ｆ is, independently for each occurrence, 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 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） cycloalkyl are optionally further substituted with 1 to 5 groups selected from halo and -OH, Each R ４ｇ is, each time it appears, 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） alkylC （３～１０） cycloalkyl, -C(O)N(R Ｎ１ )(R Ｎ２ ), a 3- to 8-membered heterocyclyl, -C （１～３） alkyl(3- to 8-membered heterocyclyl), or -C （６～１０） aryl, where 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） alkylC （３～１０） cycloalkyl, a 3- to 8-membered heterocyclyl, -C （１～３） alkyl(3- to 8-membered heterocyclyl), and -C （６～１０） aryl are optionally further substituted with 1 to 5 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 ), and R Ｎ１ and R Ｎ２ each independently represents H or -C （１～３） alkyl for each occurrence, provided that at least two of X, Y, and Z are C—H, the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

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

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

8. A is pyrazolyl or thiazolyl, the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

9. A is 【Chemical 2】 the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

10. A is [Chemical Formula 3] the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. W is CH ２ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein W is CH

12. Two of X, Y, and Z are C—H, the compound according to any one of claims 1 to 4 or 6 to 10, or a pharmaceutically acceptable salt thereof.

13. One or less of X, Y, and Z is N, the compound according to any one of claims 1 to 4 or 6 to 10, or a pharmaceutically acceptable salt thereof.

14. R Ｘ , R Ｙ , and R Ｚ is, independently of one another, fluoro or -CN, a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

15. X is C—H or C—F, Y is N, C—H, C—F, or C—CN, Z is N, C—H, or C—F, the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

16. R １ is hydrogen or -CF ３ and is a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

17. A compound of formula Id-1 to Id-5, the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof: 【Chemical Formula 4】

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

19. R ２ and R ３ is hydrogen, a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.

20. L is absent or -C （１～４） is alkylene or cyclopropylene, where said -C （１～４） alkylene is optionally substituted with one -OC （１～３） alkyl group, the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof.

21. L is absent, 【Chemical Formula 5】 or is, a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof. **Claim 22** A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, which is a compound of any one of Formulae If-1 to If-8: 【Chemical Formula 6】 **Claim 23** R ４ is -C （１～６） alkyl, -C （３～１０） cycloalkyl, 3- to 10-membered heterocyclyl, a 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: said -C （１～６） alkyl is optionally substituted with 1 to 5 R ４ａ groups, said -C （３～１０） cycloalkyl is optionally substituted with 1 to 5 R ４ｂ groups, said 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R ４ｃ groups, said 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R ４ｄ groups, said -C(O)-(3- to 10-membered heterocyclyl) is optionally substituted with 1 to 5 R ４ｅ groups, said -C （６～１０） aryl is optionally substituted with 1 to 5 R ４ｆ groups, said 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R ４ｇ groups, the compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof. **Claim 24** R ４ is -C （１～６） alkyl and is optionally substituted with from 1 to 5 R ４ａ groups, a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof. **Claim 25** Each R ４ａ is, each time it appears, 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 3- to 8-membered heterocyclyl, where the -C （１～６） haloalkyl, -C （３～８） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, and 3- to 8-membered heterocyclyl are optionally further substituted with 1 to 5 groups selected from halo and -OH, the compound according to claim 24, or a pharmaceutically acceptable salt thereof. **Claim 26** R ４ is [Chemical Formula 7] or is, a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof. **Claim 27** R ４ is -C （３～１０） cycloalkyl and is optionally substituted with 1 to 5 R ４ｂ groups, the compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof. **Claim 28** R ４ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, or spirocyclo[3.3]heptyl, each of which is optionally substituted with 1 to 3 R ４ｂ groups, the compound according to claim 27, or a pharmaceutically acceptable salt thereof. **Claim 29** Each R ４ｂ is, each time it appears, independently, halo, -OH, -CN, -C （１～６） alkyl, -C （１～６） haloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, wherein said -C （１～６） alkyl, -C （１～６） haloalkyl, -OC （１～６） alkyl, and -OC （１～６） haloalkyl are optionally further substituted with 1 to 5 groups selected from halo and -OH, the compound according to claim 28, or a pharmaceutically acceptable salt thereof. **Claim 30** Each R ４ｂ is, each time it appears, independently, halo, -OH, -CN, -C （１～６） alkyl, or -OC （１～６） alkyl, where said -C （１～６） alkyl is optionally further substituted with one -OH group, the compound according to claim 28, or a pharmaceutically acceptable salt thereof. **Claim 31** R ４ is 【Chemical Formula 8】 or is, a compound according to any one of claims 1 to 23 or 27 to 30, or a pharmaceutically acceptable salt thereof. **Claim 32** R ４ is a 3- to 10-membered heterocyclyl, optionally substituted with 1 to 5 R ４ｃ groups, a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof. **Claim 33** R ４ is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, pyrrolidin-2-onyl, piperidin-2-onyl, morpholinyl, or piperazinyl, each of which is optionally substituted with 1 to 3 R ４ｃ groups, the compound according to claim 32, or a pharmaceutically acceptable salt thereof. **Claim 34** Each R ４ｃ is, independently for each occurrence, -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, a 3- to 8-membered heterocyclyl, or a 5- to 10-membered heteroaryl, where the -C （１～６） alkyl, -C （１～６） haloalkyl, -C （３～８） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, a 3- to 8-membered heterocyclyl, and a 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -OH, and -C （１～４） alkyl, the compound according to claim 33, or a pharmaceutically acceptable salt thereof. **Claim 35** Each R ４ｃ is, independently at each occurrence, -C （１～６） alkyl, -C(O)C （１～４） alkyl, -S(O) ２ C （１～４） alkyl, a 3- to 8-membered heterocyclyl, or a 5- to 10-membered heteroaryl, wherein said -C （１～６） alkyl, 3- to 8-membered heterocyclyl, and 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -OH, and -C （１～４） alkyl, the compound according to claim 33, or a pharmaceutically acceptable salt thereof. **Claim 36** R ４ is 【Chemical Formula 9】 or is, a compound according to any one of claims 1 to 23 or 32 to 35, or a pharmaceutically acceptable salt thereof. **Claim 37** R ４ is a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, and is optionally substituted with 1 to 5 R ４ｄ groups, the compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof. **Claim 38** R ４ is a 5- to 12-membered bicyclic ring system containing 1 to 5 heteroatoms selected from O, N, and S, and the 5- to 12-membered bicyclic ring system is optionally substituted with 1 to 5 R ４ｄ groups, the compound according to claim 37, or a pharmaceutically acceptable salt thereof. **Claim 39** R ４ is a 5- to 12-membered bicyclic ring system containing one or more heteroatoms and is optionally substituted with 1 to 5 R ４ｄ groups, and the 5- to 12-membered bicyclic ring system is a 3,5-fused ring system, 5,6-fused ring system, or 6,6-fused ring system, the compound according to claim 37, or a pharmaceutically acceptable salt thereof. **Claim 40** Each R ４ｄ is, independently at each occurrence, -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, where the -C （１～６） alkyl, -C （１～６） haloalkyl, -C （３～８） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, 3- to 8-membered heterocyclyl, and 5- to 10-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -OH, and -C （１～４） alkyl, a compound according to any one of claims 37 to 39, or a pharmaceutically acceptable salt thereof. **Claim 41** Each R ４ｄ is, independently for each occurrence, -C （１～６） alkyl, -OC （１～６） alkyl, or -C(O)C （１～４） alkyl, wherein said -C （１～６） alkyl and -OC （１～６） alkyl are each optionally further substituted with from 1 to 5 groups selected from halo and -OH, a compound according to any one of claims 37 to 39, or a pharmaceutically acceptable salt thereof. **Claim 42** R ４ is 【Chemical 10】 or is a compound according to any one of claims 1 to 23 or 37 to 41, or a pharmaceutically acceptable salt thereof. **Claim 43** R ４ is -C(O)-(3- to 10-membered heterocyclyl) and is optionally substituted with 1 to 5 R ４ｅ groups, a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof. **Claim 44** R ４ is -C(O)-(3- to 10-membered heterocyclyl) and is optionally substituted with 1 to 3 -C （１～４） alkyl groups, the compound according to claim 43, or a pharmaceutically acceptable salt thereof. **Claim 45** R ４ is 【Chemical 11】 or is, a compound according to claim 43, or a pharmaceutically acceptable salt thereof. **Claim 46** R ４ is -C （６～１０） aryl and is optionally substituted with 1 to 5 R ４ｆ groups, a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof. **Claim 47** R ４ is phenyl and 1 to 5 R ４ｆ groups are optionally substituted, the compound according to claim 46, or a pharmaceutically acceptable salt thereof. **Claim 48** Each R ４ｆ is, independently at each occurrence, 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 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） cycloalkyl are optionally further substituted with 1 to 5 groups selected from halo and -OH, the compound according to claim 47, or a pharmaceutically acceptable salt thereof. **Claim 49** Each R ４ｆ is, independently at each occurrence, 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 ), the compound according to claim 47, or a pharmaceutically acceptable salt thereof. **Claim 50** R ４ is 【Chemical 12】 or is, a compound according to any one of claims 1 to 23 or 46 to 49, or a pharmaceutically acceptable salt thereof. **Claim 51** R ４ where R is a 5- to 10-membered heteroaryl optionally substituted with 1 to 5 R groups, a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof. ４ｇ ​ **Claim 52** R ４ is a 5- or 6-membered monocyclic heteroaryl or a 9-membered bicyclic heteroaryl, each of which is optionally substituted with 1 to 3 R ４ｇ groups, the compound according to claim 51, or a pharmaceutically acceptable salt thereof. **Claim 53** R ４ is pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridin-2-onyl, pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, benzimidazolyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyridinyl, or pyrazolopyrimidinyl, each of which is optionally substituted with 1 to 3 R ４ｇ groups, the compound according to claim 52, or a pharmaceutically acceptable salt thereof. **Claim 54** R ４ is pyrazolyl or pyrazolopyridinyl, each of which is optionally substituted with 1 to 3 R ４ｇ groups, a compound according to any one of claims 1 to 23 or 51 to 53, or a pharmaceutically acceptable salt thereof. **Claim 55** R ４ is 【Chemical 13】 or is, a compound according to any one of claims 1 to 23 or 51 to 53, or a pharmaceutically acceptable salt thereof. **Claim 56** R ４ is 【Chemical Formula 14】 or is, a compound according to any one of claims 1 to 23 or 51 to 55, or a pharmaceutically acceptable salt thereof. **Claim 57** Each R ４ｇ is, each time it appears, 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） alkylC （３～１０） cycloalkyl, -C(O)N(R Ｎ１ )(R Ｎ２ ), a 3- to 8-membered heterocyclyl, -C （１～３） alkyl(3- to 8-membered heterocyclyl), or -C （６～１０） aryl, where 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） alkylC （３～１０） cycloalkyl, a 3- to 8-membered heterocyclyl, -C （１～３） alkyl(3- to 8-membered heterocyclyl), and -C （６～１０） aryl are optionally further substituted with 1 to 5 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 ), a compound according to any one of claims 1 to 4, 6 to 23, or 51 to 56, or a pharmaceutically acceptable salt thereof. **Claim 58** Each R ４ｇ is, each time it appears, 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 heterocyclyl, wherein said -C （１～６） alkyl, -C （１～６） haloalkyl, -C （３～８） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, -OC （３～８） cycloalkyl, and 3- to 8-membered heterocyclyl are optionally further substituted with 1 to 5 groups selected from halo and -OH, the compound according to claim 57, or a pharmaceutically acceptable salt thereof. **Claim 59** Each R ４ｇ is, independently at each occurrence, -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 1 to 5 groups selected from halo and -OH, the compound according to claim 57, or a pharmaceutically acceptable salt thereof. **Claim 60** Each R ４ｇ is, each time it appears, independently 【Chemical Formula 15】 or is, a compound according to any one of claims 1 to 23, or 51 to 57, or a pharmaceutically acceptable salt thereof. **Claim 61** Each R ４ｇ is, for each occurrence, independently 【Chemical 16】 or is, a compound according to any one of claims 1 to 23, or 51 to 57, or a pharmaceutically acceptable salt thereof. **Claim 62** Each R ４ｇ is, for each occurrence, independently 【Chemical 17】 or is, a compound according to any one of claims 1 to 23, or 51 to 57, or a pharmaceutically acceptable salt thereof. **Claim 63** R ４ is 【Chemical Formula 18】 【Chemical Formula 19】 【Chemical 20】 or is, 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.

64. Each R ４ is 【Chemical 21】 ​ 【Chemical 23】 The compound according to any one of claims 1 to 23, or 51 to 53, 55, 57, or 60, or a pharmaceutically acceptable salt thereof.

65. Each R ４ is 【Chemical 24】 The compound according to any one of claims 1 to 23, or 51 to 61, or 63 to 64, or a pharmaceutically acceptable salt thereof.

66. Each R ４ is 【Chemical 25】 The 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.

67. The compound of formula If-1: 【Chemical 26】 (A is pyrazolyl or thiazolyl, Y is N, C-H, or C-F, Z is N, C-H, or C-F, L is absent or is -C （１～４） alkylene, R ４ is a 5- to 10-membered heteroaryl, optionally substituted with 1 to 5 R ４ｇ groups, Each R ４ｇ is, independently for each occurrence, -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 1 to 5 groups selected from halo and -OH, provided that at least one of Y and Z is C-H) The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

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

69. The following: 【Chemical 27】 【Chemical Formula 28】 The compound according to claim 68, or a pharmaceutically acceptable salt thereof, having a structure selected from the group consisting of.

70. The following formula: 【Chemical Formula 29】 The compound according to claim 69, or a pharmaceutically acceptable salt thereof, having.

71. The following formula: 【Chemical 30】 The compound according to claim 69, or a pharmaceutically acceptable salt thereof, having.

72. The following formula: 【Chemical 31】 The compound according to claim 69, or a pharmaceutically acceptable salt thereof, having.

73. The following formula: 【Chemical Formula 32】 The compound according to claim 69, or a pharmaceutically acceptable salt thereof, having.

74. The following formula: 【Chemical 33】 The compound according to claim 69, or a pharmaceutically acceptable salt thereof, having.

75. The following formula: 【Chemical Formula 34】 The compound according to claim 69, or a pharmaceutically acceptable salt thereof, having.

76. The following formula: 【Chemical 35】 The compound according to claim 69, or a pharmaceutically acceptable salt thereof, having.

77. The following formula: 【Chemical 36】 The compound according to claim 69, or a pharmaceutically acceptable salt thereof, having.

78. The following formula: 【Chemical 37】 The compound according to claim 69, or a pharmaceutically acceptable salt thereof, having.

79. The following formula: 【Chemical Formula 38】 The compound according to claim 68, or a pharmaceutically acceptable salt thereof, having.

80. The following formula: 【Chemical Formula 39】 The compound according to claim 68, or a pharmaceutically acceptable salt thereof, having.

81. The following formula: 【Chemical 40】 The compound according to claim 69, or a pharmaceutically acceptable salt thereof, having

82. The following formula: 【Chemical 41】 The compound according to claim 69, or a pharmaceutically acceptable salt thereof, having

83. The following formula: 【Chemical Formula 42】 The compound according to claim 69, or a pharmaceutically acceptable salt thereof, having

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

85. 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) the compound according to any one of claims 1 to 83, or a pharmaceutically acceptable salt thereof, or (ii) the pharmaceutical composition according to claim 84.

86. The method according to claim 85, wherein the disease, disorder or medical condition mediated by NIK activity is selected from the group consisting of inflammatory disorders and autoimmune disorders.

87. The method according to 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, Sjogren's syndrome, and lupus nephritis.

88. The method according to claim 85, wherein 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.

89. The disease, disorder or medical condition mediated by NIK activity is 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"), hidradenitis suppurativa ("HS"), lipodystrophy, non-alcoholic steatohepatitis ("NASH"), primary biliary cirrhosis, leukemia, lymphoma, pancreatic cancer, breast cancer, melanoma (malignant 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, and is selected from the group consisting of the method according to claim 88.

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