Pyrrolidinone derivatives as inhibitors of NF-κB-inducing kinase

Abstract

The present disclosure relates to compounds of formula I' that inhibit NIK, pharmaceutical compositions comprising such compounds, and methods of using the same. These compounds and pharmaceutical compositions are useful for preventing or treating diseases such as inflammatory and autoimmune disorders. 【Chemical 1】 TIFF2025516564000643.tif32128

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 364,549, filed May 11, 2022, the entire disclosure of which is incorporated herein by reference into the present invention.

[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 - inducible kinase inhibitors and their use in medicine.

Background Art

[0003] NF - κB - inducible 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 some of the downstream pathways that produce inflammatory molecules. Clinical validation using biologics has confirmed the important role of some 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 particularly relates to Formula I':

[0006]

Chemical Formula

[0007] This application also discloses a compound of formula I:

[0008] [Chemical formula] (wherein A, W, X, Y, R 1 , R 2 , L, and R 3 are as defined herein), or a pharmaceutically acceptable salt thereof.

[0009] This application also discloses a pharmaceutical composition comprising a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0010] 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 Formula I, or a pharmaceutically acceptable carrier thereof, or (ii) a pharmaceutical composition comprising a compound of Formula I’ or Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the disease, disorder, or medical condition mediated by NIK activity is selected from the group consisting of inflammatory disorders, autoimmune disorders, cancer, metabolic disorders, and osteoporosis. In some embodiments, the disease, disorder, or medical condition mediated by NIK activity is selected from systemic lupus erythematosus (“SLE”), rheumatoid arthritis (“RA”), 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”), 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.

BEST MODE FOR CARRYING OUT THE INVENTION

[0011] The discussion of the documents, operations, materials, devices, articles, etc. included herein is for the purpose of providing context for the present disclosure. Such discussion is not to be construed as an admission that any or all of these things constitute part of the prior art with respect to any invention disclosed or claimed herein.

[0012] (Also known as NIK and also known as MAP3K14), NF-κB-inducing kinase 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 inflammatory and autoimmune disorders.

[0013] NIK-dependent transcriptional activation is a tightly regulated signaling pathway through sequential events including phosphorylation and proteolysis. In the NIK activation pathway, 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 such as 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 ligands 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.

[0014] 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 the treatment of seropositive SLE patients (S.V. Navarra, et al., The Lancet, 2011;377(9767):721-31). The CD40L / CD40 pathway plays important roles 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 antibody has demonstrated promising efficacy in phase II 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) showed deficiencies in non-canonical activation pathways of NIK such as the BAFF and CD40L pathways, decreased B lymphocytes in peripheral blood, and decreased lymphoid organs, as well as a reduced T cell-dependent antibody response carrying NIK as a therapeutic target for SLE.

[0015] 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 induced spontaneous form of arthritis generated 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 enhanced osteoclast formation and bone resorption in both basal conditions and response to inflammatory stimuli. See Aya et al. cited above. Furthermore, constitutive activation of NIK drives enhanced osteoclast formation and bone resorption in both basal conditions and response to inflammatory stimuli.(C.Yang,et al.,PLoS ONE 2010,5(11):e15383,doi:10.1371 / journal.pone.0015383).

[0016] NIK is also a therapeutic target for other autoimmune disorders driven by BAFF, CD40L, or lymphotoxin β receptor ligand, 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).

[0017] 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 case of discrepancy, the specific terms used herein have the meaning as described herein.

[0018] 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.

[0019] As used herein, the terms "including", "containing", and "comprising" are used in a broad, non-limiting sense.

[0020] For the sake of providing a more concise description, some of the quantitative expressions presented in this specification are not modified by the term "about". Whether or not the term "about" is explicitly used, all the amounts presented in this specification are meant to refer to the actual given value, and also mean to refer to approximations of such given values reasonably inferred based on ordinary skill in the art, including equivalent values and approximate values resulting from experimental conditions and / or measurement conditions for such a given value.

[0021] Regarding the method of the present invention, the term "administering" means a method for prophylactically, therapeutically, or improving the syndromes, disorders, or diseases described herein by using the compounds of the present disclosure or their pharmaceutically acceptable salts, their compositions, or their pharmaceuticals. Such methods include administering a therapeutically effective amount of the compounds of the present disclosure or their pharmaceutically acceptable salts, their compositions, or their pharmaceuticals at different time points during the treatment process, or simultaneously or sequentially as combination therapies.

[0022] The term "subject" refers to a patient who can be an animal, preferably a mammal, most preferably a human, to be treated or being treated by the method according to an embodiment of the present application. 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.

[0023] The term "therapeutically effective amount" or "effective amount" means the amount of an active compound or pharmaceutical that induces a biological or medical response in a tissue system, animal, or human, sought by a researcher, veterinarian, physician, or other clinician, including preventing, treating, or improving the symptoms of the syndromes, disorders, or diseases being treated.

[0024] As used herein, the term "treatment" or "treating" refers to the application or administration of a therapeutic agent (i.e., a compound of the present disclosure, alone or in combination with another pharmaceutical agent) to a subject having a disorder or disease, its symptoms, or to an excised tissue or cell line derived from a subject (e.g., for diagnostic or ex vivo (in vitro) applications), or with respect to the potential to develop a disorder or disease, where the purpose of the application or administration is to cure, heal, relieve, mitigate, alter, treat, remit, improve, or affect a disorder or disease, its symptoms, or the potential to develop such a disorder or disease. Such treatment may be specifically adjusted or modified based on knowledge obtained from the field of pharmacogenomics.

[0025] As used herein, the term "prevent" or "prevention" means that no onset of a disorder or disease occurs when the onset has not occurred, or that no further onset of a disorder or disease occurs when an onset of a disorder or disease has already occurred. Also considered is an individual's ability to prevent some or all of the symptoms associated with a disorder or disease.

[0026] The term "C (a~b) " (wherein a and b are integers referring to the indicated number of carbon atoms) refers to, for example, an alkyl, alkenyl, alkynyl, alkoxy, or cycloalkyl radical, or the alkyl portion of a radical where alkyl is present as a prefix root containing from a to b (inclusive) carbon atoms. For example, C (1~4) means a radical containing 1, 2, 3, or 4 carbon atoms.

[0027] The term "alkyl" is a straight-chain or branched-chain saturated hydrocarbon. For example, an alkyl group has from 1 to 12 carbon atoms (i.e., (C 1 ~C 12), having 1 to 6 carbon atoms (i.e., (C 1 ~C 6 ), having 1 to 4 carbon atoms (i.e., (C 1 ~C 4 ), having 1 to 3 carbon atoms (i.e., (C 1 ~C 3 ), may be included. 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(CH 3 )CH 2 CH 2 CH 3 ), neopentyl (-CH 2 C(CH 3 ) 3 ), 1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), heptyl (-(CH2 ) 6 CH 3 )、 octyl (-(CH 2 ) 7 CH 3 )、 2,2,4 - trimethylpentyl (-(CH 2 C(CH 3 ) 2 CH 2 CH(CH 3 ) 2 )、 nonyl (-(CH 2 ) 8 CH 3 )、 decyl (-(CH 2 ) 9 CH 3 )、 undecyl (-(CH 2 ) 10 CH 3 )、 and dodecyl (-(CH 2 ) 11 CH 3 ) are included, but not limited thereto. In one embodiment, alkyl refers to C (1~6) alkyl. In another embodiment, alkyl refers to C (1~4) alkyl. In another embodiment, alkyl refers to C (1~3) alkyl.

[0028] The term "alkylene" refers to a straight-chain or branched-chain saturated divalent hydrocarbon moiety derived from an alkane having 1 to 12 carbon atoms (i.e., (C 1 ~C 12 ) alkylene), 1 to 6 carbon atoms (i.e., (C 1 ~C 6 ) alkylene), 1 to 4 carbon atoms (i.e., (C 1 ~C 4 ) alkylene), or 1 to 3 carbon atoms (i.e., (C 1 ~C 3 ) alkylene). Examples of alkylene groups include methylene (-(CH 2 -), ethylene (-(CH 2 CH 2 -), -C(CH 3 )H-, propylene (-(CH 2 CH 2 CH2 -), isopropylene (-CH(CH 3 )CH 2 -), and -CH 2 CH(CH 3 )- are included, but not limited thereto. In one embodiment, the alkylene is C (1~4) refers to alkylene. In another embodiment, the alkylene is C (1~2) refers to alkylene.

[0029] The term "halo" or "halogen" refers to bromo (-Br), chloro (-Cl), fluoro (-F), or iodo (-I). In one embodiment, halo refers to fluoro.

[0030] 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 2 F), trifluoroethyl (CH 2 CF 3 ), tetrafluorotrifluoromethyl ethyl (CF(CF 3 ) 2 ), and groups that are considered equivalent to any one of the foregoing examples based on ordinary skill in the art and the teachings provided herein. In another embodiment, the alkyl is C (1~6) refers to haloalkyl. In another embodiment, the haloalkyl is C (1~4) refers to haloalkyl. In another embodiment, the alkyl is C (1~3) refers to haloalkyl.

[0031] The term "cycloalkyl" refers to, for example, a saturated or partially unsaturated all-carbon cyclic system having from 3 to 10 carbon atoms (i.e., C (3~10) cycloalkyl), from 3 to 8 carbon atoms (i.e., C (3~8) cycloalkyl), or from 3 to 6 carbon atoms (i.e., C (3~6) cycloalkyl), where the cycloalkyl ring system has one or more rings in a fused, spirocyclic, or 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. By way of example and not limitation, an example of a spiropentyl group is

[0032] [Chemical formula] and, by way of example and not limitation, an example of a spirohexyl group is

[0033] [Chemical formula] and, by way of example and not limitation, an example of a cycloheptyl group is

[0034] [Chemical formula] and, by way of example and not limitation, an example of a cyclooctyl group is

[0035] [Chemical formula] and so on. In another embodiment, cycloalkyl is C (3~10)Refers to cycloalkyl. In another embodiment, cycloalkyl is C (3~8) Refers to cycloalkyl. In another embodiment, cycloalkyl is C (3~6) Refers to cycloalkyl.

[0036] The term "cycloalkylene" refers to, for example, a divalent saturated or partially unsaturated all-carbon cyclic system derived from a cycloalkane having 3 to 10 carbon atoms (i.e., C (3~10) cycloalkylene), a divalent saturated or partially unsaturated all-carbon cyclic system derived from a cycloalkane having 3 to 8 carbon atoms (i.e., C (3~8) cycloalkylene), or a divalent saturated or partially unsaturated all-carbon cyclic system derived from a cycloalkane having 3 to 6 carbon atoms (i.e., C (3~6) cycloalkylene), where the cycloalkyl ring system has a monocyclic or polycyclic structure with fused, spiro, or bridged structures. Examples of alkylene groups include

[0037] [Chemical formula] but are not limited thereto. In one embodiment, cycloalkylene is C (3~10) Refers to cycloalkylene. In another embodiment, cycloalkylene is C (3~8) Refers to cycloalkylene. In another embodiment, cycloalkyl is C (3~6) Refers to cycloalkylene.

[0038] The term "aryl" refers to a polyunsaturated, typically aromatic hydrocarbon group, unless otherwise specified, which can be monocyclic or polycyclic (up to 3 rings) 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.

[0039] The term "heterocyclyl" refers to a single saturated or partially unsaturated ring having 3 to 12 ring members, 3 to 10 ring members, 3 to 8 ring members, or 3 to 6 ring members, 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 and any heteroatom or carbon atom that provides a stable structure. In one embodiment, heterocyclyl refers to a 3- to 10-membered heterocyclyl. In another embodiment, heterocyclyl refers to a 3- to 8-membered heterocyclyl. In another embodiment, heterocyclyl refers to a 3- to 6-membered heterocyclyl.

[0040] 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 fully aromatic rings, however, at least one other ring in the polycyclic ring system must be saturated or partially saturated. In some embodiments, the term refers to a fused bicyclic ring system. In some embodiments, the term refers to a fused bicyclic ring system in which one 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.

[0041] 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 in the term heteroaryl are 5- or 6-membered aromatic rings, where the ring consists of carbon atoms and has at least one heteroatomic member. Suitable heteroatoms include nitrogen, oxygen, and sulfur. In the case of a 5-membered ring, in some embodiments, the heteroaryl ring contains one member of nitrogen, oxygen, or sulfur and up to an additional three members of nitrogen. In the case of a 6-membered ring, in some embodiments, the heteroaryl ring contains 1 to 3 nitrogen atoms. When a 6-membered ring has three nitrogen atoms, at most two 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, quinazoline, pyrazolopyridinyl, and pyrazolopyrimidinyl. One of ordinary skill in the art will recognize that the listed species of heteroaryl groups are not inclusive and that additional species within the scope of these defined terms may also 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.

[0042] 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 valency is permitted in the moiety.

[0043] When the compounds disclosed herein have at least one stereocenter, these compounds can exist as enantiomers (optical isomers) or diastereomers (diastereoisomers) accordingly. It is understood that all such isomers and mixtures thereof are included within the scope of the present disclosure.

[0044] "Diastereoisomer" is a stereoisomer that has at least two asymmetric atoms but is not a mirror image of each other.

[0045] "Enantiomer" is a pair of stereoisomers that are mirror images that cannot be superimposed on 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.

[0046] When a mixture of stereoisomers results from the process for preparing the compounds according to the present disclosure, these isomers may be separated by conventional techniques such as preparative chromatography. These compounds may be prepared in racemic form, and the scalemic mixture or the individual enantiomers may be prepared by either enantioselective synthesis or resolution. These compounds may be resolved, for example, into their constituent enantiomers by forming diastereomeric pairs by forming salts with an optically active acid such as, for example, (-)-di-p-tolyloyl-D-tartaric acid and / or (+)-di-p-tolyloyl-L-tartaric acid by standard techniques, followed by 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.

[0047] 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, when the R enantiomer and S enantiomer of a compound are presented side by side under the heading "Example X and Example Y", unless otherwise specified in the following methods and characterizations, Example X may be either the R enantiomer or the S enantiomer of the compound, and Example Y is the opposite enantiomer, regardless of the order in which the IUPAC name or chemical structure of the compound is presented.

[0048] A particular example includes a chemical structure denoted or represented as ( * R) or ( * S). When ( * R * ) or ( * S) is used in the name of a compound or the chemical representation of a compound, it is intended to convey that the compound is a pure single isomer at that stereocenter, but the absolute configuration of that stereocenter has not been established. Thus, ( *The compound designated as (R) refers to a compound that is a pure single isomer at its stereocenter having either the (R) or (S) absolute configuration, * The compound designated as (S) refers to a compound that is a pure single isomer at its stereocenter having either the (R) or (S) absolute configuration. For example, (R)-3-hydroxy-1-methyl-3-(3-(6-(2-((( * (S)-6-methyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)amino)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one:

[0049]

Chemical formula

[0050]

Chemical formula

[0051] Pseudoasymmetric stereocenters are treated in the same way as chiral centers, but are given the lowercase symbols r or s (Angew. Chem. Int. Ed. Engl. 1982, 21, 567 - 583).

[0052] 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 may be achieved by conventional protecting group means such as 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 subsequent stage using methods well known in the art.

[0053] Furthermore, within the scope of the present disclosure, particularly when reference is made to the compounds of the present 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 synthetically produced, in either natural abundance or in isotopically enriched form. For example, reference to hydrogen or "H" includes, within its scope, 1 H, 2 H (i.e., deuterium or D), and 3 H (i.e., tritium or T). In some embodiments, the compounds described herein contain 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 thereof, such as C 1 H 2 C 1 H 3 not only C 1 HDC 1 HD 2 C 1 HDC 1 H 2 D, C 1 H 2 C 1 H 3 CD 2 CD 3 and other isotopic 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

[0054]

Chemical formula

[0055]

Chem.

[0056] 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 the medium in which such compounds are considered to be present at the time of designation. For example, a reference to a compound such as R-COOH in this specification refers to, for example, R-COOH (s) , R-COOH (sol) , and R-COO - (sol) any one of. In this example, R-COOH (s) refers to a solid compound when it may be present, for example, in a pharmaceutical composition or preparation in the form of a tablet or some other solid, R-COOH (sol) refers to the undissociated form of the compound in a solvent, and R-COO -(sol) refers to the dissociated form of a compound in a solvent, such as the dissociated form of a compound in an aqueous environment, 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 compound R-COOH that is present 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" refers to (a) the entity in a chemically relevant form of such entity that is present in the medium in which such reaction occurs, and (b) the chemically relevant form of compound R-COOH that is present in the medium in which such reaction occurs, reacting with each other. In this context, when such an entity is present, for example, in an aqueous environment, since compound R-COOH is present in such the same medium, the entity is R-COOH (aq) and / or R-COO - (aq)It is understood that it is exposed to species such as, in which case, in accordance with its customary meaning in chemistry and biochemistry, the subscript “(aq)” means “aqueous solution”. In these examples of nomenclature, a carboxylic acid functional group was selected, but this selection 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 nitrogen members in amines, and any other groups that interact or transform in a well-known manner in a medium containing the compound. Such interactions and transformations 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 transformations occurring in a given medium are well known to those skilled in the art.

[0057] The term “pharmaceutically acceptable” means approved or approvable by a regulatory authority of the federal or state government of the United States or the corresponding agency in a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopeias for use in animals, more specifically humans.

[0058] "Pharmaceutically acceptable salt" is intended to mean a salt of the free acid or base of a compound disclosed herein that is either 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 produce pharmaceutically acceptable salts.

[0059] The compounds of the present disclosure This application discloses a compound of formula I':

[0060]

Chemical formula

[0061] In some embodiments, disclosed herein is a compound of formula I’ as described above herein, wherein R 3 is -C(O)N(R N3 )(R N4 ) and L is absent.

[0062] In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl optionally substituted with one or more -C (1~4) alkyl groups, W is CH 2 , CHF, CF 2 , or CHR W , X is N, C-H, or C-R X , Y is N, C-H, or C-RY and R W is -C (1~4) alkyl or -C (1~4) haloalkyl, R X is halo, R Y is halo, -C (1~4) alkyl, -C (1~4) haloalkyl, -OC (1~4) alkyl, -OC (1~4) haloalkyl, or -C (1~4) alkyl -O-C (1~4) alkyl, R 1 is hydrogen, -C (1~4) alkyl, or -C (1~4) haloalkyl, or R W and R 1 together with the carbon atom to which they are attached form a C (3~5) cycloalkyl, R 2 is hydrogen, or -C (1~4) alkyl, L is absent or is -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, -OH, -N(R N1 )(R N2 ), -C (1~3) alkyl, -C (1~3) haloalkyl, -C (3~5) cycloalkyl, and -OC (1~3) alkyl, R 3 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 (6~10) aryl, a 5- to 10-membered heteroaryl, or -C(O)N(R N3 )(R N4 ), where -C(1~6) Alkyl, -C (3~10) Cycloalkyl, 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, -C (6~10) Aryl, and 5- to 10-membered heteroaryl are each, optionally, substituted with 1 to 5 R 3x groups, Each R 3x 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 (3~10) cycloalkylC (1~3) alkyl, -C(O)C (1~4) alkyl, -S(O) 2 C (1~4) alkyl, -S(O) 2 C (3~8) cycloalkyl, -N(H)S(O) 2 C (1~4) alkyl, -C (0~3) alkylC(O)N(R N1 )(R N2 ), 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, -C(O)C (1~4) alkyl, -S(O)2 C (1~4) alkyl, -S(O) 2 C (3~8) cycloalkyl, -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, and 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, -C (1~4) haloalkyl, -OC (1~4) alkyl, -OC (1~4) haloalkyl, and 1 to 5 groups selected from 3- to 5-membered heterocyclyl, or R 2 and L-R 3 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally further substituted with 1 to 3 groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1~6) alkyl, and -OC (1~6) alkyl, where -C (1~6) alkyl and -OC (1~6) alkyl are each optionally further substituted with 1 to 5 halo groups, R 4 is hydrogen, halo, or -C (1~4) alkyl, R 5 is hydrogen, halo, or -C (1~4) alkyl, R N1 and R N2 are each, each time they occur, independently hydrogen, -C (1~3) alkyl, or -C (1~3) haloalkyl, R N3 is hydrogen, or -C (1~4) alkyl, and R N4 is hydrogen, -C (1~4) alkyl, or phenyl, or R N3 and R N4 together with the nitrogen atom to which they are attached, optionally form a 3- to 10-membered heterocyclyl optionally 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 (1~4) haloalkyl, wherein, when R 3 is -C(O)N(R N3 )(R N4 ), L is absent.

[0063] In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl optionally substituted with one -C (1~4) alkyl group, W is CH 2 , CF 2 , or CHR W . X is N, C-H, or C-R X . Y is N, C-H, or C-R Y . R W is -C (1~4) alkyl, -C (1~4) haloalkyl, or R W and R 1 together with the carbon atom to which they are attached form C (3~5) cycloalkyl, R X is halo, R Y is halo, -C (1~4) alkyl, -C (1~4) haloalkyl, -OC (1~4) alkyl, -OC(1~4) haloalkyl, or -C (1~4) alkyl-O-C (1~4) is alkyl, R 1 is hydrogen, -C (1~4) alkyl, or -C (1~4) is haloalkyl, R 2 is hydrogen, 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 1 to 3 groups selected from halo, -OH, -N(R N1 )(R N2 )、-C (1~3) alkyl, -C (1~3) haloalkyl, -C (3~5) cycloalkyl, and -OC (1~3) alkyl, R 3 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 (6~10) aryl, 5- to 10-membered heteroaryl, or -C(O)N(R N3 )(R N4 ),where -C (1~6) alkyl is optionally substituted with 1 to 5 R 3a groups, C (3~10) cycloalkyl is optionally substituted with 1 to 5 R 3b groups, 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R 3c groups, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R 3d groups, -C (6~10) aryl is optionally substituted with 1 to 5 R 3e groups, and 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R 3foptionally substituted on the basis, each R 3a is, each time it appears, independently, halo, -OH, -N(R N1 )(R N2 ), -CN, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~8) cycloalkyl, -S(O) 2 C (1~4) alkyl, -N(H)S(O) 2 C (1~4) alkyl, or 3- to 8-membered heterocyclyl, where -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, -C (1~4) haloalkyl, -OC (1~4) alkyl, and -OC (1~4) haloalkyl, R 3b , R 3c , and R 3d 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, -C (1~3) alkylC (3~10) cycloalkyl, -C(O)C (1~4) alkyl, -S(O) 2 C (1~4) alkyl, -S(O) 2 C (3~8) cycloalkyl, -N(H)S(O) 2 C (1~4) alkyl, -C (0~3)alkyl C(O)N(R N1 )(R N2 ), a 3- to 8-membered heterocyclyl, or a 5- to 10-membered heteroaryl, wherein -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, -C (1~4) haloalkyl, -OC (1~4) alkyl, and -OC (1~4) haloalkyl, R 3e and R 3f 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) alkyl C (3~10) cycloalkyl, -C(O)C (1~4) alkyl, -S(O) 2 C (1~4) alkyl, -N(H)S(O) 2 C (1~4) alkyl, -C (0~3) alkyl C(O)N(R N1 )(R N2 ), 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, 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 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 (1~4) Haloalkyl, and 3- to 5-membered heterocyclyl, or R 2 and L-R 3 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with 1 to 3 groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1~6) Alkyl, C (1~6) Haloalkyl, -OC (1~6) Alkyl, and -OC (1~6) Haloalkyl, R 4 is hydrogen, halo, or -C (1~4) Alkyl, R 5 is hydrogen, halo, or -C (1~4) Alkyl, R N1 and R N2 each independently, upon each occurrence, is hydrogen or -C (1~3) Alkyl, R N3 is hydrogen or -C (1~4) Alkyl, and R N4 is hydrogen, -C (1~4) Alkyl, or phenyl, or R N3 and RN4 together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocyclyl optionally 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 (1~4) haloalkyl, wherein, when R 3 is -C(O)N(R N3 )(R N4 ), L is absent.

[0064] In some embodiments, disclosed herein is a compound of formula I' or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl optionally substituted with one -C (1~4) alkyl group, W is CH 2 , CF 2 , or CHR W , X is N, C-H, or C-R X , Y is N, C-H, or C-R Y , R W is -C (1~4) alkyl, -C (1~4) haloalkyl, or R W and R 1 together with the carbon atom to which they are attached form C (3~5) cycloalkyl, R X is halo, R Y is -C (1~4) alkyl, -C (1~4) haloalkyl, -OC (1~4) alkyl, or -C (1~4) alkyl-O-C (1~4) alkyl, R 1 is hydrogen, -C (1~4)alkyl, or -C (1~4) is haloalkyl, R 2 is hydrogen, 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, -OH, -N(R N1 )(R N2 ), -C (1~3) alkyl, -C (1~3) haloalkyl, -C (3~5) cycloalkyl, and -OC (1~3) alkyl, R 3 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 (6~10) aryl, 5- to 10-membered heteroaryl, or -C(O)N(R N3 )(R N4 ), where -C (1~6) alkyl is optionally substituted with one to five R 3a groups, C (3~10) cycloalkyl is optionally substituted with one to five R 3b groups, 3- to 10-membered heterocyclyl is optionally substituted with one to five R 3c groups, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with one to five R 3d , and 5- to 10-membered heteroaryl is optionally substituted with one to five R 3f groups, each R 3a is, each time it appears, independently halo, -OH, -N(R N1 )(R N2 ), -CN, -OC (1~6) alkyl, or -OC (1~6) haloalkyl, R 3b , R3c and R 3d each independently, upon 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 (1~3) alkylC (3~10) cycloalkyl, -S(O) 2 C (1~4) alkyl, or -S(O) 2 C (3~8) cycloalkyl, 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, -OH, -N(R N1 )(R N2 ), -CN, and -OC (1~4) alkyl, each R 3f independently, upon 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, -OC (3~8) cycloalkyl, -C (1~3) alkylC (3~10) cycloalkyl, -C (0~3) alkylC(O)N(R N1 )(R N2 ), 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 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 (1~4) Haloalkyl, and 3- to 5-membered heterocyclyl, or R 2 and L-R 3 together with the nitrogen atom to which they are attached form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally further substituted with 1 to 3 groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1~6) Alkyl, C (1~6) Haloalkyl, -OC (1~6) Alkyl, and -OC (1~6) Haloalkyl, R 4 is hydrogen, halo, or -C (1~4) Alkyl, R 5 is hydrogen, halo, or -C (1~4) Alkyl, R N1 and R N2 each independently, upon each occurrence, is hydrogen or -C (1~3) Alkyl, R N3 is hydrogen or -C (1~4) Alkyl, and R N4 is hydrogen, -C (1~4) Alkyl, or phenyl, or R N3 and RN4 together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocyclyl optionally 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 (1~4) haloalkyl, wherein when R 3 is -C(O)N(R N3 )(R N4 ), L is absent.

[0065] In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl optionally substituted with one -CH 3 group, W is CH 2 , CF 2 , or CHR W , X is N, C-H, or C-R X , Y is N, C-H, or C-R Y , R W is -C (1~4) alkyl, -C (1~4) haloalkyl, or alternatively R W and R 1 together with the carbon atom to which they are attached form C (3~5) cycloalkyl, R X is halo, R Y is -C (1~4) alkyl, -C (1~4) haloalkyl, -OC (1~4) alkyl, or -C (1~4) alkyl-O-C (1~4) alkyl, R 1 is hydrogen, -C (1~4)alkyl, or -C (1~4) is haloalkyl, R 2 is hydrogen, L is absent or -C (1~4) alkylene, or -C (3~6) cycloalkylene, where -C (1~4) alkylene is optionally substituted with 1 to 3 groups selected from halo, -OH, -N(R N1 )(R N2 ), and cyclopropyl, R 3 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, phenyl, 5- to 10-membered heteroaryl, or -C(O)N(R N3 )(R N4 ), where -C (1~6) alkyl is optionally substituted with 1 to 5 R 3a groups, C (3~10) cycloalkyl is optionally substituted with 1 to 5 R 3b groups, 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R 3c groups, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R 3d s, 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R 3f groups, each R 3a is, each time it appears, independently, halo, -OH, -OC (1~6) alkyl, or -OC (1~6) haloalkyl, each R 3b is, each time it appears, independently, halo, -OH, -C (1~6) haloalkyl, or -OC (1~6) alkyl, R 3c 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, -C (1~3) Alkyl C (3~10) Cycloalkyl, -S(O) 2 C (1~4) Alkyl, or -S(O) 2 C (3~8) Is cycloalkyl, where -C (1~6) Alkyl, and -OC (1~6) Alkyl is optionally further substituted with 1 to 5 groups selected from halo, and -OC (1~4) Alkyl, Each R 3d 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, or -C (1~3) Alkyl C (3~10) Is cycloalkyl, Each R 3f 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 (0~3) Alkyl C(O)N(R N1 )(R N2 ), 3- to 8-membered heterocyclyl, -C (1~3) 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, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), and 5- to 10-membered heteroaryl are each optionally further substituted with 1 to 5 groups selected from halo, -OH, -N(R N1 )(R N2 )、-C (1~4) Alkyl, -C (1~4) Haloalkyl, -OC (1~4) Alkyl, -OC (1~4) Haloalkyl, and 1 to 5 groups selected from 3- to 5-membered heterocyclyl, or R 2 and L-R 3 together with the nitrogen atom to which they are attached form a 5- to 12-membered bicyclic ring system or a 5- to 10-membered heteroaryl containing one or more heteroatoms, each of which is optionally further substituted with 1 to 3 groups selected from -N(R N1 )(R N2 ) and -C (1~6) Alkyl, R 4 is hydrogen, halo, or -C (1~4) Alkyl, R 5 is hydrogen, halo, or -C (1~4) Alkyl, R N1 and R N2 each independently, upon each occurrence, is hydrogen or -C (1~3) Alkyl, R N3 is hydrogen or -C (1~4) Alkyl, and R N4 is hydrogen, -C (1~4) Alkyl, or phenyl, or R N3 and R N4 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl optionally substituted with 1 to 5 groups selected from halo, -C (1~4) Alkyl, and -C (1~4) Haloalkyl, wherein R 3 is -C(O)N(RN3 )(R N4 ) is present, L does not exist.

[0066] In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein A is pyrazolyl, imidazolyl, triazolyl, thiazolyl, isoxazolyl, thiazolyl, or thiadiazolyl, and pyrazolyl is optionally substituted with one -CH 3 group. W is CH 2 , CF 2 , or CHR W , and when W is CHR W , R W and R 1 together with the carbon atom to which they are attached form C (3~5) cycloalkyl. X is N, C-H, or C-R X . Y is N, C-H, or C-R Y . R X is fluorine. R Y is CH 3 , -CHF 2 , -CF 3 , -OCH 3 , or -CH 2 OCH 3 . R 1 is hydrogen, -CH 3 , or -CF 3 . R 2 is hydrogen. L is absent or -C (1~4) alkylene or -C (3~6) cycloalkylene, where -C (1~4) alkylene is optionally substituted with 1 to 3 groups selected from halo, -OH, -N(R N1 )(R N2 ), and cyclopropyl. R 3is -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, phenyl, a 5- to 10-membered heteroaryl, or -C(O)N(R N3 )(R N4 ), where -C (1~6) alkyl is optionally substituted with 1 to 5 R 3a atoms, C (3~10) cycloalkyl is optionally substituted with 1 to 5 R 3b groups, the 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R 3c groups, the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R 3d groups, the 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R 3f groups, each R 3a is, independently at each occurrence, halo, -OH, -OC (1~6) alkyl, each R 3b is, independently at each occurrence, halo, -OH, -C (1~6) haloalkyl, or -OC (1~6) alkyl, each R 3c is, independently at each occurrence, halo, -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -S(O) 2 C (1~4) alkyl, or -S(O) 2 C (3~8) cycloalkyl, where -C (1~6) alkyl and -OC (1~6) alkyl are optionally further substituted with 1 to 5 groups selected from halo and -OC (1~4) alkyl, each R 3d is, independently at each occurrence, -C (1~6) alkyl, -C (1~6)Haloalkyl, or -C (1~3) alkyl C (3~10) is cycloalkyl, each R 3f 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 (0~3) alkyl C(O)N(R N1 )(R N2 ), 3- to 8-membered heterocyclyl, -C (1~3) 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, -C (1~3) 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, -N(R N1 )(R N2 ), -C (1~4) alkyl, -C (1~4) haloalkyl, -OC (1~4) alkyl, -OC (1~4) haloalkyl, and 3- to 5-membered heterocyclyl, or R 2 and L-R 3 together with the nitrogen atom to which they are attached form a 5- to 12-membered bicyclic ring system or a 5- to 10-membered heteroaryl containing one or more heteroatoms, each of which is optionally further substituted with 1 to 3 groups selected from -N(R N1 )(R N2 ) and -C (1~6) alkyl, R4 is hydrogen, chlorine, fluorine, or -CH 3 and R 5 is hydrogen, chlorine, fluorine, or -CH 3 and R N1 and R N2 are each, independently at each occurrence, hydrogen or -C (1~3) alkyl, R N3 is hydrogen or -C (1~4) alkyl and R N4 is hydrogen, -C (1~4) alkyl, or phenyl, or R N3 and R N4 together with the nitrogen atom to which they are attached, optionally form a 3- to 10-membered heterocyclyl optionally substituted with 1 to 5 groups selected from halo, -C (1~4) alkyl, and -C (1~4) haloalkyl, wherein when R 3 is -C(O)N(R N3 )(R N4 ), L is absent.

[0067] In some embodiments, disclosed herein is a compound of formula I' or a pharmaceutically acceptable salt thereof having the structure according to formula I:

[0068]

Chemical formula

[0069] This application further discloses a compound of formula I:

[0070]

Chemical formula

[0071] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl optionally substituted with one -C (1~4) alkyl group, W is CH 2 , or CF 2 , X is N, or C-H, Y is N, C-H, or C-R Y , R Y is -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, L is absent, -C (1~4) alkylene, or -C (3~6) cycloalkylene, where -C (1~4) alkylene and -C (3~6) cycloalkylene are optionally substituted with halo, -C (1~3) alkyl, and -OC (1~3)Optionally substituted with 1 to 3 groups selected from alkyl, R 3 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 (6~10) aryl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with 1 to 5 R 3x groups, each R 3x 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 (0~3) alkylC(O)N(R N1 )(R N2 ), 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(O)C (1~4) alkyl, -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, and 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, -C (1~4) haloalkyl, -OC (1~4) alkyl, and -OC (1~4) haloalkyl, or R 2 and L-R 3 together with the nitrogen atom to which they are attached form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with 1 to 3 groups selected from halo, -OH, -N(RN 1 )(RN 2 ), -CN, -C (1~6) alkyl, C (1~6) haloalkyl, -OC (1~6) alkyl, and -OC (1~6) haloalkyl, and R N1 and R N2 are each, independently at each occurrence, hydrogen, or -C (1~3) alkyl, or -C (1~3) haloalkyl.

[0072] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl, W is CH 2 or CF 2 and X is N, or C-H, Y is N, C-H, or C-R Y and R Y is -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, L is absent or -C (1~4) alkylene, or -C (3~6) cycloalkylene, R 3 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 (6~10) aryl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with 1 to 5 R 3x groups, each R 3x 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, 3- to 8-membered heterocyclyl, -C (1~3) 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, -C(O)C (1~4) alkyl, -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), and 5- to 10-membered heteroaryl are halo, -OH, -C (1~4) alkyl, -C (1~4) haloalkyl, -OC (1~4) alkyl, and -OC (1~4)Optionally further substituted with 1 to 5 groups selected from haloalkyl, or R 2 and L-R 3 together with the nitrogen atom to which they are attached form a 5- to 12-membered bicyclic ring system or a 5- to 10-membered heteroaryl containing one or more heteroatoms, each of which is optionally substituted with 1 to 3 groups selected from -N(R N1 )(R N2 ) and -C (1~6) alkyl, and R N1 and R N2 are each, independently at each occurrence, hydrogen, or -C (1~3) alkyl.

[0073] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is pyrazolyl, triazolyl, thiazolyl, or isoxazolyl, W is CH 2 or CF 2 and X is N, or C-H, Y is C-H, or C-R Y and R Y is -CF 3 and R 1 is hydrogen, or -CF 3 and R 2 is hydrogen, L is absent, -C (1~4) alkylene, or -C (3~6) cycloalkylene, R 3 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 (6~10) aryl, or a 5- to 10-membered heteroaryl, each of which is substituted with 1 to 5 R 3xis optionally replaced at the base, each R 3x 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, a 3- to 8-membered heterocyclyl, -C (1~3) alkyl(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, -C(O)C (1~4) alkyl, -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), and a 5- to 10-membered heteroaryl are optionally further replaced by 1 to 5 groups selected from halo, -OH, -C (1~4) alkyl, -C (1~4) haloalkyl, -OC (1~4) alkyl, and -OC (1~4) haloalkyl, or R 2 and L-R 3 together with the nitrogen atom to which they are attached form a 5,6-fused bicyclic ring system or a 5-membered heteroaryl containing one or more heteroatoms, each of which is optionally substituted by 1 to 3 groups selected from -N(R N1 )(R N2 ) and -C (1~6) alkyl, R N1 and R N2 are, each time they appear, each independently hydrogen, or -C(1~3) It is alkyl.

[0074] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl optionally substituted with one or more -C (1~4) alkyl groups; W is CH 2 , CHF, or CF 2 ; X is N, or C-H; Y is N, C-H, or C-R Y ; R Y is halo, -C (1~4) alkyl, -C (1~4) haloalkyl, -OC (1~4) alkyl, or -OC (1~4) haloalkyl; R 1 is hydrogen, -C (1~4) alkyl, or -C (1~4) haloalkyl; R 2 is hydrogen, or -C (1~4) alkyl; L is absent, -C (1~4) alkylene, or -C (3~6) cycloalkylene, wherein -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 3 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 (6~10) aryl, a 5- to 10-membered heteroaryl, wherein -C (1~6) alkyl is optionally substituted with 1 to 5 R 3a groups; C (3~10)The cycloalkyl is optionally substituted with 1 to 5 R 3b groups, the 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R 3c groups, the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R 3d , -C (6~10) The aryl is optionally substituted with 1 to 5 R 3e groups, the 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R 3f groups, R 3a , R 3b , R 3c , R 3d , R 3e , and R 3f , each time it appears, is independently of the others 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, -S(O) 2 C (1~4) alkyl, -N(H)S(O) 2 C (1~4) alkyl, -C (0~3) alkylC(O)N(R N1 )(R N2 ), 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, -C(O)C (1~4) Alkyl, -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, 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, and -OC (1~4) Haloalkyl and are optionally further substituted with 1 to 5 groups selected therefrom, or R 2 and L-R 3 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with 1 to 3 groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1~6) Alkyl, C (1~6) Haloalkyl, -OC (1~6) Alkyl, and -OC (1~6) Haloalkyl and are optionally substituted with 1 to 3 groups selected therefrom, and R N1 and R N2 each occurrence is independently hydrogen, -C (1~3) Alkyl, or -C (1~3) Haloalkyl.

[0075] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is one -C (1~4)A 5-membered heteroaryl optionally substituted with an alkyl group, W is CH 2 , or CF 2 , and X is N, or C-H, Y is N, C-H, or C-R Y , and R Y is halo, -C (1~4) alkyl, -C (1~4) haloalkyl, -OC (1~4) alkyl, or -OC (1~4) haloalkyl, R 1 is hydrogen, -C (1~4) alkyl, or -C (1~4) haloalkyl, R 2 is hydrogen, L is absent, -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 3 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 (6~10) aryl, a 5- to 10-membered heteroaryl, where -C (1~6) alkyl is optionally substituted with 1 to 5 R 3a groups, C (3~10) cycloalkyl is optionally substituted with 1 to 5 R 3b groups, a 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R 3c groups, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R 3d , and -C (6~10)Aryl is optionally substituted with 1 to 5 R 3e groups, and 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R 3f groups, Each R 3a , upon each occurrence, is independently halo, -OH, -N(R N1 )(R N2 ), -CN, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~8) cycloalkyl, -S(O) 2 C (1~4) alkyl, -N(H)S(O) 2 C (1~4) alkyl, or 3- to 8-membered heterocyclyl, where -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, -C (1~4) haloalkyl, -OC (1~4) alkyl, and -OC (1~4) haloalkyl, R 3b , R 3c , and R 3d , upon each occurrence, are 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, -C(O)C (1~4) alkyl, -S(O) 2 C (1~4) alkyl, -N(H)S(O) 2 C (1~4) alkyl, -C (0~3) alkylC(O)N(RN1 )(R N2 )、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 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 (1~4) haloalkyl, R 3e and R 3f 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(O)C (1~4) alkyl, -S(O) 2 C (1~4) alkyl, -N(H)S(O) 2 C (1~4) alkyl, -C (0~3) alkylC(O)N(R N1 )(R N2 ), 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) 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 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 (1~4) Haloalkyl and are optionally further substituted with 1 to 5 groups selected therefrom, or R 2 and L-R 3 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with 1 to 3 groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1~6) Alkyl, C (1~6) Haloalkyl, -OC (1~6) Alkyl, and -OC (1~6) Haloalkyl and are optionally substituted with 1 to 3 groups selected therefrom, and R N1 and R N2 each occurrence is independently hydrogen or -C (1~3) Alkyl.

[0076] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl optionally substituted with one -C (1~4) Alkyl group, W is CH 2 or CF 2 and X is N or C-H Y is N, C-H or C-R Y and R Y is -C (1~4) alkyl, -C (1~4) haloalkyl, or -OC (1~4) alkyl, and R 1 is hydrogen, -C (1~4) alkyl, or -C (1~4) haloalkyl, and R 2 is hydrogen, and 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, and R 3 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 3a groups, C (3~10) cycloalkyl is optionally substituted with 1 to 5 R 3b groups, the 3 - to 10 - membered heterocyclyl is optionally substituted with 1 to 5 R 3c groups, the 5 - to 12 - membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R 3d groups, and the 5 - to 10 - membered heteroaryl is optionally substituted with 1 to 5 R 3f groups, and each R 3a is, each time it appears, independently halo, -OH, -N(R N1 )(R N2 ), or -CN, and R 3b , R 3c , and R 3dis, 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, 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, each R 3f 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 (0~3) alkylC(O)N(R N1 )(R N2 ), 3- to 8-membered heterocyclyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), -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), -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 (1~4) optionally further substituted with 1 to 5 groups selected from haloalkyl, or R 2 and L-R 3 together with the nitrogen atom to which they are attached form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1~6) alkyl, C (1~6) haloalkyl, -OC (1~6) alkyl, and -OC (1~6) optionally substituted with 1 to 3 groups selected from haloalkyl, and R N1 and R N2 each, each occurrence, is independently hydrogen, or -C (1~3) alkyl.

[0077] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl, W is CH 2 , or CF 2 . X is N, or C-H, Y is N, C-H, or C-R Y . R Y is -C (1~4) alkyl, -C (1~4) haloalkyl, or -OC (1~4) alkyl, R 1 is hydrogen, -C (1~4) alkyl, or -C (1~4) haloalkyl, R 2 is hydrogen, L is absent or -C (1~4)An alkylene, or -C (3~6) is a cycloalkylene, R 3 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 halo groups, C (3~10) cycloalkyl is optionally substituted with 1 to 5 OH groups, the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R 3d s, and the 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R 3f groups, each R 3d 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, each R 3f is, each time it appears, independently halo, -OH, -N(R N1 )(R N2 ), -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~8) cycloalkyl, a 3- to 8-membered heterocyclyl, or -C (1~3) 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, a 3- to 8-membered heterocyclyl, and -C (1~3)Alkyl(3- to 8-membered heterocyclyl) 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, and -OC (1~4) haloalkyl, or R 2 and L-R 3 together with the nitrogen atom to which they are attached form a 5- to 12-membered bicyclic ring system or a 5- to 10-membered heteroaryl containing one or more heteroatoms, each of which is optionally substituted with 1 to 3 groups selected from -N(R N1 )(R N2 ) and -C (1~6) alkyl, and R N1 and R N2 each, each occurrence, is independently hydrogen or -C (1~3) alkyl.

[0078] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is pyrazolyl, triazolyl, thiazolyl, or isoxazolyl, W is CH 2 , or CF 2 , X is N or C-H, Y is C-H or C-R Y , R Y is -CF 3 , R 1 is hydrogen or -CF 3 , R 2 is hydrogen, L is absent, -C (1~4) alkylene, or -C (3~6) cycloalkylene, R 3 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 fluorine atoms, C (3~10) cycloalkyl is optionally substituted with one OH group, and the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 -C (1~6) alkyl groups, and the 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R 3f groups, each R 3f is, each time it appears, independently, -N(R N1 )(R N2 ), -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~8) cycloalkyl, 3- to 8-membered heterocyclyl, or -C (1~3) 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, 3- to 8-membered heterocyclyl, and -C (1~3) alkyl(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, and -OC (1~4) haloalkyl, or R 2 and L-R 3 together with the nitrogen atom to which they are attached form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms or a 5- to 10-membered heteroaryl, each of which is -N(RN1 )(R N2 ) and -C (1~6) optionally substituted with one to three groups selected from alkyl, and R N1 and R N2 is, each time it appears, independently hydrogen or -C (1~3) alkyl.

[0079] 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':

[0080]

Chemical formula

[0081] 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':

[0082]

Chemical formula

[0083] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, which is a compound of formula Ia-1:

[0084]

Chemical formula

[0085] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, which is a compound of formula Ia-2:

[0086]

Chemical formula

[0087] In some embodiments, disclosed herein is a compound of Formula I’ or Formula I, or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl substituted with one -C (1~4) alkyl group. In some embodiments, disclosed herein is a compound of Formula I’ or Formula I, or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl. In some embodiments, disclosed herein is a compound of Formula I’ or Formula I, or a pharmaceutically acceptable salt thereof, wherein A is pyrazolyl, triazolyl, thiazolyl, or isoxazolyl. In some embodiments, disclosed herein is a compound of Formula I’ or Formula I, or a pharmaceutically acceptable salt thereof, wherein A is triazolyl or isoxazolyl. In some embodiments, disclosed herein is a compound of Formula I’ or Formula I, or a pharmaceutically acceptable salt thereof, wherein A is pyrazolyl. In some embodiments, disclosed herein is a compound of Formula I’ or Formula I, or a pharmaceutically acceptable salt thereof, wherein A is triazolyl. In some embodiments, disclosed herein is a compound of Formula I’ or Formula I, or a pharmaceutically acceptable salt thereof, wherein A is thiazolyl. In some embodiments, disclosed herein is a compound of Formula I’ or Formula I, or a pharmaceutically acceptable salt thereof, wherein A is isoxazolyl.

[0088] In some embodiments, disclosed herein is a compound of Formula I’ or Formula I, or a pharmaceutically acceptable salt thereof, wherein A is

[0089]

Chemical formula

[0090] In some embodiments, disclosed herein is a compound of Formula I’ or Formula I, or a pharmaceutically acceptable salt thereof, wherein A is

[0091] [Chemistry] is as follows.

[0092] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein A is

[0093] [Chemistry] is as follows.

[0094] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein A is

[0095] [Chemistry] is as follows.

[0096] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein A is

[0097] [Chemistry] is as follows.

[0098] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein A is

[0099] [Chemistry] is as follows.

[0100] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein A is

[0101] [Chemistry] is.

[0102] 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’:

[0103]

Chemical formula

[0104] In some embodiments, disclosed herein is a compound of formula I’, or a pharmaceutically acceptable salt thereof, which is a compound of formula Ib-2’:

[0105]

Chemical formula

[0106] 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’:

[0107]

Chemical formula

[0108] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, which is a compound of formula Ib-1:

[0109]

Chemical formula

[0110] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, which is a compound of formula Ib-2:

[0111] [Chemical formula]

[0112] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, which is a compound of formula Ib-3:

[0113] [Chemical formula]

[0114] In some embodiments, disclosed herein is a compound of formula I', or a pharmaceutically acceptable salt thereof, wherein W is CH 2 , CDH, CD 2 , CF 2 , or CHR W . In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein W is CH 2、 CDH, CD 2 , or CF 2 . In some embodiments, disclosed herein is a compound of formula I' or 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 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 formula I, or a pharmaceutically acceptable salt thereof, wherein W is CF 2 . In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein W is CHR W .

[0115] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein X is N. In some embodiments, disclosed herein is a compound of formula I’ or 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 is. In some embodiments, disclosed herein is a compound of formula I’, or a pharmaceutically acceptable salt thereof, wherein X is C-F. In some embodiments, disclosed herein is a compound of formula I’, or a pharmaceutically acceptable salt thereof, wherein X is N, C-H, or C-F.

[0116] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein Y is N, C-H, C-CH 3 , C-CHF 2 , C-CF 3 , C-OCH 3 , or C-CH 2 OCH 3 is. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein Y is N. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-H, or C-R Y is. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-H or C-CF 3 is. In some embodiments, disclosed herein is a compound of formula I’ or 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 formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-R Yis. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-CH 3 is. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-CHF 2 is. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-CF 3 is. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-OCH 3 is. In some embodiments, disclosed herein is a compound of formula I’, or a pharmaceutically acceptable salt thereof, wherein Y is C-CH 2 OCH 3 is.

[0117] In some embodiments, disclosed herein is a compound of formula I’, or a pharmaceutically acceptable salt thereof, wherein R W is -C (1~4) alkyl. In some embodiments, disclosed herein is a compound of formula I’, or a pharmaceutically acceptable salt thereof, wherein R W is -C (1~4) haloalkyl. In some embodiments, disclosed herein is a compound of formula I’, or a pharmaceutically acceptable salt thereof, wherein when W is CHR W then R W and R 1 together with the carbon atom to which they are attached form a C (3~5) cycloalkyl. In some embodiments, disclosed herein is a compound of formula I’, or a pharmaceutically acceptable salt thereof, wherein when W is CHR W then R W and R 1 together with the carbon atom to which they are attached form a C (3) cycloalkyl.

[0118] In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R X is halo. In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R X is fluorine.

[0119] In some embodiments, disclosed herein is a compound of formula I’ or formula I or a pharmaceutically acceptable salt thereof, wherein R Y is -C (1~4) alkyl, -C (1~4) haloalkyl, or -OC (1~4) alkyl. In some embodiments, disclosed herein is a compound of formula I’ or formula I or a pharmaceutically acceptable salt thereof, wherein R Y is -C (1~4) alkyl, or -C (1~4) haloalkyl. In some embodiments, disclosed herein is a compound of formula I’ or formula I or a pharmaceutically acceptable salt thereof, wherein R Y is -C (1~4) alkyl. In some embodiments, disclosed herein is a compound of formula I’ or formula I or a pharmaceutically acceptable salt thereof, wherein R Y is -CH 3 . In some embodiments, disclosed herein is a compound of formula I’ or formula I or a pharmaceutically acceptable salt thereof, wherein R Y is -C (1~4) haloalkyl. In some embodiments, disclosed herein is a compound of formula I’ or formula I or a pharmaceutically acceptable salt thereof, wherein R Y is -CF 3 .

[0120] In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, which is a compound of formula Ic-1’:

[0121] [Chemistry]

[0122] In some embodiments, disclosed herein is a compound of Formula I’ or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ic-2’:

[0123] [Chemistry]

[0124] In some embodiments, disclosed herein is a compound of Formula I’ or Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ic-1:

[0125] [Chemistry]

[0126] In some embodiments, disclosed herein is a compound of Formula I’ or Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ic-2:

[0127] [Chemistry]

[0128] In some embodiments, disclosed herein is a compound of Formula I’ or 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 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 Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1is hydrogen. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH 3 . In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is -CF 3 . In some embodiments, disclosed herein is a compound of formula I’, or a pharmaceutically acceptable salt thereof, wherein R W and R 1 , together with the carbon atom to which they are attached, form a C (3~5) cycloalkyl. In some embodiments, disclosed herein is a compound of formula I’, or a pharmaceutically acceptable salt thereof, wherein R W and R 1 , together with the carbon atom to which they are attached, form a C (3) cycloalkyl.

[0129] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, which is any one compound of formula Id-1 to formula Id-7:

[0130]

Chemical formula

[0131] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, which is any one compound of formula Id-1 to formula Id-5:

[0132]

Chemical formula

[0133] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

[0134] In some embodiments, disclosed herein is a compound of Formula I’ or a pharmaceutically acceptable salt thereof, wherein L is absent or -C (1~4) alkylene, or -C (3~6) cycloalkylene, wherein -C (1~4) alkylene is optionally substituted with from 1 to 3 groups selected from halo, -OH, -N(R N1 )(R N2 ), and cyclopropyl. In some embodiments, disclosed herein is a compound of Formula I’ or Formula I or a pharmaceutically acceptable salt thereof, wherein L is absent or -C (1~4) alkylene, or -C (3~6) cycloalkylene, wherein -C (1~4) alkylene is optionally substituted with one -OC (1~3) alkyl group. In some embodiments, disclosed herein is a compound of Formula I’ or Formula I or a pharmaceutically acceptable salt thereof, wherein L is absent or -C (1~4) alkylene, or -C (3~6) cycloalkylene. In some embodiments, disclosed herein is a compound of Formula I’ or Formula I or a pharmaceutically acceptable salt thereof, wherein L is absent or -C (1~4) alkylene, or cyclopropylene.

[0135] In some embodiments, disclosed herein is a compound of Formula I’ or a pharmaceutically acceptable salt thereof, wherein L is absent or

[0136]

Chemical Formula

[0137] In some embodiments, disclosed herein is a compound of Formula I’ or Formula I or a pharmaceutically acceptable salt thereof, wherein L is absent or

[0138]

Chem.

[0139] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein L is absent or

[0140]

Chem.

[0141] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein L is absent or

[0142]

Chem.

[0143] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein L is absent.

[0144] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein L is

[0145]

Chem.

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

[0147]

Chem.

[0148] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein L is,

[0149]

Chemical formula

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

[0151]

Chemical formula

[0152] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein L is,

[0153]

Chemical formula

[0154] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein L is,

[0155]

Chemical formula

[0156] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein L is,

[0157]

Chemical formula

[0158] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, which is any one of the compounds of formula Ie-1 to formula Ie-10:

[0159]

Chemical formula

[0160] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, which is any one of the compounds of formula If-1 to formula If-10:

[0161]

Chemical formula

[0162] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is -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 3x groups.

[0163] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is a 5- to 12-membered bicyclic ring system or 5- to 10-membered heteroaryl containing one or more heteroatoms, each of which is optionally substituted with 1 to 5 R 3x groups.

[0164] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3xis, 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 (0~3) alkylC(O)N(R N1 )(R N2 ), 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(O)C (1~4) alkyl, -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, 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, and -OC (1~4) haloalkyl.

[0165] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R3x 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, 3- to 8-membered heterocyclyl, -C (1~3) 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, -C(O)C (1~4) alkyl, -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), 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, and -OC (1~4) haloalkyl.

[0166] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3x 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, 3- to 8-membered heterocyclyl, -C (1~3) 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, -C(O)C (1~4) Alkyl, -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), 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, and -OC (1~4) Haloalkyl.

[0167] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is a 5- to 12-membered bicyclic ring system containing one or more heteroatoms or a 5- to 10-membered heteroaryl, where the 5- to 12-membered bicyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R 3d and the 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R 3f groups.

[0168] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is -C (1~6) which is optionally substituted with 1 to 5 R 3a groups.

[0169] In some embodiments, disclosed herein is a compound of Formula I’ or Formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3a 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 (3~10) cycloalkylC (1~3) alkyl, -C(O)C (1~4) alkyl, -S(O) 2 C (1~4) alkyl, -N(H)S(O) 2 C (1~4) alkyl, -C (0~3) alkylC(O)N(R N1 )(R N2 ), 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, 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, -C (3~10) cycloalkylC (1~3) alkyl, -C(O)C (1~4) alkyl, -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, 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, and -OC (1~4) haloalkyl.

[0170] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3a is, independently at each occurrence, halo, -OH, -N(R N1 )(R N2 ), -CN, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~8) cycloalkyl, -S(O) 2 C (1~4) alkyl, -N(H)S(O) 2 C (1~4) alkyl, or 3- to 8-membered heterocyclyl, where -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~8) cycloalkyl, and 3- to 8-membered heterocyclyl 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, and -OC (1~4) haloalkyl.

[0171] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3a is, independently at each occurrence, halo, -OH, -OC (1~6) alkyl, or -OC (1~6) haloalkyl.

[0172] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3a is, independently at each occurrence, halo, -OH, -N(R N1 )(R N2 ), -CN, -OC (1~6) alkyl, or -OC (1~6) haloalkyl.

[0173] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3a is, independently at each occurrence, halo, -OH, -N(R N1 )(R N2 ), or -CN.

[0174] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3a is, independently at each occurrence, halo, -OH, or -OC (1~6) alkyl.

[0175] A compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3a is halo. A compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3a is fluorine. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3a is -OH. A compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3a is -OC (1~6) alkyl. A compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3a is -OCH 3 .

[0176] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0177]

Chemical formula

[0178] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0179]

Chemical formula

[0180] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is -C (3~10) cycloalkyl, which is optionally substituted with 1 to 5 R 3b groups. In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is -C (3~10) cycloalkyl, which is optionally substituted with 1 to 3 R 3b groups. In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is cyclopentyl, which is optionally substituted with 1 to 3 R 3b groups.

[0181] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3b 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 (3~10) Cycloalkyl C (1~3) Alkyl, -C(O)C (1~4) Alkyl, -S(O) 2 C (1~4) Alkyl, -N(H)S(O) 2 C (1~4) Alkyl, -C (0~3) Alkyl C(O)N(R N1 )(R N2 ), 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, -C(O)C (1~4) Alkyl, -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, 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, and -OC (1~4)Optionally further substituted with 1 to 5 groups selected from haloalkyl.

[0182] In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein each R 3b 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 (1~3) alkylC (3~10) cycloalkyl, -C(O)C (1~4) alkyl, -S(O) 2 C (1~4) alkyl, -S(O) 2 C (3~8) cycloalkyl, -N(H)S(O) 2 C (1~4) alkyl, -C (0~3) alkylC(O)N(R N1 )(R N2 ), 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, -C (1~4) haloalkyl, -OC (1~4) alkyl, and -OC (1~4) haloalkyl.

[0183] In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein each R 3bis, 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, -C(O)C (1~4) alkyl, -S(O) 2 C (1~4) alkyl, -N(H)S(O) 2 C (1~4) alkyl, -C (0~3) alkylC(O)N(R N1 )(R N2 ), 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, -C (1~4) haloalkyl, -OC (1~4) alkyl, and -OC (1~4) haloalkyl.

[0184] In some embodiments, what is disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein each R 3b 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, -C (1~3) alkylC (3~10) cycloalkyl, -S(O) 2 C(1~4) alkyl, or -S(O) 2 C (3~8) is cycloalkyl, 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, -OH, -N(R N1 )(R N2 ), -CN, and -OC (1~4) alkyl.

[0185] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3b 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, or -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.

[0186] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3b 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, or -OC (1~6) haloalkyl.

[0187] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3b is, independently at each occurrence, halo, -OH, -C (1~6) haloalkyl, or -OC (1~6) alkyl.

[0188] A compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3b is halo. A compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3b is fluorine. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3b is -OH. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3b is -C (1~6) haloalkyl. A compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3b is -CF 3 . A compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3b is -OC (1~6) alkyl. A compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3b is -OCH 3 .

[0189] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is -C (3~10) cycloalkyl, which is optionally substituted with one -OH group.

[0190] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0191] [Chem.] is.

[0192] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0193] [Chem.] is.

[0194] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is a 3- to 10-membered heterocyclyl, which is optionally substituted with 1 to 5 R 3c groups.

[0195] In some embodiments, disclosed herein is a compound of formula I', or a pharmaceutically acceptable salt thereof, wherein each R 3c , 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 (1~3) alkylC (3~10) cycloalkyl, -C (3~10) cycloalkylC (1~3) alkyl, -C(O)C (1~4) alkyl, -S(O) 2 C (1~4) alkyl, -S(O) 2 C (3~8) cycloalkyl, -N(H)S(O) 2 C (1~4) alkyl, -C (0~3) alkylC(O)N(RN1 )(R N2 )、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, 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, -C (3~10) cycloalkylC (1~3) alkyl, -C(O)C (1~4) alkyl, -S(O) 2 C (1~4) alkyl, -S(O) 2 C (3~8) cycloalkyl, -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, 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 (1~4) haloalkyl, and a 3- to 5-membered heterocyclyl.

[0196] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3c 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 (3~10) Cycloalkyl C (1~3) Alkyl, -C(O)C (1~4) Alkyl, -S(O) 2 C (1~4) Alkyl, -N(H)S(O) 2 C (1~4) Alkyl, -C (0~3) Alkyl C(O)N(R N1 )(R N2 ), 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, -C(O)C (1~4) Alkyl, -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, 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, and -OC (1~4) Haloalkyl.

[0197] In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein each R 3c 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 (1~3) alkylC (3~10) cycloalkyl, -C(O)C (1~4) alkyl, -S(O) 2 C (1~4) alkyl, -S(O) 2 C (3~8) cycloalkyl, -N(H)S(O) 2 C (1~4) alkyl, -C (0~3) alkylC(O)N(R N1 )(R N2 ), 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, -N(R N1 )(R N2 ), -CN, -C (1~4) alkyl, -C (1~4) haloalkyl, -OC (1~4) alkyl, and -OC (1~4) haloalkyl.

[0198] In some embodiments, disclosed herein is a compound of formula I’ or formula I or a pharmaceutically acceptable salt thereof, wherein each R 3c 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, -N(H)S(O) 2 C (1~4) Alkyl, -C (0~3) Alkyl C(O)N(R N1 )(R N2 ), a 3- to 8-membered heterocyclyl, or a 5- to 10-membered heteroaryl, wherein, -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, -C (1~4) Haloalkyl, -OC (1~4) Alkyl, and -OC (1~4) Haloalkyl.

[0199] In some embodiments, disclosed herein is a compound of formula I', or a pharmaceutically acceptable salt thereof, wherein each R 3c 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, -C (1~3) Alkyl C (3~10) Cycloalkyl, -S(O) 2 C (1~4) Alkyl, or -S(O) 2 C (3~8) Cycloalkyl, wherein, -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, -OH, -N(R N1 )(R N2 ), -CN, and -OC (1~4) Alkyl.

[0200] In some embodiments, disclosed herein is a compound of formula I' or a pharmaceutically acceptable salt thereof, wherein each R 3c 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, -C (1~3) AlkylC (3~10) Cycloalkyl, -S(O) 2 C (1~4) Alkyl, or -S(O) 2 C (3~8) Cycloalkyl, wherein -C (1~6) Alkyl, and -OC (1~6) Alkyl are optionally further substituted with 1 to 5 groups selected from halo and -OC (1~4) Alkyl.

[0201] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3c is, 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, wherein -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, -OH, -N(R N1 )(R N2 ), and -CN.

[0202] In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein each R 3c is, each occurrence, independently, halo, -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -S(O) 2 C (1~4) alkyl, or -S(O) 2 C (3~8) cycloalkyl, where -C (1~6) alkyl and -OC (1~6) alkyl are optionally further substituted with 1 to 5 groups selected from halo and -OC (1~4) alkyl.

[0203] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3c is, each occurrence, independently, halo. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3c is, each occurrence, independently, -C (1~6) alkyl, which is optionally further substituted with 1 to 5 groups selected from halo and -OC (1~4) alkyl. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3c is, each occurrence, independently, -C (1~6) haloalkyl. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3cis, independently for each occurrence, -C (3~8) is cycloalkyl. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3c is, independently for each occurrence, -OC (1~6) alkyl, which is optionally further substituted with from 1 to 5 groups selected from halo and -OC (1~4) alkyl. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3c is, independently for each occurrence, -S(O) 2 C (1~4) alkyl.

[0204] In some embodiments, disclosed herein is a compound of formula I’, or a pharmaceutically acceptable salt thereof, wherein each R 3c is, independently for each occurrence, -S(O) 2 C (3~8) cycloalkyl.

[0205] In some embodiments, disclosed herein is a compound of formula I’, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0206]

Chemical formula

[0207] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0208]

Chemical formula

[0209] In some embodiments, disclosed herein is a compound of Formula I’ or Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 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 3d groups. In some embodiments, disclosed herein is a compound of Formula I’ or Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, which is optionally substituted with 1 to 5 R 3d groups.

[0210] In some embodiments, disclosed herein is a compound of Formula I’ or Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 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 3d groups. In some embodiments, disclosed herein is a compound of Formula I’ or Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, which is optionally substituted with 1 to 5 R 3d groups, and the 5- to 12-membered bicyclic ring system is a 5,6-fused bicyclic ring system.

[0211] In some embodiments, disclosed herein is a compound of Formula I’ or Formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3d 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 (3~10) Cycloalkyl C (1~3) Alkyl, -C(O)C (1~4) Alkyl, -S(O) 2 C (1~4) Alkyl, -N(H)S(O) 2 C (1~4) Alkyl, -C (0~3) Alkyl C(O)N(R N1 )(R N2 ), 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, -C (3~10) Cycloalkyl C (1~3) Alkyl, -C(O)C (1~4) Alkyl, -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, 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, and -OC (1~4) Haloalkyl.

[0212] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3dis, 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, -N(H)S(O) 2 C (1~4) alkyl, -C (0~3) alkylC(O)N(R N1 )(R N2 ), 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, -C (1~4) haloalkyl, -OC (1~4) alkyl, and -OC (1~4) haloalkyl.

[0213] In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein each R 3d 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 (1~3) alkylC (3~10) cycloalkyl, -S(O) 2 C(1~4) alkyl, or -S(O) 2 C (3~8) is cycloalkyl, 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, -OH, -N(R N1 )(R N2 ), -CN, and -OC (1~4) alkyl.

[0214] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3d 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, or -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.

[0215] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3d 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, or -C (1~3) alkylC (3~10) is cycloalkyl.

[0216] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3d 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, or -OC (1~6) haloalkyl.

[0217] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3d is, independently at each occurrence, -C (1~6) alkyl, -C (1~6) haloalkyl, or -C (1~3) alkylC (3~10) cycloalkyl.

[0218] A compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3d is -C (1~6) alkyl. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3d is methyl. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3d is -C (1~6) haloalkyl. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3d is -CH 2 CF 3 . In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3d is -C (1~3) alkylC (3~10)It is cycloalkyl. In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3d is -CH 2 - cyclopropyl.

[0219] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0220]

Chemical formula

[0221] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0222]

Chemical formula

[0223] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is -C (6~10) aryl, which is optionally substituted with 1 to 5 R 3e groups. In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl.

[0224] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3e 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 (3~10) Cycloalkyl C (1~3) Alkyl, -C(O)C (1~4) Alkyl, -S(O) 2 C (1~4) Alkyl, -N(H)S(O) 2 C (1~4) Alkyl, -C (0~3) Alkyl C(O)N(R N1 )(R N2 ), 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, -C(O)C (1~4) Alkyl, -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, 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, and -OC (1~4) Haloalkyl.

[0225] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3e 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, -S(O) 2 C (1~4) alkyl, -N(H)S(O) 2 C (1~4) alkyl, -C (0~3) alkylC(O)N(R N1 )(R N2 ), 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 halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1~4) alkyl, -C (1~4) haloalkyl, -OC (1~4) alkyl, and -OC (1~4)Optionally further substituted with 1 to 5 groups selected from haloalkyl.

[0226] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3e 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, or -OC (1~6) haloalkyl.

[0227] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is a 5- to 10-membered heteroaryl, which is optionally substituted with 1 to 5 R 3f groups. In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is a 5- to 6-membered monocyclic heteroaryl or a 9-membered bicyclic heteroaryl, each of which is optionally substituted with 1 to 3 R 3f groups.

[0228] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or a 9-membered fused nitrogen-containing bicyclic heteroaryl, each of which is optionally substituted with 1 to 3 R 3f groups. In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3is pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazolopyridinyl, or pyrazolopyrimidinyl, each of which is optionally substituted with 1 to 3 R 3f groups. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is pyrazolyl, triazolyl, isoxazolyl, pyridinyl, pyrazolopyridinyl, or pyrazolopyrimidinyl, each of which is optionally substituted with 1 to 3 R 3f groups.

[0229] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is pyrazolyl, isoxazolyl, or pyrazolopyrimidinyl, each of which is optionally substituted with 1 to 3 R 3f groups. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is pyrazolyl, which is optionally substituted with 1 to 3 R 3f groups. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is isoxazolyl, which is optionally substituted with 1 to 3 R 3f groups. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is pyridinyl, which is optionally substituted with 1 to 3 R 3f groups. In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is pyrazolopyrimidinyl, which is optionally substituted with 1 to 3 R 3f groups.

[0230] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0231]

Chemical formula

[0232]

Chemical formula

[0233] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0234]

Chemical formula

[0235] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0236]

Chemical formula

[0237] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0238]

Chemical formula

[0239] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R3 is

[0240] [Chem.] as follows.

[0241] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0242] [Chem.] as follows.

[0243] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3f 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 (3~10) cycloalkylC (1~3) alkyl, -C(O)C (1~4) alkyl, -S(O) 2 C (1~4) alkyl, -N(H)S(O) 2 C (1~4) alkyl, -C (0~3) alkylC(O)N(R N1 )(R N2 ), 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, 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, -C (3~10) Cycloalkyl C (1~3) Alkyl, -C(O)C (1~4) Alkyl, -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, 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, and -OC (1~4) Haloalkyl and are optionally further substituted with 1 to 5 groups selected from haloalkyl and -OC

[0244] In some embodiments, disclosed herein is a compound of formula I', or a pharmaceutically acceptable salt thereof, wherein each R 3f 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) Alkyl C (3~10) Cycloalkyl, -C(O)C (1~4) Alkyl, -S(O) 2 C (1~4) Alkyl, -N(H)S(O) 2 C (1~4) Alkyl, -C (0~3) Alkyl C(O)N(R N1)(R N2 ) or 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 (1~4) haloalkyl, and a 3- to 5-membered heterocyclyl.

[0245] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3f 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, -S(O) 2 C (1~4) alkyl, -N(H)S(O) 2 C (1~4) alkyl, -C (0~3)Alkyl C(O)N(R N1 )(R N2 )、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) alkyl C (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, and -OC (1~4) haloalkyl.

[0246] In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein each R 3f 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 (0~3) alkyl C(O)N(R N1 )(R N2 ), 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 the 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 (1~4) Haloalkyl, and a 3- to 5-membered heterocyclyl.

[0247] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3f 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 (0~3) AlkylC(O)N(R N1 )(R N2 ), a 3- to 8-membered heterocyclyl, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), -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), -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 (1~4) Haloalkyl and is optionally further substituted with 1 to 5 groups selected therefrom.

[0248] In some embodiments, disclosed herein are compounds of formula I' or formula I, or pharmaceutically acceptable salts thereof, wherein each R 3f 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 (0~3) Alkyl C(O)N(R N1 )(R N2 ), 3- to 8-membered heterocyclyl, -C (1~3) 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, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), and 5- to 10-membered heteroaryl are halo, -OH, -N(RN1 )(R N2 )、 -C (1~4) alkyl, -C (1~4) haloalkyl, -OC (1~4) alkyl, -OC (1~4) haloalkyl, and is optionally further substituted with 1 to 5 groups selected from 3- to 5-membered heterocyclyl.

[0249] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3f is, independently at each occurrence, halo, -OH, -N(R N1 )(R N2 )、 -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~8) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~8) cycloalkyl, 3- to 8-membered heterocyclyl, or -C (1~3) 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, 3- to 8-membered heterocyclyl, and -C (1~3) alkyl(3- to 8-membered heterocyclyl) 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, and -OC (1~4) haloalkyl.

[0250] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3f is, independently at each occurrence, -N(R N1 )(R N2 )、 -C (1~6)Alkyl, -C (1~6) Haloalkyl, -C (3~8) Cycloalkyl, -OC (1~6) Alkyl, -OC (1~6) Haloalkyl, -OC (3~8) Cycloalkyl, 3- to 8-membered heterocyclyl, or -C (1~3) 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, 3- to 8-membered heterocyclyl, and -C (1~3) Alkyl(3- to 8-membered heterocyclyl) 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, and -OC (1~4) Haloalkyl.

[0251] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3f is, independently at each occurrence, halo, -C (1~6) Alkyl, -CO (3~8) Cycloalkyl, -OC (1~6) Alkyl, or -OC (3~8) Cycloalkyl, where -C (1~6) Alkyl, -OC (3~8) Cycloalkyl, -OC (1~6) Alkyl, and -OC (3~8) Cycloalkyl is optionally further substituted with 1 to 5 groups selected from halo and -OH.

[0252] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3f is, independently at each occurrence, -C (1~6) Alkyl, -C (1~6)Haloalkyl, -OC (3~8) Cycloalkyl, -OC (1~6) Alkyl, -OC (1~6) Haloalkyl, or -OC (3~8) Cycloalkyl, each of which is optionally further substituted with 1 to 3 -OH groups.

[0253] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3f is, independently at each occurrence, -C (1~6) Alkyl, -O (3~8) Cycloalkyl, -OC (1~6) Alkyl, or -OC (3~8) Cycloalkyl, each of which is optionally further substituted with 1 to 5 groups selected from fluorine and -OH.

[0254] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3f is, independently at each occurrence, -C (1~6) Alkyl, which is optionally further substituted with 1 to 5 groups selected from fluorine and -OH. In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3f is, independently at each occurrence, -C (1~6) Alkyl. In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, where each R 3f is methyl.

[0255] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3f is, independently at each occurrence, -OC (3~8)is cycloalkyl, which is optionally further substituted with 1 to 5 groups selected from fluorine and -OH. In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3f is, independently at each occurrence, -OC (3~8) cycloalkyl.

[0256] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3f is, independently at each occurrence, -OC (1~6) alkyl, which is optionally further substituted with 1 to 5 groups selected from fluorine and -OH. In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3f is, independently at each occurrence, -OC (1~6) alkyl.

[0257] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3f is, independently at each occurrence, -OC (3~8) cycloalkyl, which is optionally further substituted with 1 to 5 groups selected from fluorine and -OH. In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3f is, independently at each occurrence, -OC (3~8) cycloalkyl.

[0258] In some embodiments, disclosed herein is a compound of formula I', or a pharmaceutically acceptable salt thereof, wherein each R 3f is, independently at each occurrence,[[]]

[0259]

Chemical formula

[0260] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3f is, independently at each occurrence,

[0261]

Chem.

[0262] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3f is, independently at each occurrence,

[0263]

Chem.

[0264] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3f is, independently at each occurrence,

[0265]

Chem.

[0266] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3f is, independently at each occurrence,

[0267]

Chem.

[0268] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0269]

Chem.

[0270]

Chem.

[0271] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0272]

Chem.

[0273] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0274]

Chem.

[0275] In some embodiments, disclosed herein is a compound of formula I', or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0276]

Chem.

[0277] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0278]

Chem.

[0279] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0280]

Chemical formula

[0281] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0282]

Chemical formula

[0283] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0284]

Chemical formula

[0285] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0286]

Chemical formula

[0287] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0288] [Chem.] is.

[0289] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0290] [Chem.] is.

[0291] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0292] [Chem.] is.

[0293] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 and L-R 3 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one to three groups selected from halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1~6) alkyl, C (1~6) haloalkyl, -OC (1~6) alkyl, and -OC (1~6) haloalkyl.

[0294] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 and L-R3 together with the nitrogen atom to which they are attached, form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1~6) alkyl, C (1~6) haloalkyl, -OC (1~6) alkyl, and -OC (1~6) haloalkyl, optionally substituted with one to three groups selected from the group consisting of.

[0295] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 and L-R 3 together with the nitrogen atom to which they are attached, form a 5- to 12-membered bicyclic ring system or a 5- to 10-membered heteroaryl containing one or more heteroatoms, each of which is optionally substituted with one to three groups selected from -N(R N1 )(R N2 ) and -C (1~6) alkyl.

[0296] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 and L-R 3 together with the nitrogen atom to which they are attached, form a 5,6-fused bicyclic ring system or a 5-membered heteroaryl, each of which is optionally substituted with one to three groups selected from -N(R N1 )(R N2 ) and -C (1~6) alkyl.

[0297] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 and L-R 3 together with the nitrogen atom to which they are attached,

[0298]

Chem.

[0299] In some embodiments, disclosed herein is a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 and L-R 3 together with the nitrogen atom to which they are attached,

[0300]

Chem.

[0301] In some embodiments, disclosed herein is a compound of formula I', or a pharmaceutically acceptable salt thereof, wherein R 3 is -C(O)N(R N3 )(R N4 ).

[0302] In some embodiments, disclosed herein is a compound of formula I', or a pharmaceutically acceptable salt thereof, wherein R N3 is hydrogen, or -C (1~4) alkyl. In some embodiments, disclosed herein is a compound of formula I', or a pharmaceutically acceptable salt thereof, wherein R N3 is hydrogen, or -CH 3 . In some embodiments, disclosed herein is a compound of formula I', or a pharmaceutically acceptable salt thereof, wherein R N3 is hydrogen. In some embodiments, disclosed herein is a compound of formula I', or a pharmaceutically acceptable salt thereof, wherein R N3 is -C (1~4) alkyl. In some embodiments, disclosed herein is a compound of formula I', or a pharmaceutically acceptable salt thereof, wherein R N3 is -CH 3 .

[0303] In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R N4 is hydrogen, -C (1~4) alkyl, or phenyl. In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R N4 is hydrogen, -CH 3 or phenyl. In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R N4 is hydrogen. In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R N4 is -C (1~4) alkyl. In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R N4 is -CH 3 . In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R N4 is phenyl.

[0304] In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R N3 and R N4 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl optionally substituted with 1 to 5 groups selected from halo, -C (1~4) alkyl, and -C (1~4) haloalkyl. In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R N3 and R N4 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl optionally substituted with 1 to 5 groups selected from fluorine, -CH 3 , and -CF 3 .

[0305] In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R 3 is

[0306]

Chemical formula

[0307] In some embodiments, disclosed herein is a compound of formula I’ or formula I or a pharmaceutically acceptable salt thereof, wherein R N1 and R N2 are, each time they appear, independently of one another, hydrogen or -C (1~3) alkyl. In some embodiments, disclosed herein is a compound of formula I’ or formula I or a pharmaceutically acceptable salt thereof, wherein R N1 and R N2 are each hydrogen.

[0308] In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen, chlorine, fluorine, or -CH 3 as follows. In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen. In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R 4 is protium. In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R 4 is deuterium. In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R 4 is chlorine. In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R 4is fluorine. In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R 4 is -CH 3 as such.

[0309] In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen, chlorine, fluorine, or -CH 3 as such. In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen. In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R 5 is protium. In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R 5 is deuterium. In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R 5 is chlorine. In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R 5 is fluorine. In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R 5 is -CH 3 as such.

[0310] In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen and R 5 is hydrogen, R 4 is fluorine and R 5 is hydrogen, R 4 is -CH 3 as such and R 5 is hydrogen, R 4 is hydrogen and R 5is chlorine, or R 4 is hydrogen, and R 5 is -CH 3 as follows.

[0311] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, which is a compound of formula Ih:

[0312] [Chemical formula]

[0313] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, which is a compound of formula Ih-1:

[0314] [Chemical formula]

[0315] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, which is a compound of formula Ih-2:

[0316] [Chemical formula]

[0317] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, which is a compound of formula Ih-3:

[0318] [Chemical formula]

[0319] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, which is a compound of formula Ig-1:

[0320]

Chem.

[0321] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, which is a compound of formula Ig-2:

[0322]

Chem.

[0323] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, which is a compound of formula Ig-1:

[0324]

Chem.

[0325] In some embodiments, disclosed herein is a compound of formula I’ or a pharmaceutically acceptable salt thereof, wherein the formula Ii:

[0326]

Chemical Structure

[0327] In some embodiments, disclosed herein is a compound of formula I’ or formula I having a structure as shown in any one of Tables 1A to 1D, or a pharmaceutically acceptable salt thereof.

[0328]

Table 1-1

[0329]

Table 1-2

[0330]

Table 2-1

[0331]

Table 2-2

[0332]

Table 3-1

[0333]

Table 3-2

[0334]

Table 4-1

[0335]

Table 4-2

[0336] In some embodiments, disclosed herein is a compound having a structure as shown in any one of Tables 1E to 1U, or a pharmaceutically acceptable salt thereof.

[0337]

Table 5-1

[0338]

Table 5-2

[0339]

Table 6-1

[0340]

Table 6-2

[0341]

Table 7-1

[0342]

Table 7-2

[0343]

Table 8-1

[0344]

Table 8-2

[0345]

Table 9-1

[0346]

Table 9-2

[0347]

Table 10-1

[0348]

Table 10-2

[0349]

Table 11-1

[0350]

Table 11-2

[0351]

Table 12-1

[0352]

Table 12-2

[0353]

Table 13-1

[0354]

Table 13-2

[0355]

Table 14-1

[0356]

Table 14-2

[0357]

Table 15-1

[0358]

Table 15-2

[0359]

Table 16-1

[0360]

Table 16-2

[0361]

Table 17-1

[0362]

Table 17-2

[0363]

Table 18-1

[0364]

Table 18-2

[0365]

Table 19-1

[0366]

Table 19-2

[0367]

Table 20-1

[0368]

Table 20-2

[0369]

Table 21-1

[0370]

Table 21-2

[0371]

Table 21-3

[0372] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof, having a structure as shown in any one of Tables 2A to 2D.

[0373] [Table 22-1]

[0374] [Table 22-2]

[0375] [Table 23-1]

[0376] [Table 23-2]

[0377] [Table 24-1]

[0378] [Table 24-2]

[0379] [Table 25-1]

[0380] [Table 25-2]

[0381] In some embodiments, disclosed herein is a compound having a structure as shown in any one of Tables 2E to 2T, or a pharmaceutically acceptable salt thereof.

[0382] [Table 26-1]

[0383] [Table 26-2]

[0384] [Table 27-1]

[0385] [Table 27-2]

[0386] [Table 27-3]

[0387] [Table 28-1]

[0388] [Table 28-2]

[0389] [Table 28-3]

[0390] [Table 29-1]

[0391]

Table 29-2

[0392]

Table 29-3

[0393]

Table 30-1

[0394]

Table 30-2

[0395]

Table 30-3

[0396]

Table 31-1

[0397]

Table 31-2

[0398]

Table 32-1

[0399]

Table 32-2

[0400]

Table 33-1

[0401]

Table 33-2

[0402]

Table 34-1

[0403]

Table 34-2

[0404]

Table 35-1

[0405]

Table 35-2

[0406]

Table 36-1

[0407]

Table 36-2

[0408]

Table 37-1

[0409]

Table 37-2

[0410]

Table 38-1

[0411]

Table 38-2

[0412]

Table 39-1

[0413]

Table 39-2

[0414]

Table 40-1

[0415]

Table 40-2

[0416]

Table 40-3

[0417]

Table 41-1

[0418]

Table 41-2

[0419] In some embodiments, disclosed herein is a compound of formula I’ or formula I, or a pharmaceutically acceptable salt thereof,

[0420]

Chemical formula

[0421] In some embodiments, disclosed herein is a compound of Formula I' or Formula I, or a pharma- ceutically acceptable salt thereof:

[0422] [ka] is selected from the group consisting of:

[0423] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, having the following structure:

[0424] [ka] A compound of formula I' or a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0425] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, having the following structure:

[0426] [ka] A compound of formula I' or a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0427] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, having the following structure:

[0428] [ka] A compound of formula I' or a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0429] In some embodiments, disclosed herein are compounds of Formula I' or Formula I, having the following structure:

[0430] [Chemistry] A compound of formula I' or a compound of formula I having or a pharmaceutically acceptable salt thereof.

[0431] In some embodiments, disclosed herein is a compound of formula I' or formula I having the following structure:

[0432] [Chemistry] A compound of formula I' or a compound of formula I having or a pharmaceutically acceptable salt thereof.

[0433] In some embodiments, disclosed herein is a compound of formula I' or formula I having the following structure:

[0434] [Chemistry] A compound of formula I' or a compound of formula I having or a pharmaceutically acceptable salt thereof.

[0435] In some embodiments, disclosed herein is a compound of formula I' or formula I having the following structure:

[0436] [Chemistry] A compound of formula I' or a compound of formula I having or a pharmaceutically acceptable salt thereof.

[0437] In some embodiments, disclosed herein is a compound of formula I' or formula I having the following structure:

[0438] [Chemistry] A compound of formula I’ or a compound of formula I having or a pharmaceutically acceptable salt thereof.

[0439] In some embodiments, disclosed herein is a compound of formula I’ or a compound of formula I having the following structure:

[0440]

Chem.

[0441] In some embodiments, disclosed herein is a compound of formula I’ or a compound of formula I having the following structure:

[0442]

Chem.

[0443] In some embodiments, disclosed herein is a compound of formula I’ or a compound of formula I having the following structure:

[0444]

Chem.

[0445] In some embodiments, disclosed herein is a compound of formula I’ or a compound of formula I having the following structure: a compound of formula I’ or a compound of formula I having

[0446]

Chem.

[0447] In some embodiments, disclosed herein is a compound of formula I' or formula I having the following structure:

[0448]

Chemical formula

[0449] In some embodiments, disclosed herein is a compound of formula I' or formula I having the following structure:

[0450]

Chemical formula

[0451] In some embodiments, disclosed herein is a compound of formula I' or formula I having the following structure:

[0452]

Chemical formula

[0453] In some embodiments, disclosed herein is a compound of formula I' or formula I having the following structure:

[0454]

Chemical formula

[0455] In some embodiments, disclosed herein is a compound of formula I' or formula I having the following structure:

[0456] [Chemical formula] A compound of formula I' or a compound of formula I having or a pharmaceutically acceptable salt thereof.

[0457] In some embodiments, disclosed herein is a compound of formula I' or formula I having the following structure:

[0458] [Chemical formula] A compound of formula I' or a compound of formula I having or a pharmaceutically acceptable salt thereof.

[0459] In some embodiments, disclosed herein is a compound of formula I' or formula I having the following structure:

[0460] [Chemical formula] A compound of formula I' or a compound of formula I having or a pharmaceutically acceptable salt thereof.

[0461] In some embodiments, disclosed herein is a compound of formula I' or formula I having the following structure:

[0462] [Chemical formula] A compound of formula I' or a compound of formula I having or a pharmaceutically acceptable salt thereof.

[0463] In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound of formula I' or formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0464] 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 thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0465] 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 thereof 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.

[0466] 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 thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0467] 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.

[0468] 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.

[0469] 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.

[0470] 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」).

[0471] 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.

[0472] 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.

[0473] 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.

[0474] 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.

[0475] 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.

[0476] In some embodiments of the treatment methods disclosed herein, the disease, disorder, or medical condition is osteoporosis.

[0477] 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).

[0478] 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.

[0479] 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.

[0480] In some embodiments of the methods of the present disclosure, the subject is a human subject.

[0481] 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.

[0482] 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.

[0483] 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 afflicted with or diagnosed as having such a disease, disorder, or medical condition. "Effective amount" means an amount or dose 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, exemplary ranges of dosage are from about 1 to 1000 mg / day, in single or multiple dosage units.

[0484] 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.

[0485] The dosage is affected by factors such as the route of administration, the health status, weight, and age of the recipient, the frequency of treatment, and the presence of concurrent unrelated treatments.

[0486] It is also apparent to those skilled in the art that the therapeutically effective amount of the compounds or pharmaceutical compositions thereof of the present disclosure may vary depending on the desired effect. Thus, the optimal dosage may be readily determined by those skilled in the art and will vary depending on the particular compound used, the method of administration, the strength of the preparation, and the progression of the disease state. It will be necessary to adjust the dosage to an appropriate therapeutic level based on factors related to the particular subject being treated, including the subject's age, weight, diet, and time of administration. Accordingly, the dosages described above 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.

[0487] Once improvement in the patient's disease, disorder, or condition has occurred, the dosage may be adjusted for prophylactic or maintenance therapy. 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, if the symptoms have been alleviated to an appropriate level, treatment may be discontinued. However, if the symptoms recur, the patient may require long-term intermittent treatment.

[0488] 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 added to the pharmaceutical composition or, alternatively, used as vehicles or diluents to facilitate administration of the agent and are non-toxic, biologically tolerated, and biologically suitable for administration to the subject for other reasons, such as being 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 may also be components of the formulation include fillers, binders, disintegrants, and lubricants.

[0489] Delivery forms of pharmaceutical compositions containing one or more compounds of the present disclosure may be prepared using pharmaceutically acceptable excipients and compounding techniques well known or available to those skilled in the art. This composition may be administered by a suitable delivery route, such as oral, parenteral, rectal, topical, or ophthalmic route, or by inhalation, in the methods of the present disclosure.

[0490] 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, such as intravenous injection, subcutaneous injection, topical administration, or oral administration.

[0491] 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 to provide a dosage of, for example, about 1 to 1000 mg / day for a 70 kg human, in an exemplary range of single dosage units to multiple dosage units.

[0492] The oral tablets may contain the compounds of the present disclosure mixed with compatible pharmaceutically acceptable excipients, such as 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 embodiments 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 a substance such as 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.

[0493] 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 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 other suitable vehicle before use, or presented as a dry product. Such liquid compositions may optionally contain pharmaceutically acceptable excipients such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.), non-aqueous vehicles such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol or water, preservatives (e.g., methyl p-hydroxybenzoate or propyl p-hydroxybenzoate, or sorbic acid), wetting agents such as lecithin, and, if desired, flavoring or coloring agents.

[0494] 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 ampoules or disposable injection devices, multiple dosage forms such as vials from which appropriate dosages can be withdrawn, or solid or pre-concentrated forms that can be used to prepare injectable formulations. Exemplary infusion dosages are amounts in which the drug admixed with the pharmaceutical carrier is infused in the range of about 1 to 1000 μg / kg / min over a period ranging from several minutes to several days.

[0495] In the case of topical administration, the compounds of the present disclosure may be mixed with a pharmaceutical carrier. Another form of administering the compounds of the present disclosure may utilize a patch formulation for transdermal delivery.

[0496] Alternatively, the compounds of the present disclosure may be administered by inhalation via the nasal or oral route, for example, by a spray formulation that also contains a suitable carrier, in the methods of the present disclosure.

[0497] 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 by reference in their entirety.

Examples

[0498] The following specific examples are provided to further illustrate embodiments within the scope of the present disclosure.

[0499] Abbreviations Throughout this specification and this application, the following abbreviations may be used.

[0500]

Table 42-1

[0501]

Table 42-2

[0502] 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.

[0503] By way of illustration and not limitation, the compounds of the present disclosure, the compounds of formula I', or the compounds of formula I are prepared according to the following general preparation procedures given by Schemes 1-6. Those skilled in the art will understand that in order to obtain the various compounds herein, the starting materials can be suitably selected so that the ultimately desired substituents are retained through the reaction scheme, either protected or unprotected as appropriate, such that the desired product is obtained. Alternatively, instead of the ultimately desired substituents, appropriate groups are used that are carried throughout the reaction scheme and can be replaced with the desired substituents as appropriate. Unless otherwise specified, the variables are as defined in Schemes 1-6 with reference to formula I' or formula I.

[0504]

Chemical formula

[0505] 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 a reaction under Stille conditions. Those skilled in the art will also recognize that the coupling under Stille conditions can also provide the 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 such as CuI and TEA. Examples of suitable catalysts include Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , and Pd(P(Cy) 3 ) 2 Cl 2 , but are not limited thereto. Examples of suitable solvents include 1,4-dioxane, toluene, and DMF (dimethylformamide, N,N-dimethylformamide), but are not limited thereto. Using microwave or conventional heating, the reactants can be heated to a temperature of about 100 °C to about 120 °C for about 1 to 16 hours to obtain the compound of formula I'.

[0506] Alternatively, when B 1 is a boron-based coupling agent such as boronic acid or boronic acid ester, and B 2 is a halide such as Cl, Br, or I, the Suzuki coupling condition can be used to couple compound XI to compound XII. Those skilled in the art will recognize that when B 1 is a halide and B 2When it is a boron-based coupling agent, it will also be recognized that coupling under Suzuki conditions also provides the compound of formula I'. Typical Suzuki coupling conditions involve the use of a palladium catalyst (e.g., Pd(dtbpf)Cl 2 ), a base (e.g., K 3 PO 4 ), and a suitable solvent (e.g., 1,4-dioxane, water, or a mixture thereof). The reactants may be heated to a temperature of about 80 °C for about 1 hour using microwave or conventional heating to obtain the compound of formula I'.

[0507] Alternatively, when B 1 is a boron-based coupling agent such as boronic acid or boronic acid ester, and B 2 is a halide such as Cl, Br, or I, compound XI can be coupled to compound XII using Buchwald coupling conditions.

[0508] When a protecting group is present in the compound of formula XI or formula XII, a final deprotection step is added using conditions well known to those skilled in the art to obtain the compound of formula I'. For example, when the (trimethylsilyl)ethoxymethyl (SEM) group is used to protect a nitrogen atom, it can be removed using a reagent such as TFA in a solvent such as DCM.

[0509]

Chemical Formula

[0510] The compound 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 TFA or TsOH in a solvent such as DMSO or 1,4-dioxane. The reactants may be heated to a temperature of about 115 °C to about 150 °C for about 1.5 to 16 hours to obtain the compound of formula I'.

[0511] Alternatively, Compounds XIII and XIV may be combined with a suitable base such as TEA or DIPEA in a solvent such as DMSO or DMA. The reaction mixture may be heated to a temperature of about 120 °C to about 150 °C for about 1.5 to 3.5 hours to obtain the compound of Formula I'.

[0512]

Chem.

[0513] The compound of Formula I' of the present disclosure can be prepared, for example, as shown in Scheme 3. Substituent B in Compound XV 3 When 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, e.g., Pd 2 (dba) 3 but sometimes other metals), a base (e.g., Cs 2 CO 3 ), and a suitable solvent (e.g., THF). For example, a phosphate ligand such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene may also be included. The reactants may be heated to a temperature of about 120 °C for about 16 hours to obtain the compound of Formula I'.

[0514]

Chem.

[0515] The compound of Formula I' of the present disclosure can be prepared, for example, as shown in Scheme 4. Substituent B in Compound XVI 4is, for example, a halide such as F or Cl. Compounds XVI and XIV may be combined with a suitable base such as DIPEA in a solvent such as DMA or NMP. The reactants may be heated to a temperature of about 80 °C to 150 °C for 1 hour using microwave or conventional heating to obtain the compound of formula I'.

[0516] [Chemical formula]

[0517] The compound of formula I' of the present disclosure in which A is a triazolyl ring can be prepared, for example, as shown in Scheme 5. Substituent B in compound XVIII 5 is, for example, a halide such as Cl, Br, or I. Compounds XVII and XVIII may be combined in a solvent such as DMSO with a copper catalyst (e.g., CuI), a ligand (e.g., (1S,2S)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine), and NaN 3 . An additive such as sodium ascorbate may also be included. The reaction may be allowed to proceed at room temperature for about 16 hours to obtain the compound of formula XIX.

[0518] [Chemical formula]

[0519] The compound of formula I' of the present disclosure can be prepared, for example, as shown in Scheme 6. Substituent B in compound XX 6 is a halide (e.g., Cl, Br, or I), and when substituent B in compound XXI 7 is a stannyl group (e.g., Sn(Me) 3 or Sn(n-Bu) 3 ), this coupling is achieved by a reaction under Stille conditions. Those skilled in the art will also recognize that the coupling under Stille conditions can also be carried out when B in compound XX 6 is a stannyl group and B in compound XXI 7It will be appreciated that when is a halide, compounds of formula I' are provided. Typical Stille coupling conditions involve the use of a catalyst (usually palladium, but sometimes nickel), a suitable solvent, and optionally other reagents such as CuI and TEA. Examples of suitable catalysts include Pd(dppf)Cl 2 、Pd(PPh 3 ) 4 、and Pd(P(Cy) 3 ) 2 Cl 2 , but are not limited thereto. Suitable solvents include, but are not limited to, 1,4-dioxane, toluene, and DMF. Using microwave or conventional heating, the reactants may be heated to a temperature of about 100 °C to about 120 °C for about 1 to 16 hours to obtain the compound of formula I'.

[0520] Alternatively, when B 6 is a boron coupling agent such as a boronic acid or boronic ester, and B 7 is a halide such as Cl, Br, or I, compound XX can be coupled to compound XXI using Suzuki coupling conditions. One skilled in the art will recognize that when B 6 is a halide and B 7 is a boron coupling agent, coupling under Suzuki conditions also provides compounds of formula I'. Typical Suzuki coupling conditions involve the use of a palladium catalyst (e.g., Pd(dtbpf)Cl 2 ), a base (e.g., K 3 PO 4 ), and a suitable solvent (e.g., 1,4-dioxane, water, or a mixture thereof). Using microwave or conventional heating, the reactants may be heated to a temperature of about 80 °C for about 1 hour to obtain the compound of formula I'.

[0521] When a protecting group is present in the compound of formula XX or formula XXI, the final deprotection step is added using conditions well known to those skilled in the art to obtain the compound of formula I'. For example, when a (trimethylsilyl)ethoxymethyl (SEM) group is used to protect the nitrogen atom, it can be removed using a reagent such as TFA in a solvent such as DCM.

[0522] When the compounds are obtained as salts, they can be converted to the corresponding free bases by techniques well known in the art. For example, a compound obtained as a TFA salt can be converted to the corresponding free base by methods such as passing through a carbonate cartridge.

[0523] When obtaining the compounds and the corresponding analytical data described in the following examples, the following experimental and analytical protocols were followed unless otherwise indicated.

[0524] Unless otherwise specified, the reaction solution was stirred at room temperature under an N 2(g) or Ar (g) atmosphere. When the solutions were "concentrated to dryness", they were concentrated under reduced pressure using a rotary evaporator. When drying the solutions, generally, they were dried over a desiccant such as MgSO 4 or Na 2 SO 4 etc. Normal phase flash column chromatography (FCC) was performed on silica gel using a pre-packed silica gel column such as RediSep® with ethyl acetate (EtOAc) / hexane, CH 2 Cl 2 / MeOH, or CH 2 Cl 2 / MeOH with 10% 2N NH 3 as the eluent.

[0525] The compounds described in the examples can also be purified by preparative reverse-phase HPLC. A typical HPLC chromatographic separation is 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 purification is carried out under "acidic condition" or in "acidic media", both acetonitrile and water contain 0.16% TFA. When carried out under "basic condition" or in "basic media", the pH of acetonitrile and water is adjusted to pH 10 with ammonium hydroxide. The abbreviations in the following columns are also used throughout the examples.

[0526]

Table 43

[0527]

Table 44

[0528] Thin-layer chromatography (TLC) was performed using silica gel plates such as Merck silica gel 60F 254 precoated silica gel plates 2.5 cm × 7.5 cm, 250 μm, or 5.0 cm × 10.0 cm, 250 μm. Preparative thin-layer chromatography was performed using silica gel plates such as EM Science silica gel 60 F 254 precoated plates 20 cm × 20 cm 0.5 mm, using a plate with a concentrated zone of 20 cm × 4 cm. The microwave reaction was carried out in a microwave reactor, for example, CEM Discover a, was carried out at a specific temperature in a Biotage Initiator (trademark) or Optimizer (trademark) microwave. Mass spectra were obtained on a mass spectrometer such as an Agilent Series 1100 MSD using electrospray ionization (ESI) in positive mode, unless otherwise indicated. The calculated mass corresponds to the exact mass. NMR spectra were obtained on an NMR spectrometer such as a Bruker model DPX400 (400 MHz), DPX500 (500 MHz), DRX600 (600 MHz). The format of the following 1H NMR data is as follows: chemical shift (ppm) relative to tetramethylsilane (multiplicity, coupling constant J (Hz), integration value).

[0529] Whenever a 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. Reagent concentrations expressed as a percentage refer to mass ratios, unless otherwise specified. Whether or not explicitly stated, the yields given in the following examples are calculated with respect to the dry form of the compound for which any such yield is given.

[0530] Compound names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye).

[0531] Intermediate 1: (R)-3-Ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d 4 。

[0532]

Chemical Structure

[0533] Step A: 1-Methylpyrrolidin-2-one-3,3,4,4,5,5-d 6Into a 1000 mL three-necked round-bottom flask purged and maintained under a nitrogen atmosphere was placed NaH (60% in mineral oil, 52 g, 1302 mmol). THF (400 mL) was added, and then the mixture was cooled to 0 °C. To this was added pyrrolidin-2-one-3,3,4,4,5,5-d 6 (39.5 g, 434 mmol) at 0 °C. The resulting solution was stirred at 0 °C for 20 minutes, and then methyl iodide (184 g, 1302 mmol) was added dropwise at 0 °C. The resulting solution was slowly warmed to room temperature and stirred for 3.5 hours. The resulting solution was poured into ice water (800 mL) and extracted with DCM (15 × 400 mL). The organic extracts were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 1-methylpyrrolidin-2-one-3,3,4,4,5,5-d 6 as a yellow oil (67.6 g). LC-MS (ESI): C 5 H 3 F 6 Calculated mass for C + .

[0534] Step B: 3-benzoyl-1-methylpyrrolidin-2-one-4,4,5,5-d 4 Into a 2000 mL three-necked round-bottom flask purged and maintained under a nitrogen atmosphere were placed NaH (60% in mineral oil, 26 g, 651 mmol), toluene (900 mL), and methanol (1.82 mL). To this was added 1-methylpyrrolidin-2-one-3,3,4,4,5,5-d 6A mixed solution of [[ID=]], (67.6 g, 434 mmol) and methyl benzoate (65 g, 477 mmol) was added dropwise at room temperature. The resulting solution was heated at 110 °C overnight. Thereafter, the reaction mixture was cooled to 0 °C, and HOAc (39 g, 651 mmol) and water (24 g, 1302 mmol) were added. After 10 minutes, water was added, and the reaction mixture was extracted with 3 × 600 mL of DCM. The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified by silica gel chromatography (eluent: PE / EtOAc, 10 / 1 - 3 / 1). Thereby, 70.5 g (Steps A and B, 78%) of 3-benzoyl-1-methylpyrrolidin-2-one-4,4,5,5-d 4 was obtained as a yellow oil. LC-MS (ESI): C 12 H 9 F 4 NO 2 Calculated mass for, 207.1 m / z, found, 208 [M + H] + .

[0535] Step C: 3-benzoyl-3-ethynyl-1-methylpyrrolidin-2-one-4,4,5,5-d 4 . In a 2000 mL four-necked round-bottom flask equipped with a mechanical stirrer and purged and maintained under a nitrogen atmosphere, 3-benzoyl-1-methylpyrrolidin-2-one-4,4,5,5-d 4 (70.5 g, 340 mmol) and THF (dry, 1200 mL) were placed. The resulting mixture was cooled to -78 °C, 1-((trimethylsilyl)ethynyl)-1λ3-benz[d][1,2]iodoxol-3(1H-one (175 g, 510 mmol) was added all at once, and the reaction mixture was stirred at -78 °C for 10 minutes. TBAF (1 M in THF, 510 mL, 510 mmol) was added dropwise at -78 °C. The resulting solution was stirred at -70 °C for 2 hours and then warmed to room temperature over another 2 hours. The resulting mixture was saturated NH 4Quenched with Cl solution and extracted with 3×600 mL of EtOAc. The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified by silica gel chromatography (PE / EtOAc 10 / 1 - 5 / 1) to give 53.8 g (62%) of 3-benzoyl-3-ethynyl-1-methylpyrrolidin-2-one-4,4,5,5-d 4 as a yellow oil. LC-MS (ESI): C 14 H 9 F 4 NO 2 Calculated mass for, 231.1 m / z, Found, 232 [M+H] + .

[0536] Step D: 3-Ethyl-1-methyl-2-oxopyrrolidin-3-yl-4,4,5,5-d benzoate 4 . To a 5000 mL four-necked round-bottom flask equipped with a mechanical stirrer was added 3-benzoyl-3-ethynyl-1-methylpyrrolidin-2-one-4,4,5,5-d 4 (53.8 g, 233 mmol), DCM (3000 mL), KHCO 3 (116 g, 1165 mmol), and m-CPBA (236 g, 1165 mmol). The resulting mixture was stirred at room temperature overnight. Next, the reaction mixture was quenched with saturated NaHCO 3 aqueous solution, stirred for 1 hour, extracted with 2×1000 mL of DCM, the organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified by silica gel chromatography (PE / EtOAc 10 / 1 - 3 / 1) to give 27 g (47%) of 3-ethynyl-1-methyl-2-oxopyrrolidin-3-yl-4,4,5,5-d 4 benzoate as a yellow solid. LC-MS (ESI): C 14 H 9 F 4 NO 3 Calculated mass for, 247.1 m / z, Found, 248 [M+H] + .

[0537] Process E: 3-Ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d 4 To a 1000 mL four-necked round-bottom flask, add 3-ethynyl-1-methyl-2-oxopyrrolidin-3-yl-4,4,5,5-d 4 benzoic acid (27 g, 109 mmol) and THF (270 mL), and cool the mixture to 0 °C. A solution of LiOH-H 2 O (13.8 g, 327 mmol) in H 2 O (270 mL) was added at 0 °C - 10 °C, and the reaction mixture was stirred at room temperature for 5 hours. Next, the mixture was cooled to 0 °C, the pH was adjusted to pH = 7 with 1 M HCl, and the reaction mixture was concentrated under reduced pressure. The product was purified by silica gel chromatography (DCM / MeOH 300 / 1 - 100 / 1) to obtain 15.1 g (87%) of 3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d 4 as a yellow solid. LC-MS (ESI): C 7 H 5 F 4 NO 2 Calculated mass for, 143.1 m / z, found, 144 [M+H] + .

[0538] Process F: (R)-3-Ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d 4 . The (R) and (S) enantiomers of 3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d 4 were separated by SFC (column: CHIRALPAK® IH, 3 * × 25 cm, 5 μm, mobile phase A: CO 2 , mobile phase B: IPA (0.5% of 2 M NH 3 -MeOH), flow rate: 100 mL / min, gradient: 10% B, column temperature: 35 °C, back pressure: 100 bar, 220 nm, RT1: 3.62, RT2: (4.82). The first elution peak was (S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d 4and the second elution peak was (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d 4 It was. Next, (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d 4 was slurried with MTBE (60 mL), the solid was filtered off and recovered. The filter cake was washed with MTBE and the filtrate was concentrated to give 6.46 g (79%) of (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d 4 as a white solid. LC-MS (ESI): C 7 H 5 F 4 NO 2 Mass calculated for, 143.1 m / z, found, 144 [M+H] + .

[0539] Intermediate 2: (R)-3-ethynyl-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one

[0540] [Chemical formula]

[0541] Step A. (3E)-1-methyl-3-[(1-phenylethyl)imino]pyrrolidin-2-one. In a 20 L four-necked round-bottom flask, 1-methylpyrrolidine-2,3-dione (346 g, 3060 mmol), MgSO 4 (368 g, 3060 mmol), and DCM (7 L) were added. To this, (+ / -)-α-methylbenzylamine (389.21 g, 3211.74 mmol) and TFA (0.2 mL) were added. The resulting mixture was stirred at 40 °C overnight under a nitrogen atmosphere. The mixture was cooled to room temperature. The solid was filtered off and washed with DCM (1 × 1 L). The filtrate was collected and concentrated under reduced pressure. The product was slurried with diethyl ether (1.5 L). The solid was recovered by filtration to give (3E)-1-methyl-3-[(1-phenylethyl)imino]pyrrolidin-2-one (540 g) as a purple solid. 11H NMR (300 MHz, DMSO-d 6 ) δ 7.39 - 7.08 (m, 5H), 5.41 (d, J = 7.0 Hz, 1H), 4.88 (t, J = 2.4 Hz, 1H), 4.30 - 4.13 (m, 1H), 3.76 - 3.52 (m, 2H), 2.89 (s, 3H), 1.40 (d, J = 6.8 Hz, 3H).

[0542] Process 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, 2497 mmol), Na 2 SO 4 (511 g, 3600 mmol), and acetonitrile (5.4 L) were added. To this, Select-F (1946 g, 5493 mmol) was added portionwise at 0 °C. The reaction mixture was stirred at room temperature overnight, and then acetonitrile (5.4 L) was added. To the mixture, HCl (4 N, 936 mL) in 1,4-dioxane was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 1 hour. The resulting precipitate was filtered and washed with acetonitrile (1 × 2 L). The filtrate was concentrated in vacuo. This filtration and concentration were repeated two more times. The residue was purified by DAC using C18 column CH 3 CN / H 2 O (0.1% of NH 4 HCO 3 ) = 17 minutes using 1% - 15% to obtain 4,4-difluoro-3,3-dihydroxy-1-methylpyrrolidin-2-one (122 g, 23.9%, Process A and Process B) as an off-white solid. 1 1H NMR (300 MHz, DMSO-d 6 ) δ 7.29 (s, 2H), 3.65 (t, J = 12.0 Hz, 2H), 2.80 (s, 3H).

[0543] Process C. (R)-3-Ethynyl-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one. In a 5 L four-necked round-bottom flask, 4,4-difluoro-3,3-dihydroxy-1-methylpyrrolidin-2-one (122 g, 730 mmol), DMF (2440 mL), K 2 CO 3 (10.09 g, 73.00 mmol), trimethylsilylacetylene (143 g, 1460 mmol), and Cu(OAc) 2 (26.52 g, 146.0 mmol) were added under N 2 atmosphere at room temperature. The resulting mixture was stirred at 50 °C overnight. The mixture was cooled to room temperature and quenched by adding MeOH (500 mL) at room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1 to 1:1) to give (R,S)-3-ethynyl-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one (97 g, 75%) as a yellow solid. The (R) and (S) enantiomers of 3-ethynyl-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one (97 g and 6.2 g from separate syntheses) were separated by Chiral-Prep-SFC (CHIRALPAK® IC-3 (50×4.6 mm), 80% hexane containing 0.1% DEA:20% EtOH) to give the first eluting enantiomer (R)-3-ethynyl-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one (45.6 g, 88%) as an off-white solid. LC-MS (ESI): C 7 H 7 F 2 NO 2 Mass calculated for, 175.0 m / z, found, 176 [M+H] + . 1 1H NMR (300 MHz, DMSO-d 6 ) δ 7.43 (s, 1H), 3.84 - 3.80 (m, 3H), 2.82 (s, 3H).

[0544] Intermediate 3: (3R,5S)-3-ethynyl-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one.

[0545]

Chem.

[0546] Step A. Ethyl 4,4,4-trifluoro-3-(methylamino)butanoate. To a solution of ethyl (E)-4,4,4-trifluorobut-2-enoate (4400 g, 26.17 mol, 3.89 L) in THF (18.0 L) was added MeNH 2 (3330 g, 32.17 mol, purity 30%). The pale yellow solution was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give the product as a yellow liquid (4.64 kg, 89%), which was used in the next step without further purification. 1 1H NMR (400 MHz, chloroform-d) δ 4.08 - 4.26 (m, 2H), 3.40 - 3.56 (m, 1H), 2.61 - 2.68 (m, 1H), 2.51 - 2.55 (m, 3H), 2.41 - 2.50 (m, 1H), 1.22 - 1.29 (m, 3H).

[0547] 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 heated at 60 °C for 3 h under N 2 atmosphere. The reaction mixture was cooled to 25 °C and NH 4Quenched by the addition of Cl (saturated, 10.0 L), the pH of the mixture was adjusted to pH = 2 - 3 with 1 M 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 mL) and dried over anhydrous Na 2 SO 4 and filtered, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (DCM / MeOH 0% - 3%) to give the title compound as a brown oil (4.20 kg, 16.59 mol, 68.8%). 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).

[0548] Step C. 1 - Methyl - 5 - (trifluoromethyl)pyrrolidine - 2,3 - dione. A mixture of ethyl 4 - hydroxy - 1 - methyl - 5 - oxo - 2 - (trifluoromethyl)-2,5 - dihydro - 1H - pyrrole - 3 - carboxylate (2000 g, 7.90 mol) in HCl (10.96 kg, 108.23 mol, 10.75 L, 36% solution) was heated at 110 °C for 16 h. The reaction mixture was cooled to 20 °C and extracted with isopropyl acetate (5000 mL×8). The combined organic extracts were washed with brine (10000 mL) and dried over anhydrous Na 2 SO 4 and filtered, concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (5000 mL) at 25 °C for 3 h. The solid was filtered, washed with MTBE (1000 mL) and dried under high vacuum to give 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).

[0549] Step D. 3-Hydroxy-1-methyl-5-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)pyrrolidin-2-one. To a solution of trimethylsilylacetylene (1.21 kg, 12.3 mol, 1.71 L) in THF (5400 mL) was added n-BuLi (2.5 M, 4.95 L) dropwise at -70 to -60 °C over 30 minutes, and the mixture was stirred at -70 to -60 °C for 1 hour. To this mixture was added dropwise 1-methyl-5-(trifluoromethyl)pyrrolidine-2,3-dione (1120 g, 6.18 mol) in THF (9000 mL) at -70 to -60 °C over 30 minutes. The black solution was stirred at -70 to -60 °C for 2 hours. The reaction mixture was added dropwise to NH 4 Cl (saturated aqueous solution, 10000 mL), adjusted to pH = 5 with 2 M HCl (5000 mL), and the aqueous solution was extracted with EtOAc (5000 mL × 3). The combined organic extracts were washed with 5000 mL of brine, dried over anhydrous Na 2 SO 4 and evaporated to dryness. The title compound was obtained as a red solid (1.50 kg, 86%) and used without further purification. 1 1H NMR (400 MHz, chloroform-d) δ 4.08 - 4.16 (m, 1H), 2.96 - 3.06 (m, 3H), 2.72 - 2.82 (m, 1H), 2.22 - 2.35 (m, 1H), 0.08 - 0.21 (m, 8H).

[0550] Step E. (3R,5S)-3-Ethynyl-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one. 3-Hydroxy-1-methyl-5-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)pyrrolidin-2-one (1500 g, 5.37 mol) was dissolved in MeOH (10.0 L), and then K 2 CO 3 (742 g, 5.37 mol) was added. The black mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered, and the filter cake was washed with CH 2 Cl 2 (4000 mL) and poured into water (3000 mL). The organic phase was separated, and the aqueous phase was extracted with CH 2 Cl 2Extracted with (3000 mL × 2), and the combined organic extracts were washed with water (2000 mL) and brine (2000 mL), dried over anhydrous Na 2 SO 4 , concentrated to dryness under reduced pressure to obtain a mixture of (3R,5S)-3-ethynyl-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one and (3S,5R)-3-ethynyl-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one. This mixture was purified by column chromatography (PE:EA = 10:1 to 3:1) (635 g, 55%, purity 97.8%). Next, (3R,5S)-3-ethynyl-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one and (3S,5R)-3-ethynyl-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one were purified by SFC (column: DAICEL CHIRALPAK® AD (250 mm × 50 mm, 10 μm), mobile phase: [0.1% NH 3. H 2 O] in EtOH, B%: 20% to 20%, fraction) to obtain the (3R,5S)-3-ethynyl-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one of the first elution peak, the title compound, as a yellow solid (95.0 g, 45.7%). 1 1H NMR (400 MHz, chloroform-d) δ 3.97 - 4.08 (m, 1H), 3.03 (d, J = 1.0 Hz, 3H), 2.80 (dd, J = 13.6, 7.5 Hz, 1H), 2.62 (s, 1H), 2.33 (dd, J = 13.7, 7.2 Hz, 1H), 1.23 - 1.28 (m, 1H).

[0551] Intermediate 4: (Z)-6-bromo-N-hydroxypicolimidoyl chloride

[0552]

Chemical Structure

[0553] Project A. (E)-6-Bromopicolinamide Oxime. In a 1 L three-necked round-bottom flask, 6-bromopyridine-2-carbaldehyde (40.0 g, 215 mmol), EtOH (600 mL), and NH 2 OH·HCl (17.93 g, 258.1 mmol) were added at room temperature. To the above mixture, sodium acetate (35.28 g, 430.1 mmol) was added portionwise at 0 °C. The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The mixture was acidified to pH = 7 with saturated NaHCO 3 (100 mL). The resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic extracts were washed with brine (1 × 150 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by trituration with hexane (80 mL). The precipitated solid was collected by filtration and washed with hexane to obtain the title compound as a white solid (39 g, 90%).

[0554] Project B. (Z)-6-Bromo-N-hydroxypicolinimidoyl Chloride. In a 2 L four-necked round-bottom flask, (E)-N-[(6-bromopyridin-2-yl)methylidene]hydroxylamine (39.0 g, 194 mmol) and DMF (1 L) were added at room temperature. To the above mixture, NCS (31.09 g, 232.8 mmol) was added at room temperature. The resulting solution was stirred overnight at room temperature. Next, the pH of the mixture was adjusted to pH = 7 with TFA (5 L, 1 M). The resulting mixture was extracted with MTBE (2 × 1 L). The combined organic extracts were washed with brine (1 × 1 L) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by trituration with hexane (80 mL). The precipitated solid was collected by filtration and washed with hexane to obtain the title compound as a white solid (41.3 g, 90.2%). LC-MS (ESI): C 6 H 4 BrClN 2 O, calculated mass, 233.9 m / z, found, 235 [M + H] + .1 1H NMR (300 MHz, DMSO-d 6 ) δ 12.89 (s, 1H), 7.91 (d, J = 7.7, 1.2 Hz, 1H), 7.85 (t, J = 7.6 Hz, 1H), 7.76 (d, J = 7.6, 1.2 Hz, 1H).

[0555] Intermediate 5: (Z)-6-chloro-N-hydroxy-4-(trifluoromethyl)picolinimidoyl chloride.

[0556]

Chemical Structure

[0557] Step A. (E)-6-chloro-4-(trifluoromethyl)picoline aldoxime. To a 50 mL round-bottom flask charged with absolute ethanol (7.9 mL), hydroxylamine hydrochloride (182 mg, 2.63 mmol), sodium acetate (391 mg, 4.80 mmol), and 6-chloro-4-(trifluoromethyl)picoline aldehyde (500 mg, 2.4 mmol) were added. The resulting mixture was stirred under nitrogen at room temperature for 12 h. Water (50 mL) and then EtOAc (50 mL) were added. Each layer was separated and the aqueous layer was further extracted with EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the title compound as a white foam (600 mg). LC-MS (ESI): C 7 H 4 ClF 3 N 2 Calculated mass for, 224.0 m / z, found, 225.0 [M + H] + .

[0558] Step B. (Z)-6-chloro-N-hydroxy-4-(trifluoromethyl)picolinimidoyl chloride chloride. To a 50 mL round bottom flask was added DMF (anhydrous, 11 mL), followed by (E)-6-chloro-4-(trifluoromethyl)picolinaldehyde oxime (500 mg, 2.2 mmol), and NCS (387 mg, 2.90 mmol). The resulting solution was stirred at room temperature for 12 h, after which the solution was partitioned between EtOAc (30 mL) and water (30 mL). The aqueous portion was further extracted with EtOAc, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give a yellow foam. The residue was subjected to flash column chromatography using an eluent of 0% to 100% EtOAc in hexane to give the title compound as a yellow solid. LC-MS (ESI): C 7 H 3 Cl 2 F 3 N 2 Calculated mass for O, 258.0 m / z; observed mass, 258.9 [M+H] + .

[0559] Intermediate 6: (R)-3-hydroxy-1-methyl-3-(3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one.

[0560] [ka]

[0561] Step A. (R)-3-(3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. In a 25 mL round-bottom flask, add EtOAc (11.2 mL), water (1.1 mL), NaHCO 3(564 mg, 6.7 mmol), (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (623 mg, 4.5 mmol), and (Z)-6-chloro-N-hydroxy-4-(trifluoromethyl)picolinimidoyl chloride (580 mg, 2.2 mmol) were added. The resulting mixture was stirred at room temperature for 12 h. Next, the solution was partitioned between additional EtOAc (10 mL) and water (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give a yellow residue. This residue was subjected to flash column chromatography eluting with a gradient of 0% - 10% MeOH in DCM to afford the title compound as a yellow solid (700 mg, 86%). LC-MS (ESI): C 14 H 11 ClF 3 N 3 O 3 Calculated mass for, 361.0 m / z, Found, 362.0 [M+H] + 。

[0562] Project B. (R)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one. A large microwave vial filled with DMF (9 mL, anhydrous) was sparged with nitrogen for 15 minutes before adding 2-(methylthio)-4-(tributylstannyl)pyrimidine (791 mg, 1.9 mmol), tetrakis(triphenylphosphine)-palladium(0) (200 mg, 0.173 mmol), and (R)-3-(3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (627 mg, 1.7 mmol). The vial was sealed and subjected to microwave irradiation at 140 °C for 90 minutes. Thereafter, the resulting black solution was partitioned between EtOAc and water. The organic solution was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a dark brown residue. This residue was subjected to flash column chromatography using 0% - 10% MeOH in DCM as the eluent to obtain the title compound as an orange foam (470 mg, 60%). LC-MS (ESI): C 19 H 16 F 3 N 5 O 3 Calculated mass for S, 451.1 m / z, found, 452.2 [M+H] + 。

[0563] Process C. (R)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one. (R)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one (470 mg, 1.0 mmol) was dissolved in acetone (2.2 mL), water (2.2 mL), THF (2.2 mL), and MeOH (2.2 mL). To this mixture, potassium peroxymonosulfate (1.92 g, 3.10 mmol) was added, and the resulting mixture was stirred at room temperature for 12 hours. Ice water (20 mL) was added to this mixture. After 10 minutes, the solid was removed by filtration, washed with additional water (100 mL), and dried in vacuo for several hours to obtain the title compound as a white solid (300 mg, 60%). 1 1H NMR (600 MHz, DMSO-d 6 ) δ 9.34 (d, J = 5.1 Hz, 1H), 8.88 (d, J = 5.1 Hz, 1H), 8.79 (d, J = 1.4 Hz, 1H), 8.50 (d, J = 1.4 Hz, 1H), 7.39 (s, 1H), 6.84 (s, 1H), 3.58 (s, 3H), 3.54 - 3.42 (m, 2H), 2.87 (s, 3H), 2.64 (ddd, J = 13.0, 7.7, 5.0 Hz, 1H), 2.33 (ddd, J = 13.5, 8.0, 5.5 Hz, 1H).

[0564] Intermediate 7: (R)-4,4-Difluoro-3-hydroxy-1-methyl-3-(3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one.

[0565]

Chemical Structure

[0566] Project A. (R)-3-(3-(6-Bromopyridin-2-yl)isoxazol-5-yl)-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one. In a 25 mL round-bottom flask, EtOAc (7.3 mL), water (0.73 mL), NaHCO 3 (642 mg, 6.6 mmol), (R)-3-ethynyl-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 2, 535 mg, 3.1 mmol), and (Z)-6-bromo-N-hydroxypicolimidoyl chloride (Intermediate 4, 600 mg, 2.6 mmol) were obtained. This mixture was stirred at room temperature for 12 hours, and then the solution was partitioned between EtOAc (10 mL) and water (10 mL). The organic portion was extracted, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a yellow residue, which was subjected to flash column chromatography using 0% - 10% MeOH in DCM as the eluent to obtain the title compound as a yellow solid. LC-MS (ESI): C 13 H 10 BrF 2 N 3 O 3 Calculated mass for, 373.0 m / z, Found, 374.0 [M+H] + .

[0567] Process B. (R)-4,4-Difluoro-3-hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one. A large microwave vial charged with DMF (7.5 mL, anhydrous) was sparged with nitrogen for 15 minutes prior to the addition of 2-(methylthio)-4-(tributylstannyl)pyrimidine (683 mg, 1.6 mmol), tetrakis(triphenylphosphine)palladium(0) (173 mg, 0.15 mmol), and (R)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one (560 mg, 1.5 mmol). The vial was sealed and subjected to microwave irradiation at 140 °C for 90 minutes. Thereafter, the resulting black solution was partitioned between EtOAc and water, and the aqueous portion was extracted with EtOAc. The organic portion was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to afford a dark brown residue. This residue was purified by flash column chromatography (0% - 10% MeOH in DCM) to afford the title compound as an orange foam (650 mg). LC-MS (ESI): C 18 H 15 F 2 N 5 O 3 Mass calculated for S, 419.1 m / z, found, 420.2 [M+H] + 。

[0568] Process C. (R)-4,4-Difluoro-3-hydroxy-1-methyl-3-(3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one. (R)-4,4-Difluoro-3-hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one (650 mg, 1.6 mmol) was dissolved in acetone (3.3 mL), water (3.3 mL), THF (3.3 mL), and MeOH (3.3 mL). Potassium peroxymonosulfate (2.86 g, 4.70 mmol) was added and the resulting mixture was stirred at room temperature for 12 h. Next, ice water (20 mL) was added to the flask. After 10 min, the solid was filtered off, washed with additional water (100 mL), and dried in vacuo for several hours to give the title compound as a white solid (540 mg, 77%). 1 H NMR(600MHz,DMSO-d 6 )δ 9.27(d,J=5.2Hz,1H),8.86(d,J=5.2Hz,1H),8.71-8.64(m,1H),8.32-8.25(m,2H),7.99(s,1H),7.43(s,1H),4.03(t,J=12.2Hz,2H),3.55(s,3H),2.98(s,3H).

[0569] Intermediate 8: (3R,5S)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)-5-(trifluoromethyl)pyrrolidin-2-one.

[0570]

Chemical Structure

[0571] Process A. (3R,5S)-3-(3-(6-Bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one. In a 25 mL round-bottom flask, EtOAc (4.2 mL), water (0.42 mL), NaHCO3 (214 mg, 2.5 mmol), (3R,5S)-3-ethynyl-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one (211 mg, 1.0 mmol, Intermediate 3), and (Z)-6-bromo-N-hydroxypicolimidoyl chloride (Intermediate 4, 200 mg, 0.85 mmol) were added. The mixture was stirred at room temperature for 12 h. The solution was then partitioned between EtOAc (10 mL) and water (10 mL). The organic portion was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to afford a yellow residue. This residue was purified by flash column chromatography (0% - 10% MeOH in DCM as eluent) to give the title compound as a yellow solid (360 mg). LC-MS (ESI): C 14 H 11 BrF 3 N 3 O 3 Calculated mass for, 405.0 m / z, Found, 406.0 [M + H] + .

[0572] Process B. (3R,5S)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)-5-(trifluoromethyl)pyrrolidin-2-one. Before adding 2-(methylthio)-4-(tributylstannyl)pyrimidine (1.2 g, 4.6 mmol), tetrakis(triphenylphosphine)palladium(0) (484 mg, 0.42 mmol), and (3R,5S)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one (1.7 g, 1.5 mmol), a 50 mL round-bottom flask was charged with DMF (21 mL, anhydrous) and sparged with nitrogen for 15 minutes. Next, the vial was sealed and subjected to microwave irradiation at 140 °C for 90 minutes. Thereafter, the resulting black solution was partitioned between EtOAc and water, and the aqueous portion was extracted with EtOAc. The organic portion was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a dark brown residue. This residue was subjected to flash column chromatography (with 0% - 10% MeOH in DCM as the eluent) to obtain the title compound as an orange foam (1.8 g).

[0573] Process C. (3R,5S)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)-5-(trifluoromethyl)pyrrolidin-2-one. (3R,5S)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)-5-(trifluoromethyl)pyrrolidin-2-one (1.8 g, 4.1 mmol) was placed in a 100 mL flask and dissolved in acetone (10.2 mL), water (10.2 mL), THF (10.2 mL), and MeOH (10.2 mL). Potassium peroxymonosulfate (7.5 g, 12.3 mmol) was added to this mixture, and the resulting clear mixture was stirred at room temperature for 12 h. Ice water (100 mL) was added to the white reaction mixture. After 10 min, the solid was filtered, washed with additional water (100 mL), and dried under reduced pressure to obtain the title compound as a white solid, which was used without further purification (2.8 g). 1 H NMR(600MHz,DMSO-d 6 )δ 9.29(d,J=5.1Hz,1H),8.81(d,J=5.1Hz,1H),8.69-8.61(m,1H),8.28-8.27(m,1H),7.36(s,1H),7.15(s,1H),4.70-4.57(m,1H),3.56(s,3H),3.07(dd,J=14.6,8.8Hz,1H),2.96(s,3H),2.35(dd,J=14.7,4.4Hz,1H). LC-MS(ESI):C 19 H 16 F 3 N 5 O 5 Calculated for mass of C + .

[0574] Intermediate 9: (R)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one-4,4,5,5-d 4 .

[0575] [Chemical]

[0576] Process A. (R)-3-(3-(6-Bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d 4 . Using conditions similar to those described in Process A of Intermediate 8, instead of (3R,5S)-3-ethynyl-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one, (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d 4 (Intermediate 6) was used to prepare the title compound (1.49 g, 102%). LC-MS (ESI): C 13 H 8 D 4 BrN 3 O 3 Calculated mass for, 341.0 m / z, Found, 342.1 [M+H] + .

[0577] Process B. (R)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one-4,4,5,5-d 4 . Under conditions similar to those described in Process B of Intermediate 8, instead of (3R,5S)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one, (R)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d 4 was used to prepare the title compound (1.6 g, 100%). LC-MS (ESI): C 18 H 13 D 4 N 5 O 3 Calculated mass for S, 341.0 m / z, Found, 342.1 [M+H] + .

[0578] Step C. (R)-3-hydroxy-1-methyl-3-(3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one-4,4,5,5-d 4 Under conditions similar to those described in step C of intermediate 8, (R)-3-hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one-4,4,5,5-d was used instead of (3R,5S)-3-hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)-5-(trifluoromethyl)pyrrolidin-2-one. 4 The title compound (1.9 g) was prepared using LC-MS (ESI): 18 H 13 D 4 N 5 O 5 Calculated mass for S, 419.6 m / z; observed mass, 420.3 [M+H] + .

[0579] Intermediate 10: N-(1-Methyl-1H-pyrazol-3-yl)-4-(trimethylstannyl)pyrimidin-2-amine.

[0580] [ka]

[0581] 4-Chloro-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine (7.50 g, 35.8 mmol, step B of Example 25), tetrakis(triphenylphosphine)palladium(0) (4.13 g, 3.58 mmol), hexamethylditin (17.2 g, 52.5 mmol), and a mixture of 1,4-dioxane (250 mL) were 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. Next, the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure to obtain 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. LC-MS (ESI): C 11 H 17 N 5 Mass calculated for Sn, 339.1 m / z, found, 339.5 [M +] + 。

[0582] Intermediate 11: (R)-3-Hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one.

[0583]

Chemical formula

[0584] Step A: 3-Bromobenzaldoxime. To a solution of 3-bromobenzaldehyde (3.0 g, 16 mmol) in EtOH (40 mL) was added NH 2 OH (50% in water, 1.1 mL, 19 mmol). The reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was then concentrated under reduced pressure to obtain 3-bromobenzaldoxime (3.2 g, 98%) as a white solid. MS (ESI): C 7 H 6Mass calculated for BrNO, 199.0, m / z, found, 200.1 [M+H] + 。

[0585] Step B: 3-Bromo-N-hydroxybenzimidoyl chloride. To a solution of 3-bromobenzaldoxime (3.20 g, 16.0 mmol) in anhydrous DCM (20 mL) was added N-chlorosuccinimide (2.56 g, 19.2 mmol) portionwise. The reaction mixture was stirred at 25 °C for 2 h and filtered. The filtrate was concentrated to give 3-bromo-N-hydroxybenzimidoyl chloride (3.0 g, 95%) as a yellow solid. MS (ESI): C 7 H 5 Mass calculated for BrClNO, 234.5, m / z, found, 235.2 [M+H] + 。

[0586] Step C: (R)-3-(3-(3-Bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of 3-bromo-N-hydroxybenzimidoyl chloride (1.50 g, 3.20 mmol) in DCM (20 mL) was added (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (4.45 g, 3.20 mmol), followed by TEA (1.24 mL, 9.60 mmol). The reaction mixture was stirred at 25 °C for 16 h, diluted with DCM (30 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1 / 1) to give (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one as a yellow oil (0.6 g, 55%). MS (ESI): C 14 H 13 BrN 2 O 3 Mass calculated for, 336.0, m / z, found, 337.1 [M+H] + 。

[0587] Project D: (R)-3-Hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. A flask containing (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (0.60 g, 1.8 mmol) in 1,4-dioxane (10 mL) was charged with bis(pinacolato)diboron (0.90 g, 3.56 mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (130 mg, 0.180 mmol) and KOAc (540 mg, 5.34 mmol). The reaction mixture was heated at 85 °C for 16 h under an Ar atmosphere. The mixture was concentrated and the residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to give (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (0.62 g, 77%) as a brown solid. MS (ESI): C 20 H 25 BN 2 O 5 Calculated mass for, 384.2, m / z, Found, 385.2 [M+H] + .

[0588] Intermediate 12. (R)-3-(3-(3-(2-Chloropyrimidin-4-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one

[0589] [Chemical Structure]

[0590] In a 100 mL round-bottom flask, N 2Next, (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 11, 1.5 g, 3.9 mmol), 4-bromo-2-chloropyrimidine (906 mg, 4.69 mmol), K 2 CO 3 (9.76 mL, 1 M, 9.76 mmol), PdCl 2 (dppf) (143 mg, 0.195 mmol), and 1,4-dioxane (30 mL) were added. The reaction mixture was heated at 50 °C for 1 hour. After cooling the reaction mixture to room temperature, the reaction mixture was extracted with ethyl acetate from brine (saturated aqueous NaCl solution) (100 mL) (3 × 100 mL). The organic extract was dried over anhydrous MgSO 4 and filtered, and concentrated to dryness under reduced pressure. The product was purified by chromatography using 0 - 100% ethyl acetate in hexane as the eluent to obtain (R)-3-(3-(3-(2-chloropyrimidin-4-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (1.522 g). LCMS (ESI): C 18 H 15 ClN 4 O 3 Calculated mass for, 370.8, m / z, Found, 372 [M + H] + . 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.89 (d, J = 5.1 Hz, 1H), 8.64 (s, 1H), 8.39 - 8.23 (m, 2H), 8.12 (d, J = 7.7 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.20 (s, 1H), 6.77 (s, 1H), 3.54 - 3.48 (m, 1H), 3.48 - 3.43 (m, 1H), 2.87 (s, 3H), 2.67 - 2.54 (m, 1H), 2.37 - 2.24 (m, 1H).

[0591] Intermediate 13. (R)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one

[0592] [Chemical Structure]

[0593] Step A. (R)-3-(3-(6-Bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (90.0 g, 646.78 mmol) and (Z)-6-bromo-N-hydroxypicolinimidoyl chloride (Intermediate 4, 609 g, 2.59 mol) in EtOAc (900 mL) and H 2 O (450 mL), NaHCO 3 (326 g, 3.88 mol in 150 mL of H 2 O) was added. The mixture was stirred at 25 °C for 24 h, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The product was triturated with EtOH (4000 mL) at 25 °C for 12 h. The above procedure was repeated 4 times. The resulting product was triturated with petroleum ether:ethyl acetate = 1:1 (2000 mL) at 25 °C for 12 h and repeated 2 times to give the title compound as a white solid (490 g, 50.4%). LC-MS (ESI): C 13 H 12 BrN 3 O 3 Calculated mass for, 337.01, m / z, Found, 340.0 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6)δ 8.04 (d, J = 7.5 Hz, 1H), 7.92 (t, J = 7.8 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 6.94 (s, 1H), 6.77 (s, 1H), 3.52 - 3.38 (m, 2H), 2.83 (s, 3H), 2.59 (ddd, J = 4.9, 7.8, 13.2 Hz, 1H), 2.27 (ddd, J = 5.8, 7.9, 13.5 Hz, 1H).

[0594] Step B. (R)-3-Hydroxy-1-methyl-3-(3-(6-(tributylstannyl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one. A mixture of (R)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (270 g, 798 mmol), (SnBu 3 ) 2 , (926 g, 1.60 mol, 798 mL), LiCl (169 g, 3.99 mol), tricyclohexylphosphine (22.3 g, 79.8 mmol, 25.8 mL) and Pd(PPh 3 ) 2 Cl 2 , (28.0 g, 39.9 mmol) in 1,4-dioxane (2200 mL) was degassed and purged with N 2 three times, then the mixture was heated at 110 °C for 12 h under a N 2 atmosphere. The residue was diluted with H 2 O (500 mL) and extracted with EtOAc (3000 mL, 1000 mL × 3). The combined organic layers were washed with brine (800 mL × 1), dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent with a gradient of 0 - 50% ethyl acetate / petroleum ether) to give the title compound as a yellow oil (320 g, 49.1%). 11H NMR (400 MHz, chloroform-d) δ 7.85 (dd, J = 0.9, 7.9 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.42 (dd, J = 0.9, 7.4 Hz, 1H), 7.00 (s, 1H), 3.79 - 3.71 (m, 1H), 3.70 - 3.59 (m, 1H), 3.46 (dt, J = 2.1, 9.5 Hz, 1H), 2.99 (s, 3H), 2.77 (ddd, J = 2.0, 7.0, 13.3 Hz, 1H), 2.48 (td, J = 8.7, 13.2 Hz, 1H), 1.70 - 1.50 (m, 7H), 1.35 (qd, J = 7.3, 14.7 Hz, 7H), 1.23 - 1.05 (m, 6H), 0.90 (t, J = 7.3 Hz, 9H).

[0595] Step C. (R)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one. A mixture of (R)-3-hydroxy-1-methyl-3-(3-(6-(tributylstannyl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one (320 g, 583 mmol), 4-iodo-2-(methylthio)pyrimidine (161 g, 641 mmol), and Pd(PPh 3 ) 4 (23.6 g, 20.4 mmol) in DMF (3200 mL) was degassed and purged three times with N 2 and then heated at 130 °C for 12 h under a N 2 atmosphere. The reaction mixture was cooled to 25 °C, then concentrated under reduced pressure to remove DMF and diluted with EtOAc (2000 mL). Next, KF (67.81 g, 1.17 mol, 27.34 mL) in H 2 O (1500 mL) was added to the mixture and stirred at 25 °C for 0.5 h. The mixture was filtered and the filtrate was extracted with EtOAc (1500 mL × 3). The combined organic layers were washed with brine (800 mL × 1) and anhydrous Na 2 SO 4It was dried, filtered, and concentrated under reduced pressure to obtain a residue. The product was triturated with ethyl acetate: petroleum ether (1:2, 1200 mL) at 25 °C for 30 minutes to obtain the title compound as a white solid (180 g, 53%). 1 H NMR(400MHz,DMSO-d 6 )δ 8.83(d,J=5.1Hz,1H),8.59-8.46(m,1H),8.28-8.08(m,3H),7.20(s,1H),6.78(s,1H),3.58-3.39(m,2H),2.85(s,3H),2.63(s,4H),2.30(ddd,J=5.7,7.8,13.4Hz,1H).LC-MS(ESI):C 18 H 17 N 5 O 3 Calculated for C, H, N, O, S, 383.1, m / z, Found, 384.0 [M+H] + .

[0596] Step D. (R)-3-Hydroxy-1-methyl-3-(3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one. To a solution of (R)-3-hydroxy-1-methyl-3-(3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)pyrrolidin-2-one (130 g, 339 mmol) in THF (260 mL), acetone (260 mL), H 2 O (260 mL), and MeOH (260 mL) was added potassium peroxymonosulfate (416 g, 678 mmol). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with ice-cooled H 2 O (3000 mL). The resulting precipitate was collected by filtration and concentrated under reduced pressure to obtain a residue. This residue was triturated with H 2 O (2000 mL) at 25 °C for 1.0 hour. This trituration was repeated twice. The resulting residue was further triturated with MeOH (700 mL) at 25 °C for 0.5 hour to obtain the title compound as a white solid (190 g, 87.9%). 1 H NMR(400MHz,DMSO-d 6)δ 9.27 (d, J = 5.1 Hz, 1H), 8.81 (d, J = 5.3 Hz, 1H), 8.68 - 8.60 (m, 1H), 8.26 (d, J = 4.5 Hz, 2H), 7.27 (s, 1H), 6.79 (s, 1H), 3.55 (s, 3H), 3.53 - 3.42 (m, 2H), 2.85 (s, 3H), 2.62 (ddd, J = 5.1, 7.7, 13.2 Hz, 1H), 2.31 (ddd, J = 5.8, 7.8, 13.4 Hz, 1H). LC-MS (ESI): C 18 H 17 N 5 O 5 Calculated mass for S, 415.1, m / z, found, 416.0 [M + H] + 。

[0597] Intermediate 14. 3 - Cyclopropoxy - 1 - (2,2 - difluoroethyl) - 1H - pyrazol - 4 - amine

[0598]

Chemical Structure

[0599] Step A. 1,4 - Dinitro - 1H - pyrazole. KNO 3 (0.89 g, 8.84 mmol), 4 - nitro - 1H - pyrazole (1.00 g, 8.84 mmol), and anhydrous CH 2 Cl 2 (5 mL) were added to a 50 mL round - bottom flask. The mixture was cooled to 15 °C and treated with a solution of trifluoroacetic anhydride (2.46 mL, 17.7 mmol) and CH 2 Cl 2 (5 mL), and stirred at room temperature for 5 h under N 2 2. After that, the pale - yellow mixture was poured into ice - water (20 mL) and extracted with ethyl acetate (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. The pale yellow oil was purified by silica gel chromatography (0 - 20% EtOAc / petroleum ether) to obtain 1,4-dinitro-1H-pyrazole as a yellow oil (1.2 g, 86%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.97 (d, J = 0.8 Hz, 1H), 8.15 - 8.09 (m, 1H).

[0600] 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-necked round-bottom flask containing cyclopropanol (1.96 g, 33.7 mmol) and 2-MeTHF (15 mL) at 0 °C. The reaction mixture was stirred at room temperature for 10 minutes, then added dropwise at -78 °C to another solution consisting of 1,4-dinitro-1H-pyrazole (8.00 g, 50.6 mmol) and 2-MeTHF (15 mL). The resulting mixture was stirred at -78 °C for 1 hour, then warmed to room temperature and stirred for 5 hours. Thereafter, the gray mixture was poured into water, treated with aqueous HCl solution (10 mL, 3.0 N), and extracted with CH 2 Cl 2 (20 mL × 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 and filtered, and concentrated to dryness in vacuo to obtain a yellow oil. This oil was purified by silica gel chromatography (0 - 30% EtOAc / petroleum ether) to obtain 3-cyclopropoxy-4-nitro-1H-pyrazole as a yellow oil (1.1 g, 19%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.30 - 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).

[0601] Process 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 to a 100 mL three-necked round-bottom flask containing a solution of 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), N 2 was added below. The red mixture was heated at 60 °C for 12 h. The reaction vessel was removed from the oil bath and cooled gradually to room temperature. The mixture was concentrated to dryness in vacuo to afford a red oil. The red oil was purified by silica gel chromatography (20 - 50% EtOAc / petroleum ether) to give 3-cyclopropoxy-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole as a red solid (500 mg, 52%). 1 1H NMR (400 MHz, CDCl 3 ) δ 8.10 (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).

[0602] Process D. 3-Cyclopropoxy-1-(2,2-difluoroethyl)pyrazol-4-amine. To a 250 mL three-necked round-bottom flask were added at room temperature 3-cyclopropoxy-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole (9 g, 38.59 mmol), EtOH (129 mL), H 2 2O (26 mL), Fe (10.78 g, 192.99 mmol), and NH 4 4Cl (8.26 g, 154.39 mmol). The resulting mixture was heated at 70 °C for 3 h. The resulting mixture was filtered and the filter cake was washed with MeOH (1 × 250 mL). The filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (100 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with water (3 × 500 mL) and brine (3 × 500 mL), and anhydrous Na 2 2SO 4It was dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (1:1)) to obtain 3-cyclopropoxy-1-(2,2-difluoroethyl)pyrazol-4-amine as a brown oil (3.124 g, 40%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 6.99 (s, 1H), 6.18 (tt, J = 55.4, 4.0 Hz, 1H), 4.27 (td, J = 14.8, 4.0 Hz, 2H), 4.00 (tt, J = 6.0, 3.3 Hz, 1H), 3.47 (s, 2H), 0.64 (dddd, J = 9.6, 5.7, 2.3, 1.2 Hz, 4H). 19 F NMR (282 MHz, DMSO-d 6 , ppm) δ -122.30. LC-MS (ESI): C 8 H 11 F 2 N 3 O calculated mass value, 203.1, m / z, measured value, 204.0 [M+H] + .

[0603] Intermediate 15. 2-(4-Amino-3-methoxypyrazol-1-yl)ethanol

[0604]

Chemical Structure

[0605] Process A. 1-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}-3-methoxy-4-nitropyrazole. To a stirred solution of 3-methoxy-4-nitro-1H-pyrazole (10.00 g, 69.88 mmol), 2-[(tert-butyldimethylsilyl)oxy]ethanol (30.81 g, 174.7 mmol), and triphenylphosphine (45.82 g, 174.7 mmol) in tetrahydrofuran (100 mL) was added DIAD (22.87 g, 174.7 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C overnight under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic extracts were washed with brine (2 × 100 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give 1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-methoxy-4-nitropyrazole as a pale yellow oil (11 g, 52%).

[0606] Process B. 1-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}-3-methoxypyrazol-4-amine. To a solution of 1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-methoxy-4-nitropyrazole (11 g, 36.49 mmol) in EtOH (250 mL) was added Pd / C (10%, 7.77 g) in a 500 mL round-bottom flask under a nitrogen atmosphere. The mixture was stirred overnight under a hydrogen atmosphere using a hydrogen balloon, filtered through a pad of diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give 1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-methoxypyrazol-4-amine as a brown oil (8.7 g, 87.83%). LCMS (ESI): C 12 H 25 N 3 O 2Mass calculated value for Si, 271.2, m / z, measured value, 272 [M+H] + 。

[0607] Step C. 2-(4-Amino-3-methoxypyrazol-1-yl)ethanol. A solution of 1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-methoxypyrazol-4-amine (8.7 g, 32.05 mmol) and TBAF (10.06 g, 38.46 mmol) in tetrahydrofuran (87 mL) was stirred at room temperature for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give 2-(4-amino-3-methoxypyrazol-1-yl)ethanol as an off-white solid (2.258 g, 44.86%). LCMS (ESI): C 6 H 11 N 3 O 2 Mass calculated value for 157.1, m / z, measured value, 158 [M+H] + 。 1 H NMR (300 MHz, DMSO-d 6 ) δ 6.94 (s, 1H), 4.74 (t, J = 5.4 Hz, 1H), 3.80 (t, J = 5.8 Hz, 2H), 3.75 (s, 3H), 3.60 (q, J = 5.6 Hz, 2H), 3.31 (br, 2H).

[0608] Intermediate 16. 3-Methoxy-1-(1-methylpiperidin-4-yl)pyrazol-4-amine

[0609]

Chemical Structure

[0610] Project A. 4-(3-Methoxy-4-nitropyrazol-1-yl)-1-methylpiperidine. To a stirred solution of 3-methoxy-4-nitro-1H-pyrazole (5 g, 34.9 mmol), triphenylphosphine (13.75 g, 52.41 mmol), and 1-methyl-4-piperidinol (6.04 g, 52.4 mmol) in tetrahydrofuran (50 mL) was added DIAD (10.60 g, 52.42 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. The reaction was quenched by adding water / ice (100 L) at room temperature. The resulting mixture was extracted with CH 2 Cl 2 (3 × 100 mL). The combined organic extracts were washed with brine (1 × 100 L) and water (1 × 100 L), and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH 2 Cl 2 / MeOH (10:1) to give 4-(3-methoxy-4-nitropyrazol-1-yl)-1-methylpiperidine as a pale yellow solid (3.2 g, 38.12%). LCMS (ESI): C 10 H 16 N 4 O 3 calculated mass, 240.1, m / z, found, 241 [M+H] + .

[0611] Project B. 3-Methoxy-1-(1-methylpiperidin-4-yl)pyrazol-4-amine. To a solution of 4-(3-methoxy-4-nitropyrazol-1-yl)-1-methylpiperidine (3.2 g, 13.31 mmol) in EtOH (40 mL) was added Pd / C (10%, 0.5 g) in a 250 mL round-bottom flask under a nitrogen atmosphere. The mixture was stirred under a hydrogen atmosphere using a hydrogen balloon for 4 hours, filtered through a pad of diatomaceous earth, and the filtrate was concentrated under reduced pressure. Thereby, 3-methoxy-1-(1-methylpiperidin-4-yl)pyrazol-4-amine was obtained as a brown oil (2.25 g, 78%). LCMS (ESI): C10 H 18 N 4 Mass calculated value for O, 210.2, m / z, measured value, 210 [M] + 。 1 H NMR (300 MHz, DMSO-d 6 ) δ 6.97 (s, 1H), 3.75 (s, 3H), 3.69 (dt, J = 10.8, 4.6 Hz, 1H), 2.79 (dt, J = 11.9, 3.2 Hz, 2H), 2.17 (s, 3H), 1.97 (td, J = 11.6, 2.8 Hz, 2H), 1.90 - 1.69 (m, 4H).

[0612] Intermediate 17. 3-(4-Amino-3-methyl-1H-pyrazol-1-yl) cyclobutan-1-ol

[0613]

Chemical formula

[0614] Step A. 3-(Benzyloxy) cyclobutan-1-ol. In a 500 mL three-necked round-bottom flask, under N 2 atmosphere, at room temperature, 3-(benzyloxy) cyclobutan-1-one (15 g, 85.12 mmol) and MeOH (150 mL) were added. To the above mixture, NaBH 4 (3.2 g, 84.58 mmol) was added portionwise at 0 °C. The resulting mixture was stirred at 0 °C for an additional 1 hour and then concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL), and the organic layer was washed with brine (2 × 100 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to obtain 3-(benzyloxy) cyclobutan-1-ol as a yellow oil (12 g, 79%).

[0615] Step B. 3-(Benzyloxy) cyclobutyl 4-methylbenzenesulfonate. In a 250 mL three-necked round-bottom flask, under N 2Under an atmosphere, at room temperature, 3-(benzyloxy)cyclobutan-1-ol (12 g, 67.32 mmol), DCM (120 mL), DMAP (0.82 g, 6.71 mmol), and DIEA (13 g, 100.58 mmol) were added. TsCl (15.3 g, 80.25 mmol) was added portionwise to the above mixture at 0 °C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was washed with H 2 O (2 × 80 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. Thereby, 3-(benzyloxy)cyclobutyl 4-methylbenzenesulfonate was obtained as a yellow oil (16 g, 71.49%).

[0616] Step C. 1-[3-(Benzyloxy)cyclobutyl]-3-methyl-4-nitropyrazole. To a 500 mL three-necked round-bottom flask, 3-(benzyloxy)cyclobutyl 4-methylbenzenesulfonate (16 g, 48.1 mmol), DMF (160 mL), 3-methyl-4-nitro-1H-pyrazole (4.7 g, 36.97 mmol), and Cs 2 CO 3 (18 g, 55.24 mmol) were added under an N 2 atmosphere at room temperature. The resulting mixture was heated at 100 °C for 3 hours and then diluted with H 2 O (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL), and the combined organic extracts were washed with H 2 O (3 × 100 mL) and brine (1 × 100 mL), and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1 to 3:1) to give 1-[3-(benzyloxy)cyclobutyl]-3-methyl-4-nitropyrazole as a yellow solid (9 g, 65%). LCMS (ESI): C 15 H 17 N 3 O 3 calculated mass value for, 287.1, m / z, measured value, 288 [M+H] + .

[0617] Process D. 3-(4-Amino-3-methyl-1H-pyrazol-1-yl)cyclobutan-1-ol. In a 250 mL round-bottom flask, 1-[3-(benzyloxy)cyclobutyl]-3-methyl-4-nitropyrazole (9 g, 31.32 mmol), EtOH (100 mL), and Pd / C (10%, 4 g) were added at room temperature. The mixture was degassed three times with H 2 The resulting mixture was stirred overnight at room temperature under 1 atm of H 2 and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (100:0 to 1:1) to obtain the product. The product was further purified by SFC (column: CHIRALPAK® IF, 3 × 25 cm, 5 μm, mobile phase A: CO 2 , mobile phase B: MeOH (0.1% 2M NH 3 -MeOH), flow rate: 80 mL / min, gradient: isocratic 30% B, column temperature (°C): 35, back pressure (bar): 100, wavelength: 220 nm, isolating the first peak at 3.5 min, sample solvent: MeOH-HPLC, injection volume: 3 mL) to obtain 3-(4-amino-3-methylpyrazol-1-yl)cyclobutan-1-ol as a brown solid (2.527 g, 48.25%). LCMS (ESI): C 8 H 13 N 3 O, mass calculated value, 167.1, m / z, measured value, 168 [M+H] + . 1 H NMR (300 MHz, DMSO-d 6 ) δ 6.99 (s, 1H), 5.09 (d, J = 5.0 Hz, 1H), 4.72 - 4.54 (m, 1H), 4.44 - 4.26 (m, 1H), 3.55 (s, 2H), 2.59 - 2.41 (m, 2H), 2.30 - 2.13 (m, 2H), 1.99 (s, 3H).

[0618] Intermediate 18. 3-Methyl-1-(oxan-4-yl)pyrazol-4-amine

[0619]

Chemical Structure

[0620] Process A. 3-Methyl-4-nitro-1-(oxan-4-yl)pyrazole. In a 1 L three-necked round-bottom flask, 3-methyl-4-nitro-1H-pyrazole (15 g, 118.01 mmol), oxan-4-ol (30.13 g, 295.03 mmol), THF (150 mL) and PPh 3 (77.39 g, 295.03 mmol) were added at room temperature. To the above mixture, DIAD (59.66 g, 295.03 mmol) was added dropwise at 0 °C. The resulting mixture was heated at 60 °C overnight. After the reaction mixture was cooled to room temperature, it was diluted with ice / water (200 mL) and extracted with EA (3 × 100 mL). The combined organic extracts were washed with brine (1 × 100 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give 3-methyl-4-nitro-1-(oxan-4-yl)pyrazole as a black oil (12 g, 48%).

[0621] Process B. 3-Methyl-1-(oxan-4-yl)pyrazol-4-amine. To a solution of 3-methyl-4-nitro-1-(oxan-4-yl)pyrazole (12 g, 56.81 mmol) in EtOH (120 mL) in a 250 mL round-bottom flask under a nitrogen atmosphere, Pd / C (10%, 7 g) was added. Using a hydrogen balloon, a hydrogen atmosphere was created over the reaction mixture and the reactants were stirred overnight. The reaction mixture was filtered through a pad of diatomaceous earth and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / MeOH (95:5) to give the product. The product was subjected to SFC (SC 100 × 4.6 mm, 3.0 μm, co-solvent B: 10% MeOH (20 mM NH 3)、At a peak of 1.413 minutes and a total flow rate of 3.0000 mL / min, it was further purified to obtain 3-methyl-1-(oxan-4-yl)pyrazol-4-amine as a brown solid (2.57 g, 24.96%). LCMS (ESI): C 9 H 15 N 3 Calculated mass for O, 181, m / z, measured value, 182.1 [M+H] + 。 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.01 (s, 1H), 4.08 (tt, J = 10.6, 5.6 Hz, 1H), 3.98 - 3.85 (m, 2H), 3.50 - 3.33 (m, 2H), 3.34 (s, 2H), 1.99 (s, 3H), 1.91 - 1.71 (m, 4H).

[0622] Intermediate 19. 1-(4-Amino-3-methoxy-1H-pyrazol-1-yl)-2-methylpropan-2-ol

[0623]

Chemical Structure

[0624] Step A. 1-(3-Methoxy-4-nitro-1H-pyrazol-1-yl)-2-methylpropan-2-ol. 3-Methoxy-4-nitro-1H-pyrazole (2.00 g, 14.0 mmol), DMF (30 mL), 2,2-dimethyloxirane (2.02 g, 28.0 mmol), and Cs 2 CO 3 (13.7 g, 41.9 mmol) were added to a 100 mL round-bottom flask. The mixture was heated at 100 °C for 5 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with brine (100 mL) and anhydrous Na 2 SO 4It was dried and filtered. The filtrate was concentrated to obtain a white solid. The solid was purified by flash silica gel chromatography (eluent with a 0 - 30% EtOAc / petroleum ether gradient) to obtain 1-(3-methoxy-4-nitro-1H-pyrazol-1-yl)-2-methylpropan-2-ol as a white solid (2.0 g, 63%). LCMS (ESI): C 8 H 13 N 3 O 4 Calculated mass value for 215.1, m / z, measured value, 216.1 [M + H] + 。

[0625] Step B. 1-(4-Amino-3-methoxy-1H-pyrazol-1-yl)-2-methylpropan-2-ol. Pd / C (0.544 g, 10 wt%, 0.511 mmol), 1-(3-methoxy-4-nitro-1H-pyrazol-1-yl)-2-methylpropan-2-ol (2.20 g, 10.2 mmol), and MeOH (30 mL) were added to a 100 mL round-bottom flask, and the resulting mixture was stirred at room temperature for 3 hours under H 2 (15 psi). The suspension was filtered through a pad of diatomaceous earth, and the pad was washed with EtOAc (100 mL) to obtain a nearly black viscous oil. The oil was purified by flash silica gel chromatography (eluent with a 0 - 50% EtOAc / petroleum ether gradient) to obtain 1-(4-amino-3-methoxy-1H-pyrazol-1-yl)-2-methylpropan-2-ol as a blue syrup-like solid (1850.5 mg, 96%). LCMS (ESI): C 8 H 15 N 3 O 2 Calculated mass value for 185.1, m / z, measured value, 186.1 [M + H] + 。 1 H NMR (400 MHz, DMSO-d 6 ): 6.94 (s, 1H), 4.54 (s, 1H), 3.74 (s, 3H), 3.67 (s, 2H), 1.01 (s, 6H).

[0626] Intermediate 20. 3-Methoxy-1-(oxetan-3-yl)-1H-pyrazol-4-amine

[0627] [Chemical formula]

[0628] Step A. 3-Methoxy-4-nitro-1-(oxetan-3-yl)-1H-pyrazole. 3-Methoxy-4-nitro-1H-pyrazole (1.00 g, 6.99 mmol), DMF (15 mL), 3-iodooxetane (2.57 g, 14.0 mmol), and Cs 2 CO 3 (6.83 g, 21.0 mmol) were added to a 50 mL round-bottom flask. The mixture was heated at 100 °C for 5 h. After cooling the mixture to room temperature, it was diluted with water (30 mL) and extracted with EtOAc (3 × 40 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 and filtered, and concentrated in vacuo to give a yellow solid, which was purified by silica gel chromatography (0 - 50% EtOAc / petroleum ether) to give 3-methoxy-4-nitro-1-(oxetan-3-yl)-1H-pyrazole as a white solid (1.2 g, 62%). LCMS (ESI): C 7 H 9 N 3 O 4 Calculated mass for 199.1, m / z, found, 200.2 [M + H] + .

[0629] Step B. 3-Methoxy-1-(oxetan-3-yl)-1H-pyrazol-4-amine. 3-Methoxy-4-nitro-1-(oxetan-3-yl)-1H-pyrazole (2.00 g, 10.0 mmol), wet Pd / C (1 g, 10% Pd, 50% water), and anhydrous EtOH (30 mL) were added to a 100 mL round-bottom flask. The resulting mixture was sparged with H 2 three times, and then with H 2The mixture was stirred at room temperature for 4 hours under an atmosphere of 15 Psi. The mixture was filtered, and the filtrate was concentrated to dryness in vacuo to obtain a nearly black viscous oil, which was subjected to silica gel chromatography (0 - 100% ethyl acetate / petroleum ether) to give 3-methoxy-1-(oxetan-3-yl)-1H-pyrazol-4-amine as a nearly black viscous oil (1 g, 56%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.10 - 7.04 (m, 1H), 5.25 - 5.15 (m, 1H), 4.81 - 4.74 (m, 4H), 3.81 (s, 3H), 3.51 - 3.43 (m, 2H).

[0630] Intermediate 21. (R)-3-Hydroxy-1-methyl-3-(5-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)isoxazol-3-yl)pyrrolidin-2-one.

[0631] [Chemical formula]

[0632] Step A. (R)-3-Ethynyl-1-methyl-3-((trimethylsilyl)oxy)pyrrolidin-2-one. To a solution of (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (15.0 g, 107.8 mmol) and imidazole (22.0 g, 323.4 mmol) in DMF (50 mL) was added chlorotrimethylsilane (20.5 mL, 161.7 mmol) at room temperature. The reaction mixture was heated to 60 °C and stirred overnight. The mixture was poured into a separatory funnel together with a mixture of water (50 mL) and saturated aqueous NaHCO 3 (100 mL) and extracted twice with DCM (1×100 mL, then 1×50 mL). The combined organic layers were washed with water (3×50 mL) and dried (Na 2 SO 4) Filtered and concentrated. The product was purified by FCC (eluent: 10 - 70% EtOAc / hexane) to give 18.788 g (82%) of (R)-3-ethynyl-1-methyl-3-((trimethylsilyl)oxy)pyrrolidin-2-one as a colorless oil, which solidified upon standing. LCMS (ESI): C 10 H 17 NO 2 Calculated mass for Si, 211.10, measured m / z, 212.1 [M+1] + 。

[0633] Step B. (R)-3-(3-(6-Chloropyridin-2-yl)-3-oxoprop-1-yn-1-yl)-1-methyl-3-((trimethylsilyl)oxy)pyrrolidin-2-one. To a solution of (R)-3-ethynyl-1-methyl-3-((trimethylsilyl)oxy)pyrrolidin-2-one (16.4 g, 77.6 mmol) in THF (275 mL) at -20 °C were added DIPEA (26.7 mL, 155.2 mmol), Pd(PPh 3 ) 4 (2.72 g, 5 mol%), and CuI (739 mg, 5 mol%). The flask was flushed with N 2While purging with a stream, the mixture was stirred for several minutes. A solution of the acid chloride, 6-chloropicolinoyl chloride (19.1 g, 108.6 mmol) in THF (25 mL) was added via syringe at -20 °C. The reaction was warmed to 0 °C and stirred overnight. The reaction mixture was a stirred suspension of a precipitate. Additional DIPEA (7 mL) was added and the reaction mixture was passed through a 1-inch silica gel plug in a sintered glass funnel eluting with THF until the product eluted completely from the plug. The product-containing filtrate was concentrated to give a precipitate of a fine dark solid. The material was dissolved in EtOAc and filtered through a plug of diatomaceous earth. The filtrate containing the product was concentrated and purified by FCC (eluent: 30 - 70% EtOAc / hexane) to give 4.72 g of a dark brown oil which was a mixture of the starting silyl-lactam and the desired product in a 40:60 molar ratio. This mixture was 76 wt% (R)-3-(3-(6-chloropyridin-2-yl)-3-oxoprop-1-yn-1-yl)-1-methyl-3-((trimethylsilyl)oxy)pyrrolidin-2-one, giving 3.59 g (13%) of the desired product. The mixture was used as such in the next step. LCMS (ESI): C 16 H 19 ClN 2 O 3 Calculated mass for Si, 350.08, measured m / z, 351.1 [M+1] + 。

[0634] Step C. (R)-3-(5-(6-chloropyridin-2-yl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one. The mixture from the previous step containing (R)-3-(3-(6-chloropyridin-2-yl)-3-oxoprop-1-yn-1-yl)-1-methyl-3-((trimethylsilyl)oxy)pyrrolidin-2-one (3.59 g, 10.2 mmol) was stirred in THF (100 mL) at room temperature while NaN 3 (4.0 g, 61.4 mmol), AcOH (3.5 mL, 61.4 mmol), and Et 3N (0.57 mL, 4.1 mmol) was added. The mixture was stirred overnight. A 1.0 M solution of TBAF in THF (30.7 mL, 30.7 mmol) was added and the mixture was stirred overnight to complete the removal of the silyl group. The reaction mixture was poured into aqueous sodium carbonate (10.8 g Na 2 CO 3 , 102 mmol, in 110 mL of water) and stirred for 10 minutes. The mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered, and concentrated to give the product as a dark brown oil. The material was purified by FCC (eluent: 0 - 25% MeOH in 1:1 EtOAc / hexane). The desired product was isolated in 1.36 g of a mixture with the desilylated lactam starting material with a product / starting lactam molar ratio of 83:17. The product mixture was 91 wt% (R)-3-(5-(6-chloropyridin-2-yl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one, giving 1.24 g (41%) of the desired product. LCMS (ESI): C 13 H 12 ClN 3 O 3 calculated mass for, 293.06, m / z found, 294.1 [M+1] + .

[0635] Step D. (R)-3-Hydroxy-1-methyl-3-(5-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-3-yl)pyrrolidin-2-one. A mixture containing (R)-3-(5-(6-chloropyridin-2-yl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (1.2 g, 4.1 mmol), Pd(PPh 3 ), 4 , 330 mg, 7 mol%), and DMF (16 mL) was added to a 100 mL round-bottom flask. The flask was capped with a septum and N 2It was flash-heated at [temperature] for 15 minutes. Stannane, 2-(ethylthio)-4-(tributylstannyl)pyrimidine (1.53 mL, 4.5 mmol) was added, and the reaction mixture was heated at 100 °C overnight. LCMS analysis showed almost complete conversion of the starting pyridyl chloride. The reaction mixture was cooled and poured into a biphasic mixture of EtOAc (60 mL) and aqueous KF solution (1.2 g of KF / 60 mL of water), and stirred for 30 minutes. EtOAc was partially removed in vacuo, and the remaining biphasic mixture was poured into a separatory funnel and separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried (Na 2 SO 4 ), concentrated to give the product in residual DMF. The material was first purified by FCC (eluent: 0 - 10% MeOH / DCM), which partially separated it. The combined fractions were purified again by FCC (eluent: 0 - 100% in TBME / DCM, 5% MeOH). All the pure fractions were combined to give (R)-3-hydroxy-1-methyl-3-(5-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-3-yl)pyrrolidin-2-one as an off-white solid (0.65 g, 41%). LCMS (ESI): Calculated mass for C 18 H 17 N 5 O 2 S, 383.11, m / z found 384.1 [M+1] + .

[0636] Engineering E. (R)-3-Hydroxy-1-methyl-3-(5-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)isoxazol-3-yl)pyrrolidin-2-one. (R)-3-Hydroxy-1-methyl-3-(5-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)isoxazol-3-yl)pyrrolidin-2-one (0.2 g, 0.52 mmol) was placed in a 25 mL flask and dissolved in acetone (1.7 mL), water (1.7 mL), THF (1.7 mL), and MeOH (1.7 mL). To this mixture, potassium peroxymonosulfate (0.96 g, 1.6 mmol) was added and the resulting clear mixture was stirred at room temperature for 12 hours. Ice water (10 mL) was added to the white reaction mixture, and after stirring for 10 minutes, the solid was filtered, washed with additional water (20 mL), and dried under reduced pressure to obtain a white solid (0.16 g), which was used without further purification. LC-MS (ESI): C 18 H 17 N 5 O 5 Calculated mass for S, 415.1 m / z, found, 415.8 [M+H] + 。

[0637] Intermediates 22 and 23. (R)-3-Hydroxy-1-methyl-3-(1-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one, and (S)-3-Hydroxy-1-methyl-3-(1-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one.

[0638]

Chemical Structure

[0639] Project A. 2-Chloro-6-(4-iodo-1H-pyrazol-1-yl)pyridine. The following reaction was carried out in 5 batches. 4-Iodo-1H-pyrazole (200 g, 1.03 mol) and DMF (4000 mL) were added to a 5000 mL flask, to which 2,6-dichloropyridine (381 g, 2.58 mol) and Cs 2 CO 3 (1.01 kg, 3.09 mol) were charged. The mixture was heated at 100 °C for 3 hours. The reaction mixture was filtered and the solid was washed with EtOAc. The filtrate was diluted with H 2 O (8000 mL) and extracted with MTBE (5000 mL × 3). The organic layer was washed with brine (5000 mL × 1) and dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a residue. The residue was triturated with petroleum ether:ethyl acetate = 2:1 (2000 mL) at 25 °C for 1 hour to obtain 2-chloro-6-(4-iodo-1H-pyrazol-1-yl)pyridine as a white solid (1.04 kg, 3.10 mol, 60%, purity 91.0%). LCMS (ESI): C 8 H 5 ClIN 3 calculated mass for, 304.9 m / z, found, 305.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.67 (s, 1H), 8.06 (t, J = 7.9 Hz, 1H), 7.99 - 7.95 (m, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H).

[0640] Project B. 3-(1-(6-Chloropyridin-2-yl)-1H-pyrazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of 2-chloro-6-(4-iodo-1H-pyrazol-1-yl)pyridine (1000 g, 3.27 mol) in THF (15000 mL), N 2Under an atmosphere, at 0 °C, iPrMgCl-LiCl (1.30 M, 2.64 L) was added. The mixture was stirred at 0 °C for 0.5 h. 1-Methylpyrrolidine-2,3-dione (314 g, 2.78 mol) dissolved in THF (5000 mL) was added, and the resulting mixture was stirred at 25 °C for a further 12 h. The reaction mixture was quenched by the addition of NH 4 Cl (saturated aqueous solution, 10 L) at 0 °C and extracted with EtOAc 15000 mL (5000 mL × 3). The combined organic layers were washed with brine (5000 mL × 2) and dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 1 - 0 / 1) to give 3-(1-(6-chloropyridin-2-yl)-1H-pyrazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one as a yellow solid (330 g, 1.07 mol, 32%, purity 95.0%). LCMS (ESI): C 13 H 13 ClN 4 O 2 calculated mass, 292.1 m / z, found, 293.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.47 (s, 1H), 8.08 - 7.98 (m, 1H), 7.90 - 7.82 (m, 2H), 7.46 (d, J = 7.8 Hz, 1H), 6.00 (s, 1H), 3.45 - 3.36 (m, 1H), 3.35 - 3.28 (m, 3H), 2.78 (s, 3H), 2.26 - 2.17 (m, 1H).

[0641] Step C. 3-Hydroxy-1-methyl-3-(1-(6-(tributylstannyl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one. 3-(1-(6-Chloropyridin-2-yl)-1H-pyrazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (280 g, 956 mmol) in 1,4-dioxane (2500 mL), (SnBu 3 ) 2(1.11 kg, 1.91 mol, 956 mL), LiCl (202 g, 4.78 mol), Cy 3 P (26.8 g, 95.6 mmol, 31.0 mL), Pd(PPh 3 ) 2 Cl 2 (33.5 g, 47.8 mmol) was degassed and purged three times with N 2 . The mixture was heated at 110 °C for 36 h under a N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H 2 O (1000 mL) and extracted with EtOAc (1000 mL × 3). The combined organic layers were washed with brine (800 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent with a gradient of 0 - 46% ethyl acetate / petroleum ether) to give 3-hydroxy-1-methyl-3-(1-(6-(tributylstannyl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one as a yellow oil (225 g, 411 mmol, 42%). LCMS (ESI): C 25 H 40 N 4 O 2 Calculated mass for Sn, 548.1 m / z, found, 549.2 [M + H] + . 1 H NMR: (400 MHz, DMSO-d 6 ) δ 8.57 (s, 1H), 7.76 - 7.68 (m, 2H), 7.61 - 7.52 (m, 1H), 7.27 (s, 1H), 3.41 - 3.25 (m, 3H), 2.88 (s, 3H), 2.54 - 2.40 (m, 2H), 1.63 - 1.46 (m, 7H), 1.37 - 1.23 (m, 7H), 1.14 - 1.03 (m, 6H), 0.85 (t, J = 7.3 Hz, 10H).

[0642] R and S enantiomers of 3-hydroxy-1-methyl-3-(1-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one. A mixture of 3-hydroxy-1-methyl-3-(1-(6-(tributylstannyl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one (200 g, 365 mmol), 4-iodo-2-(methylthio)pyrimidine (101 g, 401 mmol) and Pd(PPh) 4 (14.7 g, 12.7 mmol, 0.035 eq) in DMF (1600 mL) was degassed and purged with N 2 three times, and then the mixture was heated at 120 °C for 12 h under a N 2 atmosphere. The reaction mixture was cooled to 25 °C and diluted with EtOAc (3000 mL). KF (42.2 g) in H 2 O (800 mL) was added to the mixture and stirred at 25 °C for 0.5 h. The mixture was filtered and the filtrate was extracted with EtOAc (1500 mL × 3). The combined organic layers were washed with brine (800 mL × 1), dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to give a residue. This was then triturated with EtOAc (500 mL) at 25 °C for 60 min to give (R,S)-3-hydroxy-1-methyl-3-(1-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one as a yellow solid (90 g). The (R) and (S) enantiomers of (R,S)-3-hydroxy-1-methyl-3-(1-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one were separated by SFC (DAICEL CHIRALPAK AS (250 mm × 50 mm, 10 μm), mobile phase: 65% [0.1% NH 3 H 2 O in EtOH], 35% CO 2) was separated to obtain two elution peaks. The second elution peak was designated as enantiomer 1 of 3-hydroxy-1-methyl-3-(1-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one. LCMS(ESI): C 18 H 18 N 6 O 2 Calculated mass for S, 382.1 m / z, measured value, 383.3 [M+H] + 。 1 H NMR(400 MHz, DMSO-d 6 ) δ 8.88 - 8.80 (m, 2H), 8.36 (d, J = 7.6 Hz, 1H), 8.23 - 8.20 (m, 1H), 8.19 - 8.16 (m, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.88 (s, 1H), 6.01 (s, 1H), 3.42 (br dd, J = 4.5, 8.1 Hz, 1H), 3.39 - 3.35 (m, 1H), 2.80 (s, 3H), 2.63 (s, 3H), 2.61 - 2.54 (m, 1H), 2.30 - 2.21 (m, 1H). The first elution peak (retention time = 2.25 minutes) was designated as enantiomer 2 of 3-hydroxy-1-methyl-3-(1-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one and obtained as a white solid (39.0 g, 98.9 mmol, purity 97.0%). LCMS(ESI): C 18 H 18 N 6 O 2 Calculated mass for S, 382.1 m / z, measured value, 383.3 [M+H] + 。 1 H NMR(400 MHz, DMSO-d 6)δ 8.88 - 8.80 (m, 2H), 8.36 (d, J = 7.6 Hz, 1H), 8.23 - 8.20 (m, 1H), 8.19 - 8.16 (m, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.88 (s, 1H), 6.01 (s, 1H), 3.42 (dd, J = 4.5, 8.1 Hz, 1H), 3.39 - 3.35 (m, 1H), 2.80 (s, 3H), 2.63 (s, 3H), 2.61 - 2.54 (m, 1H), 2.30 - 2.21 (m, 1H).

[0643] Step E: To a solution of enantiomer 1 of 3 - hydroxy - 1 - methyl - 3-(1-(6-(2-(methylthio)pyrimidin - 4 - yl)pyridin - 2 - yl)-1H - pyrazol - 4 - yl)pyrrolidin - 2 - one (33.0 g, 86.2 mmol) in a mixture of THF (495 mL) / acetone (495 mL) / H₂O (495 mL), potassium peroxymonosulfate (159.14 g, 258 mmol) was added. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H 2 O (1500 mL) and extracted with CH 2 Cl 2 (1500 mL × 3). The combined extracts were washed with brine (1000 mL), dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure to obtain a residue. This residue was triturated with H 2 O (500 mL) at 25 °C for 1 h and then isolated. Next, this isolated product was triturated with MeOH (500 mL) twice at 25 °C for 1 h to obtain enantiomer 1 of 3 - hydroxy - 1 - methyl - 3-(1-(6-(2-(methylsulfonyl)pyrimidin - 4 - yl)pyridin - 2 - yl)-1H - pyrazol - 4 - yl)pyrrolidin - 2 - one as a white solid (Intermediate 22, 29.0 g, 66.4 mmol, 77%, purity 95.0%). LCMS (ESI): C 18 H 18 N 6 O 4 S calculated mass value for, 414.1 m / z, measured value, 415.3 [M + H] + . 1 H NMR (400 MHz, DMSO - d 6)δ 9.28 (d, J = 5.1 Hz, 1H), 8.89 (s, 1H), 8.83 (d, J = 5.3 Hz, 1H), 8.46 (d, J = 7.5 Hz, 1H), 8.25 (t, J = 7.9 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.90 (s, 1H), 6.02 (br s, 1H), 3.55 (s, 3H), 3.48 - 3.41 (m, 1H), 3.40 - 3.35 (m, 1H), 2.80 (s, 3H), 2.66 - 2.53 (m, 1H), 2.36 - 2.21 (m, 1H).

[0644] Step F: Enantiomer 2 of 3-hydroxy-1-methyl-3-(1-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one (Intermediate 23) was prepared in a similar manner to Intermediate 22, using enantiomer 2 of 3-hydroxy-1-methyl-3-(1-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one (prepared in Step D) instead of enantiomer 1 of 3-hydroxy-1-methyl-3-(1-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)-1H-pyrazol-4-yl)pyrrolidin-2-one. LCMS (ESI): C 18 H 18 N 6 O 4 Calculated mass for S, 414.1 m / z, found, 415.3 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ 9.28 (d, J = 5.3 Hz, 1H), 8.89 (s, 1H), 8.83 (d, J = 5.1 Hz, 1H), 8.46 (d, J = 7.5 Hz, 1H), 8.25 (t, J = 7.9 Hz, 1H), 8.13 (d, J = 8.3 Hz, 1H), 7.90 (s, 1H), 6.02 (s, 1H), 3.55 (s, 3H), 3.49 - 3.41 (m, 1H), 3.40 - 3.34 (m, 1H), 2.80 (s, 3H), 2.59 (ddd, J = 4.6, 7.6, 12.7 Hz, 1H), 2.33 - 2.21 (m, 1H).

[0645] Intermediate 24. N-(1-Methyl-1H-pyrazol-3-yl)-4-(tributylstannyl)pyrimidin-2-amine.

[0646]

Chem.

[0647] 4-Chloro-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine (300 mg, 1.43 mmol, Step B of Example 25), LiCl (364 mg, 8.59 mmol), 1,1,1,2,2,2-hexabutyldistannane (1.79 g, 3.09 mmol), and 1,4-dioxane (10 mL) were added to a 50 mL flask equipped with a reflux condenser. The resulting mixture was purged with N 2 three times and then treated with Pd 2 (dba) 3 (66 mg, 0.072 mmol) and tricyclohexylphosphine (40 mg, 0.14 mmol). The resulting mixture was further purged with N 2 three times and heated at 120 °C for 16 h. Thereafter, the reaction vessel was removed from the oil bath and gradually cooled to room temperature. The reaction mixture was quenched with saturated KF (30 mL), stirred for 1 h, and extracted with EtOAc (20 mL × 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and filtered, and concentrated to dryness in vacuo to give a brown solid. The solid was subjected to silica gel chromatography (0 - 30% EtOAc / petroleum ether) to give N-(1-methyl-1H-pyrazol-3-yl)-4-(tributylstannyl)pyrimidin-2-amine as a white solid (350 mg, 53%). MS (ESI + ): m / z = 466.0.

[0648] Intermediate 25. 3-(2-(6-Chloropyridin-2-yl)thiazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one

[0649]

Chem.

[0650] Process A. 3-(2-Bromothiazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. 2,5-Dibromothiazole (2.8 g, 11.5 mmol) and anhydrous THF (30 mL) were added to a 100 mL three-necked round-bottom flask, and the mixture was cooled to -78 °C. Next, i-PrMgCl·LiCl (9.5 mL, 1.3 M in hexane, 12.4 mmol) was added dropwise. The resulting mixture was stirred at -78 °C for 30 minutes, and then 1-methylpyrrolidine-2,3-dione (1.0 g, 8.8 mmol) in THF (10 mL) was added dropwise to the mixture. The resulting mixture was stirred for 16 hours while gradually warming to room temperature. Thereafter, the mixture was poured into water (80 mL) and extracted with ethyl acetate (80 mL × 3). The organic extract was washed with brine (60 mL) and dried over anhydrous Na 2 SO 4 and filtered, and concentrated to dryness in vacuo to obtain a brown oil. The oil was purified by silica gel chromatography (0 - 100% EtOAc / petroleum ether) to obtain 3-(2-bromothiazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one as a yellow oil (560 mg, 19%). LCMS (ESI): C 8 H 9 BrN 2 O 2 Calculated mass for S, 276.0 m / z, Found, 276.9 [M+1] + .

[0651] Process B. 3-(2-(6-Chloropyridin-2-yl)thiazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. 3-(2-Bromothiazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (560 mg, 2.0 mmol), 1,4-dioxane (8 mL), H 2 O (2 mL), 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (580 mg, 2.4 mmol), and K 2 CO 3(590 mg, 6.0 mmol) was added to a 10 mL flask purged with nitrogen, and Pd(dppf)Cl 2 (150 mg, 0.21 mmol) was charged. The resulting mixture was purged with N 2 for 3 minutes and heated at 90 °C for 5 hours. After that, the mixture was cooled to room temperature, poured into water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic extracts were washed with brine (60 mL) and dried over anhydrous Na 2 SO 4 , filtered, and concentrated to dryness in vacuo to obtain a brown oil. Next, the oil was subjected to silica gel chromatography (0 - 100% EtOAc / petroleum ether) to give 3-(2-(6-chloropyridin-2-yl)thiazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one as a yellow solid (180 mg, 20%). LCMS (ESI): C 13 H 12 ClN 3 O 2 Calculated mass for S, 309.0 m / z, Found, 309.8 [M + 1] + .

[0652] Intermediate 26. 3-(2-(6-Chloropyridin-2-yl)thiazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one

[0653]

Chem.

[0654] Step A. 6-Chloropyridine-2-carbothioamide. 6-Chloropicolinamide (1.0 g, 6.4 mmol) and THF (20 mL) were added to a 40 mL flask purged with nitrogen, and Lawesson's reagent (1.3 g, 3.2 mmol) was charged. The resulting mixture was heated at 45 °C for 2 hours and concentrated to dryness under reduced pressure to obtain a yellow solid. The solid was subjected to silica gel chromatography (0 - 35% EtOAc / pet ether) to give 6-chloropyridine-2-carbothioamide as a yellow solid (1 g, 90%). LCMS (ESI): C 6 H5 ClN 2 Mass calculated value for S, 172.0 m / z, measured value, 172.7 [M+1] + 。

[0655] Step B. 3-(1-Ethoxyvinyl)-3-hydroxy-1-methylpyrrolidin-2-one. Ethoxyethene (12.0 mL, 125 mmol) and THF (50 mL) were added to a 250 mL three-necked round-bottom flask that had been oven-dried and purged with nitrogen. Subsequently, this was cooled to -72 °C, and the resulting mixture was treated portionwise with t-BuLi (40 mL, 1.3 M in pentane, 52 mmol) over 5 minutes. The mixture was warmed to 0 °C and stirred until the color of the solution became pale yellow. Thereafter, 1-methylpyrrolidin-2,3-dione (2.00 g, 17.7 mmol) was added to the mixture. The mixture was stirred at -72 °C for 1 hour and then at room temperature for 12 hours. Next, the reaction mixture was diluted with EtOAc (150 mL) and washed with H 2 O (60 mL × 3), dried over anhydrous Na 2 SO 4 and filtered, and concentrated to dryness in vacuo to obtain a yellow oil. Next, the oil was subjected to silica gel chromatography (0 - 80% EtOAc / petroleum ether) to obtain 3-(1-ethoxyvinyl)-3-hydroxy-1-methylpyrrolidin-2-one as a yellow oil (400 mg, 12%). LCMS (ESI): C 9 H 15 NO 3 Mass calculated value for, 185.1 m / z, measured value, 186.2 [M+1] + 。

[0656] Step C. 3-(2-Bromoacetyl)-3-hydroxy-1-methylpyrrolidin-2-one. 3-(1-Ethoxyvinyl)-3-hydroxy-1-methylpyrrolidin-2-one (370 mg, 2.00 mmol) and acetone / H 2O=9:1 (5 mL) was added to a nitrogen-purged 40 mL flask, and NBS (370 mg, 2.1 mmol) was charged at 0 °C. The resulting mixture was then stirred at room temperature for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL × 3). The combined extracts were washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 , filtered, and concentrated to dryness in vacuo to afford 3-(2-bromoacetyl)-3-hydroxy-1-methylpyrrolidin-2-one as a yellow oil (330 mg). LCMS (ESI): C 7 H 10 BrNO 3 calculated mass for, 235.0 m / z, found, 235.6 [M+1] + .

[0657] Step D. 3-(2-(6-Chloropyridin-2-yl)thiazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one. 3-(2-Bromoacetyl)-3-hydroxy-1-methylpyrrolidin-2-one (330 mg, 1.4 mmol) and EtOH (7 mL) were added to a 40 mL flask, and 6-chloropyridine-2-carbothioamide (270 mg, 1.6 mmol) was charged. The resulting mixture was stirred at 100 °C for 1.5 hours. Thereafter, the mixture was cooled to room temperature, diluted with EtOAc (50 mL), washed with H 2 O (20 mL × 3), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to dryness in vacuo to afford a yellow solid. Next, the solid was subjected to silica gel chromatography (0 - 100% EtOAc / petroleum ether) to afford 3-(2-(6-chloropyridin-2-yl)thiazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one as a yellow solid (270 mg, 57%). LCMS (ESI): C 13 H 12 ClN 3 O 2 calculated mass for S, 309.0 m / z, found, 309.9 [M+1] + .

[0658] Intermediate 27. 3-(5-(6-Chloropyridin-2-yl)thiazol-2-yl)-3-hydroxy-1-methylpyrrolidin-2-one

[0659] [Chemical formula]

[0660] Step A. 3-Hydroxy-1-methyl-3-(thiazol-2-yl)pyrrolidin-2-one. 2-Bromothiazole (1.0 mL, 11 mmol) and anhydrous THF (20 mL) were added to a 100 mL three-necked round-bottom flask, which was cooled to -78 °C, and then i-PrMgCl·LiCl (8.80 mL, 1.3 M in hexane, 11.4 mmol) was added dropwise. The resulting mixture was stirred at -78 °C for 30 minutes, and then 1-methylpyrrolidine-2,3-dione (1.00 g, 8.8 mmol) in THF (10 mL) was added dropwise to the mixture. The resulting mixture was stirred at room temperature for 3 hours. Then, the mixture was quenched with water (40 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to obtain a yellow oil. Next, the oil was subjected to silica gel chromatography (0 - 100% EtOAc / petroleum ether) to obtain 3-hydroxy-1-methyl-3-(thiazol-2-yl)pyrrolidin-2-one as a yellow solid (460 mg, 25%). LCMS (ESI): C 8 H 10 N 2 O 2 Calculated mass for S, 198.1 m / z, Measured value, 199.0 [M+H] + .

[0661] Step B. 3-(5-Bromothiazol-2-yl)-3-hydroxy-1-methylpyrrolidin-2-one. 3-Hydroxy-1-methyl-3-(thiazol-2-yl)pyrrolidin-2-one (500 mg, 2.52 mmol), NBS (500 mg, 2.8 mmol), and ACN (15 mL) were added to a 40 mL flask, and the resulting mixture was heated at 40 °C for 16 h. Thereafter, the mixture was concentrated to dryness in vacuo to give a yellow oil. Next, the solid was subjected to silica gel chromatography (0 - 100% EtOAc / petroleum ether) to give 3-(5-bromothiazol-2-yl)-3-hydroxy-1-methylpyrrolidin-2-one as a white solid (530 mg, 69%). LCMS (ESI): C 8 H 9 BrN 2 O 2 Calculated for S, 276.0 m / z, Found, 276.9 [M+1] + 。 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.80 (s, 1H), 7.35 - 6.69 (m, 1H), 3.48 - 3.43 (m, 1H), 3.56 - 3.32 (m, 1H), 3.17 (s, 1H), 2.79 (s, 3H), 2.70 - 2.61 (m, 1H), 2.50 (br s, 1H), 2.29 - 2.17 (m, 1H).

[0662] Step C. 3-(5-(6-Chloropyridin-2-yl)thiazol-2-yl)-3-hydroxy-1-methylpyrrolidin-2-one. 3-(5-Bromothiazol-2-yl)-3-hydroxy-1-methylpyrrolidin-2-one (450 mg, 1.6 mmol), 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (790 mg, 3.3 mmol), K 2 CO 3 (680 mg, 4.9 mmol), and 1,4-dioxane / H 2 O (4:1) (20 mL) were added to a 100 mL round-bottom flask, and then this was evacuated and refilled with argon (×3), and then Pd(dppf)Cl 2(130 mg, 0.18 mmol) was treated, and the resulting mixture was heated at 110 °C for 16 h. Thereafter, the mixture was cooled to room temperature, poured into water (30 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic extracts were washed with brine (40 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to dryness in vacuo to afford a brown solid. Next, the solid was subjected to silica gel chromatography (0 - 10% MeOH / DCM) to give 3-(5-(6-chloropyridin-2-yl)thiazol-2-yl)-3-hydroxy-1-methylpyrrolidin-2-one as a black solid (420 mg, 61%). LCMS (ESI): C 13 H 12 ClN 3 O 2 S calculated mass, 309.0 m / z, found, 310.0 [M + H] + .

[0663] Intermediate 28. N-(1-Methyl-1H-pyrazol-3-yl)-4-(6-(tributylstannyl)pyridin-2-yl)pyrimidin-2-amine.

[0664]

Chemical Structure

[0665] Step A. 4-(6-Bromopyridin-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-2-amine. N-(1-Methyl-1H-pyrazol-3-yl)-4-(tributylstannyl)pyrimidin-2-amine (Intermediate 24, 4.66 g, 10 mmol), 2,6-dibromopyridine (2.8 g, 12 mmol), TEA (2.8 mL, 20 mmol), and toluene (50 mL) were added to a 250 mL round-bottom flask, and Pd(PPh 3 ) 4(1.2 g, 1.0 mmol) was charged. The mixture was sparged with Ar for 5 minutes and then heated at 120 °C for 16 hours. The reaction vessel was removed from the oil bath and gradually cooled to room temperature. Next, the reaction product was diluted with water (80 mL), extracted with ethyl acetate (100 mL × 3), the combined extracts were washed with brine (60 mL), dried over anhydrous Na 2 SO 4 and filtered, and concentrated to dryness in vacuo to give a yellow solid. Next, the yellow solid was subjected to silica gel chromatography (0 - 100% ethyl acetate / petroleum ether) to give 4-(6-bromopyridin-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrimidine-2-amine as a yellow solid (2.28 g, 43%). LCMS (ESI): C 13 H 11 BrN 6 calculated mass for, 330.0 m / z, found, 333.1 [M + H] + .

[0666] Step B. N-(1-Methyl-1H-pyrazol-3-yl)-4-(6-(tributylstannyl)pyridin-2-yl)pyrimidine-2-amine. 4-(6-Bromopyridin-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrimidine-2-amine (2.0 g, 6.0 mmol), LiCl (1.5 g, 35 mmol), and 1,4-dioxane (50 mL) were added to a 250 mL flask equipped with a reflux condenser and charged with 1,1,1,2,2,2-hexabutyldistannane (5.83 g, 10.1 mmol). The resulting mixture was purged with N 2 three times and then treated with Pd 2 (dba) 3 (273 mg, 0.298 mmol) and tricyclohexylphosphine (167 mg, 0.596 mmol). The resulting mixture was purged with N 2 again three times and heated at 120 °C for 16 hours. Thereafter, the mixture was cooled to room temperature, quenched with saturated KF (20 mL), and stirred for 1 hour. Next, the reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (60 mL × 3), the combined extracts were washed with brine (40 mL), dried over anhydrous Na 2 SO4 It was dried, filtered, and concentrated to dryness in vacuo to obtain a yellow solid. Next, the yellow solid was subjected to silica gel chromatography (0 - 50% ethyl acetate / petroleum ether) to obtain N-(1-methyl-1H-pyrazol-3-yl)-4-(6-(tributylstannyl)pyridin-2-yl)pyrimidin-2-amine as a yellow solid (1.26 g, 37%). LCMS (ESI): C 25 H 38 N 6 Calculated mass for Sn, 542.22 m / z, found, 543.15 [M + H] + 。

[0667] Intermediate 29. 3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0668]

Chemical formula

[0669] Step A. 3,5-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole. 3,5-Dibromo-1H-pyrazole (8.0 g, 35 mmol), TEA (7.4 mL, 53 mmol), and DCM (100 mL) were added to a 250 mL flask. SEM-Cl (8.8 mL, 50 mmol) was added. After stirring at room temperature for 30 minutes, the mixture was concentrated to dryness under reduced pressure to obtain a colorless oil, which was then subjected to HPLC (Xtimate C18 column, 10 μm, 150×40 mm, 65 - 95% ACN / water (containing 0.04% NH 3 ·H 2 O + 10 mM NH 4 HCO 3 ), and after lyophilization, 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole was obtained as a colorless oil (6.1 g, 48%). LCMS (ESI): C 9 H 16 Br 2 N 2Mass calculated value for OSi, 353.94 m / z, measured value, 354.9 [M+H] + 。

[0670] Step B.3 - (3 - Bromo - 1 - ((2 - (trimethylsilyl)ethoxy)methyl)-1H - pyrazol - 5 - yl)-3 - hydroxy - 1 - methylpyrrolidin - 2 - one. Tetrahydrofuran (30 mL) and 3,5 - dibromo - 1 - ((2 - (trimethylsilyl)ethoxy)methyl)-1H - pyrazole (6.0 g, 17 mmol) were added to a N 2 purged 250 mL three - necked flask. The mixture was cooled to - 72 °C. n - Butyllithium (7.41 mL, 2.5 M in hexane, 18.5 mmol) was added dropwise to the mixture. The mixture was stirred at - 72 °C for 30 minutes and treated with a solution consisting of 1 - methylpyrrolidine - 2,3 - dione (2.29 g, 20.2 mmol) and THF (50 mL), and then stirred at - 72 °C for 1 hour. Thereafter, the mixture was quenched with H 2 O (80 mL) and extracted with EtOAc (80 mL×3). The combined organic extracts were concentrated to dryness under reduced pressure to obtain a brown oil, which was subjected to HPLC (Xtimate C18 column, 10 μm, 150×40 mm, 40 - 70% (v / v) ACN / water (0.05% NH 3 ·H 2 O + 10 mM NH 4 HCO 3 )) and, after lyophilization, 3 - (3 - bromo - 1 - ((2 - (trimethylsilyl)ethoxy)methyl)-1H - pyrazol - 5 - yl)-3 - hydroxy - 1 - methylpyrrolidin - 2 - one was obtained as a white solid (3.2 g, 49%). LCMS (ESI): C 14 H 24 BrN 3 O 3 Mass calculated value for Si, 389.1 m / z, measured value, 390.0 [M+H] + 。

[0671] Intermediate 30. 3 - (1 - (6 - Chloropyridin - 2 - yl)-1H - imidazol - 4 - yl)-3 - hydroxy - 1 - methylpyrrolidin - 2 - one.

[0672]

Chem.

[0673] Process A. 2-Chloro-6-(4-iodo-1H-imidazol-1-yl)pyridine. A mixture of 4-iodoimidazole (1.0 g, 5.2 mmol), 2,6-dichloropyridine (1.91 g, 12.9 mmol), cesium carbonate (5.04 g, 15.5 mmol), and DMA (20 mL) was heated at 100 °C for 2 h. The reaction mixture was cooled to room temperature and then poured into 150 mL of water to form a precipitate. The precipitate was collected by vacuum filtration and washed with water. The filter cake was recovered and purified by FCC (silica, 40 - 100% EtOAc in hexane) to give 2-chloro-6-(4-iodo-1H-imidazol-1-yl)pyridine as a white solid (685 mg, 43%). 1 1H NMR (500 MHz, DMSO-d 6 ) δ 8.51 - 8.40 (m, 1H), 8.18 - 8.12 (m, 1H), 8.08 (t, J = 7.9 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H). LCMS (ESI + ): m / z = 306.0.

[0674] Process B. 3-(1-(6-Chloropyridin-2-yl)-1H-imidazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of 2-chloro-6-(4-iodo-1H-imidazol-1-yl)pyridine (540 mg, 1.768 mmol) in THF (10 mL) at 0 °C was added dropwise isopropylmagnesium chloride-lithium chloride complex (1.36 mL, 1.3 M in THF, 1.77 mmol) over 2 min. The resulting mixture was stirred for 10 min and then 1-methylpyrrolidine-2,3-dione (220 mg, 1.94 mmol) was added as a solid in one portion. The resulting mixture was stirred for 50 min and then diluted with saturated NH 4 4Cl aqueous solution, water, and extracted with ethyl acetate. The organic extract was dried over MgSO 4It was dried, filtered, and concentrated. The residue was purified by FCC (silica, 0 - 10% MeOH in EtOAc) to obtain 3-(1-(6-chloropyridin-2-yl)-1H-imidazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one as a white solid (81 mg, 15.6%). 1 H NMR(400MHz,CDCl 3 )δ 8.25(d,J=1.5Hz,1H),7.73(t,J=7.9Hz,1H),7.69(d,J=1.5Hz,1H),7.22(d,J=7.8Hz,1H),7.19(d,J=8.0Hz,1H),4.61(s,1H),3.64 - 3.52(m,1H),3.51 - 3.39(m,1H),2.96(s,3H),2.84 - 2.71(m,1H),2.48 - 2.29(m,1H). LCMS(ESI + ):m / z=293.1.

[0675] Intermediate 31. (R)-3-(3-(6-(2-chloropyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0676]

Chemical Structure

[0677] A solution of TMPMgCl·LiCl (1.00 M in THF, 813 mL, 813 mmol) was cooled in a dry ice - EtOH bath. A solution of 2-chloropyrimidine (84.6 g, 739 mmol) in THF (1000 mL) was added dropwise over 2 hours via a pressure - equalizing funnel. The resulting solution was stirred for an additional 2 hours in a dry ice - EtOH bath. ZnCl 21.00 M, 1.11 L, 1.11 mol) was added dropwise over 2 h using a dropping funnel. Next, the mixture was slowly warmed to 25 °C and stirred for 12 h. The resulting solution was added dropwise over 6 h using a dropping funnel to another flask containing (R)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (100 g, 295.72 mmol from Step A in the preparation of Intermediate 13), Pd(PPh 3 ) 4 (42.7 g, 36.9 mmol), and THF (800 mL). The resulting mixture was stirred for an additional 1 h. The reaction was cooled to 25 °C, poured into saturated NH 4 Cl aqueous solution (4000 mL), and extracted with ethyl acetate (2000 mL × 3). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The residue was triturated with MeOH (500 mL) at 25 °C for 12 h. The reaction was carried out in 8 batches. (R)-3-(3-(6-(2-chloropyrimidin-4-yl)pyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one was obtained as a yellow solid (670 g, 1.78 mol, 61.0%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.97 (d, J = 5.1 Hz, 1H), 8.55 (d, J = 5.1 Hz, 1H), 8.50 - 8.43 (m, 1H), 8.24 - 8.17 (m, 2H), 7.22 (s, 1H), 6.78 (s, 1H), 3.57 - 3.40 (m, 2H), 2.85 (s, 3H), 2.62 (ddd, J = 5.1, 7.8, 13.2 Hz, 1H), 2.30 (ddd, J = 5.8, 7.8, 13.4 Hz, 1H), 1.98 (s, 1H). LCMS (ESI + ): m / z = 371.9.

[0678] Intermediate 32. (R)-3-(1-(6-(2-chloropyrimidin-4-yl)pyridin-2-yl)-1H-1,2,3-triazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one

[0679] [Chemical]

[0680] (R)-3-(1-(6-(2-Chloropyrimidin-4-yl)pyridin-2-yl)-1H-1,2,3-triazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a stirred solution of 2-chloropyrimidine (103 g, 899 mmol) in tetrahydrofuran (1200 mL), TMPMgCl·LiCl (1.0 M in THF, 1174 mL) was added dropwise at -72 °C under a nitrogen atmosphere. The resulting mixture was stirred at -72 °C for 2 hours under a nitrogen atmosphere. To the above mixture, zinc chloride (1927 mL, 1349 mmol, 0.7 M in THF) was added dropwise at -72 °C. The resulting solution was stirred overnight at room temperature. A solution of (R)-3-(1-(6-bromopyridin-2-yl)-1H-1,2,3-triazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (152 g, 450 mmol, Intermediate 51), and tetrakis(triphenylphosphine)palladium(0) (52 g, 45 mmol) in tetrahydrofuran (1500 mL) was added dropwise to the above mixture at 60 °C under a nitrogen atmosphere. The final reaction mixture was stirred at 60 °C f...

Claims

1. A compound of formula I', 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein, A is a 5-membered heteroaryl optionally substituted with one or more -C （１～４） alkyl groups and is a 5-membered heteroaryl, W is CH ２ , CHF, CF ２ , or CHR Ｗ and X is N, C-H, or C-R Ｘ wherein Y is N, C-H, or C-R Ｙ and R Ｗ is -C （１～４） alkyl or -C （１～４） haloalkyl, and R Ｘ is halo, -C （１～４） alkyl, -C （１～４） haloalkyl, -OC （１～４） alkyl, -OC （１～４） haloalkyl, or -C （１～４） alkyl-O-C （１～４） alkyl, and R Ｙ is halo, -C （１～４） alkyl, -C （１～４） haloalkyl, -OC （１～４） alkyl, -OC （１～４） haloalkyl, or -C （１～４） alkyl-O-C （１～４） alkyl, and R １ is hydrogen, -C （１～４） alkyl, or -C （１～４） haloalkyl, or R Ｗ and R １ together with the carbon atom to which they are attached form a C （３～５） cycloalkyl, R ２ is hydrogen or -C （１～４） alkyl, L is absent or -C （１～４） is alkylene or -C （３～６） is cycloalkylene, where the -C （１～４） alkylene and -C （３～６） cycloalkylene are optionally substituted with one to three groups selected from halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -C （１～３） alkyl, -C （１～３） haloalkyl, -C （３～５） cycloalkyl, and -OC （１～３） alkyl, R ３ is -C （１～１０） 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 （６～１０） aryl, 5- to 10-membered heteroaryl, or -C(O)N(R Ｎ３ )(R Ｎ４ ), where the -C （１～１０） 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 （６～１０） aryl, and 5- to 10-membered heteroaryl are each optionally substituted with 1 to 5 R ３ｘ groups, each R ３ｘ is, independently for each occurrence, halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -CN, -C （１～８） alkyl, -C （１～８） haloalkyl, -C （３～８） cycloalkyl, -OC （１～８） alkyl, -OC （１～８） haloalkyl, -OC （３～８） cycloalkyl, -C （１～８） alkylC （３～１０） cycloalkyl, -C （３～１０） cycloalkylC （１～８） alkyl, -C(O)C （１～８） alkyl, -S(O) ２ C （１～８） alkyl, -S(O) ２ C （３～８） cycloalkyl, -N(H)S(O) ２ C （１～８） alkyl, -C （０～８） alkylC(O)N(R Ｎ１ )(R Ｎ２ ), a 3- to 8-membered heterocyclyl, -C （１～８） alkyl(3- to 8-membered heterocyclyl), -C （６～１０） aryl, or a 5- to 10-membered heteroaryl, where the -C （１～８） alkyl, -C （１～８） haloalkyl, -C （３～８） cycloalkyl, -OC （１～８） alkyl, -OC （１～８） haloalkyl, -OC （３～８） cycloalkyl, -C （１～８） alkylC （３～１０） cycloalkyl, -C （３～１０） cycloalkylC （１～８） alkyl, -C(O)C （１～８） alkyl, -S(O) ２ C （１～８） alkyl, -S(O) ２ C （３～８） cycloalkyl, -N(H)S(O) ２ C （１～８） alkyl, a 3- to 8-membered heterocyclyl, -C （１～８） 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 （１～８） alkyl, -C （１～８） haloalkyl, -OC （１～８） alkyl, -OC （１～８） haloalkyl, and 3- to 5-membered heterocyclyl, or R ２ and L-R ３ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally further substituted with 1 to 3 groups selected from halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -CN, -C （１～８） alkyl, and -OC （１～８） alkyl, wherein said -C （１～８） alkyl and -OC （１～８） alkyl are optionally further substituted with 1 to 5 halo groups R ４ is hydrogen, halo, or -C （１～４） alkyl, and R ５ is hydrogen, halo, or -C （１～４） alkyl, and R Ｎ１ and R Ｎ２ are, each time they appear, independently of one another, hydrogen, -C （１～８） alkyl, or -C （１～８） haloalkyl, R Ｎ３ is hydrogen or -C （１～８） alkyl, and R Ｎ４ is hydrogen, -C （１～８） alkyl, or phenyl, or R Ｎ３ and R Ｎ４ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl optionally substituted with 1 to 5 groups selected from halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -CN, -C （１～８） alkyl, -C （１～８） haloalkyl, -OC （１～８） alkyl, and -OC （１～８） haloalkyl, Here, R ３ is, -C(O)N(R Ｎ３ )(R Ｎ４ ) and in this case, a compound of formula I in which L is absent.

2. A is a 5-membered heteroaryl optionally substituted with one or more -C （１～４） alkyl groups, W is CH ２ , CHF, CF ２ , or CHR Ｗ and X is N, C-H, or C-R Ｘ wherein Y is N, C-H, or C-R Ｙ wherein R Ｗ is -C （１～４） alkyl or -C （１～４） haloalkyl, and R Ｘ is a halo, and R Ｙ is halo, -C （１～４） alkyl, -C （１～４） haloalkyl, -OC （１～４） alkyl, -OC （１～４） haloalkyl, or -C （１～４） alkyl-O-C （１～４） alkyl, and R １ is hydrogen, -C （１～４） alkyl, or -C （１～４） haloalkyl, or R Ｗ and R １ together with the carbon atom to which they are attached form a C （３～５） cycloalkyl, R ２ is hydrogen or -C （１～４） alkyl, L is absent or -C （１～４） is alkylene, or -C （３～６） is cycloalkylene, where the -C （１～４） alkylene and -C （３～６） cycloalkylene are optionally substituted with one to three groups selected from halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -C （１～３） alkyl, -C （１～３） haloalkyl, -C （３～５） cycloalkyl, and -OC （１～３） alkyl, R ３ 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 （６～１０） aryl, 5- to 10-membered heteroaryl, or -C(O)N(R Ｎ３ )(R Ｎ４ ), where the -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 （６～１０） aryl, and 5- to 10-membered heteroaryl are each optionally substituted with 1 to 5 R ３ｘ groups. Each R ３ｘ 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, -S(O) ２ C （１～４） alkyl, -S(O) ２ C （３～８） cycloalkyl, -N(H)S(O) ２ C （１～４） alkyl, -C （０～３） alkylC(O)N(R Ｎ１ )(R Ｎ２ ), 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, -C(O)C （１～４） alkyl, -S(O) ２ C （１～４） alkyl, -S(O) ２ C （３～８） cycloalkyl, -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, 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 （１～４） haloalkyl, and 3- to 5-membered heterocyclyl, or R ２ and L-R ３ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally further substituted with one to three groups selected from halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -CN, -C （１～６） alkyl, and -OC （１～６） alkyl, wherein said -C （１～６） alkyl and -OC （１～６） alkyl are optionally further substituted with one to five halo groups, R ４ is hydrogen, halo, or -C （１～４） alkyl, and R ５ is hydrogen, halo, or -C （１～４） alkyl, and R Ｎ１ and R Ｎ２ are, each time they appear, each independently hydrogen, -C （１～３） alkyl, or -C （１～３） haloalkyl, and R Ｎ３ is hydrogen or -C （１～４） alkyl, and R Ｎ４ is hydrogen, -C （１～４） alkyl, or phenyl, or R Ｎ３ and R Ｎ４ together with the nitrogen atom to which they are attached optionally form a 3- to 10-membered heterocyclyl optionally 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 （１～４） haloalkyl, Here, R ３ is -C(O)N(R Ｎ３ )(R Ｎ４ ), and when there is no L, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. A compound of formula I, 【Chemical 2】 or a pharmaceutically acceptable salt thereof, wherein, A is a 5-membered heteroaryl optionally substituted with one or more -C （１～４） alkyl groups and is a 5-membered heteroaryl optionally substituted with one or more -C W is CH ２ , CHF, or CF ２ and X is N or C—H, Y is N, C-H, or C-R Ｙ wherein R Ｙ is a halo, -C （１～４） alkyl, -C （１～４） haloalkyl, -OC （１～４） alkyl, or -OC （１～４） haloalkyl, and R １ is hydrogen, -C （１～４） alkyl, or -C （１～４） haloalkyl, and R ２ is hydrogen or -C （１～４） alkyl, 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 ３ 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 （６～１０） aryl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with 1 to 5 R ３ｘ groups, each R ３ｘ 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, -S(O) ２ C （１～４） alkyl, -N(H)S(O) ２ C （１～４） alkyl, -C （０～３） alkylC(O)N(R Ｎ１ )(R Ｎ２ ), 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, -C(O)C （１～４） alkyl, -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, 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, and -OC （１～４） optionally further substituted with 1 to 5 groups selected from haloalkyl, or R ２ and L-R ３ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally further substituted with one to three groups selected from halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -CN, -C （１～６） alkyl, and -OC （１～６） alkyl, where said -C （１～６） alkyl and -OC （１～６） alkyl are optionally further substituted with one to five halo groups, and R Ｎ１ and R Ｎ２ each independently, upon each occurrence, is hydrogen, -C （１～３） alkyl, or -C （１～３） haloalkyl, a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. A is a 5-membered heteroaryl optionally substituted with one -C （１～４） alkyl group, and W is CH ２ , CF ２ , or CHR Ｗ and R Ｗ is -C （１～４） alkyl, -C （１～４） haloalkyl, or R Ｗ and R １ together with the carbon atom to which they are attached form C （３～５） cycloalkyl, R ２ is hydrogen, and R ３ 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 （６～１０） aryl, 5- to 10-membered heteroaryl, or -C(O)N(R Ｎ３ )(R Ｎ４ ), where the -C （１～６） alkyl is optionally substituted with 1 to 5 R ３ａ groups, the C （３～１０） cycloalkyl is optionally substituted with 1 to 5 R ３ｂ groups, the 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R ３ｃ groups, the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R ３ｄ , the -C （６～１０） aryl is optionally substituted with 1 to 5 R ３ｅ groups, and the 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R ３ｆ groups, Each R ３ａ is, independently at each occurrence, halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -CN, -C （３～８） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, -OC （３～８） cycloalkyl, -S(O) ２ C （１～４） alkyl, -N(H)S(O) ２ C （１～４） alkyl, or 3- to 8-membered heterocyclyl, where the -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, -C （１～４） haloalkyl, -OC （１～４） alkyl, and -OC （１～４） haloalkyl, R ３ｂ 、R ３ｃ 、and R ３ｄ 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, -C （１～３） alkylC （３～１０） cycloalkyl, -C(O)C （１～４） alkyl, -S(O) ２ C （１～４） alkyl, -S(O) ２ C （３～８） cycloalkyl, -N(H)S(O) ２ C （１～４） alkyl, -C （０～３） alkylC(O)N(R Ｎ１ )(R Ｎ２ ), 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, the 3- to 8-membered heterocyclyl, and the 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, and -OC （１～４） haloalkyl), R ３ｅ and R ３ｆ each independently, upon 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, -OC （３～８） cycloalkyl, -C （１～３） alkylC （３～１０） cycloalkyl, -C(O)C （１～４） alkyl, -S(O) ２ C （１～４） alkyl, -N(H)S(O) ２ C （１～４） alkyl, -C （０～３） alkylC(O)N(R Ｎ１ )(R Ｎ２ ), 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, 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 （１～４） haloalkyl, and a 3- to 5-membered heterocyclyl, or R ２ and L-R ３ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one to three groups selected from halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -CN, -C （１～６） alkyl, -C （１～６） haloalkyl, -OC （１～６） alkyl, and -OC （１～６） haloalkyl, and R Ｎ１ and R Ｎ２ each independently represents, at each occurrence, hydrogen or -C （１～３） alkyl, the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

5. A is a 5-membered heteroaryl optionally substituted with one -C （１～４） alkyl group, W is CH ２ or CF ２ and R ２ is hydrogen, and R ３ 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 （６～１０） aryl, 5- to 10-membered heteroaryl, where the -C （１～６） alkyl is optionally substituted with 1 to 5 R ３ａ groups, the C （３～１０） cycloalkyl is optionally substituted with 1 to 5 R ３ｂ groups, the 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R ３ｃ groups, the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R ３ｄ s, the -C （６～１０） aryl is optionally substituted with 1 to 5 R ３ｅ groups, the 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R ３ｆ groups, Each R ３ａ is, each time it appears, independently, halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -CN, -C （３～８） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, -OC （３～８） cycloalkyl, -S(O) ２ C （１～４） alkyl, -N(H)S(O) ２ C （１～４） alkyl, or 3- to 8-membered heterocyclyl, where the -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, -C （１～４） haloalkyl, -OC （１～４） alkyl, and -OC （１～４） haloalkyl, R ３ｂ 、R ３ｃ 、and R ３ｄ 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, -C(O)C （１～４） alkyl, -S(O) ２ C （１～４） alkyl, -N(H)S(O) ２ C （１～４） alkyl, -C （０～３） alkylC(O)N(R Ｎ１ )(R Ｎ２ ), 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, the 3- to 8-membered heterocyclyl, and the 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, and -OC （１～４） haloalkyl), R ３ｅ and R ３ｆ each independently, upon 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, -OC （３～８） cycloalkyl, -C （１～３） alkylC （３～１０） cycloalkyl, -C(O)C （１～４） alkyl, -S(O) ２ C （１～４） alkyl, -N(H)S(O) ２ C （１～４） alkyl, -C （０～３） alkylC(O)N(R Ｎ１ )(R Ｎ２ ), 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, 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, and -OC （１～４） haloalkyl, or R ２ and L-R ３ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one to three groups selected from halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -CN, -C （１～６） alkyl, -C （１～６） haloalkyl, -OC （１～６） alkyl, and -OC （１～６） haloalkyl, and R Ｎ１ and R Ｎ２ each independently represents hydrogen or —C （１～３） alkyl at each occurrence, the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. A is a 5-membered heteroaryl optionally substituted with one -C （１～４） alkyl group, and R Ｙ is -C （１～４） alkyl, -C （１～４） haloalkyl, -OC （１～４） alkyl, or -C （１～４） alkyl -O -C （１～４） alkyl, and R ３ 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 （６～１０） aryl, 5 - to 10 - membered heteroaryl, or -C(O)N(R Ｎ３ )(R Ｎ４ ), where the -C （１～６） alkyl is optionally substituted with 1 to 5 R ３ａ groups, the C （３～１０） cycloalkyl is optionally substituted with 1 to 5 R ３ｂ groups, the 3 - to 10 - membered heterocyclyl is optionally substituted with 1 to 5 R ３ｃ groups, the 5 - to 12 - membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R ３ｄ , and the 5 - to 10 - membered heteroaryl is optionally substituted with 1 to 5 R ３ｆ groups. Each R ３ａ is, each time it appears, independently, halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -CN, -OC （１～６） alkyl, or -OC （１～６） haloalkyl, and R ３ｂ 、 R ３ｃ 、 and R ３ｄ 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, -C （１～３） alkylC （３～１０） cycloalkyl, -S(O) ２ C （１～４） alkyl, or -S(O) ２ C （３～８） cycloalkyl, 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 ), -CN, and -OC （１～４） alkyl, Each R ３ｆ 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 （０～３） alkylC(O)N(R Ｎ１ )(R Ｎ２ ), 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, 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 （１～４） haloalkyl, and a 3- to 5-membered heterocyclyl, or R ２ and L-R ３ together with the nitrogen atom to which they are attached form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally further substituted with one to three groups selected from halo, -OH, -N(RN １ )(RN ２ ), -CN, -C （１～６） alkyl, C （１～６） haloalkyl, -OC （１～６） alkyl, and -OC （１～６） haloalkyl, and R Ｎ１ and R Ｎ２ each independently, upon each occurrence, is hydrogen or -C （１～３） alkyl, the compound according to any one of claims 1, 2 or 4, or a pharmaceutically acceptable salt thereof.

7. A is a 5-membered heteroaryl optionally substituted with one -C （１～４） alkyl group and is R Ｙ is -C （１～４） alkyl, -C （１～４） haloalkyl, or -OC （１～４） alkyl, and R ３ 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 the -C （１～６） alkyl is optionally substituted with 1 to 5 R ３ａ groups, the C （３～１０） cycloalkyl is optionally substituted with 1 to 5 R ３ｂ groups, the 3- to 10-membered heterocyclyl is optionally substituted with 1 to 5 R ３ｃ groups, the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R ３ｄ s, and the 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R ３ｆ groups. Each R ３ａ is, each time it appears, independently, halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), or -CN, R ３ｂ 、 R ３ｃ 、 and R ３ｄ each independently represents, at each occurrence, halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -CN, -C （１～６） alkyl, -C （１～６） haloalkyl, -OC （１～６） alkyl, or -OC （１～６） haloalkyl, wherein 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, -OH, -N(R Ｎ１ )(R Ｎ２ ), and -CN, Each R ３ｆ 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 （０～３） alkylC(O)N(R Ｎ１ )(R Ｎ２ ), a 3- to 8-membered heterocyclyl, -C （１～３） alkyl(3- to 8-membered heterocyclyl), -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, -N(R Ｎ１ )(R Ｎ２ ), -CN, -C （１～４） alkyl, -C （１～４） haloalkyl, -OC （１～４） alkyl, -OC （１～４） haloalkyl, or R ２ and L-R ３ together with the nitrogen atom to which they are attached form a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally further substituted with one to three groups selected from halo, -OH, -N(RN １ )(RN ２ ), -CN, -C （１～６） alkyl, C （１～６） haloalkyl, -OC （１～６） alkyl, and -OC （１～６） haloalkyl, and R Ｎ１ and R Ｎ２ each independently, upon each occurrence, is hydrogen, or -C （１～３） alkyl, a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

8. A is a 5-membered heteroaryl optionally substituted with one -CH ３ group and is W is CH ２ , CF ２ , or CHR Ｗ and R Ｗ is -C （１～４） alkyl, -C （１～４） haloalkyl, or R Ｗ and R １ together with the carbon atom to which they are attached form a C （３～５） cycloalkyl, R ２ is hydrogen, and L is absent or -C （１～４） is alkylene or -C （３～６） is cycloalkylene, where said -C （１～４） alkylene is optionally substituted with 1 to 3 groups selected from halo, -OH, -N(R Ｎ１ )(R Ｎ２ ) and cyclopropyl, R ３ 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, phenyl, a 5 - to 10 - membered heteroaryl, or -C(O)N(R Ｎ３ )(R Ｎ４ ), where the -C （１～６） alkyl is optionally substituted with 1 to 5 R ３ａ groups, the C （３～１０） cycloalkyl is optionally substituted with 1 to 5 R ３ｂ groups, the 3 - to 10 - membered heterocyclyl is optionally substituted with 1 to 5 R ３ｃ groups, the 5 - to 12 - membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R ３ｄ , and the 5 - to 10 - membered heteroaryl is optionally substituted with 1 to 5 R ３ｆ groups, Each R ３ａ is, independently for each occurrence, halo, -OH, -OC （１～６） alkyl, or -OC （１～６） haloalkyl, and Each R ３ｂ is, independently for each occurrence, halo, -OH, -C （１～６） haloalkyl, or -OC （１～６） alkyl, and R ３ｃ is, at 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 （１～３） alkylC （３～１０） cycloalkyl, -S(O) ２ C （１～４） alkyl, or -S(O) ２ C （３～８） cycloalkyl, where the -C （１～６） alkyl, and -OC （１～６） alkyl are optionally further substituted with 1 to 5 groups selected from halo, and -OC （１～４） alkyl, Each R ３ｄ 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, or -C （１～３） alkylC （３～１０） cycloalkyl, and each R ３ｆ 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 （０～３） alkylC(O)N(R Ｎ１ )(R Ｎ２ ), a 3- to 8-membered heterocyclyl, -C （１～３） alkyl(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, -OC （３～８） cycloalkyl, a 3- to 8-membered heterocyclyl, -C （１～３） alkyl(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 ), -C （１～４） alkyl, -C （１～４） haloalkyl, -OC （１～４） alkyl, -OC （１～４） haloalkyl, and a 3- to 5-membered heterocyclyl, or R ２ and L-R ３ together with the nitrogen atom to which they are attached form a 5- to 12-membered bicyclic ring system or a 5- to 10-membered heteroaryl containing one or more heteroatoms, each of which is optionally further substituted with 1 to 3 groups selected from -N(R Ｎ１ )(R Ｎ２ ) and -C （１～６） alkyl; R Ｎ１ and R Ｎ２ each independently represents hydrogen or —C （１～３） alkyl each time it appears, R Ｎ３ is hydrogen or -C （１～４） alkyl, and R Ｎ４ is hydrogen, -C （１～４） alkyl, or phenyl, or R Ｎ３ and R Ｎ４ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl optionally substituted with 1 to 5 groups selected from halo, -C （１～４） alkyl, and -C （１～４） haloalkyl, a compound according to any one of claims 1, 2, 4 or 6, or a pharmaceutically acceptable salt thereof.

9. A is a 5-membered heteroaryl, W is CH ２ , or CF ２ and R ２ is hydrogen, and L is absent or -C （１～４） alkylene, or -C （３～６） is cycloalkylene, R ３ 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, wherein the -C （１～６） alkyl is optionally substituted with 1 to 5 halo groups, the C （３～１０） cycloalkyl is optionally substituted with 1 to 5 OH groups, the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R ３ｄ , and the 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R ３ｆ groups. Each R ３ｄ 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 ３ｆ is, independently for each occurrence, halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -C （１～６） alkyl, -C （１～６） haloalkyl, -C （３～８） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, -OC （３～８） cycloalkyl, a 3- to 8-membered heterocyclyl, or -C （１～３） alkyl(3- to 8-membered heterocyclyl), 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, and -C （１～３） alkyl(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, and -OC （１～４） haloalkyl, or R ２ and L-R ３ together with the nitrogen atom to which they are attached form a 5- to 12-membered bicyclic ring system or a 5- to 10-membered heteroaryl containing one or more heteroatoms, each of which is optionally further substituted with 1 to 3 groups selected from -N(R Ｎ１ )(R Ｎ２ ) and -C （１～６） alkyl, R Ｎ１ and R Ｎ２ each independently, upon each occurrence, is hydrogen or -C （１～３） alkyl, a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

10. A is pyrazolyl, imidazolyl, triazolyl, thiazolyl, isoxazolyl, thiazolyl, or thiadiazolyl, and the pyrazolyl is optionally substituted with one -CH ３ group, W is CH ２ , CF ２ , or CHR Ｗ , where when W is CHR Ｗ , R Ｗ and R １ together with the carbon atom to which they are attached form a C （３～５） cycloalkyl, R Ｘ is fluorine, and R Ｙ is CH ３ , -CHF ２ , -CF ３ , -OCH ３ , or -CH ２ OCH ３ and R １ is hydrogen, -CH ３ or -CF ３ and R ２ is hydrogen, and L is absent or -C （１～４） is alkylene or -C （３～６） is cycloalkylene, where the -C （１～４） alkylene is optionally substituted with 1 to 3 groups selected from halo, -OH, -N(R Ｎ１ )(R Ｎ２ ) and cyclopropyl, R ３ 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, phenyl, a 5 - to 10 - membered heteroaryl, or -C(O)N(R Ｎ３ )(R Ｎ４ ), where the -C （１～６） alkyl is optionally substituted with 1 to 5 R ３ａ atoms, the C （３～１０） cycloalkyl is optionally substituted with 1 to 5 R ３ｂ groups, the 3 - to 10 - membered heterocyclyl is optionally substituted with 1 to 5 R ３ｃ groups, the 5 - to 12 - membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R ３ｄ groups, and the 5 - to 10 - membered heteroaryl is optionally substituted with 1 to 5 R ３ｆ groups, Each R ３ａ is, each time it appears, independently, halo, ～ OH, -OC （１～６） alkyl, Each R ３ｂ is, each time it appears, independently, halo, -OH, -C （１～６） haloalkyl, or -OC （１～６） alkyl, and Each R ３ｃ is, independently at each occurrence, halo, -C （１～６） alkyl, -C （１～６） haloalkyl, -C （３～８） cycloalkyl, -OC （１～６） alkyl, -S(O) ２ C （１～４） alkyl, or -S(O) ２ C （３～８） cycloalkyl, 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 -OC （１～４） alkyl, Each R ３ｄ is, each time it appears, independently, -C （１～６） alkyl, -C （１～６） haloalkyl, or -C （１～３） alkylC （３～１０） cycloalkyl, Each R ３ｆ 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 （０～３） alkylC(O)N(R Ｎ１ )(R Ｎ２ ), a 3- to 8-membered heterocyclyl, -C （１～３） alkyl(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, -OC （３～８） cycloalkyl, a 3- to 8-membered heterocyclyl, -C （１～３） alkyl(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 ), -C （１～４） alkyl, -C （１～４） haloalkyl, -OC （１～４） alkyl, -OC （１～４） haloalkyl, and a 3- to 5-membered heterocyclyl, or R ２ and L-R ３ together with the nitrogen atom to which they are attached form a 5- to 12-membered bicyclic ring system or a 5- to 10-membered heteroaryl containing one or more heteroatoms, each of which is optionally further substituted with 1 to 3 groups selected from -N(R Ｎ１ )(R Ｎ２ ) and -C （１～６） alkyl R ４ is hydrogen, chlorine, fluorine, or -CH ３ and R ５ is hydrogen, chlorine, fluorine, or -CH ３ and R Ｎ１ and R Ｎ２ each independently represents hydrogen or -C （１～３） alkyl every time it appears, R Ｎ３ is hydrogen or -C （１～４） alkyl, and R Ｎ４ is hydrogen, -C （１～４） alkyl, or phenyl, or R Ｎ３ and R Ｎ４ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl optionally substituted with 1 to 5 groups selected from halo, -C （１～４） alkyl, and -C （１～４） haloalkyl, a compound according to any one of claims 1, 2, 4, 6 or 8, or a pharmaceutically acceptable salt thereof.

11. A is pyrazolyl, triazolyl, thiazolyl, or isoxazolyl, W is CH ２ or CF ２ and Y is C-H or C-R Ｙ wherein R Ｙ is -CF ３ and R １ is hydrogen or -CH ３ and R ２ is hydrogen, and L is absent or -C （１～４） alkylene, or -C （３～６） is cycloalkylene, R ３ 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, wherein the -C （１～６） alkyl is optionally substituted with 1 to 5 fluorine atoms, the C （３～１０） cycloalkyl is optionally substituted with 1 OH group, the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 -C （１～６） alkyl groups, and the 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R ３ｆ groups, Each R ３ｆ is, independently for each occurrence, -N(R Ｎ１ )(R Ｎ２ ), -C （１～６） alkyl, -C （１～６） haloalkyl, -C （３～８） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, -OC （３～８） cycloalkyl, a 3- to 8-membered heterocyclyl, or -C （１～３） alkyl(3- to 8-membered heterocyclyl), 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, and -C （１～３） alkyl(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, and -OC （１～４） haloalkyl, or R ２ and L-R ３ together with the nitrogen atom to which they are attached form a 5- to 12-membered bicyclic ring system or a 5- to 10-membered heteroaryl containing one or more heteroatoms, each of which is optionally further substituted with 1 to 3 groups selected from -N(R Ｎ１ )(R Ｎ２ ) and -C （１～６） alkyl R Ｎ１ and R Ｎ２ each independently represents hydrogen or —C （１～３） alkyl upon each occurrence, the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein A is triazolyl or isoxazolyl.

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

14. A is [Chemical Formula 3] The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, which is a compound of formula Ib-1. 【Chemical Formula 4】

16. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, which is a compound of formula Ib-2. 【Chemical Formula 5】

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

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

19. Y is N, C-H, C-CH ３ , C-CHF ２ , C-CF ３ , C-OCH ３ , or C-CH ２ OCH ３ and is a compound according to any one of claims 1, 2, 4 to 6, 8 to 10, or 12 to 18, or a pharmaceutically acceptable salt thereof.

20. Y is C—H or C—CF ３ The compound according to any one of claims 1 to 10 or 12 to 19, or a pharmaceutically acceptable salt thereof, wherein Y is C—H or C—CF

21. The compound according to any one of claims 1 to 14 or 18 to 20, or a pharmaceutically acceptable salt thereof, which is a compound of formula Ic-1. 【Chemical Formula 7】

22. The compound according to any one of claims 1 to 14 or 18 to 20, or a pharmaceutically acceptable salt thereof, which is a compound of formula Ic-2. [Chemical Formula 8]

23. R １ is hydrogen or -CF ３ and is a compound according to any one of claims 1 to 10 or 12 to 22, or a pharmaceutically acceptable salt thereof.

24. The compound according to any one of claims 1, 2, 4, 6, 8, 10, 12 to 14 or 18 to 20, or a pharmaceutically acceptable salt thereof, which is any one compound of formulas Id-1 to Id-7. 【Chemical Formula 9】

25. The compound according to any one of claims 1 to 14, 18 to 20, or 23, or a pharmaceutically acceptable salt thereof, which is any one compound of formulas Id-1 to Id-5. 【Chemical Formula 10】

26. L is absent or -C （１～４） alkylene or -C （３～６） is cycloalkylene, and said -C （１～４） alkylene is optionally substituted with 1 to 3 groups selected from halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), and cyclopropyl, the compound according to any one of claims 1, 2, 4, or 6, or a pharmaceutically acceptable salt thereof.

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

28. L is absent or 【Chemical Formula 11】 The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.

29. The compound according to any one of claims 1 to 14, 18 to 20, 23, or 26 to 28, which is any one compound of Formula Ie-1 to Formula Ie-10, or a pharmaceutically acceptable salt thereof. 【Chemical Formula 12】

30. The compound according to any one of claims 1 to 14, 18 to 20, 23, or 26 to 28, which is any one compound of Formula If-1 to Formula If-10, or a pharmaceutically acceptable salt thereof. 【Chemical 13】

31. R ３ wherein R is optionally substituted with 1 to 5 R ３ａ groups and is -C （１～６） alkyl, a compound according to any one of claims 4 to 8, 10, or 12 to 30, or a pharmaceutically acceptable salt thereof.

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

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

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

35. R ３ is 【Chemical Formula 14】 The compound according to any one of claims 1 to 6, 8, or 12 to 31, or a pharmaceutically acceptable salt thereof.

36. R ３ is 【Chemical 15】 The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof.

37. R ３ wherein 1 to 5 R ３ｂ groups are optionally substituted on -C （３～１０） cycloalkyl, the compound according to any one of claims 4 to 8, 10, or 12 to 30, or a pharmaceutically acceptable salt thereof.

38. R ３ wherein 1 to 3 R ３ｂ groups are optionally substituted -C （３～６） cycloalkyl, a compound according to any one of claims 4 to 8, 10, 12 to 30, or 37, or a pharmaceutically acceptable salt thereof.

39. R ３ wherein R is cyclopentyl optionally substituted with 1 to 3 R groups, the compound according to any one of claims 4 to 8, 10, 12 to 30, 37, or 38, or a pharmaceutically acceptable salt thereof. ３ｂ ​

40. Each R ３ｂ 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, a compound according to any one of claims 4 to 8, 10, 12 to 30, or 37 to 39, or a pharmaceutically acceptable salt thereof.

41. R ３ｂ is, each time of appearance, independently, halo, -OH, -C （１～６） haloalkyl, or -OC （１～６） alkyl, a compound according to any one of claims 4 to 8, 10, 12 to 30, or 37 to 40, or a pharmaceutically acceptable salt thereof.

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

43. R ３ is 【Chemical 16】 The compound according to any one of claims 1 to 8, 10, 12 to 30, 37, or 38, or a pharmaceutically acceptable salt thereof.

44. R ３ is 【Chemical 17】 The compound according to any one of claims 1 to 30 or 37 to 43, or a pharmaceutically acceptable salt thereof.

45. R ３ is a 3- to 10-membered heterocyclyl optionally substituted with 1 to 5 R ３ｃ groups, a compound according to any one of claims 4 to 8, 10, or 12 to 30, or a pharmaceutically acceptable salt thereof.

46. R ３ｃ is, each time it appears, independently, halo, -C （１～６） alkyl, -C （１～６） haloalkyl, -C （３～８） cycloalkyl, -OC （１～６） alkyl, -S(O) ２ C （１～４） alkyl, or -S(O) ２ C （３～８） cycloalkyl, and wherein the -C （１～６） alkyl and -OC （１～６） alkyl are each optionally further substituted with from 1 to 5 groups selected from halo and -OC （１～４） alkyl, the compound according to any one of claims 4, 6, 8, 10, 12 to 30, or 45, or a pharmaceutically acceptable salt thereof.

47. R ３ is 【Chemical Formula 18】 The compound according to any one of claims 1, 2, 4, 6, 8, 10, 12 to 30, 45, or 46, or a pharmaceutically acceptable salt thereof.

48. R ３ is 【Chemical 19】 The compound according to any one of claims 1 to 30 or 45 to 47, or a pharmaceutically acceptable salt thereof.

49. R ３ 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 ３ｄ groups, the compound according to any one of claims 4 to 10 or 12 to 30, or a pharmaceutically acceptable salt thereof.

50. R ３ 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 ３ｄ groups, a compound according to any one of claims 4 to 30 or 49, or a pharmaceutically acceptable salt thereof.

51. R ３ is a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, and is optionally substituted with 1 to 5 R ３ｄ groups, and the 5- to 12-membered bicyclic ring system is a 5,6-fused ring system, the compound according to any one of claims 4 to 30, 49, or 50, or a pharmaceutically acceptable salt thereof.

52. Each R ３ｄ is, each time of appearance, 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, a compound according to any one of claims 4 to 8, 10, 12 to 30, or 49 to 51, or a pharmaceutically acceptable salt thereof.

53. R ３ｄ is, each time of appearance, independently, -C （１～６） alkyl, -C （１～６） haloalkyl, or -C （１～３） alkylC （３～１０） cycloalkyl, a compound according to any one of claims 4, 6, 8, 10, 12 to 30, or 49 to 52, or a pharmaceutically acceptable salt thereof.

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

55. R ３ is 【Chemical 20】 The compound according to any one of claims 1, 2, 4, 6, 8, 10, 12 to 30, or 49 to 54, or a pharmaceutically acceptable salt thereof.

56. R ３ is 【Chemical 21】 The compound according to any one of claims 1 to 30 or 49 to 55, or a pharmaceutically acceptable salt thereof.

57. R ３ wherein R is a 5- to 10-membered heteroaryl optionally substituted with 1 to 5 R groups ３ｆ The compound according to any one of claims 4 to 30, or a pharmaceutically acceptable salt thereof.

58. R ３ 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 ３ｆ groups, the compound according to any one of claims 4 to 30, or 57, or a pharmaceutically acceptable salt thereof.

59. R ３ is pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or a 9-membered fused nitrogen-containing bicyclic heteroaryl, each of which is optionally substituted with 1 to 3 R ３ｆ groups, a compound according to any one of claims 4 to 30, 57, or 58, or a pharmaceutically acceptable salt thereof.

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

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

62. R ３ is 【Chemical 22】 【Chemical 23】 The compound according to any one of claims 4 to 30 or 57 to 61, or a pharmaceutically acceptable salt thereof.

63. R ３ is 【Chemical 24】 The compound according to any one of claims 4 to 30 or 57 to 62, or a pharmaceutically acceptable salt thereof.

64. each R ３ｆ 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 （０～３） alkylC(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, 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, -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, -N(R Ｎ１ )(R Ｎ２ ), -CN, -C （１～４） alkyl, -C （１～４） haloalkyl, -OC （１～４） alkyl, and -OC （１～４） haloalkyl, a compound according to any one of claims 4 to 6, 12 to 30, or 57 to 63, or a pharmaceutically acceptable salt thereof.

65. each R ３ｆ 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 （０～３） alkylC(O)N(R Ｎ１ )(R Ｎ２ ), a 3- to 8-membered heterocyclyl, -C （１～３） alkyl(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, -C （１～３） alkyl(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 ), -C （１～４） alkyl, -C （１～４） haloalkyl, -OC （１～４） alkyl, -OC （１～４） haloalkyl, and a 3- to 5-membered heterocyclyl, the compound according to any one of claims 4, 6, 8, 10, 12 to 30, or 57 to 63, or a pharmaceutically acceptable salt thereof.

66. Each R ３ｆ is, each time it appears, independently, halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -C （１～６） alkyl, -C （１～６） haloalkyl, -C （３～８） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, -OC （３～８） cycloalkyl, a 3- to 8-membered heterocyclyl, or -C （１～３） alkyl(3- to 8-membered heterocyclyl), 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, and -C （１～３） alkyl(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, and -OC （１～４） haloalkyl, a compound according to any one of claims 4 to 8, 12 to 30, or 57 to 65, or a pharmaceutically acceptable salt thereof.

67. Each R ３ｆ is, independently at each occurrence, -C （１～６） alkyl, -O （３～８） cycloalkyl, -OC （１～６） alkyl, or -OC （３～８） cycloalkyl, each of which is optionally further substituted with 1 to 5 groups selected from fluorine and -OH, the compound according to any one of claims 4 to 30, or 57 to 65, or a pharmaceutically acceptable salt thereof.

68. R ３ｆ appears independently each time 【Chemical 25】 The compound according to any one of claims 4, 6, 8, 10, 12 to 30, or 57 to 63, or a pharmaceutically acceptable salt thereof.

69. R ３ｆ appears independently each time 【Chemical 26】 The compound according to any one of claims 4 to 30, 57 to 63, or 68, or a pharmaceutically acceptable salt thereof.

70. R ３ is 【Chemical 27】 【Chemical Formula 28】 The compound according to any one of claims 1, 2, 4, 6, 8, 10, 12 to 30, or 57 to 59, or a pharmaceutically acceptable salt thereof.

71. R ３ is 【Chemical Formula 29】 The compound according to any one of claims 1, 2, 4, 6, 8, 10, 12 to 30, or 57 to 59, or a pharmaceutically acceptable salt thereof.

72. R ３ is 【Chemical 30】 The compound according to any one of claims 1, 2, 4, 6, 8, 10, 12 to 30, or 57 to 59, or a pharmaceutically acceptable salt thereof.

73. R ３ is 【Chemical 31】 The compound according to any one of claims 1, 2, 4, 6, 8, 10, 12 to 30, or 57 to 59, or a pharmaceutically acceptable salt thereof.

74. R ３ is 【Chemical 32】 The compound according to any one of claims 1 to 30, or 57 to 59, or a pharmaceutically acceptable salt thereof.

75. R ２ and L-R ３ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl, a 5- to 12-membered bicyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one to three groups selected from halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -CN, -C （１～６） alkyl, C （１～６） haloalkyl, -OC （１～６） alkyl, and -OC （１～６） haloalkyl, the compound according to any one of claims 1 to 5, or 12 to 30, or a pharmaceutically acceptable salt thereof.

76. R ２ and L-R ３ together with said nitrogen atom to which they are attached form a 5,6-fused bicyclic ring system or a 5-membered heteroaryl containing one or more heteroatoms, each of which is -N(R Ｎ１ )(R Ｎ２ ) and -C （１～６） optionally substituted with 1 to 3 groups selected from alkyl, a compound according to any one of claims 1 to 30 or 75, or a pharmaceutically acceptable salt thereof.

77. R ２ and L-R ３ together with the nitrogen atom to which they are attached 【Chemical 33】 The compound according to any one of claims 1 to 30, 75 or 76, or a pharmaceutically acceptable salt thereof, which forms

78. R ２ and L-R ３ together with the nitrogen atom to which they are attached 【Chemical 34】 The compound according to any one of claims 1 to 30, or 75 to 77, or a pharmaceutically acceptable salt thereof, which forms

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

80. R Ｎ３ is hydrogen or -CH ３ and R Ｎ４ is hydrogen, -CH ３ , or phenyl, or R Ｎ３ and R Ｎ４ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl optionally substituted with 1 to 5 groups selected from fluorine, -CH ３ , and -CF ３ The compound according to any one of claims 1, 2, 4, 6, 8, 10, 12 to 30, or 79, or a pharmaceutically acceptable salt thereof.

81. R ３ is 【Chemical 35】 The compound according to any one of claims 1, 2, 4, 6, 8, 10, 12 to 30, 79, or 80, or a pharmaceutically acceptable salt thereof.

82. R ４ is hydrogen, chlorine, fluorine, or -CH ３ and R ５ is hydrogen, chlorine, fluorine, or -CH ３ and is a compound according to any one of claims 1, 2, 4, 6, 8, 10, or 12 to 14, 18 to 20, 23, 26 to 28, or 30 to 81, or a pharmaceutically acceptable salt thereof.

83. R １ is hydrogen, and R ５ is hydrogen, R ４ is fluorine, and R ５ is hydrogen, R ４ is -CH ３ and R ５ is hydrogen, R ４ is hydrogen and R ５ is chlorine or R １ is hydrogen and R ５ is -CH ３ The compound according to any one of claims 1, 2, 4, 6, 8, 10, or 12 to 14, 18 to 20, 23, 26 to 28, or 30 to 81, or a pharmaceutically acceptable salt thereof.

84. The compound according to any one of claims 1 to 14, 18 to 20, 23, 26 to 28, or 30 to 81, which is a compound of formula Ih, or a pharmaceutically acceptable salt thereof. 【Chemical 36】

85. The compound according to claim 84, which is a compound of any one of formulas Ih-1 to Ih-3, or a pharmaceutically acceptable salt thereof. 【Chemical 37】

86. A compound of formula Ig-1, wherein 【Chemical 38】 In the formula, W is CH ２ , or CF ２ and X is N or C—H. R １ is hydrogen, and R ２ is hydrogen, and L is absent or is -C （１～４） is an alkylene, R ３ is a 5- to 10-membered heteroaryl, optionally substituted with 1 to 5 R ３ｅ groups, Each R ３ｅ is independently, -C （１～６） alkyl, -O （３～８） cycloalkyl, -OC （１～６） alkyl, or -OC （３～８） cycloalkyl, each of which is optionally further substituted with 1 to 5 groups selected from fluorine and -OH, the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

87. A compound of formula Ii, wherein 【Chemical Formula 39】 In the formula, A is triazolyl or isoxazolyl, X is N or C—H. R ３ is a 5-membered heterocyclyl, optionally substituted with 1 to 5 R ３ｅ groups, Each R ３ｅ independently is -C （１～６） alkyl, -O （３～８） cycloalkyl, -OC （１～６） alkyl, or -OC （３～８） cycloalkyl, each of which is optionally further substituted with 1 to 5 groups selected from fluorine and -OH, R ５ is protium ( １ H), or deuterium ( ２ H), the compound according to any one of claims 1, 2, 4, 6, 8, or 10, or a pharmaceutically acceptable salt thereof.

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

89. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, having a structure selected from the group consisting of the following. 【Chemical 40】 【Chemical 41】 【Chemical 42】 【Chemical 43】 【Chemical Formula 44】 【Chemical 45】 【Chemical 46】

90. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, having a structure selected from the group consisting of the following. 【Chemical 47】 【Chemical 48】

91. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, having a structure selected from the group consisting of the following. 【Chemical 49】

92. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, having the following structure. 【Chemical Formula 50】

93. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, having the following structure. 【Chemical 51】

94. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, having the following structure. 【Chemical 52】

95. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, having the following structure. 【Chemical Formula 53】

96. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, having the following structure. 【Chemical 54】

97. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, having the following structure. 【Chemical 55】

98. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, having the following structure. 【Chemical 56】

99. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, having the following structure. 【Chemical 57】

100. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, having the following structure. 【Chemical 58】

101. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, having the following structure. 【Chemical Formula 59】

102. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, having the following structure. 【Chemical Formula 60】

103. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, having the following structure. 【Chemical Formula 61】

104. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, having the following structure. 【Chemical Formula 62】

105. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, having the following structure. 【Chemical Formula 63】

106. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, having the following structure. 【Chemical Formula 64】

107. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, having the following structure. 【Chemical 65】

108. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, having the following structure. 【Chemical Formula 66】

109. The compound according to claim 88 having the following structure, or a pharmaceutically acceptable salt thereof. 【Chemical 67】

110. The compound according to claim 88 having the following structure, or a pharmaceutically acceptable salt thereof. 【Chemical Formula 68】

111. The compound according to claim 88 having the following structure, or a pharmaceutically acceptable salt thereof. 【Chemical Formula 69】

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

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

114. The method according to claim 113, wherein the disease, disorder or medical condition mediated by NIK activity is selected from the group consisting of inflammatory disorders and autoimmune disorders.

115. The method according to claim 114, wherein the disease, disorder or medical condition mediated by NIK activity is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, and lupus nephritis.

116. The method according to claim 113, 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.

117. 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 113.

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