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

Abstract

The present disclosure relates to compounds of formula (I) that inhibit NIK, pharmaceutical compositions containing such compounds, and methods of using the same. These compounds and pharmaceutical compositions are useful for preventing or treating diseases such as inflammatory and autoimmune disorders. 【Chemical 1】 TIFF2025516597000505.tif22128

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 364,552, filed May 11, 2022, which is incorporated herein by reference in its entirety.

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

Background Art

[0003] NF - κB - inducing kinase (NIK) is a serine / threonine kinase transcription factor that regulates the expression of various genes involved in immune response disorders. Due to this role in immune system regulation, inhibition of NIK blocks some downstream pathways that produce inflammatory molecules. Clinical validation with 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 discloses a compound of formula I:

[0006]

Chemical Formula

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

[0008] This application also discloses a method for treating a disease, disorder, or medical condition mediated by NIK activity, the method comprising administering to a subject in need of such treatment an effective amount of (i) a compound of Formula I or a pharmaceutically acceptable carrier thereof, or (ii) a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In some embodiments, the disease, disorder, or medical condition mediated by NIK activity is selected from the group consisting of inflammatory disorders, autoimmune disorders, cancer, metabolic disorders, and osteoporosis. In some embodiments, the disease, disorder, or medical condition mediated by NIK activity is systemic lupus erythematosus ("SLE"), rheumatoid arthritis ("RA"), Sjogren'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, 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, selected from the group consisting of.

[0009] Additional embodiments, features, and advantages of the present disclosure will become apparent from the following "DETAILED DESCRIPTION" and through the practice of the present invention.

Mode for Carrying Out the Invention

[0010] The discussions of documents, operations, materials, devices, articles, etc. included in this specification are for providing the context of the present disclosure. Such discussions do not admit that any or all of these things constitute a part of the prior art with respect to any of the inventions disclosed or claimed.

[0011] (NF-κB-inducing kinase, referred to as NIK and also well-known as MAP3K14) is a regulator and driver of non-standard 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.

[0012] 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 weak inducer of apoptosis (TWEAK) cytokine, and receptor activator of nuclear factor kappa-B ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11). NIK has been shown to be required for 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 a non-canonical pathway is stimulated by a ligand under pathological / abnormal conditions, the activated receptor is thought to compete here for TRAF (TNF receptor-associated factor), dissociating the TRAF-BIRC3-NIK complex, thereby increasing the level of NIK (for a more detailed analysis of this context, see, for example, S.-C. Sun (cited above) as well as 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.

[0013] BAFF / BAFF-R is a clinically validated therapeutic target whose inhibition is thought to be beneficial for the treatment of systemic lupus erythematosus (SLE). Belimumab (anti-BAFF antibody) is approved for treating serum-positive SLE patients (S.V. Navarra, et al., The Lancet, 2011; 377(9767): 721-31). The CD40L / CD40 pathway plays an important role in T cell-dependent B cell activation, dendritic cell maturation, and tissue inflammation / immunity (R. Elgueta, et al., Immunol. Rev. 2009; 229(1): 152-72). Anti-CD40L 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 defects in non-canonical activation pathways of NIK such as the BAFF and CD40L pathways, reduction of B lymphocytes in peripheral blood, and reduction of lymphoid organs, as well as decreased T cell-dependent antibody responses bearing NIK as a therapeutic target for SLE.

[0014] NIK has been characterized as "important in the immune and bone destructive components of inflammatory arthritis and a potential 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 genetically induced spontaneous forms of arthritis generated in mice expressing both the KRN T cell receptor and H-2g7. Transgenic mice with OC-lineage expression of NIK lacking the TRAF3-binding domain (NT3) were used to demonstrate that constitutive activation of NIK drives enhanced osteoclast formation and bone resorption in both basal conditions and in 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 in response to inflammatory stimuli. (C. Yang, et al., PLoS ONE 2010, 5(11):e15383, doi:10.1371 / journal.pone.0015383).

[0015] 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).

[0016] Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the case where they are not, the specific terms used herein have the meaning set forth herein.

[0017] For the benefit of the reader of this application, the description is divided into various paragraphs or sections or is directed to various embodiments of this application. These separations should not be regarded as separating the substance of a paragraph or section or embodiment from the substance of another paragraph or section or embodiment. On the contrary, one of ordinary skill in the art will understand that this description has broad applications and encompasses all combinations of the various sections, paragraphs, and passages that can be contemplated. The consideration of any embodiment is intended to be merely illustrative and is not intended to suggest that the scope of this disclosure, including the claims, is limited to these examples.

[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 shown in this specification are not modified by the term "about". Whether or not the term "about" is explicitly used, all amounts shown in this specification are meant to refer to the actual given value, and also mean to refer to approximations of such given values that are 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] With respect to the method of the present invention, the term "administering" means a method for prophylactically, therapeutically, or improvingly treating a syndrome, disorder, or disease described herein by using a compound of the present disclosure or a pharmaceutically acceptable salt thereof, a composition thereof, or a pharmaceutical thereof. Such methods include administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, a composition thereof, or a pharmaceutical thereof at different time points during the treatment process, or simultaneously or sequentially as a combination therapy.

[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 (NHP) such as cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys or apes, humans, etc., 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, as sought by a researcher, veterinarian, physician, or other clinician, including preventing, treating, or improving the symptoms of a syndrome, disorder, or disease being treated.

[0024] As used herein, the terms "treatment" or "treating" refer 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 patient having a disorder or disease, its symptoms, or a patient having a potential to develop such a disorder or disease as described herein, or the application or administration of a therapeutic agent to an isolated tissue or cell line derived from a patient (e.g., for diagnostic or ex vivo (in vitro) applications), the purpose of which application or administration is to cure, heal, relieve, alleviate, change, 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 terms "prevent" or "prevention" mean that in the case where the onset of a disorder or disease has not occurred, there is no onset of the disorder or disease at all, or in the case where the onset of a disorder or disease has already occurred, there is no onset of further disorder or disease. The ability of an individual to prevent some or all of the symptoms associated with a disorder or disease is also considered.

[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 that exists as a prefix root containing a to b (including the boundary values) 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 1 to 12 carbon atoms (i.e., (C 1 ~C 12), 1 to 6 carbon atoms (i.e., (C 1 ~C 6 ), 1 to 4 carbon atoms (i.e., (C 1 ~C 4 ), or 1 to 3 carbon atoms (i.e., (C 1 ~C 3 ), may be possessed. 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 mentioned, but not limited thereto. In one embodiment, the alkyl is C (1~6) alkyl. In another embodiment, the alkyl is C (1~4) alkyl. In another embodiment, the alkyl is C (1~3) alkyl.

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

[0029] The term "haloalkyl" refers to a linear or branched alkyl group having 1 to 12 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms in the chain, and optionally having one or more H 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 (CHFCF3 ) Monofluoroethyl (CH 2 CH 2 F), trifluoroethyl (CH 2 CF 3 ), tetrafluorotrifluoromethyl ethyl (CF(CF 3 )) 2 ), and groups that are considered to be equivalent to any one of the foregoing examples based on ordinary skill in the art and the teachings provided herein. In another embodiment, alkyl refers to C (1~6) haloalkyl. In another embodiment, haloalkyl refers to C (1~4) haloalkyl. In another embodiment, alkyl refers to C (1~3) haloalkyl.

[0030] The term "cycloalkyl" refers to, for example, a saturated or partially unsaturated all-carbon ring system having 3 to 10 carbon atoms (i.e., C (3~10) cycloalkyl), 3 to 8 carbon atoms (i.e., C (3~8) cycloalkyl), or 3 to 6 carbon atoms (i.e., C (3~6) cycloalkyl), where the cycloalkyl ring system has 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. For example, but not limited to, an example of a spiropentyl group is

[0031]

Chemical formula

[0032]

Chemical formula

[0033] [Chemical formula] include, for example, but not limited to, examples of a cyclooctyl group are

[0034] [Chemical formula] are included. 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.

[0035] The term "aryl" refers to a polyunsaturated, typically aromatic hydrocarbon group, unless otherwise specified, which may 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.

[0036] The terms "heterocyclyl" or "heterocycloalkyl" refer 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.

[0037] As used herein, the term "5-to 12-membered bi- or tricyclic ring system containing one or more heteroatoms" has 5 to 12 ring members (or 7 to 12 ring members or 7 to 10 ring members), which contains carbon atoms and 1 to 7 heteroatoms, 1 to 5 heteroatoms, 1 to 4 heteroatoms, or 1 to 3 heteroatoms, and the heteroatoms are independently selected from the group consisting of N, O, and S, and refers to a saturated or partially saturated bridged polycyclic, fused polycyclic, or spiro polycyclic ring system. The ring system may include a completely unsaturated aromatic ring, but 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 described, the bi- or tricyclic ring system is bonded to its pendant groups and any heteroatoms or carbon atoms that result in a stable structure. In one embodiment, the 5-to 12-membered bi- or tricyclic ring system containing one or more heteroatoms refers to a 5-to 12-membered bicyclic ring system containing one or more heteroatoms.In another embodiment, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms refers to a 7- to 12-membered bicyclic ring system containing one or more heteroatoms. In another embodiment, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms refers to a 7- to 10-membered bicyclic ring system containing one or more heteroatoms.

[0038] The term "heteroaryl" refers to a monocyclic or bicyclic aryl ring system having 5 to 12 ring members, 5 to 10 ring members, or 5 to 6 ring members, which contains carbon atoms and 1 to 5 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms, and the heteroatoms are independently selected from the group consisting of N, O, and S. Included within the term heteroaryl are 5- or 6-membered aromatic rings, where the ring consists of carbon atoms and has at least 1 heteroatomic member. Suitable heteroatoms include nitrogen, oxygen, and sulfur. In some embodiments, in the case of a 5-membered ring, the heteroaryl ring contains 1 member of nitrogen, oxygen, or sulfur and, in addition, up to 3 additional nitrogens. In some embodiments, in the case of a 6-membered ring, the heteroaryl ring contains 1 to 3 nitrogen atoms. When the 6-membered ring has 3 nitrogen atoms, at most 2 nitrogen atoms are adjacent. Examples of heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzoisoxazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinazoline, pyrazolopyridinyl, and pyrazolopyrimidinyl. One of ordinary skill in the art will recognize that the listed species of heteroaryl groups are not comprehensive and that additional species within the scope of these defined terms may also be selected. Unless otherwise stated, 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.

[0039] 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 system, the substitution is meant to occur at any position where the valence is tolerated in that system.

[0040] 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.

[0041] "Diastereoisomer" is a stereoisomer that has at least two asymmetric atoms but is not a mirror image of each other.

[0042] "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.

[0043] When a mixture of stereoisomers results from a process for preparing a compound according to the present disclosure, these isomers may be separated by conventional techniques such as preparative chromatography. These compounds may be prepared in racemic form, and the scalemic mixture or individual enantiomers may be prepared by either enantioselective synthesis or resolution. These compounds may be resolved, for example, into their constituent enantiomers by formation of diastereomeric pairs by forming salts, e.g., with an optically active acid such as (-)-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.

[0044] Absolute stereochemistry is assigned according to the Cahn-Ingold-Prelog R-S system. Chiral centers with a known absolute configuration are designated with the prefixes R and S assigned by standard sequence rule procedures, and, if necessary, appropriate locants precede (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", in the following methods and characterizations, unless otherwise specified, regardless of the order in which the IUPAC name or chemical structure of the compound is presented, Example X may be either the R enantiomer or the S enantiomer, and Example Y is the opposite enantiomer.

[0045] 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 accomplished 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 later stage using methods well known in the art.

[0046] Furthermore, within the scope of the present disclosure, especially when referring 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 produced synthetically, in any natural abundance or isotopically enriched form. For example, reference to hydrogen or "H" is intended, within its scope, to 1 include H, 2 H (i.e., deuterium or D), and 3 H (i.e., tritium or T). In some embodiments, the compounds described herein include 2 H (i.e., deuterium) isotopes. By way of example, a group denoted as -C (1~6) alkyl includes not only -C 1 H 3 but also C 1 HD 2 C 1 H 2 D, CD 3 and other isotopic forms, and a group denoted as C 1 H 2 C 1 H 3 includes not only C 1 HDC 1 HD 2 C 1 HDC 1 H 2 D, C1 H 2 C 1 H 3 and other isotopic forms such as CD 2 CD 3 are also included. 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). As an example, the group

[0047]

Chem.

[0048]

Chem.

[0049] References to compounds described herein refer to either (a) the actually recited forms of such compounds, or (b) the forms of such compounds in media in which such compounds are believed to exist 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) , including a reference to any one of them. In this example, R-COOH (s) refers to a solid compound, which may be, for example, a tablet or any other solid pharmaceutical composition or preparation, R-COOH (sol) refers to the undissociated form of the compound in a solvent, and R-COO - (sol) refers to the dissociated form of the compound in a solvent, such as the dissociated form of the compound in an aqueous environment, regardless of whether such a dissociated form is derived from R-COOH, its salt, or any other entity that gives rise to R-COO - upon dissociation in the medium under consideration. In another example, an expression such as "exposing an entity to a compound of formula R-COOH" refers to exposing such an entity to the form of the compound R-COOH that exists in the medium in which such exposure occurs. In yet another example, an expression such as "reacting an entity with a compound of formula R-COOH" refers to reacting (a) the entity in a chemically relevant form of such entity that exists in the medium in which such reaction occurs, with (b) the chemically relevant form of the compound R-COOH that exists in the medium in which such reaction occurs. In this context, if such an entity exists, for example, in an aqueous environment, the compound R-COOH exists in such the same medium, and thus, if the entity is R-COOH (aq) and / or R-COO - (aq)It is understood to be exposed to species such as, where the subscript “(aq)” means “aqueous solution” according to its customary meaning in chemistry and biochemistry. In these examples of nomenclature, a carboxylic acid functional group was chosen, but this choice is not intended to be limiting and is merely illustrative. Similar examples can be provided for other functional groups, including, but not limited to, hydroxyl, basic nitrogen members, such as the nitrogen member in an amine, and any other group that interacts or transforms 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. Further examples are not provided herein in this regard, as these interactions and transformations occurring in a given medium are well known to those skilled in the art.

[0050] The term “pharmaceutically acceptable” means approved or approvable by the regulatory authorities of the federal or state governments of the United States or the corresponding agencies in countries outside the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopeias for use in animals, more specifically humans.

[0051] "Pharmaceutically acceptable salt" is intended to mean a salt of the free acid or base of a compound disclosed herein that is non-toxic, biologically acceptable, or otherwise biologically suitable for administration to a subject. It should possess the desired pharmacological activity of the parent compound. Generally, see G.S. Paulekuhn, et al., "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database", J. Med. Chem., 2007, 50:6665 - 72, S.M. Berge, et al., "Pharmaceutical Salts", J Pharm Sci., 1977, 66:1 - 19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley - VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of a patient without undue toxicity, irritation, or allergic response. Since the compounds of the present disclosure can have sufficiently acidic groups, sufficiently basic groups, or both types of functional groups, they can react with a number of inorganic or organic bases, as well as inorganic and organic acids, to produce pharmaceutically acceptable salts.

[0052] The compounds of the present disclosure This application relates to a compound of formula I:

[0053]

Chemical formula

[0054]

Chemical formula

[0055] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, wherein A is a 5-membered heteroaryl optionally substituted with 1 to 3 groups selected from -C (1~4) Alkyl and -C (1~4) Haloalkyl, B is furanyl, piperidinyl, or the following structure:

[0056] [Chemical formula] And has a group of W is CH 2 , or CF 2 And V is N, C-H, or C-R V And X is N, C-H, or C-R X And Y is N, C-H, or C-R Y And Z is N, C-H, or C-R Z And R V R X R Y And RZ is, independently of each other, halo, -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 -N(H)(5- to 10-membered heteroaryl), -C (6~10) aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or 5- to 10-membered heteroaryl, where -N(H)(5- to 10-membered heteroaryl), -C (6~10) aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, and 5- to 10-membered heteroaryl are each optionally substituted with 1 to 5 R 3 groups, and each R 3 is, each time it appears, independently of each other, halo, -N(R N1 )(R N2 ), -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~10) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~10) cycloalkyl, -C (1~3) alkyl-N(R N1 )(R N3 ), -C(O)OH, -C(O)N(R N1 )(R N4 ), -C (1~3) alkyl(3- to 8-membered heterocyclyl), -C (1~3) alkyl(phenyl), 3- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl, where -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~10) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~10) cycloalkyl, -C (1~3)Alkyl(3- to 8-membered heterocyclyl), -C (1~3) Alkyl(phenyl), 3- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl are each optionally further substituted with 1 to 5 groups selected from halo, -C (1~4) Alkyl, -C (1~4) Haloalkyl, -C (3~6) Cycloalkyl, -OC (1~4) Alkyl, -OC (1~4) Haloalkyl, and -C (1~4) AlkylOC (1~4) is optionally further substituted with 1 to 5 groups selected from alkyl, R N1 is hydrogen or -C (1~4) Alkyl, R N2 is hydrogen, -C (1~4) Alkyl, -C (3~6) Cycloalkyl, -C(O)C (1~4) Alkyl, -C (1~4) Alkyl(4- to 6-membered heterocyclyl), 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, where the 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are each optionally further substituted with 1 to 3 groups selected from -CN, -C (1~4) Alkyl, -C (1~4) Haloalkyl, -OC (1~4) Alkyl, -OC (1~4) Haloalkyl, and -C(O)C (1~4) Alkyl, R N3 is hydrogen, -C (3~6) Cycloalkyl, or 5- to 6-membered heteroaryl, where the 5- to 6-membered heteroaryl is optionally further substituted with 1 to 3 -C (1~4) Alkyl groups, R N4 is hydrogen, -C (1~4) Alkyl, or 4- to 6-membered heterocyclyl, provided that at least two of V, X, Y, and Z are C-H, and R 2 when is pyrimidinyl, pyrimidinyl is -OC (1~6) Alkyl and -C(O)N(R N1 )(RN4 ) selected and replaced by one group selected from, and optionally further replaced by one or two R 3 groups, a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0057] 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 to three -C (1~4) alkyl groups, B is furanyl, piperidinyl, or the following structure:

[0058]

Chemical formula

[0059] 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 1 -C (1~4) alkyl group, B is

[0060]

Chemical formula

[0061] 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 to three groups selected from -C (1~4) alkyl and -C (1~4) haloalkyl; B is furanyl, piperidinyl, or the following structure:

[0062]

Chemical formula

[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 1 to 3 groups selected from -C (1~4) alkyl and -C (1~4) haloalkyl, B is furanyl, piperidinyl, or the following structure:

[0064] [Chemistry] is a group having W is CH 2 or CF 2 and V is N, C-H, or C-R V and X is N, C-H, or C-R X and Y is N, C-H, or C-R Y and Z is N, C-H, or C-R Z and R V R X R Y and R Z are each independently halo, -C (1~4) alkyl, -C (1~4) haloalkyl, or -OC (1~4) alkyl and R 1 is hydrogen, -C (1~4) alkyl, or -C (1~4) haloalkyl and R 2 is -N(H)(5- to 10-membered heteroaryl), -C (6~10) aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or 5- to 10-membered heteroaryl, where -N(H)(5- to 10-membered heteroaryl) is optionally substituted with 1 to 5 R 3a groups, -C (6~10) aryl is optionally substituted with 1 to 5 R 3b groups, the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R 3c groups, and the 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R 3d groups and R 3a and R 3b are each independently, at each occurrence, halo, -N(R N1 )(R N2 ), -C (1~6)Alkyl, -C (1~6) Haloalkyl, -OC (1~6) Alkyl, -OC (1~6) Haloalkyl, -C (1~3) Alkyl-N(R N1 )(R N3 ), or -C(O)N(R N1 )(R N4 ), and R 3c and R 3d are, each independently for each occurrence, halo, -OH, -N(R N1 )(R N2 ), -CN, -C (1~6) Alkyl, -C (1~6) Haloalkyl, -C (3~10) Cycloalkyl, -OC (1~6) Alkyl, -OC (1~6) Haloalkyl, -OC (3~10) Cycloalkyl, -C (1~3) Alkyl-N(R N1 )(R N3 ), -C(O)OH, -C(O)N(R N1 )(R N4 ), -C (1~3) Alkyl(3- to 8-membered heterocyclyl), -C (1~3) Alkyl(phenyl), 3- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl, where -C (1~6) Alkyl, -C (1~6) Haloalkyl, -C (3~10) Cycloalkyl, -OC (1~6) Alkyl, -OC (1~6) Haloalkyl, -OC (3~10) Cycloalkyl, -C (1~3) Alkyl(3- to 8-membered heterocyclyl), -C (1~3) Alkyl(phenyl), 3- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl are halo, -C (1~4) Alkyl, -C (1~4) Haloalkyl, -C (3~6) Cycloalkyl, -OC (1~4) Alkyl, -OC (1~4) Haloalkyl, and -C (1~4) AlkylOC (1~4)Optionally further substituted with 1 to 5 groups selected from alkyl, R N1 is hydrogen or -C (1~4) alkyl, R N2 , R N3 , and R N4 are, each independently upon each occurrence, hydrogen, -C (1~4) alkyl, -C (3~6) cycloalkyl, -C(O)C (1~4) alkyl, -C (1~4) alkyl(4- to 6-membered heterocyclyl), 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, where the 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with 1 to 3 groups selected from -CN, -C (1~4) alkyl, -C (1~4) haloalkyl, -OC (1~4) alkyl, -OC (1~4) haloalkyl, and -C(O)C (1~4) alkyl, provided that at least two of V, X, Y, and Z are C-H, and R 2 when is pyrimidinyl, pyrimidinyl is substituted with 1 group selected from -OC (1~6) alkyl and -C(O)N(R N1 )(R N4 ), and optionally further substituted with 1 to 2 R 3d groups, a compound of formula I, or a pharmaceutically acceptable salt thereof.

[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 1 to 3 groups selected from -C (1~4) alkyl and -C (1~4) haloalkyl, B is furanyl, piperidinyl, or the following structure:

[0066] [Chemistry] is a group having W is CH 2 or CF 2 and V is N, C-H, or C-R V and X is N, C-H, or C-R X and Y is N, C-H, or C-R Y and Z is N, C-H, or C-R Z and R V is halo R X R Y and R Z are each independently halo, -C (1~4) alkyl, -C (1~4) haloalkyl, or -OC (1~4) alkyl R 1 is hydrogen, -C (1~4) alkyl, or -C (1~4) haloalkyl R 2 is -N(H)(5- to 10-membered heteroaryl), -C (6~10) aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or 5- to 10-membered heteroaryl, where -N(H)(5- to 10-membered heteroaryl) is optionally substituted with 1 to 5 R 3a groups, -C (6~10) aryl is optionally substituted with 1 to 5 R 3b groups, the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R 3c groups, and the 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R 3d groups R 3a and R 3b are each independently, at each occurrence, -N(R N1 )(R N2) or -C(O)N(R N1 )(R N4 ), where each R 3c , each time it appears, is independently halo, -N(R N1 )(R N2 ), -C (1~6) alkyl, -C (1~6) haloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -C (1~3) alkyl-N(R N1 )(R N3 ), -C(O)OH, -C(O)N(R N1 )(R N4 ), or -C (1~3) alkyl(phenyl), where each R 3d , each time it appears, is independently halo, -N(R N1 )(R N2 ), -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~10) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~10) cycloalkyl, -C (1~3) alkyl-N(R N1 )(R N3 ), -C(O)N(R N1 )(R N4 ), -C (1~3) alkyl(3- to 8-membered heterocyclyl), 3- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl, where -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~10) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~10) cycloalkyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), 3- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl are halo, -C (1~4) alkyl, -C (1~4) haloalkyl, -C (3~6) cycloalkyl, -OC (1~4)Alkyl, -OC (1~4) Haloalkyl, and -C (1~4) AlkylOC (1~4) Optionally further substituted with 1 to 5 groups selected from alkyl, R N1 is hydrogen or -C (1~4) alkyl, R N2 is hydrogen, -C (1~4) alkyl, -C (3~6) cycloalkyl, -C(O)C (1~4) alkyl, -C (1~4) alkyl(4-6 membered heterocyclyl), 4-6 membered heterocyclyl, 5-6 membered heteroaryl, wherein the 4-6 membered heterocyclyl and 5-6 membered heteroaryl are -CN, -C (1~4) alkyl, -C (1~4) haloalkyl, -OC (1~4) alkyl, -OC (1~4) haloalkyl, and -C(O)C (1~4) Optionally further substituted with 1 to 3 groups selected from alkyl, R N3 is hydrogen, -C (3~6) cycloalkyl, or 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally further substituted with 1 to 3 -C (1~4) alkyl groups, R N4 is hydrogen, -C (1~4) alkyl, or 4-6 membered heterocyclyl, provided that at least two of V, X, Y, and Z are C-H, and R 2 when it is pyrimidinyl, the pyrimidinyl is substituted with 1 group selected from -OC (1~6) alkyl and -C(O)N(R N1 )(R N4 ), and optionally further substituted with 1 to 2 R 3d groups, a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0067] 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 1 to 3 -C (1~4) alkyl groups; B is furanyl, piperidinyl, or the following structure:

[0068]

Chemical formula

[0069] 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 1 -C (1~4) alkyl group, B is

[0070] [Chemical] and W is CH 2 or CF 2 and V is N, C-H, or C-F X is N, C-H, or C-R X and Y is N, C-H, or C-R Y and Z is N, C-H, or C-R Z and R X R Y and R Z are each independently fluorine, -CH 3 or -OCH 3 and R 1 is hydrogen or -CF 3 and R 2 is -N(H)(5- to 10-membered heteroaryl), -C (6~10) aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or 5- to 10-membered heteroaryl, where -N(H)(5- to 10-membered heteroaryl) is optionally substituted with one -NH 2 group, -C (6~10) aryl is optionally substituted with one -C(O)NH 2 group, the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R 3c groups, the 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R 3d groups, each R 3c is, each time it appears, independently -NH 2 , -C (1~6) alkyl, -C (1~6) haloalkyl, -OC (1~6) alkyl, -C(O)OH, -C(O)NH 2 , or -C (1~3) alkyl(phenyl), each R3d For each occurrence, independently, halo, -N(R N1 )(R N2 ), -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~10) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -C (1~3) alkyl-N(R N1 )(R N3 ), -C(O)N(R N1 )(R N4 ), -C (1~3) alkyl(3- to 8-membered heterocyclyl), 3- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl, where the 3- to 8-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -C (1~4) alkyl, -C (1~4) haloalkyl, -C (3~6) cycloalkyl, -OC (1~4) alkyl, -OC (1~4) haloalkyl, and -C (1~4) alkylOC (1~4) alkyl, R N1 is hydrogen, R N2 is hydrogen, -C (1~4) alkyl, -C (3~6) cycloalkyl, -C(O)C (1~4) alkyl, -C (1~4) alkyl(4- to 6-membered heterocyclyl), 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, where the 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with 1 to 3 groups selected from -CN, -C (1~4) alkyl, -C (1~4) haloalkyl, -OC (1~4) alkyl, -OC (1~4) haloalkyl, and -C(O)C (1~4) alkyl, R N3 is hydrogen, -C (3~6)Cycloalkyl, or a 5- to 6-membered heteroaryl, where the 5- to 6-membered heteroaryl is optionally further substituted with 1 to 3 -C (1~4) alkyl groups, R N4 is hydrogen, -C (1~4) alkyl, or a 4- to 6-membered heterocyclyl, provided that at least two of V, X, Y, and Z are C-H, and R 2 when it is pyrimidinyl, the pyrimidinyl is substituted with 1 group selected from -OC (1~6) alkyl and -C(O)N(R N1 )(R N4 ), and is optionally further substituted with 1 to 2 R 3d groups, a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0071] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, which is a compound of formula Ia-1:

[0072]

Chemical formula

[0073] 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:

[0074]

Chemical formula

[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)It is a 5-membered heteroaryl optionally substituted with an alkyl group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl optionally substituted with one methyl group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl.

[0076] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, or triazolyl, each of which is optionally substituted with one -C (1~4) alkyl group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, or triazolyl, each of which is optionally substituted with one methyl group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, or triazolyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is isoxazolyl or pyrazolyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is isoxazolyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A is pyrazolyl.

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

[0078] [Chemical formula] is.

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

[0080]

Chem.

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

[0082]

Chem.

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

[0084]

Chem.

[0085] 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:

[0086]

Chem.

[0087] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, which is a compound of formula Ib-2:

[0088]

Chem.

[0089] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is CH 2 , CHD, CD 2 , or CF 2 . In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is CH 2 or CF 2 . In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is CH 2 . In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is CF 2 .

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

[0091]

Chemical formula

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

[0093]

Chemical formula

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

[0095] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is N, C-H, C-F, or C-CH 3 is. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is C-H, C-F, or C-CH 3 is. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is C-H or C-R X is. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is C-H. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is C-R X 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 C-CH 3 is.

[0096] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein Y is N, C-H, C-F, C-CH 3 , or C-OCH 3 . In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-H, C-F, C-CH 3 , or C-OCH 3 . In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-H or C-R Y . In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-H. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-R Y . In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-F. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-CH 3 . In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-OCH 3 .

[0097] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein Z is N, C-H, C-F, or C-CH 3It is. In some embodiments, what is disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Z is N or C—H. In some embodiments, what is disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Z is N. In some embodiments, what is disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Z is C—H. In some embodiments, what is disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Z is C—R Z It is. In some embodiments, what is disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Z is C—F. In some embodiments, what is disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Z is C—CH 3 It is.

[0098] In some embodiments, what is disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein V is C—R V It is, and R v is halo, and X, Y, and Z are C—H. In some embodiments, what is disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein V is C—H, and X, Y, and Z are N or C—H, and at least one of X, Y, and Z is N. In some embodiments, what is disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein V is C—H, and X, Y, Z are independently N, C—H, C—(halogen), C—(C 1~4 alkyl), or C—(OC (1~4) alkyl).

[0099] In some embodiments, what is disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein V is N or C—H, X is N, or C—H, Y is N or C—H, and Z is N, C—H, or C—R ZThat is. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein V is N or C—H, X is N, or C—H, Y is N, C—H, or C—R Y wherein Z is N or C—H. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein V is N or C—H, X is N, or C—H, Y is N or C—H, Z is N or C—H, and one or less of V, X, Y, and Z is N.

[0100] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R V R X R Y and R Z are each independently halo, —C (1~4) alkyl, or —OC (1~4) alkyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R V R X R Y and R Z are each independently halo or —C (1~4) alkyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R V R X R Y and R Z are each independently fluorine, —CH 3 or —OCH 3 . In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R V R X R Y and R Z are fluorine.

[0101] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein RV is a halo. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R V is fluorine.

[0102] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R X is halo or -C (1~4) alkyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R X is fluorine or -CH 3 is.

[0103] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R Y is halo, -C (1~4) alkyl, or -OC (1~4) alkyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R Y is fluorine, -CH 3 or -OCH 3 is.

[0104] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R Z is halo or -C (1~4) alkyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R Z is fluorine or -CH 3 is.

[0105] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein V is N, C-H, or C-F, X is N, C-H, C-F, or C-CH 3 is, and Y is N, C-H, C-F, C-CH 3, or C-OCH 3 wherein Z is N, C-H, C-F, or C-CH 3 . In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein V is N, C-H, or C-F, X is C-H, C-F, or C-CH 3 , Y is C-H, C-F, C-CH 3 , or C-OCH 3 , and Z is N, C-H, C-F, or C-CH 3 .

[0106] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein B is

[0107]

Chemical formula

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

[0109]

Chemical formula

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

[0111]

Chemical formula

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

[0113]

Chemical formula

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

[0115]

Chemical formula

[0116] 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:

[0117]

Chemical formula

[0118] 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:

[0119]

Chemical formula

[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-3:

[0121]

Chemical formula

[0122] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, -C (1~4) alkyl, or -C (1~4)is haloalkyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or -C (1~4) is haloalkyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or -CF 3 In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is -CF 3 In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is any one compound of Formula Id-1 to Formula Id-5.

[0123] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is any one compound of Formula Ie-1 to Formula Ie-6.

[0124]

Chemical formula

[0125] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is any one compound of Formula Ie-1 to Formula Ie-6.

[0126]

Chemical formula

[0127] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is a 5- to 12-membered bicyclic or tricyclic ring system or a 5- to 10-membered heteroaryl containing one or more heteroatoms, each of which is optionally substituted with 1 to 5 R 3 groups.

[0128] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3 is, independently at each occurrence, halo, -N(R N1 )(R N2 ), -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~10) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~10) cycloalkyl, -C (1~3) alkyl-N(R N1 )(R N3 ), -C(O)OH, -C(O)N(R N1 )(R N4 ), -C (1~3) alkyl(3- to 8-membered heterocyclyl), -C (1~3) alkyl(phenyl), 3- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl, where -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~10) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~10) cycloalkyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), -C (1~3) alkyl(phenyl), 3- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -C (1~4) alkyl, -C (1~4) haloalkyl, -C (3~6) cycloalkyl, -OC (1~4) alkyl, -OC (1~4) haloalkyl, and -C (1~4) alkylOC (1~4) alkyl.

[0129] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3is, independently for each occurrence, halo, -N(R N1 )(R N2 ), -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~10) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -C (1~3) alkyl-N(R N1 )(R N3 ), -C(O)OH, -C(O)N(R N1 )(R N4 ), -C (1~3) alkyl(3- to 8-membered heterocyclyl), -C (1~3) alkyl(phenyl), a 3- to 8-membered heterocyclyl, or a 5- to 6-membered heteroaryl, where the 3- to 8-membered heterocyclyl and the 5- to 6-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -C (1~4) alkyl, -C (1~4) haloalkyl, -C (3~6) cycloalkyl, -OC (1~4) alkyl, -OC (1~4) haloalkyl, and -C (1~4) alkylOC (1~4) alkyl.

[0130] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3 is, independently for each occurrence, halo, -N(R N1 )(R N2 ), -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~10) cycloalkyl, -OC (1~6) alkyl, -C(O)N(R N1 )(R N4 ), or a 5- to 6-membered heteroaryl, where the 5- to 6-membered heteroaryl is halo, -C (1~4) alkyl, -C (1~4) haloalkyl, -C (3~6) cycloalkyl, -OC (1~4) alkyl, -OC (1~4) haloalkyl, and -C(1~4) Alkyl OC (1~4) Optionally further substituted with 1 to 5 groups selected from alkyl.

[0131] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3 is, independently at each occurrence, -N(R N1 )(R N2 ), -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~10) cycloalkyl, -C(O)N(R N1 )(R N4 ), or a 5- to 6-membered heteroaryl, where the 5- to 6-membered heteroaryl is optionally further substituted with 1 to 3 groups selected from -C (1~4) alkyl, -C (1~4) haloalkyl, -C (3~6) cycloalkyl, and -OC (1~4) alkyl.

[0132] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3 is, independently at each occurrence, -N(R N1 )(R N2 ), -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~10) cycloalkyl, -C(O)N(R N1 )(R N4 ), or a 5- to 6-membered heteroaryl, where the 5- to 6-membered heteroaryl is optionally further substituted with 1 to 3 -C (1~4) alkyl groups.

[0133] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2is a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or a 5- to 10-membered heteroaryl, wherein the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R 3c groups, and the 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R 3d groups.

[0134] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is -N(H)(5- to 10-membered heteroaryl), which is optionally substituted with 1 to 5 R 3a groups. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is -N(H)(9- to 10-membered heteroaryl), which is optionally substituted with 1 to 5 R 3a groups. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is -N(H)(thiazolopyrimidinyl), which is optionally substituted with 1 to 5 R 3a groups.

[0135] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3a is, each time it appears, independently halo, -N(R N1 )(R N2 ), -C (1~6) alkyl, -C (1~6) haloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -C (1~3) alkyl-N(R N1 )(R N3 ), or -C(O)N(R N1 )(R N4) It is. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3a is, independently at each occurrence, -N(R N1 )(R N2 ) or -C(O)N(R N1 )(R N4 ). In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 3a is -N(R N1 )(R N2 ). In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 3a is -NH 2 .

[0136] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0137]

Chemical formula

[0138] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is -C (6~10) aryl, which is optionally substituted with 1 to 5 R 3b groups. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl, which is optionally substituted with 1 to 3 R 3b groups.

[0139] 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, -N(R N1 )(RN2 ), -C (1~6) alkyl, -C (1~6) haloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -C (1~3) alkyl-N(R N1 )(R N3 ), or -C(O)N(R N1 )(R N4 ). In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each R 3b is, each occurrence independently, -N(R N1 )(R N2 ), or -C(O)N(R N1 )(R N4 ). In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 3b is -C(O)N(R N1 )(R N4 ). In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 3b is -C(O)NH 2 .

[0140] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0141]

Chemical formula

[0142] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, which is substituted with 1 to 5 R 3cis optionally substituted at the base. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is a 7- to 12-membered bicyclic ring system containing one or more heteroatoms, which is optionally substituted with 1 to 3 R 3c groups. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is a 7- to 12-membered tricyclic ring system containing one or more heteroatoms, which is optionally substituted with 1 to 3 R 3c groups.

[0143] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0144]

Chemical formula

[0145] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0146]

Chemical formula

[0147] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0148] [Chemistry] is.

[0149] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0150] [Chemistry] is.

[0151] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 3c is halo, -N(R N1 )(R N2 ), -C (1~6) alkyl, -C (1~6) haloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -C (1~3) alkyl-N(R N1 )(R N3 ), -C(O)OH, -C(O)N(R N1 )(R N4 ), or -C (1~3) alkyl(phenyl). In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 3c is -N(R N1 )(R N2 ), -C (1~6) alkyl, -C (1~6) haloalkyl, -OC (1~6) alkyl, -C(O)OH, -C(O)N(R N1 )(R N4 ), or -C (1~3) alkyl(phenyl). In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 3c is -NH 2 , -C (1~6) alkyl, -C (1~6) haloalkyl, -OC(1~6) alkyl, -C(O)OH, -C(O)NH 2 , or -C (1~3) is alkyl(phenyl).

[0152] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0153]

Chemical formula

[0154] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0155]

Chemical formula

[0156] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is a 5- to 10-membered heteroaryl), which is optionally substituted with 1 to 5 R 3d groups. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is a 5- to 6-membered monocyclic heteroaryl or a 9- to 10-membered bicyclic heteroaryl, each of which is optionally substituted with 1 to 5 R 3d groups.

[0157] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is a 5-membered heteroaryl, which is optionally substituted with 1 to 3 R 3dis optionally substituted with a radical. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is a 6-membered heteroaryl, which is optionally substituted with 1 to 3 R 3d radicals. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is a 9-membered heteroaryl, which is optionally substituted with 1 to 3 R 3d radicals. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is a 10-membered heteroaryl, which is optionally substituted with 1 to 3 R 3d radicals.

[0158] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is pyrazolyl, imidazolyl, furanyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, indazolyl, benzimidazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolopyridazinyl, pyrrolotriazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, triazolopyridinyl, quinazolinyl, isoquinolinonyl, quinazolinonyl, pyridopyrimidinyl, pyridopyrimidinonyl, pyrimidopyrimidinyl, benzoxazolyl, thiazolopyrimidinyl, furopyridinyl, or thienopyrimidinyl, each of which is optionally substituted with 1 to 3 R 3d radicals. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is thiazolyl, pyridinyl, pyrimidinyl, indazolyl, pyrazolopyridinyl, or imidazopyridinyl, each of which is optionally substituted with 1 to 3 R 3d radicals.

[0159] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0160]

Chem.

[0161] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0162]

Chem.

[0163] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0164]

Chem.

[0165] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0166]

Chem.

[0167]

Chem.

[0168] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0169]

Chem.

[0170] 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, -N(R N1 )(R N2 ), -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~10) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~10) cycloalkyl, -C (1~3) alkyl-N(R N1 )(R N3 ), -C(O)N(R N1 )(R N4 ), -C (1~3) alkyl(3- to 8-membered heterocyclyl), 3- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~10) cycloalkyl, -OC (1~6) alkyl, -OC (1~6) haloalkyl, -OC (3~10) cycloalkyl, -C (1~3) alkyl(3- to 8-membered heterocyclyl), 3- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl are halo, -C (1~4) alkyl, -C (1~4) haloalkyl, -C (3~6)Cycloalkyl, -OC (1~4) Alkyl, -OC (1~4) Haloalkyl, and -C (1~4) AlkylOC (1~4) Optionally further substituted with 1 to 5 groups selected from alkyl.

[0171] 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, -N(R N1 )(R N2 ), -C (1~6) Alkyl, -C (1~6) Haloalkyl, -C (3~10) Cycloalkyl, -OC (1~6) Alkyl, -OC (1~6) Haloalkyl, -C (1~3) Alkyl-N(R N1 )(R N3 ), -C(O)N(R N1 )(R N4 ), -C (1~3) Alkyl(3- to 8-membered heterocyclyl), 3- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein the 3- to 8-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -C (1~4) Alkyl, -C (1~4) Haloalkyl, -C (3~6) Cycloalkyl, -OC (1~4) Alkyl, -OC (1~4) Haloalkyl, and -C (1~4) AlkylOC (1~4) Alkyl.

[0172] 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, -N(R N1 )(R N2 ), -C (1~6) Alkyl, -C (1~6) Haloalkyl, -C (3~10) Cycloalkyl, -OC (1~6)Alkyl, -C(O)N(R N1 )(R N4 )、or 5- to 6-membered heteroaryl, where the 5- to 6-membered heteroaryl is optionally further substituted with 1 to 5 groups selected from halo, -C (1~4) alkyl, -C (1~4) haloalkyl, -C (3~6) cycloalkyl, -OC (1~4) alkyl, -OC (1~4) haloalkyl, and -C (1~4) alkylOC (1~4) alkyl.

[0173] 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, -N(R N1 )(R N2 ), -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~10) cycloalkyl, -C(O)N(R N1 )(R N4 ), or 5- to 6-membered heteroaryl, where the 5- to 6-membered heteroaryl is optionally further substituted with 1 to 3 groups selected from -C (1~4) alkyl, -C (1~4) haloalkyl, -C (3~6) cycloalkyl, and -OC (1~4) alkyl.

[0174] 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, -N(R N1 )(R N2 ), -C (1~6) alkyl, -C (1~6) haloalkyl, -C (3~10) cycloalkyl, -C(O)N(R N1 )(R N4 ), or 5- to 6-membered heteroaryl, where the 5- to 6-membered heteroaryl is 1 to 3 -C (1~4)Optionally further substituted with an alkyl group.

[0175] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0176]

Chemical formula

[0177]

Chemical formula

[0178]

Chemical formula

[0179]

Chemical formula

[0180] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0181]

Chemical formula

[0182]

Chemical formula

[0183]

Chemical formula

[0184] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R2 is

[0185] [Chem.] .

[0186] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0187] [Chem.]

[0188] [Chem.]

[0189] [Chem.] .

[0190] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0191] [Chem.]

[0192] [Chem.] .

[0193] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0194] [Chem.] is as follows.

[0195] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R N1 is hydrogen.

[0196] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R N2 is hydrogen, -C (1~4) alkyl, -C (3~6) cycloalkyl, -C(O)C (1~4) alkyl, -C (1~4) alkyl(4-6 membered heterocyclyl), 4-6 membered heterocyclyl, 5-6 membered heteroaryl, wherein the 4-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally further substituted with 1-3 groups selected from -CN, -C (1~4) alkyl, -C (1~4) haloalkyl, -OC (1~4) alkyl, -OC (1~4) haloalkyl, and -C(O)C (1~4) alkyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R N2 is hydrogen, -C (1~4) alkyl, -C (3~6) cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, wherein the 4-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally further substituted with 1-3 groups selected from -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 N2 is hydrogen, 4-6 membered heterocyclyl, or 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is 1-3 groups -C (1~4)Optionally further substituted with an alkyl group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R N2 is hydrogen. In some embodiments, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R N2 is a 4- to 6-membered heterocyclyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R N2 is a 5- to 6-membered heteroaryl, which is optionally substituted with 1 to 3 groups -C (1~4) alkyl.

[0197] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R N3 is hydrogen, -C (3~6) cycloalkyl, or a 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally further substituted with 1 to 3 -C (1~4) alkyl.

[0198] 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 a 4- to 6-membered heterocyclyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R N4 is hydrogen.

[0199] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein one or fewer of V, X, Y, and Z is N. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein at least three of V, X, Y, and Z are C-H.

[0200] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 when pyrimidinyl, pyrimidinyl is substituted with one -C(O)N(R N1 )(R N4 ) group and optionally further substituted with one or two R 3d groups.

[0201] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 when pyrimidinyl, R 2 has a structure selected from the group consisting of

[0202]

Chemical formula

[0203] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 when pyrimidinyl, R 2 is

[0204]

Chemical formula

[0205] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula If:

[0206]

Chemical formula

[0207] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula If,

[0208]

Chemical formula

[0209] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, having a structure as shown in any one of Tables 1A - 1J.

[0210]

Table 1 - 1

[0211]

Table 1 - 2

[0212]

Table 1 - 3

[0213]

Table 2 - 1

[0214]

Table 2 - 2

[0215]

Table 2 - 3

[0216]

Table 3 - 1

[0217]

Table 3 - 2

[0218]

Table 3 - 3

[0219]

Table 4-1

[0220]

Table 4-2

[0221]

Table 5-1

[0222]

Table 5-2

[0223]

Table 5-3

[0224]

Table 6-1

[0225]

Table 6-2

[0226]

Table 6-3

[0227]

Table 7-1

[0228]

Table 7-2

[0229]

Table 8-1

[0230]

Table 8-2

[0231]

Table 8-3

[0232]

Table 9-1

[0233]

Table 9-2

[0234]

Table 9-3

[0235]

Table 10-1

[0236]

Table 10-2

[0237]

Table 10-3

[0238] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, having a structure as shown in any one of Tables 2A-2J.

[0239]

Table 11-1

[0240]

Table 11-2

[0241]

Table 11-3

[0242]

Table 12-1

[0243]

Table 12-2

[0244]

Table 12-3

[0245]

Table 13-1

[0246]

Table 13-2

[0247]

Table 13-3

[0248]

Table 14-1

[0249]

Table 14-2

[0250]

Table 14-3

[0251]

Table 15-1

[0252]

Table 15-2

[0253]

Table 15-3

[0254]

Table 16-1

[0255]

Table 16-2

[0256]

Table 16-3

[0257]

Table 17-1

[0258]

Table 17-2

[0259]

Table 17-3

[0260]

Table 18-1

[0261]

Table 18-2

[0262]

Table 18-3

[0263]

Table 19-1

[0264]

Table 19-2

[0265]

Table 19-3

[0266]

Table 19-4

[0267]

Table 20-1

[0268]

Table 20-2

[0269] In some embodiments, what is disclosed herein is

[0270]

Chemical Formula

[0271] In some embodiments, disclosed herein is a compound of formula I having the following structure:

[0272]

Chem.

[0273] In some embodiments, disclosed herein is a compound of formula I having the following structure:

[0274]

Chem.

[0275] In some embodiments, disclosed herein is a compound of formula I having the following structure:

[0276]

Chem.

[0277] In some embodiments, disclosed herein is a compound of formula I having the following structure:

[0278]

Chem.

[0279] In some embodiments, disclosed herein is a compound of formula I having the following structure:

[0280]

Chem.

[0281] In some embodiments, disclosed herein is a compound of Formula I having the following structure:

[0282] [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0283] In some embodiments, disclosed herein is a compound of Formula I having the following structure:

[0284] [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0285] In some embodiments, disclosed herein is a compound of Formula I having the following structure:

[0286] [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0287] In some embodiments, disclosed herein is a compound of Formula I having the following structure:

[0288] [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0289] In some embodiments, disclosed herein is a compound of Formula I having the following structure:

[0290] [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0291] In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0292] 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.

[0293] 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.

[0294] 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. In some embodiments, the compounds described herein can be administered in combination with one or more additional therapeutic agents.

[0295] 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.

[0296] 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.

[0297] 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.

[0298] In some embodiments of the treatment methods disclosed herein, the disease, disorder, or medical condition is an autoantibody-related disease. In some embodiments, the autoantibody-related disease is selected from the group consisting of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, scleroderma, Sjögren's disease, myositis, IgG4-related disease, bullous pemphigoid, and neuromyelitis optica spectrum disorder (NMOSD).

[0299] 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.

[0300] 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.

[0301] 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.

[0302] 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.

[0303] In some embodiments of the treatment methods disclosed herein, the disease, disorder, or medical condition is a renal disease. In some embodiments, the renal 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.

[0304] In some embodiments of the treatment methods disclosed herein, the disease, disorder, or medical condition is osteoporosis.

[0305] 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).

[0306] 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.

[0307] 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, is disclosed herein.

[0308] In some embodiments of the methods of the present disclosure, the subject is a human subject.

[0309] 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.

[0310] 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.

[0311] 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 suffering from or diagnosed with 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, an exemplary range of dosage is from about 1 to 1000 mg / day in single or multiple dosage units.

[0312] 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.

[0313] The dosage administered 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.

[0314] It is also obvious to those skilled in the art that the therapeutically effective dosage of the compounds or pharmaceutical compositions thereof of the present disclosure may vary depending on the desired effect. Therefore, the optimal dosage may be easily determined by those skilled in the art and will vary depending on the specific compound used, the method of administration, the strength of the preparation, and the progression of the disease state. In addition, it is necessary to adjust the dosage to an appropriate therapeutic level according to factors related to the specific subject being treated, including the age, weight, diet, and administration time of the subject. Therefore, the above dosages are illustrative of average cases. Of course, there may be individual cases where larger or smaller dosage ranges are effective, and such cases are also within the scope of the present disclosure.

[0315] Once improvement in the patient's disease, disorder, or condition has occurred, the dosage may be adjusted for prophylactic or maintenance treatment. For example, the dosage or dosing frequency, or both, may be reduced as a function of the symptoms to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, 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.

[0316] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be formulated in a pharmaceutical composition containing any well-known pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers commonly used in pharmaceutical compositions are substances that are added to the pharmaceutical composition or, alternatively, used as vehicles or diluents to facilitate the administration of the drug and are compatible with the drug, non-toxic, biologically tolerable, and biologically suitable for administration to the subject for other reasons, such as inert substances. Exemplary carriers include, but are not limited to, any suitable solvent, dispersion medium, coating, antibacterial and antifungal agents, and isotonic agents. Exemplary excipients that can also be components of the formulation include fillers, binders, disintegrants, and lubricants.

[0317] Delivery forms of pharmaceutical compositions containing one or more compounds of the present disclosure may be prepared using pharmaceutically acceptable excipients and formulation techniques well known or available to those skilled in the art. The compositions may be administered by a suitable delivery route, for example, orally, parenterally, rectally, topically, or by the ocular route, or by inhalation, in the methods of the present disclosure.

[0318] The preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. The composition may be formulated for any one of a plurality of administration routes, for example, intravenous injection, subcutaneous injection, topical administration, or oral administration.

[0319] 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 oral compositions, the active agent may be formulated to provide a dosage of about 1 to 1000 mg / day in single or multiple dosage units, for example, for a 70 kg human, as an exemplary range.

[0320] 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, polyvinyl-pyrrolidone (PVP), sodium carboxymethyl starch, 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.

[0321] 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 prior to 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.

[0322] 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 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 doses can be withdrawn, or solid or pre-concentrated forms that can be used to prepare injectable formulations. Exemplary infusion doses are amounts in which the agent admixed with the pharmaceutical carrier is infused at a rate in the range of about 1 - 1000 μg / kg / min over a period ranging from several minutes to several days.

[0323] 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.

[0324] 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.

[0325] Embodiments of the present invention are described in connection with certain specific embodiments for purposes of illustration, but the embodiments of the present invention are not limited thereto. Accordingly, various modifications, adaptations, and combinations of the various features of the described embodiments may be practiced without departing from the scope of the present invention as set forth in the claims. Further, the following examples are illustrative of the compounds, compositions, and methods described herein, but are not limited thereto. Other suitable modifications and adaptations known to those skilled in the art are within the scope of the following embodiments. Any and all academic papers, patent applications, issued patents, or other cited references are hereby incorporated herein by reference in their entirety.

Examples

[0326] The following specific examples are provided to further illustrate embodiments within the scope of the present disclosure.

[0327] Abbreviations

[0328]

Table 21-1

[0329]

Table 21-2

[0330]

Table 21-3

[0331] 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.

[0332] By way of illustration and not limitation, the compounds of the present disclosure are prepared according to the following general procedures given in Schemes 1-7. Those skilled in the art will understand that, to obtain the various compounds herein, the starting materials can be suitably selected such that the ultimately desired substituents are retained through the reaction schemes, either appropriately protected or unprotected, so as to obtain the desired product. Alternatively, instead of the ultimately desired substituents, suitable groups can be retained throughout the reaction scheme and replaced with the desired substituents as appropriate. Unless otherwise specified, the variables in Schemes 1-7 are as defined above with reference to Formula I.

[0333]

Chemical formula

[0334] The compounds of formula I of the present disclosure can be prepared, for example, as shown in Scheme 1. Substituent B in compound XI 1 is a boron-based coupling agent such as boronic acid or boronic acid ester, and when substituent B in compound XII 2 is a halide such as Cl, Br, or I, this coupling is achieved by a reaction under Suzuki conditions. Those skilled in the art will also recognize that the coupling under Suzuki conditions can also provide the compounds of formula I when B 1 in compound XI is a halide and B 2 in compound XII is a boron-based coupling agent. Typical Suzuki coupling conditions involve the use of a palladium catalyst, a base, a suitable solvent, and other optional reagents such as a ligand (e.g., tri-tert-butylphosphine or butyldi(1-adamantyl)phosphine). Examples of suitable palladium catalysts include Pd(t-Bu 3 P) 2 , Pd(PPh 3 ) 4 , Pd(dtbpf)Cl 2 , Pd 2 (dba) 3 , RuPhos Pd G4, and Pd(dppf)Cl 2 , but are not limited thereto. Suitable bases include K 3 PO 4 , KF, Cs 2 CO 3 , NaHCO 3 , Na 2 CO 3 , and mixtures thereof, but are not limited thereto. Suitable solvents include 1,4-dioxane, 1,2-dioxane, DMF, THF, water, and mixtures thereof, but are not limited thereto. Using microwave or conventional heating, the reactants can be heated to a temperature of about 65 °C to about 170 °C for about 1 to 20 hours to obtain the compounds of formula I.

[0335] Alternatively, B 1 is a halide such as Cl, Br, or I, and B 2 is a stannyl group (e.g., Sn(Me) 3or Sn(n-Bu) 3 ) When this is the case, compound XI can be coupled to compound XII using Stille coupling conditions. One skilled in the art will also recognize that coupling under Stille conditions also provides compounds of formula I when B 1 is a stannyl group and B 2 is a halide. Typical Stille coupling conditions involve the use of a catalyst (usually palladium, but sometimes nickel), a suitable solvent, and a ligand, TEA, or other optional reagents including CuI. Examples of suitable catalysts include Pd(PPh 3 ) 4 and PdCl 2 (PPh 3 ) 2 among others, but are not limited to these. Suitable solvents include, but are not limited to, DMF, toluene, and mixtures thereof. Using microwave or conventional heating, the reactants can be heated to a temperature of about 120 °C to about 160 °C for about 1 to 16 hours to obtain the compound of formula I.

[0336] If a protecting group or masking group is present on the compound of formula XI or XII, a final deprotection step is added using conditions known to those skilled in the art to obtain the compound of formula I. For example, when using a methyl ester or ethyl ester to mask a primary amide, it can be unmasked using a reagent such as ammonia in a solvent such as MeOH or EtOH. Alternatively, when using a nitrile group to mask a primary amide, it can be converted to an amide using a reagent such as NaOMe in a solvent such as MeOH. Or further, when using a carboxylic acid to mask a primary amide, it can be converted to an amide using reagents such as NH 4 Cl, HATU, and TEA in a solvent such as DMF.

[0337] As a further example, when a tosyl group or a phthalimide group is used to protect an amino group, it can be removed using a reagent such as ammonia in a solvent such as MeOH or EtOH. Alternatively, when an amino group is protected using a tert-butyloxycarbonyl (Boc) or tetrahydropyran (THP) group, it can be removed using a reagent such as HCl in a solvent such as dioxane and / or MeOH. Alternatively, when an amino group is protected using a 2-(trimethylsilyl)ethoxymethyl (SEM) group, it can be removed using a reagent such as TBAF in a solvent such as MeOH. Alternatively, when an amino group is protected using a para-methoxybenzyl (PMB) group, it can be removed using a reagent such as TFA.

[0338] As a further example, when a nitro group is used to mask a primary amine, it can be converted to an amine using a reagent such as a porous nickel-aluminum alloy (e.g., Raney nickel) and hydrazine hydrate in a solvent such as ethanol and / or 1,2-dichloroethane. Alternatively, it can be converted to an amine using a reagent such as zinc powder and NH 4 Cl in a solvent such as MeOH and / or water.

[0339]

Chemical formula

[0340] The compound of formula I of the present disclosure can be prepared, for example, as shown in Scheme 2. The substituent B in compound XIII 3 is a boron-based coupling agent such as boronic acid or boronic ester, and when the substituent B in compound XIV 4 is a halide such as Cl, Br, or I, this coupling is achieved by a reaction under Suzuki conditions. Those skilled in the art will also recognize that a coupling under Suzuki conditions can also be carried out when B in compound XIII 3 is a halide and B in compound XIV4 It will be appreciated that when 4 is a boron-based coupling agent, a compound of formula I is provided. Typical Suzuki coupling conditions involve the use of a palladium catalyst, a base, a suitable solvent, and other optional reagents such as a ligand (e.g., tri-tert-butylphosphine or butyldi(1-adamantanyl)phosphine). Examples of suitable palladium catalysts include Pd(t-Bu 3 P) 2 Pd(PPh 3 ) 4 Pd(dtbpf)Cl 2 Pd 2 (dba) 3 RuPhos Pd G4, and Pd(dppf)Cl 2 but are not limited thereto. Suitable bases include K 3 PO 4 KF, Cs 2 CO 3 NaHCO 3 Na 2 CO 3 and mixtures thereof but are not limited thereto. Suitable solvents include 1,4-dioxane, 1,2-dioxane, DMF, THF, water, and mixtures thereof but are not limited thereto. Using microwave or conventional heating, the reactants may be heated to a temperature of about 65 °C to about 170 °C for about 1 to 20 hours to obtain a compound of formula I.

[0341] Alternatively, when B 3 is a halide such as Cl, Br, or I and B 4 is a stannyl group (e.g., Sn(Me) 3 or Sn(n-Bu) 3 ), compound XIII can be coupled to compound XIV using Stille coupling conditions. One skilled in the art will also recognize that coupling under Stille conditions can also be carried out when B 3 is a stannyl group and B 4It 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 a ligand, TEA, or other optional reagents including CuI. Examples of suitable catalysts include, but are not limited to, Pd(PPh 3 ) 4 and PdCl 2 (PPh 3 ) 2 . Suitable solvents include, but are not limited to, DMF, toluene, and mixtures thereof. The reaction may be heated using microwave or conventional heating to a temperature of about 120 °C to about 160 °C for about 1 to 16 hours to obtain the compound of formula I.

[0342] If a protecting group or masking group is present on the compound of formula XIII or XIV, a final deprotection step is added using conditions known to those skilled in the art to obtain the compound of formula I. For example, when using a 2-(trimethylsilyl)ethoxymethyl (SEM) group to protect an amino group, it can be removed using a reagent such as TBAF in a solvent such as MeOH.

[0343]

Chemical formula

[0344] When the bond between B and R 2 is between a carbon atom and a nitrogen atom, it can be prepared, for example, as shown in Scheme 3. In some embodiments, the substituent B 5 is a halide and the substituent B 6 is a hydrogen atom covalently bonded to the nitrogen atom of R 2 . Alternatively, the substituent B 5 is a hydrogen atom covalently bonded to the nitrogen atom of B and B 6 is a halide. Compounds XV and XVI may be mixed with a suitable catalyst (e.g., a palladium or copper catalyst), a suitable base, a suitable solvent, and other optional reagents including a ligand. Suitable catalysts include Pd2 (dba) 3 and CuI, but are not limited thereto. Suitable bases include t-BuONa and K 3 PO 4 but are not limited thereto. Suitable solvents include DMF and toluene, but are not limited thereto. Suitable ligands include BINAP and trans-N,N'-dimethylcyclohexane-1,2-diamine, but are not limited thereto. The reactants may be heated at a temperature of about 85 °C to about 100 °C for about 16 hours to obtain the compound of formula I.

[0345] Alternatively, compounds XV and XVI may be mixed with a suitable base and a suitable solvent. Suitable bases include Cs 2 CO 3 and TEA, but are not limited thereto. Suitable solvents include DMF and DMA, but are not limited thereto. Using microwave or conventional heating, the reactants may be heated at a temperature of about 100 °C to about 140 °C for about 3 to 24 hours to obtain the compound of formula I.

[0346] If a protecting group or masking group is present on the compound of formula XV or XVI, a final deprotection step is added using conditions known to those skilled in the art to obtain the compound of formula I. For example, when using a methyl ester or ethyl ester to mask a primary amide, it can be de-masked using a reagent such as ammonia in a solvent such as MeOH or EtOH.

[0347]

Chemical formula

[0348] The compound of formula I of the present disclosure can be prepared, for example, as shown in Scheme 4. In some embodiments, substituent B 7 is a boron-based coupling agent such as boronic acid or boronic acid ester, and substituent B 8 is R 2is a hydrogen atom covalently bonded to a nitrogen atom. Compounds XVII and XVIII may be mixed with a suitable catalyst (e.g., Cu(OAc) 2 ), a suitable base (e.g., pyridine), a suitable solvent, and other optional reagents (e.g., molecular sieves). Suitable solvents include, but are not limited to, DMF and chloroform. The reactants may be heated at a temperature of about 40 °C to about 120 °C for about 3 to 72 hours to obtain the compound of formula I.

[0349] If a protecting group or masking group is present on the compound of formula XVII or XVIII, a final deprotection step may be added using conditions known to those skilled in the art to obtain the compound of formula I. For example, when a methyl ester or ethyl ester is used to mask a primary amide, it can be de-masked using a reagent such as ammonia in a solvent such as MeOH or EtOH.

[0350]

Chemical formula

[0351] The compound of formula XXI of the present disclosure can be prepared, for example, as shown in Scheme 5. The substituent B in compound XX 9 is, for example, a halide such as Cl. Compounds XIX and XX may be mixed with a suitable base (e.g., TEA) and a suitable solvent (e.g., DCM). The reactants may be heated at a temperature of about 25 °C to about 40 °C for about 3 to 16 hours to obtain the compound of formula XXI.

[0352]

Chemical formula

[0353] The compound of formula XXIII of the present disclosure can be prepared, for example, as shown in Scheme 6. The substituent B in compound XXII 10is, for example, a halide such as I. Compounds XIX and XXII can be mixed in a solvent (e.g., DMSO and / or water) with a copper catalyst (e.g., CuI), a ligand (e.g., trans-N,N’-dimethylcyclohexane-1,2-diamine), and NaN 3 and may also contain additives such as sodium ascorbate. The reaction can be allowed to proceed at room temperature for about 16 hours to obtain a compound of formula XXIII.

[0354] If a protecting group or masking group is present on the compound of formula XXII, a final deprotection step is added using conditions known to those skilled in the art to obtain the compound of formula XXIII. For example, when a methyl ester or ethyl ester is used to mask a primary amide, it can be de-masked using a reagent such as ammonia in a solvent such as MeOH or EtOH.

[0355] [Chemical formula]

[0356] The compound of formula XXV of the present disclosure can be prepared, for example, as shown in Scheme 7. Compound XXIV can be mixed with p-toluenesulfonylhydrazide and a suitable solvent (e.g., ACN), and the reaction mixture can be allowed to proceed at room temperature for about 3 hours. Subsequently, a suitable base (e.g., NaOH) and a compound of formula XIX can be added to the reaction mixture. Then, the reaction can be heated to a temperature of about 50°C for about 16 hours to obtain the compound of formula XXV.

[0357] When obtaining the compounds and corresponding analytical data described in the following examples, unless otherwise indicated, the following experimental and analytical protocols were followed.

[0358] Unless otherwise specified, the reaction solution was N 2(g) or Ar (g)Under the atmosphere, it was stirred at room temperature. When the solution was "concentrated to dryness", they were concentrated under reduced pressure using a rotary evaporator. When drying the solution, typically, it was dried with a desiccant such as MgSO 4 or Na 2 SO 4 etc. Normal-phase flash column chromatography (FCC) was performed with silica gel using a pre-packed silica gel column such as RediSep (registered trademark), and ethyl acetate (EtOAc) / hexane, CH 2 Cl 2 / MeOH, or CH 2 Cl 2 / MeOH with 10% 2N NH 3 was used as the eluent.

[0359] Thin-layer chromatography was performed using a silica gel plate such as a Merck silica gel 60F 254 pre-coated plate with dimensions of 2.5 cm × 7.5 cm, 250 mm, or 5.0 cm × 10.0 cm, 250 μm. Preparative thin-layer chromatography was performed using a silica gel plate such as a plate pre-coated with EM Science silica gel 60 F 254 with dimensions of 20 cm x 20 cm, 0.5 mm, and using a concentrated zone with dimensions of 20 cm x 4 cm. The microwave reaction was carried out using a microwave reactor, for example, CEM Discover a, it was carried out at a specific temperature in a Biotage Initiator (trademark) or Optimizer (trademark) microwave. The mass spectrum was obtained using electrospray ionization (ESI) in positive mode on a mass spectrometer such as an Agilent Series 1100 MSD, unless otherwise indicated. The calculated mass corresponds to the exact mass. The NMR spectra were obtained on an NMR spectrometer such as a Bruker model DPX400 (400 MHz), DPX500 (500 MHz), DRX600 (600 MHz), etc. The following 1 The format of the 1H NMR data is as follows: chemical shift (ppm) relative to tetramethylsilane (multiplicity, coupling constant J (Hz), integral value).

[0360] Whenever the yield is expressed as a percentage, such a yield refers to the mass of the entity whose yield is shown relative to the maximum amount of the same entity that can be obtained under specific stoichiometric conditions. The reagent concentration shown as a percentage refers to the mass ratio, unless otherwise specified. Whether or not it is explicitly stated, the yields obtained in the following examples are calculated with respect to the dry form of any compound for which such a yield is obtained.

[0361] The compound names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye).

[0362] Intermediate 1: (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one.

[0363]

Chemical Structure

[0364] Process A: tert-Butyl 3-(methylamino)propanoate. Methylamine (500 mL, 3.48 mol, 30 wt% in EtOH) and EtOH (500 mL) were placed in a 2 L round-bottom flask equipped with an overhead stirrer, and then tert-butyl acrylate (100 g, 0.78 mol) was added dropwise at 20 - 25 °C over 3 h. The resulting mixture was stirred at room temperature for 3 h and then concentrated to dryness to obtain tert-butyl 3-(methylamino)propanoate (124 g) as a colorless oil. MS(ESI): C 8 H 17 NO 2 Mass calculation for, 159.1, m / z, found, 160.2 [M+H] + .

[0365] 1 H NMR(400MHz,CDCl 3 ) δ 2.79 (t, J = 6.5 Hz, 2H), 2.43 (s, 3H), 2.41 (t, J = 6.5 Hz, 2H), 1.44 (s, 9H).

[0366] Process B: tert-Butyl 4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate. tert-Butyl 3-(methylamino)propanoate (900 g, 5.65 mol), diethyl oxalate (827 g, 5.65 mol), and THF (18 L) were placed in a 50 L glass-lined reactor equipped with an overhead stirrer. The resulting mixture was warmed to 50 - 55 °C, and then t-BuOK (633 g, 5.65 mol) was added batchwise. After stirring for 1 h, the mixture was cooled to 20 °C, concentrated to dryness, and water (5.00 L) was added to form a suspension. The pH was adjusted to 1 - 2 with aqueous HCl, and the resulting mixture was stirred at 20 - 25 °C for 1 h, then filtered and dried to obtain tert-butyl 4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (940 g, 78%) as an off-white solid. 1 H NMR(300MHz,CDCl 3)δ8.99 (s, 1H), 3.94 (s, 2H), 3.10 (s, 3H), 1.56 (s, 9H).

[0367] Step C: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid. Into a 5 L round-bottom flask equipped with an overhead stirrer were charged tert-butyl 4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (500 g, 2.34 mol) and TFA (2.00 L). The resulting mixture was stirred at 20 - 25 °C for 3 h and then concentrated to dryness. Acetonitrile (1.50 L) was added to the residue with stirring at 20 - 25 °C for 1 h. The product was isolated by filtration and dried to obtain 4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (357 g, 97%) as an off-white solid. 1 H NMR (300 MHz, CD 3 OD δ4.04 - 3.98 (m, 2H), 3.08 (s, 3H).

[0368] Step D: 1-Methylpyrrolidine-2,3-dione. Into a 20 L round-bottom flask equipped with an overhead stirrer were charged 4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (1000 g, 6.4 mol) and THF (15 L). The resulting mixture was heated to 65 °C. After 4 h, the mixture was concentrated to dryness to obtain 1-methylpyrrolidine-2,3-dione (712 g, 99%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ3.70 (t, J = 5.7 Hz, 2H), 3.13 (s, 3H) 2.72 (t, J = 5.7 Hz, 2H).

[0369] Process E: (R,S)-3-Ethynyl-3-hydroxy-1-methylpyrrolidin-2-one. Ethynylmagnesium bromide (3.50 L, 0.5 M in THF) was placed in a 10 L round-bottom flask equipped with an overhead stirrer. The flask was purged with nitrogen and cooled to -10 °C, and then 1-methylpyrrolidine-2,3-dione (120 g, 1.06 mol) was added over 20 minutes. The resulting mixture was warmed to 20 - 25 °C and stirred for 16 hours. The resulting mixture was quenched with an NH 4 Cl aqueous solution (120 g in 360 mL of H 2 O) and subsequently diluted with DCM (3.50 L). After slurrying for 1 hour, the suspension was filtered, and the filtrate was dried over anhydrous Na 2 SO 4 (500 g) and treated with activated carbon (24 g). The activated carbon was removed by filtration, and the filtrate was concentrated to dryness under vacuum. The residue was slurried in MTBE (360 mL) at 20 - 25 °C for 1 hour. The product was isolated by filtration and subsequently dried to obtain (R,S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (81 g, 55%) as a yellow solid. MS (ESI): C 7 H 9 NO 2 mass calculation for, 139.1, m / z, measured value, 140.1 [M+H] + . 1 H NMR (300 MHz, CD 3 OD) δ 3.40 (dd, J = 7.7, 5.3 Hz, 2H), 3.03 (s, 1H), 2.88 (s, 3H), 2.52 - 2.41 (m, 1H), 2.21 (dt, J = 12.7, 7.7 Hz, 1H).

[0370] Process F: (R)-3-Ethynyl-3-hydroxy-1-methylpyrrolidin-2-one and (S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one. The enantiomers of (R,S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one were separated using an SFC column, for example, a CHIRALPAK® AS-H 5 μm, 5 × 25 cm column, with a mobile phase (80% CO 2, 20% IPA (0.1% DEA). Detection was carried out by chiral preparative SFC using UV at 25 °C (UV = 220 - 254 nM), and (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (40%) and (S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 2, 40%) were obtained. Data for (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one: MS(ESI): C 7 H 9 NO 2 Mass calculated for, 139.1, m / z, found, 140.1 [M + H] + . 1 H NMR (300 MHz, CD 3 OD) δ 3.40 (dd, J = 7.7, 5.3 Hz, 2H), 3.03 (s, 1H), 2.88 (s, 3H), 2.52 - 2.41 (m, 1H), 2.21 (dt, J = 12.7, 7.7 Hz, 1H). [α] 20 D = -100.1 (c = 1.01 in MeOH).

[0371] Intermediate 2: (S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one.

[0372]

Chemical Structure

[0373] Intermediate 1, (S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (40%) was also obtained by the chiral separation described in Step F. MS(ESI): C 7 H 9 NO 2 Mass calculation for, 139.1, m / z, found, 140.1 [M + H] + . 1 H NMR (300 MHz, CD 3 OD) δ 3.40 (dd, J = 7.7, 5.3 Hz, 2H), 3.03 (s, 1H), 2.88 (s, 3H), 2.52 - 2.41 (m, 1H), 2.21 (dt, J = 12.7, 7.7 Hz, 1H). [α] 20D = +90.5 (c = 1.19 in MeOH).

[0374] Intermediate 3: (R)-3-(3-(3-Bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0375] [Chemical formula]

[0376] Step A: 3-Bromobenzaldoxime. To a solution of 3-bromobenzaldehyde (3.0 g, 16 mmol) in EtOH (40 mL), NH 2 OH (50% in water, 1.1 mL, 19 mmol) was added. The reaction mixture was stirred at 25 °C for 4 hours. The reaction mixture was then concentrated under reduced pressure to obtain (3.2 g, 98%) of 3-bromobenzaldoxime as a white solid. MS (ESI): C 7 H 6 alculated mass for BrNO, 199.0, m / z, found, 200.1 [M + H] + .

[0377] Step B: 3-Bromo-N-hydroxybenzimidoyl chloride. To a solution of 3-bromobenzaldoxime (3.20 g, 16.0 mmol) in anhydrous DCM (20 mL), N-chlorosuccinimide (2.56 g, 19.2 mmol) was added portionwise. The reaction mixture was stirred at 25 °C for 2 hours and filtered. The filtrate was concentrated to obtain 3-bromo-N-hydroxybenzimidoyl chloride (3.0 g, 95%) as a yellow solid. MS (ESI): C 7 H 5 alculated mass for BrClNO, 234.5, m / z, found, 235.2 [M + H] + .

[0378] Project 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 (Intermediate 1, 4.45 g, 3.20 mmol), followed by TEA (1.24 mL, 9.60 mmol). The reaction mixture was stirred at 25 °C for 16 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 calculated mass for, 336.0, m / z, found, 337.1 [M+H] + .

[0379] Intermediate 4: (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.

[0380]

Chemical Structure

[0381] To a flask containing (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 3, 0.60 g, 1.8 mmol) in 1,4-dioxane (10 mL) were added 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) were added. 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] + .

[0382] Intermediate 5: (R)-3-Hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one.

[0383]

Chem.

[0384] Step A: (R)-3-(3-(3-Bromophenyl)-3-oxoprop-1-ynyl)-3-hydroxy-1-methylpyrrolidin-2-one. A solution of (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1, 3.00 g, 21.6 mmol) in THF (150 mL) was cooled to -20 °C, and PdCl 2 (PPh 3 ) 2 (0.61 g, 0.86 mmol), CuI (0.21 g, 1.08 mmol), and TEA (4.47 mL, 34.1 mmol) were added. A solution of 3-bromobenzyl chloride (4.73 g, 21.6 mmol) in THF (10 mL) was added dropwise. The reaction mixture was warmed to 0 °C, stirred for 2 h, diluted with water (80 mL), and extracted with EtOAc (3 × 60 mL). The combined organic solvent extracts were washed with brine (60 mL), and Na2 SO 4 It was dried with SO and filtered. The filtrate was concentrated and purified by FCC (DCM / MeOH = 100 / 1) to obtain (R)-3-(3-(3-bromophenyl)-3-oxoprop-1-ynyl)-3-hydroxy-1-methylpyrrolidin-2-one (1.6 g, 23%) as a yellow solid. MS (ESI): C 14 H 12 BrNO 3 Calculated mass for, 321.0, m / z, Found, 322.0 [M+H] + .

[0385] Step B: (R)-3-(5-(3-bromophenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of (R)-3-(3-(3-bromophenyl)-3-oxoprop-1-ynyl)-3-hydroxy-1-methylpyrrolidin-2-one (1.60 g, 4.37 mmol) in DCM (100 mL) was added NaN 3 (1.42 g, 21.8 mmol). The mixture was cooled to 0 °C and AcOH (1.31 g, 21.85 mmol) was added dropwise, followed by TEA (1.21 mL, 0.87 mmol). The reaction mixture was stirred at room temperature for 2 days. Saturated NaHCO 3 aqueous solution (100 mL) was added and the mixture was stirred for 10 minutes. The organic solvent portion was separated and the aqueous layer was extracted with DCM (2 × 50 mL). The combined organic solvent extracts were washed with brine (2 × 100 mL) and dried with Na 2 SO 4 and filtered. The filtrate was concentrated by blowing a continuous stream of N 2 through it, and the residue was purified by FCC (DCM / MeOH = 50 / 1) to obtain (R)-3-(5-(3-bromophenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (0.6 g, 41%) as a grey oil. MS (ESI): C 14 H 13 BrN 2 O 3 Calculated mass for, 336.0, m / z, Found, 337.0 [M+H] + .

[0386] Process C: (R)-3-Hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one. To a flask containing (R)-3-(5-(3-bromophenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (85 mg, 0.252 mmol) in 1,4-dioxane (5 mL) were added bis(pinacolato)diboron (128.0 mg, 0.50 mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (18.4 mg, 0.025 mmol), and KOAc (74.2 mg, 0.76 mmol). The mixture was heated at 65 °C for 4 h under Ar. The reaction mixture was filtered and concentrated to give (R)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one (0.10 g, 87%) as a brown oil, which was used in the next step without further purification. MS (ESI): C 20 H 25 BN 2 O 5 Calculated mass for, 384.2, m / z, Found, 385.2 [M+H] + 。

[0387] Intermediate 6: (R,S)-3-(5-(3-bromophenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0388]

Chemical Structure

[0389] Using conditions similar to those described in the preparation of intermediate 5, ((R)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one), instead of (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one, (R,S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (prepared in step E of intermediate 1) was used to prepare (R,S)-3-(5-(3-bromophenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one) (1.4 g). MS(ESI): C 14 H 13 BrN 2 O 3 Calculated mass for, 336.0, m / z, found, 337.0 [M+H] + 。

[0390] Intermediate 7: (R)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0391]

Chemical Structure

[0392] Step A: 2-Bromoisonicotinaldehyde oxime. Hydroxylamine (0.095 mL, 50% in water, 1.6 mmol) was added to a solution of 2-bromoisonicotinaldehyde (250 mg, 1.3 mmol) in EtOH (10 mL). The reaction mixture was stirred at room temperature for 16 h and concentrated to dryness to afford 2-bromoisonicotinaldehyde oxime (240 mg, 89%) as a colorless solid. MS(ESI): C 6 H 5 BrN 2 Calculated mass for O, 200.0, m / z, found, 201.1 [M+H] + 。

[0393] Step B: 2-Bromo-N-hydroxyisonicotinimidoyl chloride. To a solution of 2-bromoisonicotinamide oxime (140 mg, 0.60 mmol) in DCM (5 mL) was added N-chlorosuccinimide (120 mg, 0.90 mmol) portionwise at room temperature. The reaction mixture was stirred at room temperature for 2 h, then DMF (1 mL) was added and the reaction mixture was stirred for an additional 2 h. The mixture was diluted with EtOAc (20 mL) and washed with brine (3 × 20 mL). The organic extract was dried over Na 2 SO 4 and filtered, and concentrated in vacuo to give 2-bromo-N-hydroxyisonicotinimidoyl chloride (140 mg, 80%) as a white solid. MS (ESI): C 6 H 4 BrClN 2 O, calculated mass, 235.5; m / z, found, 199.0 [M-HCl+1] + .

[0394] Step C: (R)-3-(3-(2-Bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of bromo-N-hydroxyisonicotinimidoyl chloride (2.80 g, 11.9 mmol) and (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1, 1.64 g, 11.9 mmol) in t-BuOH:H 2 O (10 mL, 1:1) was added a solution of sodium ascorbate (0.24 g, 1.2 mmol) in H 2 O (1 mL). Then a solution of CuSO 2 ·5H 4 O (0.89 g, 3.6 mmol) in H 2 O (2 mL) was added, followed by KHCO 3(3.57 g, 1.19 mmol) was added. The reaction mixture was stirred at room temperature for 16 h, diluted with water (20 mL), and extracted with EtOAc (3 × 20 mL). The combined organic solvent extracts were dried, filtered, concentrated to dryness, and purified by preparative TLC (DCM / MeOH = 20 / 1) to give (R)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (1.8 g, 45%) as a yellow solid. MS (ESI): C 13 H 12 BrN 3 O 3 Calculated mass for, 337.0, m / z, Found, 338.3 [M+H] + .

[0395] Intermediate 8: (R)-3-Hydroxy-1-methyl-3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)pyrrolidin-2-one.

[0396] [Chemical Structure]

[0397] Project A: (R)-3-(1-(3-bromophenyl)-1H-1,2,3-triazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a suspension of 1-bromo-3-iodobenzene (281 mg, 0.99 mmol) in DMSO (2 mL) were successively added (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1, 138 mg, 0.993 mmol), sodium azide (71 mg, 1.1 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (28 mg, 0.20 mmol), and copper(I) iodide (38 mg, 0.20 mmol). A solution of sodium ascorbate (39 mg, 0.20 mmol) in water (0.5 mL) was added slowly and the reaction mixture was stirred at room temperature for 16 h under an Ar atmosphere. The mixture was diluted with EtOAc (20 mL), the organic layer was washed with brine (3×15 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by FCC (DCM / MeOH = 20 / 1) to give (R)-3-(1-(3-bromophenyl)1H-1,2,3-triazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (200 mg, 76%) as a yellow solid. MS (ESI): Calculated mass for C 13 H 13 BrN 4 O 2 , 336.0, m / z, found, 337.0 [M+H].

[0398] Project B: (R)-3-Hydroxy-1-methyl-3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)pyrrolidin-2-one. To a solution of (R)-3-(1-(3-bromophenyl)-1H-1,2,3-triazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (200 mg, 0.593 mmol) in dioxane (10 mL) was added bis(pinacolato)diboron (301 mg, 1.19 mmol), followed by [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (45 mg, 0.059 mmol) and KOAc (175 mg, 1.78 mmol). The reaction mixture was heated at 65 °C for 2 h under an Ar atmosphere. The reaction mixture was then filtered and concentrated under reduced pressure. The residue was purified by FCC (DCM / MeOH = 20 / 1) to give (R)-3-hydroxy-1-methyl-3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)pyrrolidin-2-one (260 mg, 68%) as a yellow solid. MS (ESI): C 19 H 25 BN 4 O 4 Calculated mass for, 384.2, m / z, Found, 385.2 [M+H] + 。

[0399] Intermediate 9: (R,S)-3-Hydroxy-1-methyl-3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-4-yl)pyrrolidin-2-one.

[0400]

Chemical Structure

[0401] Project A: 1-(3-Bromophenyl)-4-iodo-1H-imidazole. A mixture of 4-iodoimidazole (3.68 g, 19.0 mmol), 3-bromophenylboronic acid (7.6 g, 38 mmol), di-μ-hydroxy-bis[(N,N,N’,N’-tetramethylethylenediamine)copper(II)] chloride (9.7 g, 20.869 mmol), and molecular sieve (250 mg) in THF (100 mL) was stirred at 30 °C for 16 h under an O 2 atmosphere. The reaction mixture was then filtered through diatomaceous earth, washed with EtOAc (200 mL), and concentrated under reduced pressure. The residue was purified by FCC (petroleum ether / EA = 2 / 1) to give 1-(3-bromophenyl)-4-iodo-1H-imidazole (3.2 g, 48%) as a brown solid. MS (ESI): C 9 H 6 BrIN 2 for mass calculated value, 347.9, m / z, found value, 349.0 [M+H] + .

[0402] Project B: 3-(1-(3-Bromophenyl)-1H-imidazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one. A solution of isopropylmagnesium chloride-lithium chloride (3.6 mL, 1.3 M in THF) was added dropwise to a solution of 1-(3-bromophenyl)-4-iodo-1H-imidazole (1.35 g, 3.87 mmol) in THF (30 mL) cooled to 0 °C. After 1 h, a solution of 1-methylpyrrolidine-2,3-dione (0.87 g, 7.74 mmol) in THF (10 mL) was added and the mixture was stirred at 0 °C for 2 h. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was then cooled to 0 °C, quenched with ice water (6 mL) and MeOH (10 mL), and concentrated under reduced pressure. The residue was purified using preparative TLC (DCM / MeOH = 15 / 1) to give 3-(1-(3-bromophenyl)-1H-imidazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (0.29 mg, 22%) as a brown solid. MS (ESI): C 14 H 14 BrN 3 O 2Mass calculated value for, 336.2, m / z, measured value, 336.0 [M+H] + 。

[0403] Step C: 3-Hydroxy-1-methyl-3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-4-yl)pyrrolidin-2-one. A mixture of bis(pinacolato)diboron (242 mg, 0.95 mmol), 3-(1-(3-bromophenyl)-1H-imidazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (160 mg, 0.48 mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (36.3 mg, 0.048 mmol), and KOAc (140.1 mg, 1.428 mmol) was heated at 80 °C for 16 h under an Ar atmosphere. The reaction mixture was used directly in the next reaction. MS(ESI): C 20 H 26 BN 3 O 4 Mass calculated value for, 383.3, m / z, measured value, 384.0 [M+H] + 。

[0404] Intermediate 10: (R)-(3-(5-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)boronic acid.

[0405]

Chemical formula

[0406] A suspension of (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 3, 500 mg, 1.5 mmol) in MeOH (15 mL) was treated with tetrakis(dimethylamino)diborane (881 mg, 4.45 mmol), followed by the addition of chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (43.4 mg, 59.3 mmol), and the reaction was heated at 60 °C for 16 h under an argon atmosphere. The mixture was concentrated to dryness and purified by FCC (8% MeOH / DCM) to give (R)-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)boronic acid (160 mg, 36%) as a yellow solid. MS (ESI): C 14 H 15 BN 2 O 5 Calculated for, 302.11, m / z, Found, 303.2 [M+H] + 。

[0407] Intermediate 11: 5-Chloro-3-nitro-1H-pyrazolo[4,3-b]pyridine.

[0408]

Chem.

[0409] To a flask containing 5-chloro-1H-pyrazolo[4,3-b]pyridine (5.0 g, 32.56 mmol) was added H 2 SO 4 (10 mL), followed by the addition of KNO 3 (8.2 g, 81.397 mmol) at 0 °C. The mixture was stirred at room temperature for 3 h and then heated at 115 °C for 8 h. The reaction mixture was then poured into ice water and NH 4The pH was adjusted to pH 9 using an aqueous OH solution. A precipitate formed and was collected by filtration. The filter cake was dried to obtain 5-chloro-3-nitro-1H-pyrazolo[4,3-b]pyridine (5.2 g, 80%) as a yellow solid. MS(ESI): C 6 H 3 ClN 4 O 2 Calculated mass for, 198.6, m / z, found, 199.0 [M+H] + 。

[0410] Intermediate 12: 5-Chloro-1-methyl-3-nitro-1H-pyrazolo[4,3-b]pyridine.

[0411]

Chemical formula

[0412] To a solution of 5-chloro-3-nitro-1H-pyrazolo[4,3-b]pyridine (Intermediate 11, 500 mg, 2.5 mmol) and iodomethane (357 mg, 2.52 mmol) in DMF (4 mL) was added potassium carbonate (348 mg, 2.52 mmol). The reaction mixture was heated at 50 °C for 2 h, then diluted with EtOAc (30 mL) and washed with brine (3 × 10 mL). The combined organic layers were concentrated to dryness and the resulting residue was purified by preparative TLC (100% EtOAc) to obtain 5-chloro-1-methyl-3-nitro-1H-pyrazolo[4,3-b]pyridine (200 mg, 37%) as a yellow solid. MS(ESI): C 7 H 5 ClN 4 O 2 Calculated mass for, 212.0, m / z, found, 213.0 [M+H] + 。

[0413] Intermediate 13: 8-Chloro-2-(methylthio)pyrido[3,4-d]pyrimidine.

[0414]

Chemical formula

[0415] Step A: Methyl (E)-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxylate. A mixture of methyl-5-bromo-2-(methylthio)pyrimidine-4-carboxylate (3.00 g, 11.4 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.26 g, 11.40 mmol), Pd(dppf)Cl 2 (0.43 g, 0.57 mmol), water (10 mL), and Na 2 CO 3 (3.63 g, 34.2 mmol) in THF (70 mL) was heated at 65 °C for 16 h under an Ar atmosphere. The reaction mixture was concentrated to dryness, and the residue was purified by FCC eluting with petroleum ether / ethyl acetate (20 / 1 - 8 / 1, gradient elution) to give methyl (E)-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxylate (1.2 g, 41%) as a yellow solid. MS(ESI): C 11 H 14 N 2 O 3 Calculated mass for C + .

[0416] Step B: (E)-5-(2-Ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxamide. A mixture of methyl (E)-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxylate (1.2 g, 4.7 mmol) in a solution of NH 3 (7 M, 12 mL, 84 mmol) in MeOH was heated at 80 °C for 16 h in a sealed tube. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to give (E)-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxamide (950 mg, 84%) as a yellow solid, which was used in the next step without further purification. MS(ESI): C 10 H 13 N 3 O 2Calculated mass value for S, 239.1, m / z, measured value, 240.1 [M+H] + .

[0417] Step C: 2-(Methylthio)pyrido[3,4-d]pyrimidin-8-ol. To a solution of (E)-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxamide (950 mg, 3.97 mmol) in toluene (25 mL) was added p-toluenesulfonic acid monohydrate (113 mg, 0.60 mmol). The resulting mixture was heated at 90 °C for 2 h, cooled to room temperature, and then concentrated under reduced pressure to give 2-(methylthio)pyrido[3,4-d]pyrimidin-8-ol (700 mg, 91%) as a yellow solid, which was used in the next step without further purification. MS(ESI): C 8 H 7 N 3 Calculated mass value for O S, 193.0, m / z, measured value, 194.1 [M+H] + .

[0418] Step D: 8-Chloro-2-(methylthio)pyrido[3,4-d]pyrimidine. POCl 3 (25 mL, 269 mmol) of a mixture of 2-(methylthio)pyrido[3,4-d]pyrimidin-8-ol (700 mg, 3.62 mmol) was heated at 70 °C for 16 h. The mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc (20 mL) and saturated NaHCO 3 aqueous solution (20 mL). The aqueous layer was extracted with EtOAc (2×10 mL), and the combined organic solvent extracts were washed with brine (20 mL), dried over Na 2 SO 4 and filtered and concentrated. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 3 / 1, R f = 0.4) to give 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine (500 mg, 65%) as a white solid. MS(ESI): C 8 H 6 Cl N 3 Calculated mass value for S, 211.0, m / z, measured value, 212.1 [M+H] + .

[0419] Intermediate 14: Methyl 6-(3-iodophenyl)picolinate.

[0420]

Chem.

[0421] A mixture of methyl 6-bromopicolinate (1.0 g, 4.63 mmol), (3-iodophenyl)boronic acid (1.0 g, 4.21 mmol), KF (733 mg, 12.6 mmol), PdCl 2 (dppf) (128 mg, 0.17 mmol), 1,4-dioxane (15 mL), and water (2 mL) was heated at 80 °C for 15 h under a N 2 atmosphere. The mixture was concentrated, diluted with water (35 mL), and extracted with EtOAc (4 × 35 mL). The combined organic solvent extracts were washed with brine (20 mL) and dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 5 / 1) to give methyl 6-(3-iodophenyl)picolinate (89 mg, 6.2%) as a yellow oil. MS (ESI): C 13 H 10 INO 2 for mass calculation, 339.1, m / z, found, 340.0 [M + H] + .

[0422] Intermediate 15: 6-Chloro-4-methoxypicolinamide.

[0423]

Chem.

[0424] A solution of 6-chloro-4-methoxypicolinic acid (200 mg, 1.07 mmol) in DCM (3 mL) and DMF (3 mL) was added with ammonium chloride (160 mg, 2.99 mmol), followed by DIEA (689 mg, 5.33 mmol), and HATU (567 mg, 1.49 mmol). The reaction mixture was stirred overnight at room temperature and then diluted with water (20 mL). The aqueous phase was extracted with EtOAc (3 × 15 mL), concentrated to dryness, and purified by FCC (petroleum ether / ethyl acetate = 1:1) to obtain 6-chloro-4-methoxypicolinamide (130 mg, 65%) as a yellow solid. MS (ESI): C 7 H 7 ClN 2 O 2 Calculated mass for, 186.0, m / z, found, 187.0 [M+H] + 。

[0425] Intermediate 16: 6-Chloro-2-methylpyrido[3,2-d]pyrimidin-4-amine.

[0426]

Chemical formula

[0427] To a vial containing 3-amino-6-chloropicolinonitrile (100 mg, 0.65 mmol) were added ethanimidamide hydrochloride (57.0 mg, 0.98 mmol), tribasic potassium phosphate (553 mg, 2.6 mmol), and THF (3 mL). The vial was sealed and heated at 80 °C for 16 h. The resulting mixture was cooled to room temperature and concentrated to dryness. Water (3 mL) was added to this residue, and the resulting mixture was heated at 70 °C. After stirring for 30 min, the resulting mixture was cooled to room temperature and stirred for an additional 30 min. The resulting solid was isolated by filtration and washed sequentially with water (3 mL) and Et 2 O (10 mL) to obtain 6-chloro-2-methylpyrido[3,2-d]pyrimidin-4-amine (70 mg, 55%) as a pale yellow solid. MS (ESI): C 8 H 7 ClN 4Mass calculated value for, 194.0, m / z, measured value, 195.0 [M+H] + . 1 H NMR(400MHz,CDCl 3 ) δ 8.00 (d, J = 8.7Hz, 1H), 7.62 (d, J = 8.7Hz, 1H), 6.76 (s, 2H), 2.63 (s, 3H).

[0428] Intermediate 17: 6-Chloropyrido[3,2-d]pyrimidine-2-d-4-amine.

[0429]

Chemical Structure

[0430] Into a 1L round-bottom flask, 3-Amino-6-chloropicolinonitrile (22.0 g, 0.14 mol), formamide-d 3 (20.6 g, 0.43 mol), K 3 PO 4 (122 g, 0.57 mol), and cyclopentyl methyl ether (440 mL) were added. The resulting mixture was heated at 65 °C for 16 hours and then cooled to room temperature. Subsequently, the reaction mixture was filtered, and the filter cake was slurried in water (100 mL) at 20 °C for 3 hours. The solid was isolated by filtration and dried to obtain 6-Chloropyrido[3,2-d]pyrimidine-2-d-4-amine (23.9 g, 94%) as a yellow solid. MS(ESI): C 7 H 4 DClN 4 Mass calculated value for, 181.0, m / z, measured value, 182.0 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 ) δ 8.15 (d, J = 8.8Hz, 1H), 8.05 (br s, 1H), 7.95 (br s, 1H), 7.88 (d, J = 8.8Hz, 1H).

[0431] Intermediate 18: 6-(3-Iodophenyl)pyrido[3,2-d]pyrimidine-2-d-4-amine.

[0432]

Chem.

[0433] Process A: 6-(3-(Trimethylsilyl)phenyl)pyrido[3,2-d]pyrimidin-2-d-4-amine. To a 1 L flask equipped with an overhead stirrer containing 6-chloropyrido[3,2-d]pyrimidin-2-d-4-amine (Intermediate 17, 31 g, 0.14 mol), 4-(Trimethylsilyl)phenylboronic acid (32 g, 0.17 mol), Pd(dppf)Cl 2 (10.2 g, 13.8 mmol), CH 3 CN (500 mL), and Cs 2 CO 3 aqueous solution (1 M, 125 mL) were successively added under an N 2 atmosphere. The resulting mixture was heated at 75 °C for 3 h. Water (375 mL) was added and the reaction mixture was heated at 65 °C for an additional 0.5 h. The resulting mixture was then gradually cooled to room temperature and stirred for 1 h. The product was isolated by filtration and dried to give 6-(3-(Trimethylsilyl)phenyl)pyrido[3,2-d]pyrimidin-2-d-4-amine (39 g, 94%) as a brown solid. MS (ESI): C 16 H 17 DN 4 Mass calculation for Si, 295.1, m / z, found, 296.1 [M + H] + . 1 H-NMR (300 MHz, DMSO-d 6 ) δ 8.46 (t, J = 8.9 Hz, 2H), 8.39 (s, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 10.3 Hz, 2H), 7.65 (d, J = 7.1 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 0.35 (s, 9H).

[0434] Project B: 6-(3-Iodophenyl)pyrido[3,2-d]pyrimidin-2-d-4-amine. In a 10 L round-bottom flask equipped with an overhead stirrer, 6-(3-(Trimethylsilyl)phenyl)pyrido[3,2-d]pyrimidin-2-d-4-amine (49.0 g, 0.17 mol) and DCM (980 mL) were added. Then, a solution of ICl (134 g, 0.830 mol) in CH 2 Cl 2 (735 mL) was added dropwise at -5 °C, and the reaction mixture was warmed to 15 °C and stirred for 1 hour. A precipitate formed, which was isolated by filtration and dried under vacuum at 50 °C. The resulting solid was combined with several additional batches of this material and dissolved in DMSO (800 mL). Then, an aqueous solution (10 wt%) of K 2 HPO 4 was added dropwise to the above solution, and stirring was continued at 20 °C for 2 hours. The precipitate was isolated by filtration and then slurried in water (1600 mL) at 20 °C for 4 hours. The solid was isolated and dried to obtain 6-(3-Iodophenyl)pyrido[3,2-d]pyrimidin-2-d-4-amine as a light brown solid (135 g). MS (ESI): C 13 H 8 DIN 4 mass calculation for, 349.0, m / z, measured value, 350.0 [M+H] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.84 (m, 1H), 8.47 (m, 1H), 8.40 (m, 2H), 8.12 (m, 2H), 7.86 (m, 1H), 7.34 (m, 1H).

[0435] Intermediate 19: 3-Amino-6-(3-iodophenyl)picolylamide.

[0436]

Chemical Structure

[0437] Project A: 3-Amino-6-(3-(trimethylsilyl)phenyl)picolylamide. To a solution of 3-amino-6-chloropicolylamide (1.00 g, 5.83 mmol) and (3-(trimethylsilyl)phenyl)boronic acid (1.11 g, 5.83 mmol) in dioxane (58 mL) and water (15 mL) purged with N 2 was added (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1′-biphenyl)]palladium(II) methanesulfonate (0.48 g, 0.58 mmol), followed by Cs 2 CO 3 (5.70 g, 17.5 mmol). The reaction mixture was heated at 80 °C for 1 h, partitioned between EtOAc (40 mL) and water (60 mL), the organic layer was separated, concentrated in vacuo, and purified by FCC (0–40% EtOAc:hexanes) to afford 3-amino-6-(3-(trimethylsilyl)phenyl)picolylamide (1.2 g, 73%) as an orange solid. MS (ESI): C 15 H 19 N 3 Calculated for OSi, 285.1, m / z, Found, 286.1 [M+H] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.12–8.03 (m, 2H), 8.02 (s, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.49–7.44 (m, 1H), 7.43–7.37 (m, 2H), 7.25 (d, J = 8.7 Hz, 1H), 6.95 (s, 2H), 0.30 (s, 9H).

[0438] Project B: 3-Amino-6-(3-iodophenyl)picolylamide. To a solution of 3-amino-6-(3-(trimethylsilyl)phenyl)picolylamide (0.20 g, 0.70 mmol) in DCM (7 mL) at 0 °C was added dropwise a solution of ICl (3.5 mL, 2 M in DCM, 3.50 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. Saturated Na 2 S 2 O 3An aqueous solution (25 mL) was added and the solid was isolated by filtration. The solid was purified by FCC (0 - 10% MeOH:DCM) to give 3-amino-6-(3-iodophenyl)picolylamide (133 mg, 56%) as a beige solid. MS (ESI): C 12 H 10 IN 3 Calculated mass for C, H, IN, O, 339.0, m / z, found, 340.0 [M + H] + 。 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.45 - 8.39 (m, 1H), 8.16 (s, 1H), 8.12 - 8.01 (m, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.70 - 7.62 (m, 1H), 7.40 (s, 1H), 7.25 - 7.17 (m, 2H), 7.03 (s, 2H).

[0439] Intermediate 20: 2-(5-iodo-2-methylphenyl)thiazolo[5,4-d]pyrimidin-7-amine.

[0440]

Chemical Structure

[0441] Step A: N-(4-amino-6-oxo-1,6-dihydropyrimidin-5-yl)-5-iodo-2-methylbenzamide. To a 2 L round-bottom flask equipped with an overhead stirrer were successively charged 5,6-diaminopyrimidin-4(3H)-one (47.3 g, 375 mmol), 5-iodo-2-methylbenzoic acid (108 g, 412 mmol), DMF (710 mL), and DIEA (153 g, 1.18 mol). The flask was purged with nitrogen and cooled to 0 - 10 °C, then 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (148 g, 390 mmol) was added. The resulting mixture was stirred at 0 - 10 °C for 1 h and then warmed to room temperature with stirring for 18 h. The mixture was diluted with acetonitrile (709 mL) while stirring for an additional 30 min. The resulting solid was filtered and washed with CH 3It was washed with CN (190 mL × 3). The filter cake was recovered and dried under vacuum at 50 - 55 °C to obtain N-(4-amino-6-oxo-1,6-dihydropyrimidin-5-yl)-5-iodo-2-methylbenzamide (108 g, 78.0%) as a light brown solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.68 (s, 1H), 8.89 (s, 1H), 8.01 (s, 1H), 7.78 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.39 (s, 2H), 2.35 (s, 3H).

[0442] Step B: 2-(5-Iodo-2-methylphenyl)thiazolo[5,4-d]pyrimidin-7-amine. In a 2 L round-bottom flask equipped with an overhead stirrer, N-(4-amino-6-oxo-1,6-dihydropyrimidin-5-yl)-5-iodo-2-methylbenzamide (110 g, 297 mmol), pyridine (1.10 L), and P 2 S 5 (165 g, 742 mmol) were added. The resulting mixture was heated at 100 °C for 1 hour and then cooled to room temperature. The mixture was concentrated to dryness, diluted with acetonitrile (550 mL), and neutralized with 1N aqueous HCl solution (1.20 L). The resulting mixture was stirred for 1 hour, the suspension was filtered, washed with MeOH (110 mL × 3), and dried under vacuum at 50 - 55 °C. The obtained solid was further purified by adding MeOH (1150 mL) at 60 °C and stirring for 1 hour. The solid was recovered by filtration and dried under vacuum at 50 - 55 °C to obtain 2-(5-iodo-2-methylphenyl)thiazolo[5,4-d]pyrimidin-7-amine (88.4 g, 80.8%) as a light yellow solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.33 (s, 1H), 8.15 (d, J = 1.9 Hz, 1H), 7.81 (d, J = 2.0 Hz, 2H), 7.78 (d, J = 1.9 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 2.57 (s, 3H).

[0443] Intermediate 21: 2-(3-Iodophenyl)thiazolo[5,4-d]pyrimidin-7-amine.

[0444]

Chem.

[0445] Step A: N-(4-Amino-6-oxo-1,6-dihydropyrimidin-5-yl)-3-iodobenzamide. To a solution of 5,6-diaminopyrimidin-4-ol and NaOH (2 M, 50 mL, 100 mmol) at 0 °C, 3-iodobenzoyl chloride (4.23 g, 15.9 mmol) was added. The reaction mixture was stirred at 0 °C for 4 h, warmed to room temperature, and then stirred overnight. The solid was removed by filtration, and the pH of the filtrate was adjusted to pH 4 - 5 with acetic acid. The resulting precipitate was filtered, washed with water (50 mL), and the obtained solid was suspended in EtOH (100 mL), stirred for 10 min, and filtered. The filter cake was washed with EtOH (30 mL) and then dried to obtain N-(4-amino-6-oxo-1,6-dihydropyrimidin-5-yl)-3-iodobenzamide (0.64 g, 23%) as a brown solid. MS(ESI): C 11 H 9 IN 4 O 2 Mass calculated for, 356.0, m / z, found, 357 [M+H] + .

[0446] Project B: 2-(3-Iodophenyl)thiazolo[5,4-d]pyrimidin-7-amine. A solution of N-(4-amino-6-oxo-1,6-dihydropyrimidin-5-yl)-3-iodobenzamide (640 mg, 1.80 mmol) and 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (727 mg, 1.80 mmol) in toluene (15 mL) was heated to reflux for 16 hours, cooled to room temperature, and the solid was isolated by filtration. The filter cake was washed with toluene (5 mL), the solid was suspended in MeOH (3 mL), stirred for 2 minutes, and isolated by filtration to give 2-(3-iodophenyl)thiazolo[5,4-d]pyrimidin-7-amine (420 mg, 66%) as a white solid. MS(ESI): C 11 H 7 IN 4 Mass calculation for S, 353.9, m / z, found, 355.0 [M+H] + 。

[0447] Intermediate 22: 4-(Azetidin-1-yl)-6-chloropyrido[3,2-d]pyrimidine.

[0448]

Chemical Structure

[0449] To a mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (250 mg, 1.25 mmol), DIPEA (0.87 mL, 5.00 mmol), and DMF (2.5 mL) was added azetidine (71.3 mg, 1.25 mmol), and the resulting mixture was stirred at room temperature. After 1.5 hours, the mixture was filtered, and the filter cake was dried under reduced pressure to give 4-(azetidin-1-yl)-6-chloropyrido[3,2-d]pyrimidine (200 mg, 73%) as a white solid. MS(ESI): C 10 H 9 ClN 4 Calculated mass value for, 220.1, m / z, found, 221.1 [M+H] + 。 1 H NMR(400MHz,CD 3OD) δ 8.34 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 4.88 (t, J = 7.7 Hz, 2H), 4.36 (t, J = 7.7 Hz, 2H), 2.82 - 2.21 (m, 2H).

[0450] Intermediate 23: (R)-3-Hydroxy-3-(3-(3-iodophenyl)isoxazol-5-yl)-1-methylpyrrolidin-2-one.

[0451]

Chemical formula

[0452] Step A: 3-Iodobenzaldoxime. To a solution of 3-iodobenzaldehyde (1.5 g, 6.5 mmol) in EtOH (20 mL), NH 2 OH (50% in water) (0.46 mL, 7.8 mmol) was added. The mixture was stirred at 25 °C for 16 h and then concentrated to dryness to give 3-iodobenzaldoxime (1500 mg, 6.072 mmol) as a pale yellow solid, which was used in the next step without further purification. MS (ESI): C 7 H 6 Mass calculation for C + .

[0453] Step B: N-Hydroxy-3-iodobenzimidoyl chloride. N-Chlorosuccinimide (973 mg, 7.29 mmol) was added portionwise to a solution of 3-iodobenzaldoxime (1.5 g, 6.1 mmol) in dry DCM (30 mL). The reaction mixture was stirred at 25 °C for 2 h. Then the mixture was concentrated to give N-hydroxy-3-iodobenzimidoyl chloride (1450 mg, 5.151 mmol) as a pale yellow oil, which was used in the next step without further purification. MS (ESI): C 7 H 5 Mass calculated value for C + .

[0454] Process C: (R)-3-Hydroxy-3-(3-(3-iodophenyl)isoxazol-5-yl)-1-methylpyrrolidin-2-one. To a solution of N-hydroxy-3-iodobenzimidoyl chloride (650 mg, 2.31 mmol) in DCM (15 mL) was added (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1, 385 mg, 2.77 mmol) and TEA (934 mg, 9.24 mmol). The mixture was stirred at 50 °C for 4 h. Then the mixture was cooled to room temperature, washed with brine (20 mL), dried over Na 2 SO 4 and filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 20 / 1, R f = 0.4) to give (R)-3-hydroxy-3-(3-(3-iodophenyl)isoxazol-5-yl)-1-methylpyrrolidin-2-one (110 mg, 0.266 mmol) as a yellow solid. MS (ESI): Calculated for C 14 H 13 IN 2 O 3 : mass, 384.0, m / z, found, 385.0 [M+H] + .

[0455] Intermediate 24: tert-Butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate.

[0456]

Chemical Structure

[0457] Process A: 3-Iodo-1H-pyrrolo[2,3-b]pyridine. To a solution of 1H-pyrrolo[2,3-b]pyridine (5 g, 42.324 mmol) in MeCN (60 mL) was added N-iodosuccinimide (11.427 g, 50.789 mmol) portionwise. The mixture was stirred at 25 °C for 2 h, then the solid from the reaction mixture was collected by vacuum filtration. This solid was washed with MeCN (30 mL) and the filtrate was concentrated to give 3-iodo-1H-pyrrolo[2,3-b]pyridine (8.0 g, 31 mmol) as a yellow solid. MS(ESI): C 7 H 5 IN 2 Mass calculation for, 244.0, m / z, found, 245.1 [M+H] + 。

[0458] Process B: tert-Butyl 3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. To a solution of 3-iodo-1H-pyrrolo[2,3-b]pyridine (8.00 g, 32.8 mmol), DMAP (0.40 g, 3.28 mmol), and TEA (13.2 g, 131 mmol) in DCM (130 mL) was added di-tert-butyl dicarbonate (8.58 g, 39.3 mmol) dropwise. The mixture was stirred at 25 °C for 2 h. Then the reaction mixture was diluted with DCM (130 mL) and washed with saturated Na 2 SO 3 aqueous solution (100 mL), then brine (120 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (8 / 1) to give tert-butyl 3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (11.8 g) as a yellow oil. MS(ESI): C 12 H 13 IN 2 O 2 Mass calculated for, 344.0, m / z, found, 345.1 [M+H] + 。

[0459] Project C: tert-Butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. To a solution of tert-butyl 3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (11.8 g, 34.3 mmol) in 1,4-dioxane (50 mL) was added bis(pinacolato)diboron (17.4 g, 68.6 mmol), PdCl 2 (dppf) (0.78 g, 1.03 mmol), and KOAc (10.1 g, 103 mmol). The mixture was heated at 85 °C for 16 h under an argon atmosphere. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), washed with brine (50 mL), dried over Na 2 SO 4 , filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (gradient of 20 / 1 to 8 / 1) to give tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (8 g, 9 mmol) as a pale yellow solid. MS (ESI): C 18 H 25 BN 2 O 4 calculated mass for, 344.2, m / z, found, 345.3 [M+H] + .

[0460] Intermediate 25: 6-(3-Chlorophenyl)pyrido[3,2-d]pyrimidin-2-d-4-amine.

[0461]

Chemical formula

[0462] 1,1'-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (144 mg, 0.22 mmol) was added to 6-chloropyrido[3,2-d]pyrimidin-2-d-4-amine (Intermediate 17, 400 mg, 2.20 mmol), (3-chlorophenyl)boronic acid (413 mg, 2.64 mmol), K3 PO 4 (1.4 g, 6.6 mmol), 1,4-dioxane (6.4 mL), and H 2 O (1.6 mL) was added to the mixture. The resulting mixture was sparged with Ar for 5 minutes and then irradiated with microwave at 90 °C for 1.5 hours. Then, the mixture was cooled to room temperature and concentrated to dryness under reduced pressure to obtain the product, which was purified by FCC (eluent: petroleum ether: ethyl acetate = 1:0 to 1:1) to obtain 6-(3-chlorophenyl)pyrido[3,2-d]pyrimidin-2-d-4-amine (300 mg, 51%) as a yellow solid. MS(ESI): C 13 H 8 ClDN 4 Mass calculated for, 257.7, m / z found, 258.1 [M+1] + .

[0463] Intermediate 26: (S)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0464]

Chem.

[0465] In Step C, using Intermediate 2 instead of Intermediate 1 and using the same conditions as described for Intermediate 3, the title compound was prepared. MS(ESI): C 14 H 13 BrN 2 O 3 Mass calculated for, 336.0, m / z, found, 337.1 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δ 8.01 (t, J = 1.8 Hz, 1H), 7.81 (td, J = 7.8, 1.2 Hz, 1H), 7.67 - 7.61 (m, 1H), 7.41 (t, J = 7.9 Hz, 1H), 6.92 - 6.89 (m, 1H), 3.62 - 3.49 (m, 2H), 2.95 (s, 3H), 2.72 (ddd, J = 13.5, 6.8, 5.1 Hz, 1H), 2.45 - 2.33 (m, 1H).

[0466] Intermediate 27: (S)-3-Hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one.

[0467]

Chem.

[0468] In Step C, using (S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one, the title compound was prepared in the same manner as (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Steps A - C), and the boronation reaction was the same as that of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. MS(ESI): C 20 H 25 BN 2 O 5 Calculated mass for, 384.2, m / z, Found, 385.2 [M + H] + .

[0469] Intermediate 28: (R)-3-Hydroxy-1-methyl-3-(3-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one.

[0470]

Chem.

[0471] Step A: 3-Bromo-5-methylbenzaldoxime. To a solution of 3-bromo-5-methylbenzaldehyde (2 g, 10.05 mmol) in EtOH (20 mL), NH 2OH (50% in water) (0.71 mL, 12.06 mmol) was added. The reaction mixture was stirred at 25 °C for 16 h, concentrated under reduced pressure, and 3-bromo-5-methylbenzaldoxime (2.1 g, 97%) was obtained as a white solid. MS (ESI): C 8 Calculated mass for C + .

[0472] Step B: 3-Bromo-N-hydroxy-5-methylbenzimidoyl chloride. To a solution of 3-bromo-5-methylbenzaldoxime (600 mg, 2.80 mmol) in anhydrous DCM (20 mL) was added N-chlorosuccinimide (450 mg, 3.36 mmol) portionwise. The reaction mixture was stirred at 25 °C for 2 h, filtered, and the filtrate was concentrated under reduced pressure to give 3-bromo-N-hydroxy-5-methylbenzimidoyl chloride (0.6 g, 86%) as a yellow solid. MS (ESI): C 8 Calculated mass for C + .

[0473] Step C: (R)-3-(3-(3-Bromo-5-methylphenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. (R)-3-Ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1, 336 mg, 2.41 mmol), 3-bromo-N-hydroxy-5-methylbenzimidoyl chloride (600 mg, 2.41 mmol), and TEA (0.99 mL, 7.24 mmol) in DCM (20 mL) were stirred at 25 °C for 16 h. The reaction mixture was diluted with DCM (80 mL), washed with brine (60 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to give (R)-3-(3-(3-bromo-5-methylphenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (0.3 g, 35%) as a yellow oil. MS (ESI): C 15 H15 BrN 2 O 3 Mass calculated value for, 351.2, m / z, measured value, 351.0 [M+H] + 。

[0474] Step D: (R)-3-Hydroxy-1-methyl-3-(3-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. Bis(pinacolato)diboron (398 mg, 1.57 mmol), (R)-3-(3-(3-bromo-5-methylphenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (275 mg, 0.78 mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (59.6 mg, 0.078 mmol), KOAc (230.5 mg, 2.35 mmol), and 1,4-dioxane (8 mL) were heated at 80 °C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by FCC (DCM / MeOH = 60 / 1) to give (R)-3-hydroxy-1-methyl-3-(3-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (0.3 g, 96%) as a yellow solid. MS(ESI): C 21 H 27 BN 2 Mass calculated value for O5, 398.3, m / z, measured value, 399.3 [M+H] + 。

[0475] Intermediate 29: (R)-3-Hydroxy-1-methyl-3-(3-(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one.

[0476]

Chemical Structure

[0477] The title compound was prepared in a manner similar to (R)-3-hydroxy-1-methyl-3-(3-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one, steps A-D, using 5-bromo-2-methylbenzaldehyde instead of 3-bromo-5-methylbenzaldehyde in step A. MS(ESI): C 21 H 27 BN 2 O 5 Calculated mass for, 398.3, m / z, Measured mass, 399 [M+H] + .

[0478] Intermediate 30: (R)-3-hydroxy-1-methyl-3-(3-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one

[0479] [ka]

[0480] The title compound was prepared in a manner similar to (R)-3-hydroxy-1-methyl-3-(3-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one, steps A-D, using 3-bromo-4-methylbenzaldehyde instead of 3-bromo-5-methylbenzaldehyde in step A. MS(ESI): C 21 H 27 BN 2 O 5 Calculated mass for, 398.3, m / z, Measured mass, 399 [M+H] + .

[0481] Intermediate 31: (R)-3-Hydroxy-3-(3-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)-1-methylpyrrolidin-2-one.

[0482]

Chem.

[0483] Using 3-bromo-5-methoxybenzaldehyde instead of 3-bromo-5-methylbenzaldehyde in Step A, (R)-3-hydroxy-1-methyl-3-(3-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one was prepared in the same manner as Steps A - D. MS(ESI): C 21 H 27 BN 2 O 6 Calculated mass for, 414.2, m / z, Found, 415.2 [M + H] + .

[0484] Intermediate 32: (R)-3-Hydroxy-1-methyl-3-(3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furan-2-yl)isoxazol-5-yl)pyrrolidin-2-one.

[0485]

Chem.

[0486] Using 5-bromofuran-2-carbaldehyde instead of 3-bromo-5-methylbenzaldehyde in Step A, (R)-3-hydroxy-1-methyl-3-(3-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one was prepared in the same manner as Steps A - D. MS(ESI): C 18 H23 BN 2 O 6 Mass calculated value for, 374.2, m / z, measured value, 293 [M - C 6 H 12 + 。

[0487] Intermediate 33: (R)-3-(3-(5-(6-chloropyridin-2-yl)furan-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0488]

Chemical formula

[0489] Step A: 5-(6-chloropyridin-2-yl)furan-2-carbaldehyde. To a solution of 2-chloro-6-(furan-2-yl)pyridine (1.8 g, 10 mmol) in THF (40 mL) was added LDA (2N, 6 mL, 12 mmol), and the reaction mixture was stirred at -78 °C for 1 hour. A solution of DMF (1.5 g, 20 mmol) in THF (5 mL) was added dropwise, and the reaction was stirred at -78 °C for 2 hours and then diluted with water (50 mL). The mixture was warmed to room temperature and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over Na 2 SO 4 and filtered. The filtrate was concentrated to dryness and then stirred with petroleum ether (50 mL) and EtOAc (5 mL) for 10 minutes. The solid was separated by filtration to give 5-(6-chloropyridin-2-yl)furan-2-carbaldehyde (1.5 g, 72.0%) as a yellow solid. MS (ESI): C 10 H 6 ClNO 2 Mass calculated value for, 207.6, m / z, measured value, 208 [M + H] + 。

[0490] ​Process B: 5-(6-chloropyridin-2-yl)furan-2-carbaldehyde oxime. Hydroxylamine (50% in water, 827 mg, 12.52 mmol) was added to a solution of 5-(6-chloropyridin-2-yl)furan-2-carbaldehyde (1.3 g, 6.26 mmol) in EtOH (100 mL). The mixture was stirred at 25 °C for 6 h and then concentrated to give 5-(6-chloropyridin-2-yl)furan-2-carbaldehyde oxime (1.3 g, 93%) as a yellow solid. MS(ESI): C 10 H 7 ClN 2 O 2 Calculated mass for, 222.6, m / z, found, 223.1 [M+H] + 。

[0491] Process C: 5-(6-chloropyridin-2-yl)-N-hydroxyfuran-2-carboximidoyl chloride. N-chlorosuccinimide (360 mg, 2.7 mmol) was added portionwise to a solution of 5-(6-chloropyridin-2-yl)furan-2-carbaldehyde oxime (500 mg, 2 mmol) in dry DMF (8 mL), and the reaction was stirred at 30 °C for 4 h. The reaction mixture was concentrated to dryness to give 5-(6-chloropyridin-2-yl)-N-hydroxyfuran-2-carboximidoyl chloride (550 mg, 95%) as a yellow solid, which was used in the next step without further purification. MS(ESI): C 10 H 6 Cl 2 N 2 O 2 Calculated mass for, 257.1, m / z, found, 257 [M+H] + 。

[0492] Project D: (R)-3-(3-(5-(6-chloropyridin-2-yl)furan-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of 5-(6-chloropyridin-2-yl)-N-hydroxyfuran-2-carboximidoyl chloride (550 mg, 2.14 mmol) in DCM (30 mL) was added (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1, 298 mg, 2.14 mmol) and TEA (648 mg, 6.42 mmol). The mixture was stirred at 25 °C for 16 h. The mixture was washed with brine (2 × 50 mL) and dried over Na 2 SO 4 and filtered. The filtrate was concentrated and the residue was purified by preparative TLC (UV-254, silica, DCM:MeOH / 20:1) to give (R)-3-(3-(5-(6-chloropyridin-2-yl)furan-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (110 mg, 14%) as a brown oil. MS (ESI): C 17 H 14 ClN 3 O 4 calculated mass for, 359.8, m / z, found, 360 [M+H] + .

[0493] Intermediate 34: (R,S)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0494]

Chemical Structure

[0495] The title compound (700 mg, 30% in step A; 1.4 g, 69% in step B) was prepared in step A using (R,S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one instead of (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one under the same conditions as described in steps A - B. MS(ESI): C 14 H 13 BrN 2 O 3 Calculated mass for, 337.2, m / z, found, 337 [M + H] + 。

[0496] Intermediate 35: (R,S)-3-(5-(3-aminophenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0497]

Chemical formula

[0498] Process A: (R,S)-3-(5-(3((diphenylmethylene)amino)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one. A solution of (R,S)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 34, 260 mg, 0.77 mmol), diphenylmethanimine (210 mg, 0.16 mmol), cesium carbonate (502 mg, 1.54 mmol), BINAP (72 mg, 0.12 mmol), and palladium(II) acetate (17 mg, 0.12 mmol) in dioxane (8 mL) was heated at 100 °C for 16 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, and purified by FCC (DCM:MeOH, 20:1) to afford (R,S)-3-(5-(3-((diphenylmethylene)amino)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (200 mg, 59% yield) as a yellow oil. MS (ESI): Calculated mass for C 27 H 23 N 3 O 3 437.5, m / z, found 438 [M + H] + .

[0499] Process B: (R,S)-3-(5-(3-aminophenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one. A solution of (R,S)-3-(5-(3-((diphenylmethylene)amino)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (210 mg, 0.48 mmol) in EtOH (10 mL) was treated with aqueous HCl solution (2.7 mL, 1 M, 2.7 mmol), and the reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with saturated NaHCO 3 aqueous solution (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried (Na 2 SO 4) Filtered, concentrated, and purified by preparative TLC (DCM:MeOH, 15:1) to obtain (R,S)-3-(5-(3-aminophenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (95 mg, 72% yield) as a colorless solid. MS (ESI): C 14 H 15 N 3 O 3 Calculated mass for, 273.1, m / z, found, 274.2 [M+H] + .

[0500] Intermediate 36: (R,S)-(3-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)boronic acid.

[0501] [Chemical formula]

[0502] Step A: (R,S)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one. Using (R,S)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 34) instead of (R)-3-(5-(3-bromophenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one, the title compound was prepared in the same manner as Step C of (R)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one to obtain (R,S)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one (200 mg, 88% yield) as a yellow solid. MS (ESI): C 20 H 25 BN 2O 5 Mass calculated value for, 384.2, m / z, measured value, 385.2 [M+H] + 。

[0503] Step B: (R,S)-(3-(3-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)boronic acid. Using (R,S)-3-Hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one, the title compound was synthesized in the same manner as (R)-3-(5-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenylboronic acid to obtain (R,S)-(3-(3-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)boronic acid (40 mg, yield 61%) as a pale yellow solid. MS(ESI): C 14 H 15 BN 2 O 5 Mass calculated value for, 302.1, m / z, measured value, 303.1 [M+H] + 。

[0504] Intermediate 37: (5R,8S)-2-(3-Formylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyrimidine-4-carboxamide.

[0505]

Chemical Structure

[0506] Project A: (5R,8S)-2-(3-Vinylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyrimidine-4-carboxamide. (5R,8S)-2-(3-Iodophenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyrimidine-4-carboxamide (350 mg, 0.86 mmol), potassium trifluoro(vinyl)borate (173 mg, 1.23 mmol), tetrakis(triphenylphosphine)palladium(0) (99 mg, 0.086 mmol), Na 2 CO 3 (274 mg, 2.58 mmol), a mixture of 1,4-dioxane (10 mL), and water (1 mL) was stirred at 85 °C for 16 h under nitrogen. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated. The product was purified by preparative TLC (DCM / MeOH = 40 / 1, silica, UV = 254 nm) to give (5R,8S)-2-(3-vinylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyrimidine-4-carboxamide (250 mg, 82.5%) as a yellow solid. MS (ESI): C 18 H 17 N 3 O 2 Calculated mass for, 307.3, m / z, Found, 308 [M+H] + .

[0507] Project B: (5R,8S)-2-(3-Formylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyrimidine-4-carboxamide. To a solution of (5R,8S)-2-(3-vinylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyrimidine-4-carboxamide (250 mg, 0.81 mmol) in t-BuOH (4.5 mL), THF (3.0 mL), and H 2 O (1.5 mL) was added N-methylmorpholine N-oxide (114.4 mg, 0.98 mmol), followed by OsO 4(10 mg, 0.041 mmol) was added. The reaction mixture was stirred at room temperature for 7 h, followed by addition of NaHCO 3 (820 mg, 9.76 mmol), NaIO 4 (557 mg, 2.60 mmol), and H 2 O (3 mL). The mixture was stirred for 45 min and then poured into saturated Na 2 SO 3 aqueous solution. The mixture was extracted with diethyl ether. The organic layer was dried over MgSO 4 , filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 40 / 1, silica, UV = 254 nm) to give (5R,8S)-2-(3-formylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyrimidine-4-carboxamide (200 mg, 80%). MS (ESI): calculated mass for C 17 H 15 N 3 O 3 , 309, m / z, found, 309.8 [M + H] + .

[0508] Intermediate 38: 2-Chloro-7-fluorobenzoxazin-4-carboxamide.

[0509]

Chemical Structure

[0510] Step A: 7-Fluorobenzoxazine-2,4(1H,3H)-dione. An aqueous solution of potassium nitrate (10 mL, 4.8 M, 48.3 mmol) was added dropwise to a mixture of 2-amino-4-fluorobenzoic acid (5.0 g, 32.2 mmol) and water (20 mL) in AcOH (3.5 g, 58.0 mmol). The reaction mixture was heated at 50 °C for 16 h, then NaOH (5.1 g, 129 mmol) was added portionwise. Stirring was continued at 50 °C for 4 h, then the pH was adjusted to 1 with concentrated HCl (aq)It was slowly adjusted to pH < 1. The precipitate was isolated by filtration and washed with water to obtain 7-fluoroquinazoline-2,4(1H,3H)-dione (2.8 g, yield 48%) as a yellow solid. MS(ESI): C 8 H 5 FN 2 O 2 Mass calculated for, 180.0, m / z, found, 212.1 [M+H] + .

[0511] Step B: 2,4-dichloro-7-fluoroquinazoline. A mixture of 7-fluoroquinazoline-2,4(1H,3H)-dione (2.8 g, 15.5 mmol), POCl 3 (10 mL, 107.6 mmol), and DIEA (5.36 mL, 31.1 mmol) was heated to reflux for 4 h. The reaction mixture was concentrated in vacuo and treated with ice water. The precipitate was isolated by filtration, washed with water, and dried under reduced pressure to obtain 2,4-dichloro-7-fluoroquinazoline (3.0 g, yield 89%) as a brown solid. MS(ESI): C 8 H 3 Cl 2 FN 2 Mass calculated for, 217, m / z found, 217 [M+H].

[0512] Step C: 2-chloro-4-(1-ethoxyvinyl)-7-fluoroquinazoline. To a solution of 2,4-dichloro-7-fluoroquinazoline (3.0 g, 13.8 mmol) in DMF (26 mL) was added tributyl(1-ethoxyvinyl)stannane (5.0 g, 13.8 mmol), followed by dichlorobis(triphenylphosphine)palladium(II) (0.48 g, 0.69 mmol). The reaction mixture was heated to 60 °C for 16 h, then cooled to room temperature and quenched with KF (aq) . EtOAc was added, the mixture was filtered, and the filtrate was washed with water and then brine. The product was purified by FCC (ether:EtOAc, 10:1) to obtain 2-chloro-4-(1-ethoxyvinyl)-7-fluoroquinazoline (2.2 g, yield 63%) as a yellow solid. MS(ESI): C 12 H 10 ClFN2 Calculated mass value for O, 252.1, m / z, measured value, 253 [M+H] + .

[0513] Step D: 2-Chloro-7-fluoroquinazoline-4-carboxylic acid. A solution of 2-chloro-4-(1-ethoxyvinyl)-7-fluoroquinazoline (2.2 g, 8.7 mmol) in dioxane (20 mL) was treated with a solution of sodium periodate (3.7 g, 17.4 mmol) in water (2 mL), followed by KMnO 4 (0.69 g, 4.4 mmol), and the mixture was stirred at room temperature for 16 h. The pH was adjusted to 7-8 with saturated saturated K 2 CO 3 aqueous solution, the precipitate was removed by filtration and washed with DCM. The filtrate was washed with water, the organic layer was isolated, dried and concentrated under reduced pressure. The product was purified by preparative TLC (ether:EtOAc, 3:1) to give ethyl 2-chloro-7-fluoroquinazoline-4-carboxylate (900 mg, 41%). The pH of the aqueous layer was adjusted to pH 1-3 with 2M HCl aqueous solution and extracted with DCM (2×20 mL). The organic layer was concentrated to give 2-chloro-7-fluoroquinazoline-4-carboxylic acid (0.26 g, yield 13%) as a yellow solid. MS (ESI): C 9 H 4 ClFN 2 O 2 Calculated mass value for, 226, m / z, measured value, 226 [M+H] + .

[0514] Step E: 2-Chloro-7-fluoroquinazoline-4-carboxamide. A solution of 2-chloro-7-fluoroquinazoline-4-carboxylic acid (150 mg, 0.66 mmol) in DCM (2 mL) was treated with oxalyl chloride (0.17 mL, 1.98 mmol) and DMF (0.036 mL, 0.47 mmol) at 0 °C. The solution was stirred for 0.5 h and then 28% NH 3It was treated with an aqueous solution (0.15 mL, 2.29 mmol) and stirred at 0 °C for an additional 0.5 h. The mixture was diluted with water (10 mL) and extracted with DCM (3 × 5 mL). The combined organic extracts were concentrated to afford 2-chloro-7-fluoroquinazoline-4-carboxamide (60 mg, 40% yield) as a yellow solid. MS (ESI): C 9 H 5 ClFN 3 Mass calcd for, 225.0, m / z, found, 226 [M+H] + 。

[0515] Intermediate 39: Ethyl 2-chloro-7-fluoroquinazoline-4-carboxylate.

[0516]

Chem.

[0517] The title compound was prepared in a similar manner to Steps A–D of 2-chloro-7-fluoroquinazoline-4-carboxamide to afford ethyl 2-chloro-7-fluoroquinazoline-4-carboxylate (900 mg, 41%). MS (ESI): C 11 H 8 ClFN 2 O 2 Mass calcd for, 254.7, m / z, found, 255 [M+H] + 。

[0518] Intermediate 40: 6-(Tributylstannyl)picolinamide.

[0519]

Chem.

[0520] To a solution of 6-bromopicolinamide (0.50 g, 2.49 mmol) in toluene (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.14 g, 0.12 mmol) followed by bis(tributyltin) (2.89 g, 4.96 mmol) and the mixture was heated at 100° C. for 16 h. The reaction mixture was cooled to room temperature, concentrated to dryness and purified by preparative TLC (DCM:EtOAC 4:1) to give 6-(tributylstannyl)picolinamide (0.80 g, 78% yield) as a colorless oil. MS (ESI): C 18 H 32 N 2 Calculated mass for OSn, 412.2, m / z, observed, 413 [M+H] + .

[0521] Intermediate 41: 3-amino-6-(tributylstannyl)picolinamide.

[0522] [ka]

[0523] The title compound was synthesized using similar conditions to 6-(tributylstannyl)picolinamide, substituting 3-amino-6-bromopicolinamide for 6-bromopicolinamide, to give 3-amino-6-(tributylstannyl)picolinamide (0.11 g, 46% yield) as a colorless oil. MS(ESI):C 18 H 33 N 3 Calculated mass for OSn, 427.2; m / z, observed, 427.0 [M+H] + .

[0524] Intermediate 42: (R)-3-Hydroxy-1-methyl-3-(3-(2-(tributylstannyl)pyridin-4-yl)isoxazol-5-yl)pyrrolidin-2-one.

[0525] [ka]

[0526] Instead of 6-bromopicolinamide, (R)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 7) was used, and the title compound was synthesized using the same conditions as for 6-(tributylstannyl)picolinamide to give (R)-3-hydroxy-1-methyl-3-(3-(2-(tributylstannyl)pyridin-4-yl)isoxazol-5-yl)pyrrolidin-2-one (0.25 g, yield 22%) as a brown oil. MS (ESI): C 25 H 39 N 3 O 3 Calculated mass for Sn, 549.2, m / z, found, 550.0 [M + H] + 。

[0527] Intermediate 43: (R)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0528]

Chemical formula

[0529] Step A. (E)-6-Bromopicolinamide oxime. To a 1 L three-necked round-bottom flask, 6-bromopyridine-2-carbaldehyde (40 g, 215 mmol), EtOH (600 mL), and NH 2 OH·HCl (17.93 g, 258.05 mmol) were added at room temperature. Sodium acetate (35.28 g, 430.09 mmol) was added portionwise to the above mixture 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 aqueous solution (100 mL). The resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic extracts were washed with brine (1 × 150 mL) and anhydrous Na 2 SO 4It was dried. 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%).

[0530] Step B. (Z)-6-Bromo-N-hydroxypicolinimidoyl chloride. To a 2 L four-necked round-bottom flask, (E)-N-[(6-bromopyridin-2-yl)methylidene]hydroxylamine (39 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 at room temperature overnight. 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 It was dried. 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 (41.2607 g, 90.19%). LC-MS (ESI): C 6 H 4 BrClN 2 Calculated mass for O, 233.9, m / z, found, 235 [M + H] + . 1 H 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).

[0531] Step C. (R)-3-(3-(6-Bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. EtOAc (900 mL) and H 2A solution of (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (90.0 g, 646.78 mmol, Intermediate 1) and (Z)-6-bromo-N-hydroxypicolinimidoyl chloride (609 g, 2.59 mol) in O (450 mL) was added with NaHCO 3 (326 g, 3.88 mol, in 150 mL of H 2 O). The mixture was stirred at 25 °C for 24 hours, then filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The product was triturated with EtOH (4000 mL) at 25 °C for 12 hours. The above procedure was repeated 4 times. The resulting product was triturated with petroleum ether:ethyl acetate = 1:1 (2000 mL) at 25 °C for 12 hours and repeated 2 times to obtain 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).

[0532] Intermediate 44: (R)-3-ethynyl-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one.

[0533]

Chemical Structure

[0534] Project 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 and washed with DCM (1 × 1 L). The filtrate was collected and concentrated under reduced pressure. The product was slurried with ether (1.5 L). The solid was collected by filtration to obtain (3E)-1-methyl-3-[(1-phenylethyl)imino]pyrrolidin-2-one (540 g) as a purple solid. 1 H 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).

[0535] Project B. 4,4-Difluoro-3,3-dihydroxy-1-methylpyrrolidin-2-one. In a 10 L four-necked round-bottom flask, (3E)-1-methyl-3-[(1-phenylethyl)imino]pyrrolidin-2-one (540 g, 2496.71 mmol), Na 2 SO 4 (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 (4N in 1,4-dioxane, 936 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 1 hour. The resulting precipitate was filtered 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 a C18 column (CH 3CN / H 2 O(0.1% NH 4 HCO 3 ) was purified by DAC using 1% to 15% for 17 minutes, and 4,4-difluoro-3,3-dihydroxy-1-methylpyrrolidin-2-one (122 g, 23.9%, Steps A and B) was obtained as an off-white solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.29 (s, 2H), 3.65 (t, J = 12.0 Hz, 2H), 2.80 (s, 3H).

[0536] Step C. (3R)-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, 730.04 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, 146.01 mmol) were added under N 2It was added at room temperature under an atmosphere. 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 preparative SFC (CHIRALPAK® IC-3 (50×4.6 mm), 80% hexane containing 0.1% DEA:20% EtOH) to give (3R)-3-ethynyl-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-one (45.6 g, 88%) as an off-white solid as the first eluting enantiomer. LC-MS (ESI): C 7 H 7 F 2 NO 2 Mass calculated for, 175.0, m / z, found, 176 [M+H] + 。 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.43 (s, 1H), 3.84 - 3.80 (m, 3H), 2.82 (s, 3H).

[0537] Intermediate 45: (3R,5S)-3-ethynyl-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one.

[0538]

Chem.

[0539] 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%) was added. The pale yellow solution was stirred at 25 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the product as a yellow liquid (4.64 kg, 89%), which was used in the next step without further purification. 1 H NMR (400 MHz, chloroform-d) δ 4.08 - 4.26 (m, 2H), 3.40 - 3.56 (m, 1H), 2.61 - 2.68 (m, 1H), 2.51 - 2.55 (m, 3H), 2.41 - 2.50 (m, 1H), 1.22 - 1.29 (m, 3H).

[0540] 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 hours under N 2 atmosphere. The reaction mixture was quenched by adding NH 4 Cl (saturated aqueous solution, 10.0 L) at 25 °C. Then, the pH of the mixture was adjusted to pH = 2 - 3 with 1 M aqueous HCl (9.00 L), and the resulting mixture was extracted twice with EtOAc (5.00 L). The combined organic extracts were washed with brine (15.0 L), dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (DCM / MeOH 0% - 3%) to obtain the title compound as a brown oil (4.20 kg, 16.59 mol, 68.8%). 1 H NMR (400 MHz, chloroform-d) δ 4.63 (q, J = 5.0 Hz, 1H), 4.24 - 4.42 (m, 4H), 3.10 - 3.14 (m, 3H), 1.19 - 1.26 (m, 2H).

[0541] Process C. 1-Methyl-5-(trifluoromethyl)pyrrolidine-2,3-dione, HCl. 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 Na 2 SO 4 , filtered, and 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).

[0542] Process 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 dropwise n-BuLi (2.5 M, 4.95 L) at -70 to -60 °C over 30 min, and the mixture was stirred at -70 to -60 °C for 1 h. 1-Methyl-5-(trifluoromethyl)pyrrolidine-2,3-dione (1120 g, 6.18 mol) in THF (9000 mL) was added dropwise to the mixture at -70 to -60 °C over 30 min. The black solution was stirred at -70 to -60 °C for 2 h. The reaction mixture was added dropwise to NH 4 Cl (saturated aqueous solution, 10000 mL) at 0 °C, then the pH of the mixture was 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 and dried over Na 2 SO 4It was dried, filtered, 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).

[0543] 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 2 (3000 mL × 2). The combined organic extracts were washed with water (2000 mL) and brine (2000 mL), and Na 2 SO 4It was dried and 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) to obtain a mixture of diastereomers (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 mm), mobile phase: [0.1% NH 3 H 2 O] in EtOH, B%: 20% to 20%, minutes) to obtain (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).

[0544] Intermediate 46: (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d 4 。

[0545]

Chemical formula

[0546] Step A: 1-methylpyrrolidin-2-one-3,3,4,4,5,5-d 6。A 1000 mL three-necked round-bottom flask purged and maintained with a nitrogen atmosphere was charged with 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, filtered, and concentrated under reduced pressure to give LC-MS (ESI): C 5 H 3 D 6 Mass calculated for C + H 6 D

[0547] NO, 105.1, m / z, found, 106 [M+H] 4 of 1-methylpyrrolidin-2-one-3,3,4,4,5,5-d 6 as a yellow oil (67.6 g).

[0547] Step B: 3-benzoyl-1-methylpyrrolidin-2-one-4,4,5,5-d 4 。A 2000 mL three-necked round-bottom flask purged and maintained with a nitrogen atmosphere was charged with 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 x 600 mL of DCM. The combined organic extracts were 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 D 4 NO 2 For, mass calculated value, 207.1, m / z, measured value, 208 [M + H] + .

[0548] 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, 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, and 1-((trimethylsilyl)ethynyl)-1l3-benzo[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 aqueous Cl solution, extracted with 3 × 600 mL of EtOAc, combined the organic extracts, dried over anhydrous sodium sulfate, filtered, 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 D 4 NO 2 Calculated mass for, 231.1, m / z, found, 232 [M + H] + .

[0549] 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. Then, the reaction mixture was quenched with saturated aqueous NaHCO 3 solution, stirred for 1 hour, extracted with 2 × 1000 mL of DCM, combined the organic extracts, 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 D 4 NO 3 Calculated mass for, 247.1, m / z, found, 248 [M + H] + .

[0550] 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 to 10 °C, and the reaction mixture was stirred at room temperature for 5 hours. Then, the mixture was cooled to 0 °C, the pH was adjusted to pH = 7 with 1 M aqueous HCl, and the reaction mixture was concentrated under reduced pressure. The product was purified by silica gel chromatography (DCM / MeOH 300 / 1 to 100 / 1) to give 15.1 g (87%) of 3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d 4 as a yellow solid. LC-MS (ESI): C 7 H 5 D 4 NO 2 For the mass calculated value, 143.1, m / z, the measured value, 144 [M+H] + .

[0551] 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 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 D 4 NO 2 Mass calculated for, 143.1, m / z, found, 144 [M+H] + .

[0552] Intermediate 47: (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one-4,4,5,5-d 4 .

[0553] [Chemical formula]

[0554] Step A. (R)-3-(3-(3-Bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d 4 . (R)-3-Ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d 4 (Intermediate 46, 250 mg, 1.75 mmol) and (Z)-3-bromo-N-hydroxybenzimidoyl chloride (409 mg, 1.75 mmol) were placed in a microwave vial containing DCM (11 mL), followed by Et 3N (0.73 mL) was added. The vial was sealed and the resulting homogeneous mixture was stirred at room temperature. After about 10 minutes, a white suspension formed and after 3.5 hours, the reaction was judged to be complete by TLC. The contents were filtered through a pad of diatomaceous earth and rinsed with DCM. The colorless eluent was concentrated to afford the product as an off-white solid. This material was redissolved in CHCl 3 -MeOH, diatomaceous earth (3 g) was added, and the mixture was concentrated to dryness. The material was purified by FCC (using 100% DCM and increasing to 5% MeOH-DCM) to afford the title compound (405 mg, 67%) as a yellowish solid after drying. MS (ESI): C 14 H 13 BrN 2 O 3 Calculated mass for, 341.2, m / z, Found, 342.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.87 (t, J = 1.8 Hz, 1H), 7.63 (dt, J = 7.9, 1.3 Hz, 1H), 7.54 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 6.64 (s, 1H), 4.25 (s, 1H), 2.99 (s, 3H).

[0555] Step B. (R)-3-Hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one-4,4,5,5-d 4 . In a microwave vial, (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-d 4(400 mg, 1.17 mmol), bis(pinacolato)diboron (416.8 mg, 1.64 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (92.2 mg, 0.12 mmol), KOAc (460 mg, 4.69 mmol), and 1,4-dioxane (21 mL, degassed with nitrogen for 20 minutes before use) were added. The vial was sealed, evacuated / purged with nitrogen, and then placed in an aluminum heating mantle at 110 °C. After 2.5 h, the reaction mixture was filtered through a pad of diatomaceous earth (while still warm), rinsed with EtOAc and THF, and the eluent was concentrated to afford an orange viscous oil. This material was dissolved in EtOAc and purified by FCC (using 100% hexane and increasing to 100% EtOAc) to give the title compound as an off-white solid (223 mg, 49%). MS (ESI): C 20 H 25 BN 2 O 5 Calculated mass for, 388.3, m / z, Found, 339.3 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 8.15 (t, J = 1.5 Hz, 1H), 7.89 (ddt, J = 18.6, 7.4, 1.4 Hz, 2H), 7.44 (t, J = 7.6 Hz, 1H), 6.74 (s, 1H), 3.72 (d, J = 12.3 Hz, 1H), 2.99 (s, 3H), 1.36 (s, 12H).

[0556] Intermediate 48: (3R,5S)-3-Hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)-5-(trifluoromethyl)pyrrolidin-2-one.

[0557]

Chemical Structure

[0558] Project A. (3R,5S)-3-(3-(3-Bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one. To a 50 mL flask containing (3R,5S)-3-ethynyl-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one (Intermediate 45, 500 mg, 2.41 mmol) and (Z)-3-bromo-N-hydroxybenzimidoyl chloride (566 mg, 2.41 mmol), DCM (15 mL) was added, followed by Et 3 N (1 mL). The flask was maintained under nitrogen and the resulting homogeneous mixture was stirred at room temperature. After 24 hours, the reaction was judged to be complete by TLC. The contents were filtered through a pad of diatomaceous earth and rinsed with DCM. The colorless eluent was concentrated to give the product as an off-white solid. The product was dissolved in CHCl 3 -MeOH containing diatomaceous earth (3 g), concentrated, and purified by FCC (increasing from 100% hexane to 100% EtOAc). After drying, the title compound was obtained as an off-white amorphous solid (815 mg, 83.0%). MS (ESI): C 15 H 12 BrF 3 N 2 O 3 Calculated mass for, 405.2, m / z, Found, 406.0 [M+H] + . 1 H NMR (500 MHz, chloroform-d) δ 7.88 (t, J = 1.8 Hz, 1H), 7.65 (ddd, J = 7.8, 1.6, 1.0 Hz, 1H), 7.57 (ddd, J = 8.1, 2.0, 1.0 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 6.70 (s, 1H), 4.35 - 4.20 (m, 1H), 4.10 - 3.98 (m, 1H), 3.09 (q, J = 1.2 Hz, 3H), 3.06 - 2.93 (m, 2H), 2.48 (dd, J = 14.2, 6.8 Hz, 1H).

[0559] Project B: (3R,5S)-3-Hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)-5-(trifluoromethyl)pyrrolidin-2-one. In a microwave vial, (3R,5S)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one (400 mg, 0.99 mmol), bis(pinacolato)diboron (351 mg, 1.38 mmol), chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) (77 mg, 0.099 mmol), KOAc (387.5 mg, 3.95 mmol), and 1,4-dioxane (18 mL, degassed with nitrogen for 20 minutes before use) were added. The vial was sealed, evacuated / purged with nitrogen, and then placed in an aluminum heating mantle at 110 °C. After 4 hours, the reaction mixture was filtered through a pad of diatomaceous earth (while still warm), rinsed with EtOAc and THF, and the mixture was concentrated to give a brownish viscous oil. This material was dissolved in EtOAc and purified by FCC (using 100% hexane and increasing to 100% EtOAc) to give the title compound (404 mg, 90.0%) initially as a viscous amber gum, which solidified to an amorphous solid under vacuum but was not completely pure by HPLC analysis and was used as such. MS(ESI): C 21 H 24 BF 3 N 2 O 5 Calculated mass for, 452.2, m / z, Found, 453.3 [M+H] + 。

[0560] Intermediate 49: (R)-3-Ethynyl-3-hydroxy-1-(methyl-d 3 )pyrrolidin-2-one.

[0561]

Chemical Structure

[0562] Process A: 4-((tert-Butoxycarbonyl)amino)-2-hydroxybutanoic acid. A solution of 4-amino-2-hydroxybutanoic acid (200 g, 1.67 mol) in water (1 L) was placed in a 5 L three-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen. Subsequently, K 2 CO 3 (695 g, 4.99 mol) was added portionwise at 0 °C. To this mixture, a solution of di-tert-butyl dicarbonate (436 g, 2 mol) in dioxane (1 L) was added dropwise with stirring at 0 °C. The resulting solution was stirred at 20 - 25 °C for 24 h. The resulting mixture was washed with petroleum ether (1 L × 2). The combined aqueous phase was cooled to 0 °C in a water / ice bath and adjusted to pH = 4 - 5 with aqueous HCl solution (6 N). The resulting solution was extracted with ethyl acetate (1 L × 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain 4-((tert-butoxycarbonyl)amino)-2-hydroxybutanoic acid (260 g, 71%) as a yellow oil.

[0563] Process B: Methyl 4-((tert-butoxycarbonyl)amino)-2-hydroxybutanoate. A solution of 4-[[(tert-butoxy)carbonyl]amino]-2-hydroxybutanoic acid (260 g, 1.19 mol) and Cs 2 CO 3 (503 g, 1.54 mol) in N,N-dimethylformamide (2.5 L) was placed in a 5 L three-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen. After 10 min, iodomethane (202 g, 1.42 mol) was added dropwise to the mixture with stirring at room temperature. After 4.5 h, the mixture was poured into water / ice (2 L) and extracted with ethyl acetate (2 L × 2). The combined organic extracts were washed with brine (1 L × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. Thereby, methyl 4-((tert-butoxycarbonyl)amino)-2-hydroxybutanoate (180 g, 65%) was obtained as a yellow oil.

[0564] Process C: Methyl 4-((tert-butoxycarbonyl)amino)-2-((tert-butyldimethylsilyl)oxy)butanoate. A solution of methyl 4-[[(tert-butoxy)carbonyl]amino]-2-hydroxybutanoate (180 g, 0.77 mol) and imidazole (108 g, 1.54 mol) in dichloromethane (1.8 L) was placed in a 5 L three-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen. Subsequently, tert-butyl(chloro)dimethylsilane (231 g, 1.53 mol) was added portionwise at 0 °C in several portions. The resulting solution was warmed to room temperature and stirred for 16 h. Thereafter, the mixture was poured into water / ice (1 L) and extracted with dichloromethane (1.5 L × 3). The combined organic extracts were washed with brine (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by FCC (1:10, ethyl acetate / petroleum ether) to give methyl 4-((tert-butoxycarbonyl)amino)-2-((tert-butyldimethylsilyl)oxy)butanoate (200 g, 75%) as a pale yellow oil.

[0565] Process D: Methyl 4-((tert-butoxycarbonyl)(methyl-d 3 )amino)-2-((tert-butyldimethylsilyl)oxy)butanoate. Methyl 4-[[(tert-butoxy)carbonyl]amino]-2-[(tert-butyldimethylsilyl)oxy]butanoate (50.0 g, 144 mmol), N,N-dimethylformamide (500 mL), and CD 3 I (62.6 g, 432 mmol) were placed in a 1 L three-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen. The resulting solution was cooled to 0 °C, and sodium hydride (8.60 g, 358 mmol, 60% in mineral oil) was added portionwise at 0 °C in several portions. After 2 h at 0 °C, the mixture was poured into a saturated aqueous NH 4 Cl solution (250 mL). The resulting mixture was extracted with ethyl acetate (500 mL × 2). The combined organic extracts were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The above procedure (Process D) was repeated three times to give methyl 4-((tert-butoxycarbonyl)(methyl-d3 ) (Amino)-2-((tert-butyldimethylsilyl)oxy)butanoate (200 g, 95%) was obtained as a pale yellow oil.

[0566] Step E: Methyl 4-((tert-butoxycarbonyl)(methyl-d 3 ) amino)-2-hydroxybutanoate. In a 3 L three-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, methyl 4-((tert-butoxycarbonyl)(methyl-d 3 ) amino)-2-((tert-butyldimethylsilyl)oxy)butanoate (200 g, 549 mmol), methanol (2 L), and amine hydrofluoride (204 g, 5.51 mol) were added. The resulting solution was heated at 50 °C. After 12 hours, the resulting solution was cooled to room temperature, concentrated to dryness, and diluted with water (1 L). The resulting mixture was extracted with ethyl acetate (1 L × 3). The combined organic extracts were washed with brine (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. Thereby, methyl 4-((tert-butoxycarbonyl)(methyl-d 3 ) amino)-2-hydroxybutanoate (137 g) was obtained as a pale yellow oil and used directly in the next step without further purification.

[0567] Step F: Methyl 4-((tert-butoxycarbonyl)(methyl-d 3 ) amino)-2-oxobutanoate. In a 3 L three-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, methyl 4-((tert-butoxycarbonyl)(methyl-d 3Amino)-2-hydroxybutanoate (137 g, 547 mmol), dichloromethane (1.4 L), and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one, (dess-martin periodinane, 348 g, 821 mmol) were placed at 5 °C. The resulting mixture was stirred at room temperature for 3 hours. Then, the mixture was poured into an aqueous sodium bicarbonate solution (2 L). The resulting solid was filtered off, and the filtrate was extracted with dichloromethane (1.5 L × 3). The combined organic extracts were washed with brine (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by FCC (1:3, ethyl acetate / petroleum ether) to give methyl 4-((tert-butoxycarbonyl)(methyl-d 3 )amino)-2-oxobutanoate (81 g, 60%) as a yellow oil. 1 H NMR (300 MHz, CDCl 3 ) δ 3.90 (s, 3H), 3.56 (t, J = 6.6 Hz, 2H), 3.08 (t, J = 6.6 Hz, 2H), 1.48 (s, 9H).

[0568] Step G: Methyl 2-(2-((tert-butoxycarbonyl)(methyl-d 3 )amino)ethyl)-2-hydroxybut-3-ynoate. A solution of methyl 4-((tert-butoxycarbonyl)(methyl-d 3 )amino)-2-oxobutanoate (20 g, 81 mmol) in THF (0.2 L) was placed in a 1 L three-necked round-bottom flask maintained under an inert atmosphere of nitrogen. The solution was cooled to -78 °C, and then bromo(ethynyl)magnesium (274 mL, 138 mmol) was added dropwise. The resulting solution was stirred at -40 °C. After 2 hours, saturated NH 4 Cl solution (100 mL) was added dropwise at -70 °C. The resulting mixture was slowly warmed to room temperature and extracted with ethyl acetate (800 mL × 3). The combined organic extracts were washed with brine (800 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The above procedure (Step G) was repeated 3 times, and from the combined residues, methyl 2-(2-((tert-butoxycarbonyl)(methyl-d3 ) (Amino)ethyl)-2-hydroxybut-3-enoate (82 g) was obtained as a yellow oil.

[0569] Step H: Methyl 2-hydroxy-2-(2-((methyl-d 3 ) amino)ethyl)but-3-enoate. A 1 L three-necked round-bottom flask purged and maintained in an inert atmosphere of nitrogen was charged with a solution of methyl 2-(2-((tert-butoxycarbonyl)(methyl-d 3 ) amino)ethyl)-2-hydroxybut-3-enoate (70.0 g, 255 mmol), dichloromethane (420 mL), and trifluoroacetic acid (140 mL). The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated to dryness and used in the next step without further purification.

[0570] Step I. (R)-3-Ethynyl-3-hydroxy-1-(methyl-d 3 ) pyrrolidin-2-one. A 1 L three-necked round-bottom flask purged and maintained in an inert atmosphere of nitrogen was charged with a solution of methyl 2-hydroxy-2-(2-((methyl-d 3 ) amino)ethyl)but-3-enoate (70.0 g, 243 mmol), methanol (700 mL), and potassium carbonate (133 g, 964 mmol). The resulting solution was stirred at room temperature for 3 hours. The resulting solid was filtered off and the filtrate was concentrated to dryness. The resulting residue was purified by FCC (1:5, ethyl acetate / petroleum ether) and then recrystallized from diethyl ether (100 mL) to give racemic 3-ethynyl-3-hydroxy-1-(methyl-d 3 ) pyrrolidin-2-one (16 g, 46%) as a yellow solid. This material was further purified by preparative chiral SFC (CHIRALPAK® AS-H, 5 × 25 cm, 5 μm; mobile phase, CO 2 (80%) and IPA (0.1% DEA)(20%), detector, UV = 220 nm at 25 °C) to give (R)-3-ethynyl-3-hydroxy-1-(methyl-d 3)Pyrrolidin-2-one (5.4 g, 34%, >97% ee) as a brown solid, and (S)-3-ethynyl-3-hydroxy-1-(methyl-d 3 )Pyrrolidin-2-one (5.2 g, 33%, >97% ee) was obtained as a brown solid. (R)-3-ethynyl-3-hydroxy-1-(methyl-d 3 )Data for pyrrolidin-2-one: MS (ESI): C 7 H 6 D 3 NO 2 Mass calculated for, 142.1, m / z, found, 143.2 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δ 3.41 - 3.38 (t, J = 5.2 Hz, 2H), 3.03 (s, 1H), 2.48 - 2.43 (m, 1H), 2.24 - 2.17 (m, 1H). (S)-3-ethynyl-3-hydroxy-1-(methyl-d 3 )Data for pyrrolidin-2-one: MS (ESI): C 7 H 6 D 3 NO 2 Mass calculated for, 142.08, m / z, found, 143.2 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δ 3.41 - 3.38 (t, J = 5.2 Hz, 2H), 3.03 (s, 1H), 2.48 - 2.43 (m, 1H), 2.24 - 2.17 (m, 1H).

[0571] Intermediate 50: (R)-3-hydroxy-1-(methyl-d 3 )-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one.

[0572]

Chem.

[0573] Project A: (R)-3-(3-(3-Bromophenyl)isoxazol-5-yl)-3-hydroxy-1-(methyld 3 )pyrrolidin-2-one. A vial containing (R)-3-ethynyl-3-hydroxy-1-(methyld 3 )pyrrolidin-2-one (Intermediate 49, 500 mg, 3.52 mmol) and (Z)-3-bromo-N-hydroxybenzimidoyl chloride (800 mg, 3.41 mmol) was charged with DCM (22 mL), followed by Et 3 N (1.5 mL). The flask was sealed and the homogeneous mixture was stirred at room temperature. After 24 h, the contents were filtered through a pad of diatomaceous earth and rinsed with DCM. The mixture was concentrated to give the product as a viscous orange rubbery solid. The product was dissolved in DCM (40 mL), water (20 mL) was added, and the layers were separated. The aqueous portion was back-extracted three times with CHCl 3 (10 mL), the combined organic extracts were dried over MgSO 4 , filtered, and concentrated to give an orange oil, which was purified by FCC (increasing from 100% DCM to 5% MeOH-DCM) to give the title compound (810 mg, 67%) as a hygroscopic semi-solid. Calculated for C 14 H 13 BrN 2 O 3 , 340.2, m / z, found, 341.7 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.87 (t, J = 1.8 Hz, 1H), 7.69 - 7.47 (m, 2H), 7.27 (t, J = 7.9 Hz, 2H), 6.67 (s, 1H), 4.66 (s, 1H), 3.76 (s, 1H), 3.60 - 3.67 (m, 1H), 3.57 - 3.27 (m, 2H), 2.72 - 2.77 (m, 1H), 2.59 - 2.38 (m, 2H), 2.25 - 2.33 (m, 1H).

[0574] Project B. (R)-3-Hydroxy-1-(methyld 3)-3-(3-(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. (R)-3-(3-(3-Bromophenyl)isoxazol-5-yl)-3-hydroxy-1-(methyl-d 3 ) Pyrrolidin-2-one (800 mg, 2.35 mmol) was contained in a 50 mL flask, and bis(pinacolato)diboron (836 mg, 3.29 mmol), chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) (185 mg, 0.24 mmol), KOAc (923 mg, 9.41 mmol), and 1,4-dioxane (42 mL, degassed with nitrogen for 20 minutes before use) were added. A reflux condenser was attached to the flask, evacuated / purged with nitrogen, and then placed in an aluminum heating mantle at 105 °C. After 4.5 hours, TLC (20% EtOAc-DCM) indicated that the reaction was complete. The mixture was filtered through a pad of diatomaceous earth (while still warm), rinsed with EtOAc and THF, and the filtrate was concentrated to give a brownish viscous oil. This material was dissolved in EtOAc and purified by FCC (increasing from 100% hexane to 100% EtOAc) to give the title product (211 mg, 23%) as an amber amorphous solid. MS (ESI): C 20 H 25 BN 2 O 5 Calculated mass for, 387.3, m / z, Found, 388.3 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.15 (d, J = 1.6 Hz, 1H), 7.85 - 7.94 (m, 2H), 7.44 (t, J = 7.6 Hz, 1H), 6.74 (s, 1H), 3.68 - 3.74 (m, 1H), 3.58 - 3.66 (m, 1H), 3.42 - 3.47 (m, 1H), 2.77 - 2.81 (m, 1H), 2.41 - 2.50 (m, 1H), 1.36 (s, 12H).

[0575] Intermediate 51: 4-Bromo-6-chloropicolinamide

[0576]

Chem.

[0577] To a 25 mL round-bottom flask containing 4-bromo-6-chloropicolinonitrile (360 mg, 1.7 mmol) was added acetone (8.3 mL), water (2.8 mL), and K 2 CO 3 (114 mg, 0.8 mmol). Then, urea-hydrogen peroxide (1.6 g, 16.6 mmol) was added to the stirred mixture, and the resulting mixture was stirred at room temperature. After 90 minutes, the resulting solution was washed with water and extracted with ethyl acetate. The resulting organic solution was then dried over MgSO 4 , filtered, and evaporated to dryness to give a white solid (320 mg, 82%) which was used without further purification. LC-MS (ESI): C 6 H 4 BrClN 2 O, calculated mass, 233.9, m / z, found, 234.9 [M+H] + .

[0578] Intermediate 52: 6-Chloro-4-(1-methyl-1H-pyrazol-5-yl)picolinamide

[0579]

Chem.

[0580] Subsequently, a mixture consisting of 4-bromo-6-chloropicolinamide (100 mg, 0.43 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (132 mg, 0.63 mmol), K 3 PO 4 (276 mg, 1.27 mmol), 1,4-dioxane (1.1 mL), and water (0.2 mL) was evacuated and refilled with N 2 three times and then treated with Pd(dppf)Cl 2 (46 mg, 0.064 mmol) and N2 It was heated at 100 °C for 3 hours. The reaction vessel was taken out of the heating mantle and gradually cooled to room temperature. The resulting mixture was diluted with water and extracted with ethyl acetate. Subsequently, the obtained organic solution was dried over MgSO 4 and filtered, and concentrated to dryness. The residue was subjected to flash column chromatography using a gradient of 0% - 10% MeOH in DCM over 15 minutes to obtain an orange oil (100 mg). MS (ESI): C 10 H 9 ClN 4 O, calculated mass value, 236.1, measured m / z value, 237.0 [M + H] + .

[0581] Intermediate 53: 6-Chloro-4-(isothiazol-5-yl)picolinamide.

[0582]

Chemical Structure

[0583] Using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole instead of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and under the same conditions as described for Intermediate 52, the title compound (60 mg, 59%) was prepared. MS (ESI): C 9 H 6 ClN 3 OS, calculated mass value, 239.0, m / z, measured value, 240.0 [M + H] + .

[0584] Intermediate 54: 6-Chloro-4-(thiazol-5-yl)picolinamide.

[0585]

Chemical Structure

[0586] Using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole instead of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and under the same conditions as described for Intermediate 52, the title compound (60 mg, 59%) was prepared. MS (ESI): C 9 H 6 ClN 3 Mass calculated for C H ClN O S, 239.0, m / z, found, 239.9 [M+H] + 。

[0587] Intermediate 55: (R)-4-chloro-6-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinic acid.

[0588]

Chemical formula

[0589] To a mixture of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 10.0 g, 26.0 mmol) and methyl 4,6-dichloropicolinate (10.7 g, 52.1 mmol) in 1,4-dioxane (75.0 mL) and water (25.0 mL) was added K 2 CO 3 (7.19 g, 52.1 mmol) and Pd(PPh 3 ) 4 (1.50 g, 1.30 mmol). The resulting mixture was degassed and purged three times with N 2 , and then the mixture was heated at 90 °C for 4 h under a N 2 atmosphere. The reaction mixture was diluted with water (40 mL), the pH of the mixture was adjusted to pH 3, and the mixture was extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (50.0 mL × 1) and Na 2 SO 4It was dried, filtered, and concentrated under reduced pressure to obtain a residue. The product was triturated with ethyl acetate (15 mL) at 25 °C for 15 minutes. The title compound was obtained as a white solid (8.50 g, 19.3 mmol, 74.2%). MS (ESI): C 20 H 16 ClN 3 O 5 Calculated mass for, 413.1, m / z, found, 414.1 [M+H] + 。

[0590] Intermediate 56: Methyl (R)-4-chloro-6-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinate.

[0591]

Chem.

[0592] To a solution of (R)-4-chloro-6-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinic acid (16.0 g, 38.7 mmol, Intermediate 55) in MeOH (35.0 mL) and THF (35.0 mL), trimethylsilyl-diazomethane (2 M, 58.00 mL) was slowly added at 0 °C under N 2 The mixture was slowly stirred and warmed from 0 to 25 °C over 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to obtain the product. The product was triturated with MTBE (60 mL, at 25 °C for 48 hours). The compound was obtained as a white solid (11.8 g, 26.3 mmol, 68.0%). MS (ESI): C 21 H 18 ClN 3 O 5 Calculated mass for, 427.1, m / z, found, 428.3 [M+H] + 。 1 H NMR (400 MHz, DMSO-d 6)δ8.53 - 8.66 (m, 2H), 8.31 (br d, J = 7.88 Hz, 1H), 7.99 - 8.10 (m, 2H), 7.69 (t, J = 7.75 Hz, 1H), 7.19 (s, 1H), 6.75 (s, 1H), 3.95 (s, 3H), 3.38 - 3.55 (m, 2H), 2.85 (s, 3H), 2.53 - 2.64 (m, 1H), 2.29 (ddd, J = 13.38, 7.63, 6.00 Hz, 1H).

[0593] Intermediate 57: (R)-4-Chloro-6-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinamide

[0594]

Chemical Structure

[0595] A solution of ammonia (11.7 mL, 2 M in MeOH) and methyl (R)-4-chloro-6-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinate (Intermediate 56, 1 g, 2.3 mmol) was stirred in a microwave at 100 °C for 80 minutes. The resulting solution was evaporated to dryness to obtain a white solid (1 g), which was used as such. MS (ESI): Calculated mass for C 20 H 17 ClN 4 O 4 is 412.1, m / z, found 413.1 [M + H] + .

[0596] Intermediate 58: 6,8-Dichloropyrido[3,2-d]pyrimidin-4-amine

[0597]

Chemical Structure

[0598] Into a flask, 3-amino-4,6-dichloropicolinonitrile (1.21 g, 6.34 mmol), K3 PO 4 (13.6 g, 64.0 mmol), and a solution of 1,4-dioxane (50 mL), followed by formimidamide acetate (3.87 g, 37.1 mmol) was added. The resulting mixture was heated at 100 °C for 16 h. The resulting mixture was cooled to room temperature and concentrated to dryness. The residue was diluted with H 2 O (50 mL) and stirred at room temperature for 16 h. The resulting mixture was filtered, and the filter cake was washed with water (200 mL) to recover the solid. The resulting solid was added to DCM (50 mL), and the mixture was stirred at room temperature for 40 min. The resulting solid was recovered by filtration and dried to obtain 6,8-dichloropyrido[3,2-d]pyrimidin-4-amine (1.35 g, 97.5%) as a white solid. MS (ESI): C 7 H 4 Cl 2 N 4 Calculated mass for, 214.0, m / z, Found, 215.0 [M+H] + . 1 H NMR (500 MHz, CDCl 3 ) δ 8.72 (s, 1H), 7.81 (s, 1H), 5.95 - 5.48 (m, 2H).

[0599] Intermediate 59: 6-Chloropyrido[3,2-d]pyrimidin-4-amine

[0600]

Chemical Structure

[0601] Formimidamide acetate (25.0 g, 240 mmol) was added to a solution of 3-amino-6-chloropicolinonitrile (8.80 g, 57.3 mmol) and K 3 PO 4 (78.0 g, 367 mmol) in 1,4-dioxane (400 mL). The reaction mixture was heated at 100 °C for 2 h. After the reaction mixture was cooled to room temperature, the reaction mixture was concentrated to dryness in vacuo to obtain the product, which was poured into H 2 O (500 mL) and stirred at room temperature for 16 h. The suspension was filtered. The filter cake was washed with H 2Wash with O(100 mL), and pour the filtrate into CHCl 3 (70 mL). Heat the mixture at 50 °C for 30 minutes. After isolating the suspension by filtration, cool it to room temperature and wash the filter cake with CHCl 3 (30 mL). Dry the filter cake in vacuo to obtain the product (7.8 g, 75%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.41 (s, 1H), 8.10 (d, J = 8.8 Hz, 1H), 8.04 - 7.90 (m, 2H), 7.84 (d, J = 8.6 Hz, 1H).

[0602] Intermediate 60: tert-Butyl 3-((hydroxyimino)methyl)piperidine-1-carboxylate

[0603]

Chem.

[0604] A mixture of tert-butyl 3-formylpiperidine-1-carboxylate (3.50 g, 16.4 mmol), hydroxylamine hydrochloride (1.71 g, 24.6 mmol), and Na 2 CO 3 (2.61 g, 24.6 mmol) in EtOH (50 mL) and water (5 mL) was heated at 80 °C for 16 hours. Remove the reaction vessel from the oil bath and cool it gradually to room temperature. Concentrate the mixture in vacuo, dilute it with water (40 mL), and extract with EtOAc (100 mL × 3). Dry the combined organic layers over anhydrous Na 2 SO 4 , filter, and concentrate in vacuo to obtain tert-butyl 3-((hydroxyimino)methyl)piperidine-1-carboxylate as a solid (3.2 g), which was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl 3)δ 7.36 (d, J = 5.5 Hz, 1H), 4.12 - 3.70 (m, 3H), 2.90 - 2.79 (m, 2H), 2.44 - 2.33 (m, 1H), 1.98 - 1.76 (m, 2H), 1.46 (s, 9H). 1 1H NMR (400 MHz, MeOD) δ 7.26 (d, J = 5.7 Hz, 1H), 4.01 - 3.64 (m, 3H), 3.06 - 2.87 (m, 2H), 2.34 - 2.24 (m, 1H), 1.91 - 1.81 (m, 1H), 1.75 - 1.62 (m, 2H), 1.43 (s, 9H).

[0605] Intermediate 61: tert - butyl 3 - (chloro(hydroxyimino)methyl)piperidine - 1 - carboxylate

[0606]

Chemical Structure

[0607] To a solution consisting of tert - butyl 3 - ((hydroxyimino)methyl)piperidine - 1 - carboxylate (Intermediate 60, 3.2 g, 14 mmol) and N,N - dimethylformamide (100 mL), NCS (1.87 g, 14.0 mmol) was added, and the resulting mixture was stirred at room temperature under nitrogen for 16 hours. Thereafter, the mixture was diluted with ethyl acetate (200 mL) and washed with water (50 mL × 3). The combined organic layers were dried over anhydrous Na 2 SO 4 and filtered, and concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0 - 30% EtOAc / petroleum ether) to obtain tert - butyl 3 - (chloro(hydroxyimino)methyl)piperidine - 1 - carboxylate as a colorless oil (1.36 g, 29%). MS (ESI): C 11 H 19 ClN 2 O 3 Calculated mass for, 262.1, m / z, Found, 207.1 [M - 55] + .

[0608] Intermediate 62: tert-Butyl 3-(5-((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)piperidine-1-carboxylate

[0609]

Chemical Structure

[0610] (R)-3-Ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1, 500 mg, 3.59 mmol), tert-butyl 3-(chloro(hydroxyimino)methyl)piperidine-1-carboxylate (Intermediate 61, 1.3 g, 4.9 mmol), and NaHCO 3 (604 mg, 7.19 mmol) were stirred at room temperature for 16 h. The mixture was then concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (10 - 100% EtOAc / petroleum ether) to give tert-butyl 3-(5-((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)piperidine-1-carboxylate (1.32 g, 99.8%) as a white solid. MS (ESI): C 18 H 27 N 3 O 5 Calculated mass for, 365.2, m / z, Found, 266.2 [M - 99] + .

[0611] Intermediate 63: (3R)-3-Hydroxy-1-methyl-3-(3-(piperidin-3-yl)isoxazol-5-yl)pyrrolidin-2-one

[0612]

Chemical Structure

[0613] TFA (3.6 mL, 48 mmol) was added to a solution of tert-butyl 3-(5-((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)piperidine-1-carboxylate (Intermediate 62, 1.2 g, 3.3 mmol) in DCM (36 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. Thereafter, the mixture was treated with saturated NaHCO 3 aqueous solution (50 mL) to bring the pH to 8 - 9 and freeze-dried to dryness. The residue was triturated with DCM / EtOAc / MeOH (200 mL, 10:10:1), filtered, and the filtrate was concentrated to dryness in vacuo to obtain (3R)-3-hydroxy-1-methyl-3-(3-(piperidin-3-yl)isoxazol-5-yl)pyrrolidin-2-one as a viscous solid (4 g). The product was used directly in the next step without further purification. MS (ESI): C 13 H 19 N 3 O 3 Calculated mass for, 265.1, m / z, found, 266.0 [M+1]+.

[0614] Intermediate 64: Ethyl 3-bromo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate

[0615]

Chemical Structure

[0616] Ethyl 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate hydrochloride (1.0 g, 4.3 mmol) and MeCN (10 mL) were added to a 40 mL flask, and NBS (768 mg, 4.32 mmol) was added. The resulting mixture was stirred at room temperature for 2 h and quenched with saturated Na 2 S 2 O 3 aqueous solution (20 mL) and stirred at room temperature for 15 min. Thereafter, the mixture was treated with saturated NaHCO 3The solution was basified to pH = 8 with an aqueous solution and concentrated to dryness in vacuo to obtain a yellow solid. Subsequently, the yellow solid was subjected to silica gel chromatography (0 - 10% MeOH / DCM) to obtain ethyl 3-bromo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate as a yellow solid (290 mg, 21%). LCMS (ESI): C 9 H 12 BrN 3 O 2 Mass calculated for, 273.0, m / z, found, 276.0 [M+H] + 。

[0617] Intermediate 65: (R)-3-(3-(2-chloropyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0618]

Chemical Structure

[0619] Using 2-chloronicotinaldehyde instead of 2-bromonicotinaldehyde, (R)-3-(3-(2-chloropyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (512 mg) was prepared in the same manner as Intermediate 7: (R)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. MS (ESI): C 13 H 12 ClN 3 O 3 Mass calculated for, 293.1, m / z, found, 293.9 [M+H] + 。

[0620] Example 1: (R)-3-(3-(3-(4-amino-2-methylpyrido[3,2-d]pyrimidin-6-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0621] [Chemical]

[0622] 1,4 - Dioxane (8 mL) and H 2 A solution of (R)-3 - hydroxy - 1 - methyl - 3-(3-(3-(4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)phenyl)isoxazol - 5 - yl)pyrrolidin - 2 - one (Intermediate 4, 150 mg, 0.39 mmol) in H 2 O (1 mL) was added to 6 - chloro - 2 - methylpyrido[3,2 - d]pyrimidin - 4 - amine (Intermediate 16, 152 mg, 0.780 mmol), followed by bis(tri - tert - butylphosphine)palladium(0) (20 mg, 0.04 mmol) and KF (68 mg, 1.2 mmol). The mixture was heated at 85 °C for 3 h under N 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) using a 5% - 38% gradient and purified by reverse - phase HPLC using an HPLC column such as Xtimate C18 10 μm, 21.2×250 mm column to obtain (R)-3-(3-(3-(4 - amino - 2 - methylpyrido[3,2 - d]pyrimidin - 6 - yl)phenyl)isoxazol - 5 - yl)-3 - hydroxy - 1 - methylpyrrolidin - 2 - one (5.9 mg, 4%) as a white solid. MS(ESI): C 22 H 20 N 6 O 3 Calculated mass for, 416.4, m / z, Found, 417.2 [M + H] + . 1 H NMR (400 MHz, DMSO - d 6)δ8.75(s,1H),8.52 - 8.56(m,2H),8.30(s,1H),8.13(s,1H),8.08(d,J = 8.0Hz,1H),8.01(d,J = 8.0Hz,1H),7.93(s,1H),7.67(t,J = 7.6Hz,1H),7.32(s,1H),3.41 - 3.53(m,2H),2.85(s,3H),2.55 - 2.61(m,1H),2.47(s,3H),2.26 - 2.33(m,1H).

[0623] Example 2: (R)-3-(3-(3-(4-aminopyrido[3,2-d]pyrimidin-6-yl-2-d)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0624]

Chemical formula

[0625] 1,2-dioxane (2 mL) and H 2 A solution of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 15 mg, 0.39 mmol) in O (0.2 mL) was added to 6-chloropyrido[3,2-d]pyrimidin-2-d-4-amine (Intermediate 17, 71 mg, 0.39 mmol), followed by bis(tri-tert-butylphosphine)palladium(0) (20 mg, 0.04 mmol) and K 3 PO 4 (249 mg, 1.17 mmol). The mixture was stirred at 90 °C for 16 h under an N 2 atmosphere, cooled to room temperature, and concentrated under reduced pressure. The residue was taken up in CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4Purified by reverse-phase HPLC using a 20 - 35% gradient of (OH) and an HPLC column such as an Xtimate 10 μm, 150 Å, 21.2×250 mm column to obtain (R)-3-(3-(3-(4-aminopyrido[3,2-d]pyrimidin-6-yl-2-d)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (28 mg, 18%) as a brown solid. MS(ESI): C 21 H 17 DN 6 O 3 Calculated mass for, 403.1, m / z, found, 404.0 [M+H] + 。 1 HNMR(400MHz, DMSO-d 6 ) δ 8.78 (s, 1H), 8.59 (d, J = 7.2 Hz, 2H), 8.28 (s, 1H), 8.17 (d, J = 8.8 Hz, 1H), 8.00 - 8.10 (m, 2H), 7.68 (t, J = 8.0 Hz, 1H), 7.34 (s, 1H), 6.78 (s, 1H), 3.40 - 3.60 (m, 2H), 2.86 (s, 3H), 2.50 - 2.60 (m, 1H), 2.20 - 2.40 (m, 1H).

[0626] Example 3: (R)-3-(5-(3-(4-amino-2-methylpyrido[3,2-d]pyrimidin-6-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0627]

Chemical Structure

[0628] Instead of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one, (R)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one (Intermediate 5) was used, and under the same conditions as described in Example 1, (R)-3-(5-(3-(4-amino-2-methylpyrido[3,2-d]pyrimidin-6-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (57.8 mg, 53%) was prepared. MS(ESI): C 22 H 20 N 6 O 3 Calculated mass for, 416.4, m / z, found, 417.2 [M+H] + 。 1 1H NMR(400MHz, DMSO-d 6 ) δ 8.83(s, 1H), 8.53 - 8.56(m, 2H), 8.17(s, 1H), 8.08(d, J = 8.8Hz, 1H), 7.94 - 7.97(m, 2H), 7.69(t, J = 8.0Hz, 1H), 7.39(s, 1H), 6.52(s, 1H), 3.37 - 3.49(m, 2H), 2.85(s, 3H), 2.63 - 2.71(m, 1H), 2.47(s, 3H), 2.22 - 2.29(m, 1H).

[0629] Example 4: (R)-3-(3-(3-(3-Amino-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0630]

Chemical Structure

[0631] Project A: (R)-3-Hydroxy-1-methyl-3-(3-(3-(3-nitro-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. To a solution of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 50 mg, 0.1 mmol) in dioxane (2 mL) and DMF (1 mL) was added 5-chloro-3-nitro-1H-pyrazolo[4,3-b]pyridine (26 mg, 0.13 mmol), followed by Pd(t-Bu 3 P) 2 (7.0 mg, 0.013 mmol) and K 3 PO 4 (83 mg, 0.39 mmol). The mixture was heated at 95 °C for 16 h under a N 2 atmosphere, then cooled to room temperature and diluted with water (20 mL). The resulting aqueous mixture was extracted with DCM (4 × 15 mL). The combined organic solvent extracts were concentrated and purified using preparative TLC (DCM / MeOH = 20 / 1) to give (R)-3-hydroxy-1-methyl-3-(3-(3-(3-nitro-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (8 mg, 15%) as a brown solid. MS (ESI): Calculated mass for C 20 H 16 N 6 O 5 , 420.4, m / z, found, 421.0 [M+H] + .

[0632] Project B: (R)-3-(3-(3-(3-Amino-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of (R)-3-hydroxy-1-methyl-3-(3-(3-(3-nitro-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (15 mg, 0.036 mmol) in ethanol (2 mL) and 1,2-dichloroethane (1 mL) was added a porous nickel-aluminum alloy (nickel aluminide) such as Raney Ni (50 mg), followed by hydrazine hydrate (71 mg, 1.4 mmol). The mixture was stirred at 20 °C for 1 h, then filtered and concentrated. The resulting residue was purified by reverse-phase HPLC using an HPLC column such as Xtimate C18 10 μm, 21.2×250 mm column with a 5 - 35% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) to give (R)-3-(3-(3-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (5 mg, 36%) as an off-white solid. MS (ESI): C 20 H 18 N 6 O 3 calculated mass for, 390.4, m / z, found, 391.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.7 (s, 1H), 8.60 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.15 (s, 1H), 6.74 (s, 1H), 5.49 (s, 2H), 3.40 - 3.50 (m, 2H), 2.86 (s, 3H), 2.50 - 2.60 (m, 1H), 2.26 - 2.33 (m, 1H).

[0633] Example 5: (R)-3-(3-(3-(3-Amino-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0634]

Chemical formula

[0635] Step A: (R)-3-Hydroxy-1-methyl-3-(3-(3-(1-methyl-3-nitro-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. To a solution of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 271 mg, 0.710 mmol) in DMF (2 mL) and H 2 O (0.2 mL), 5-chloro-1-methyl-3-nitro-1H-pyrazolo[4,3-b]pyridine (26 mg, 0.13 mmol) was added, followed by Pd(t-Bu 3 P) 2 (36 mg, 0.071 mmol) and K 3 PO 4 (449 mg, 2.12 mmol). The mixture was heated at 90 °C for 16 h under a N 2 atmosphere. The mixture was cooled to room temperature, filtered, and washed with CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4Purified by reverse-phase HPLC using an 18% to 35% gradient of OH) and an HPLC column such as an Xtimate C18 10 μm, 21.2 × 250 mm column to obtain (R)-3-hydroxy-1-methyl-3-(3-(3-(1-methyl-3-nitro-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (37 mg, 12%). MS(ESI): C 21 H 18 N 6 O 5 Mass calculated for, 434.4, m / z, found, 435.0 [M+H] + 。

[0636] Step B: (R)-3-(3-(3-(3-Amino-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. A solution of (R)-3-hydroxy-1-methyl-3-(3-(3-(1-methyl-3-nitro-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (30 mg, 0.07 mmol), saturated NH 4 Cl aqueous solution (10 mL), and zinc powder (45 mg, 0.69 mmol) in MeOH (10 mL) was heated at 37 °C for 16 h. The reaction mixture was concentrated to dryness, and CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) with a 5% gradient for 3 min, then CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% of NH 4Purification was carried out by reverse-phase HPLC using an Xtimate C18 10 μm, 21.2×250 mm column and a gradient of 27 - 35% to obtain (R)-3-(3-(3-(3-amino-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (8.6 mg, 31%) as a yellow solid. MS(ESI): C 21 H 20 N 6 O 3 Calculated mass for, 404.2, m / z, found, 405.0 [M+H] + 。 1 H NMR(400 MHz, DMSO-d 6 ) δ 9.06 (s, 1H), 8.85 (d, J = 5.2 Hz, 1H), 8.68 (s, 1H), 8.13 (d, J = 2.8 Hz, 1H), 7.98 (dd, J = 1.2, 5.2 Hz, 1H), 7.84 (s, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.48 (s, 1H), 6.83 (s, 1H), 4.00 (s, 3H), 3.43 - 3.52 (m, 2H), 2.86 (s, 3H), 2.56 - 2.62 (m, 1H), 2.29 - 2.34 (m, 1H).

[0637] Example 6: (R)-3-(5-(3-(3-amino-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0638]

Chemical Structure

[0639] Instead of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one, (R)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one (Intermediate 5) was used, and under the same conditions as described in Example 5, (R)-3-(5-(3-(3-amino-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one was prepared. MS(ESI): C 21 H 20 N 6 O 3 Calculated mass for, 404.2, m / z, Found, 405.0 [M+H] + 。 1 H NMR(400MHz, DMSO-d 6 ) δ 12.30 (s, 1H), 8.70 (s, 1H), 8.61 (s, 1H), 8.55 (d, J = 2.8 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.34 (d, J = 2.8 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.07 (s, 1H), 6.75 (s, 1H), 3.52 - 3.41 (m, 2H), 2.85 (s, 3H), 2.62 - 2.55 (m, 1H), 2.32 - 2.25 (m, 1H).

[0640] Example 7: (R)-3-Amino-6-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolylamide.

[0641]

Chemical Structure

[0642] DMF (2 mL) and H 2A solution of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 105 mg, 0.270 mmol) in O(0.2 mL) was treated with 3-amino-6-bromopicolinamide (70 mg, 0.4 mmol), followed by Pd(t-Bu 3 P) 2 (14 mg, 0.026 mmol), and K 3 PO 4 (174 mg, 0.820 mmol). The mixture was heated at 90 °C for 16 h under a N 2 atmosphere. The mixture was then cooled to room temperature and concentrated. The residue was purified by reverse-phase HPLC using a gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) with a 20–35% gradient using an HPLC column such as an Xtimate 10 μm, 150 Å, 21.2 × 250 mm column to give (R)-3-amino-6-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinamide as a brown solid (5.2 mg, 5%). MS (ESI): C 20 H 19 N 5 O 4 calculated mass for, 393.1, m / z, found, 394.0 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.44 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.20 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.22 (s, 2H), 7.04 (s, 1H), 6.73 (s, 1H), 3.51–3.44 (m, 2H), 2.85 (s, 3H), 2.55–2.48 (m, 1H), 2.35–2.25 (m, 1H).

[0643] Example 8: (R)-6-(3-(5-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-4-methoxypicolinamide.

[0644]

Chemical formula

[0645] Using 6-chloro-4-methoxypicolinamide (Intermediate 15) instead of 3-amino-6-bromopicolinamide and under the same conditions as described in Example 7, (R)-6-(3-(5-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-4-methoxypicolinamide (2 mg, 2%) was prepared. MS (ESI): C 21 H 20 N 4 O 5 Mass calculated for, 408.1, m / z, found, 409.0 [M+H] + . 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.63 (s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 8.41 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.78 (s, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.30 (s, 1H), 6.77 (s, 1H), 4.00 (s, 3H), 3.60 - 3.40 (m, 2H), 2.85 (s, 3H), 2.62 - 2.52 (m, 1H), 2.36 - 2.23 (m, 1H).

[0646] Example 9: (R,S)-3-(5-(3-(1H-Pyrrolo[2,3-b]pyridin-3-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0647]

Chemical formula

[0648] Process A: tert-Butyl 3-(3-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. Instead of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one, (R,S)-3-(5-(3-bromophenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 6) was used, and instead of 3-amino-6-bromopicolinamide, tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Intermediate 24) was used. Under the same conditions as described in Example 7, tert-butyl 3-(3-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (80 mg, 76%) was prepared. MS(ESI): C 26 H 26 N 4 O 5 Mass calculated for, 474.2, m / z, found, 475.2 [M+H] + 。

[0649] Process B: (R,S)-3-(5-(3-((1H-Pyrrolo[2,3-b]pyridin-3-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one. A solution of tert-butyl 3-(3-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (80 mg, 0.17 mmol) in 4M HCl (15 mL, 60 mmol) in 1,4-dioxane was stirred at room temperature for 16 h and then concentrated to dryness. The residue was saturated with NaHCO 3It was diluted with an aqueous solution and extracted with EtOAc (2 × 15 mL). The organic solvent extracts were combined, concentrated to dryness, and purified by reverse-phase HPLC using an Agela Durashell C18 10 μm, 21.2 × 250 mm column with an 18 - 35% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) to obtain (R,S)-3-(5-(3-(1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (42 mg, 67%) as a white solid. MS (ESI): C 21 H 18 N 4 O 3 for mass calculated value, 374.1, m / z, measured value, 375.2 [M + H] + 、 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.05 (s, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.30 (d, J = 4.0 Hz, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.88 (t, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.21 (s, 1H), 7.19 (t, J = 4.0 Hz, 1H), 6.50 (s, 1H), 3.45 - 3.38 (m, 2H), 2.81 (s, 3H), 2.70 - 2.64 (m, 1H), 2.28 - 2.23 (m, 1H).

[0650] Example 10: (R)-3-(3-(3-(8-aminopyrido[3,4-d]pyrimidin-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0651]

Chemical formula

[0652] Project A: (R)-3-(3-(3-(8-chloropyrido[3,4-d]pyrimidin-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a suspension of 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine (Intermediate 13, 90.0 mg, 0.43 mmol), (R)-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)boronic acid (Intermediate 10, 154 mg, 0.51 mmol), and copper(I) thiophene-2-carboxylate (162 mg, 0.85 mmol) in THF (2 mL) was added Pd(PPh 3 ) 4 (49 mg, 0.04 mmol). The mixture was heated at 105 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 20 / 1, R f = 0.4) to give (R)-3-(3-(3-(8-chloropyrido[3,4-d]pyrimidin-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (40 mg, 22%) as a yellow solid. MS (ESI): C 21 H 16 ClN 5 O 3 calculated for, 421.1, m / z, found, 422.1 [M+H ]+ .

[0653] Project B: (R)-3-(3-(3-(8-aminopyrido[3,4-d]pyrimidin-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of (R)-3-(3-(3-(8-chloropyrido[3,4-d]pyrimidin-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (50 mg, 0.1 mmol) in dioxane (1 mL) was added aqueous ammonium hydroxide solution (12 N, 5 mL, 60 mmol). The mixture was heated at 70 °C for 16 h in a sealed tube and then concentrated under reduced pressure. The residue was taken up in CH 3 CN and H 2Purify by reverse-phase HPLC using a 30 - 54% gradient of O(0.1% FA) and an HPLC column such as a Boston pHlex ODS 10μm, 21.2×250mm column to obtain (R)-3-(3-(3-(8-aminopyrido[3,4-d]pyrimidin-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (1 mg, 2%) as a yellow solid. MS(ESI): C 21 H 18 N 6 O 3 Calculated mass for, 402.1, m / z, found, 403.1 [M+H] + 。 1 H NMR(400MHz,CD 3 OD)δ9.48(s,1H),9.14 - 9.16(m,1H),8.78(d,J = 8.0Hz,1H),8.03(d,J = 8.0Hz,1H),7.96(d,J = 5.6Hz,1H),7.70(d,J = 8.0Hz,1H),7.10(s,1H),7.09(d,J = 5.6Hz,1H),3.63 - 3.60(m,2H),3.00(s,3H),2.80 - 2.76(m,1H),2.46 - 2.42(m,1H).

[0654] Example 11: (R)-3-(3-(3-(4-(azetidin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0655]

Chemical Structure

[0656] DMF(3mL) and H 2A solution of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 140 mg, 0.36 mmol) in O(0.3 mL) was treated with 4-(azetidin-1-yl)-6-chloropyrido[3,2-d]pyrimidine (80 mg, 0.4 mmol), followed by Pd(t-Bu 3 P) 2 (18 mg, 0.04 mmol) and K 2 CO 3 (151 mg, 1.09 mmol). The mixture was heated at 105 °C for 16 h under a N 2 atmosphere, then cooled to room temperature and concentrated. The resulting compound was purified by reverse-phase HPLC using an Xtimate C18 10 μm, 21.2×250 mm column with a 36–41% gradient of CH 3 CN / H 2 O(10 mM NH 4 HCO 3 and 0.025% NH 4 OH) to give (R)-3-(3-(3-(4-azetidin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (37 mg, 23%) as an off-white solid. MS (ESI): mass calculated for C 24 H 22 N 6 O 3 , 442.47, m / z, found, 443.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ 8.68 (s, 1H), 8.56 (d, J = 8.8 Hz, 1H), 8.45 (s, 1H), 8.34 (d, J = 7.6, 1H), 8.17 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 7.6, 1H), 7.17 (t, J = 7.6, 1H), 7.19 (s, 1H), 6.77 (s, 1H), 5.04 (t, J = 7.2, 2H), 4.34 (t, J = 7.2, 2H), 3.50 - 3.44 (m, 2H), 2.86 (s, 3H), 2.62 - 2.57 (m, 2H), 2.33 - 2.27 (m, 2H).

[0657] Example 12: (R)-3-(3-(3-(7-Aminothiazolo[5,4-d]pyrimidin-2-yl)-4-methylphenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0658]

Chemical Structure

[0659] Step A: 3-(7-Aminothiazolo[5,4-d]pyrimidin-2-yl)-4-methylbenzaldehyde. A mixture of 2-(5-iodo-2-methylphenyl)thiazolo[5,4-d]pyrimidin-7-amine (Intermediate 20, 400 mg, 1 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride DCM complex (44 mg, 0.054 mmol), triethylsilane (379 mg, 3.26 mmol), and Na 2 CO 3 (138 mg, 1.30 mmol) in DMF (8 mL) was heated at 80 °C for 24 h under a CO atmosphere. The reaction mixture was cooled, diluted with EtOAc (20 mL), and washed with brine (3 × 10 mL). The organic solvent layer was separated, dried over Na 2 SO 4 and filtered, then concentrated. The residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to give 3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-4-methylbenzaldehyde (0.22 g, 75%) as a yellow solid. MS (ESI): C 13 H10 N 4 Mass calculated value for OS, 270.3, m / z, measured value, 271.1 [M+H] + 。

[0660] Step B: 3-(7-Aminothiazolo[5,4-d]pyrimidin-2-yl)-4-methylbenzaldehyde oxime. Hydroxylamine (50% in water) (0.24 mL, 4.07 mmol) was added to a solution of 3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-4-methylbenzaldehyde (220 mg, 0.81 mmol) in EtOH (10 mL). The mixture was stirred at 25 °C for 2 h and then concentrated to give 3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-4-methylbenzaldehyde oxime (200 mg, 86%) as a white solid. MS (ESI): C 13 H 11 N 5 Mass calculated value for OS, 285.3, m / z, measured value, 286.1 [M+H] + 。

[0661] Step C: 3-(7-Aminothiazolo[5,4-d]pyrimidin-2-yl)-N-hydroxy-4-methylbenzimidoyl chloride. N-Chlorosuccinimide (281 mg, 2.10 mmol) was added portionwise to a solution of 3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-4-methylbenzaldehyde oxime (200 mg, 0.7 mmol) in DCM (10 mL) and DMF (15 mL). The reaction mixture was stirred at 25 °C for 5 h and then diluted with EtOAc (50 mL) and washed with brine (3x60 mL). The organic solvent portion was dried over Na 2 SO 4 and filtered and concentrated to give 3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-N-hydroxy-4-methylbenzimidoyl chloride (0.18 g, 80%) as a yellow solid. MS (ESI): C 13 H 10 ClN 5 Mass calculated value for OS, 319.8, m / z, measured value, 284.1 [M-HCl] + 。

[0662] Process D: (R)-3-(3-(3-(7-Aminothiazolo[5,4-d]pyrimidin-2-yl)-4-methylphenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. To a solution of 3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-N-hydroxy-4-methylbenzimidoyl chloride (180 mg, 0.28 mmol) in DCM (15 mL) was added (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1, 39.2 mg, 0.28 mmol), followed by triethylamine (0.12 mL, 0.84 mmol). The reaction mixture was stirred at 25 °C for 16 h, diluted with DCM (30 mL), and washed with brine (20 mL). The organic solvent portion was dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by reverse-phase HPLC using a Boston pHlex ODS 10 μm, 21.2 × 250 mm column with a 20% - 60% gradient of CH 3 CN / H 2 O (0.1% FA) to give (R)-3-(3-(3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-4-methylphenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (1.9 mg, 1%) as a yellow oil. MS (ESI): Calculated for C 20 H 18 N 6 O 3 S, 422.1, m / z, Found, 423.1 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.43 (s, 4H), 8.29 (s, 1H), 8.20 (d, J = 1.2 Hz, 1H), 7.87 (dd, J = 8.0, 1.6 Hz, 1H), 8.51 (d, J = 8.0 Hz, 1H), 6.96 (s, 1H), 3.41 - 3.47 (m, 2H), 2.84 (s, 3H), 2.66 (s, 3H), 2.54 - 2.61 (m, 1H), 2.26 - 2.32 (m, 1H).

[0663] Example 13: (R)-3-(3-(3-(7-Aminothiazolo[5,4-d]pyrimidin-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0664]

Chemical formula

[0665] Using 2-(3-Iodophenyl)thiazolo[5,4-d]pyrimidin-7-amine (Intermediate 21) instead of 6-Chloro-2-methylpyrido[3,2-d]pyrimidin-4-amine (Intermediate 16) and using conditions similar to those described in Example 1, (R)-3-(3-(3-(7-Aminothiazolo[5,4-d]pyrimidin-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one was prepared. MS(ESI): C 19 H 16 N 6 O 3 Calculated mass for S, 408.1, m / z, Observed, 409 [M+H] + 。 1 H NMR(400MHz, DMSO-d 6 ) δ8.56(s, 1H), 8.33(s, 1H), 8.17(d, J = 8.0Hz, 1H), 8.08(d, J = 8.0Hz, 1H), 7.85(s, 2H), 7.74(t, J = 8.0Hz, 1H), 7.15(s, 1H), 6.78(s, 1H), 3.53 - 3.44(m, 2H), 2.85(s, 3H), 2.62 - 2.55(m, 1H), 2.33 - 2.26(m, 1H).

[0666] Example 14: (R)-6-(3-(4-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)picolylamide.

[0667]

Chemical formula

[0668] Process A: Methyl (R)-6-(3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)picolinate. A mixture of methyl 6-(3-iodophenyl)picolinate (64 mg, 0.19 mmol), (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1, 32 mg, 0.23 mmol), NaN 3 (13.5 mg, 0.210 mmol), CuI (7 mg, 0.04 mmol), and trans-N,N'-dimethyl-cyclohexane-1,2-diamine (5.4 mg, 0.038 mmol) in DMSO (2 mL) was added with water (0.5 mL), followed by sodium ascorbate (7.5 mg, 0.038 mmol). The mixture was stirred at room temperature for 16 h under a N 2 atmosphere, poured into water (20 mL), and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine (2 × 20 mL), dried over Na 2 SO 4 and filtered, and concentrated to dryness. The residue was purified by preparative TLC (EA / petroleum ether = 2 / 1, R f = 0.5) to give methyl (R)-6-(3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)picolinate (70 mg, 94%) as a white solid. MS (ESI): C 20 H 19 N 5 O 4 Calculated mass for, 393.4, m / z, Found, 394 [M+H] + .

[0669] Project B: (R)-6-(3-(4-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)picolylamide. A mixture of methyl (R)-6-(3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)picolinate (60 mg, 0.15 mmol) and ammonia in MeOH (7N, 5 mL) was heated at 75 °C for 16 h. The solution was concentrated and purified by reverse-phase HPLC using an Xtimate 10 mm 150 Å, 21.2×250 mm column and a 5% - 33% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) to give (R)-6-(3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)picolylamide (19 mg, 33%) as a white solid. MS (ESI): C 19 H 18 N 6 O 3 calculated mass for, 378.4, m / z, found, 379.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.96 (s, 1H), 8.73 (s, 1H), 8.52 (s, 1H), 8.43 (d, J = 7.6 Hz, 1H), 8.37 (d, J = 8.0, 1H), 8.12 (t, J = 7.6 Hz, 1H), 8.05 (d, J = 7.6 Hz, 2H), 7.80 - 7.70 (m, 2H), 6.28 (s, 1H), 3.55 - 3.45 (m, 2H), 2.83 (s, 3H), 2.80 - 2.65 (m, 1H), 2.35 - 2.25 (m, 1H).

[0670] Example 15: (R)-1-(3-(4-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide.

[0671]

Chem.

[0672] A solution of (R)-3-hydroxy-1-methyl-3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)pyrrolidin-2-one (Intermediate 8, 100 mg, 0.26) in DMF (10 mL) and water (1 mL) was treated with 1-bromoimidazo[1,5-a]pyridine-3-carboxamide (62 mg, 0.26 mmol), followed by Pd(t-Bu 3 P) 2 (13 mg, 0.026 mmol) and K 3 PO 4 (166 mg, 0.78 mmol). The mixture was heated at 90 °C for 16 h under a nitrogen atmosphere, cooled to room temperature and then concentrated under reduced pressure. The residue was purified by preparative HPLC to give (R)-1-(3-(4-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide (19.4 mg, 18%) as a yellow solid. MS (ESI): C 21 H 19 N 7 O 3 Calculated for, 417.2, m / z, Found, 418.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.51 (d, J = 7.6 Hz, 1H), 8.79 (s, 1H), 8.45 (t, J = 2 Hz, 1H), 8.24 (d, J = 9.2 Hz, 1H), 8.10 (d, J = 8.4 Hz, 2H), 7.88 - 7.85 (m, 1H), 7.74 - 7.65 (m, 2H), 7.29 - 7.26 (m, 1H), 7.09 (t, J = 6.8 Hz, 1H), 6.28 (s, 1H), 3.51 - 3.47 (m, 2H), 2.83 (s, 3H), 2.77 - 2.66 (m, 1H), 2.34 - 2.26 (m, 1H).

[0673] Example 16: (R)-3-(5-(3-(4-Aminopyrido[3,2-d]pyrimidin-6-yl-2-d)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0674]

Chemical formula

[0675] A mixture of 6-chloropyrido[3,2-d]pyrimidine-2-d-4-amine (Intermediate 17, 78 mg, 0.43 mmol), (R)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one (Intermediate 5, 110 mg, 0.29 mmol), bis(tri-tert-butylphosphine)palladium(0) (15 mg, 0.029 mmol), K 3 PO 4 (182 mg, 0.86 mmol), 1,4-dioxane (10 mL), and water (1 mL) was heated at 65 °C for 16 h under an argon atmosphere. The reaction mixture was filtered and concentrated. The residue was purified by reverse-phase HPLC using an Xtimate C18 10 μm, 21.2 × 250 mm column with a 20% - 35% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) to give (R)-3-(5-(3-(4-aminopyrido[3,2-d]pyrimidin-6-yl-2-d)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (51 mg, 44%) as a white solid. MS (ESI): C 21 H 17 DN 6 O 3 Calculated mass for, 403.4, m / z, found, 404.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ 8.86 (s, 1H), 8.61 (d, J = 4.8 Hz, 1H), 8.57 (d, J = 8 Hz, 1H), 8.31 (s, 1H), 8.17 (d, J = 4.8 Hz, 1H), 8.05 (s, 1H), 7.98 (d, J = 8 Hz, 1H), 7.71 (t, J = 8 Hz, 1H), 7.40 (s, 1H), 6.53 (s, 1H), 3.49 - 3.38 (m, 2H), 2.82 (s, 3H), 2.72 - 2.65 (m, 1H), 2.31 - 2.23 (m, 1H).

[0676] Example 17: (R)-3-(5-(3-(3-Amino-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0677] [Chemical formula]

[0678] Step A: (R)-3-(5-(3-(3-Nitro-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one. A solution of (R)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one (Intermediate 5, 100 mg, 0.26 mmol) in 1,4-dioxane (4 mL), H 2 O (1 mL), and DMF (5 mL) was added with 5-chloro-3-nitro-1H-pyrazolo[4,3-b]pyridine (103 mg, 0.52 mmol), Pd(t-Bu 3 P) 2 (13 mg, 0.026 mmol), and K 3 PO 4 (166 mg, 0.78 mmol). The mixture was heated at 80 °C for 16 h under an Ar atmosphere, cooled to room temperature, and then concentrated. The residue was purified by CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH4 Purified by reverse-phase HPLC using an HPLC column such as Xtimate C18 10 μm, 21.2 × 250 mm column with a gradient of 15% - 35% of OH), (R)-3-(5-(3-(3-nitro-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (20 mg, 18%) was obtained as a white solid. MS(ESI): C 20 H 16 N 6 O 5 Mass calculated for, 420.4, m / z, found, 421.2 [M+H] + 。

[0679] Step B: (R)-3-(5-(3-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one. Saturated NH 4 To a solution of (R)-3-(5-(3-(3-nitro-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (20 mg, 0.05 mmol) in aqueous NH 3 Cl (2 mL) and MeOH (2 mL), zinc powder (200 mg, 3.06 mmol) was added. The mixture was stirred at 30 °C for 1 hour, filtered, and the filtrate was concentrated. The residue was purified by reverse-phase HPLC using an HPLC column such as Xtimate C18 10 μm, 21.2 × 250 mm column with a gradient of 5% - 40% of CH 2 CN / H 4 O (10 mM NH 3 HCO 4 and 0.025% NH 20 H 18 N 6 O 3Mass calculated value for [substance], 390.4, m / z, measured value, 391.2 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δ 8.54 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.95 - 7.88 (m, 3H), 7.66 (t, J = 8.0 Hz, 1H), 7.07 (s, 1H), 3.58 - 3.55 (m, 2H), 2.95 (s, 3H), 2.88 - 2.80 (m, 1H), 2.41 - 2.37 (m, 1H).

[0680] Example 18: (R)-6-(3-(3-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)picolylamide.

[0681] [Chemical formula]

[0682] Step A: Methyl (R)-6-(3-(3-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)picolinate. A mixture of methyl 6-bromopicolinate (76 mg, 0.35 mmol), (R)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one (Intermediate 5, 90 mg, 0.23 mmol), bis(tri-tert-butylphosphine)palladium(0) (11.9 mg, 0.02 mmol), and K 3 PO 4 (149 mg, 0.70 mmol) in 1,4-dioxane (8 mL) and water (1 mL) was heated at 75 °C for 16 h under an Ar atmosphere. The reaction mixture was filtered, concentrated, and the residue was purified by preparative TLC (DCM:MeOH = 20:1) to give methyl (R)-6-(3-(3-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)picolinate (87 mg, 94%) as a white solid. MS (ESI): C 21 H19 N 3 O 5 Mass calculated value for, 393.1, m / z, measured value, 394.1 [M+H] + 。

[0683] Step B: (R)-6-(3-(3-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)picolinamide. NH 3 (7N, in 5 mL of EtOH) A solution of methyl (R)-6-(3-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)picolinate (75.9 mg, 0.35 mmol) was heated at 75 °C for 16 h. The reaction mixture was concentrated and the residue was purified by reverse-phase HPLC using an Xtimate 10 mm, 21.2×250 mm column and a 15-45% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) to give (R)-6-(3-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)picolinamide (18 mg, 23%) as a white solid. MS (ESI): C 20 H 18 N 4 O 4 Mass calculated value for, 378.1, m / z, measured value, 379.1 [M+H] + 。 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.73 (s, 1H), 8.47 (s, 1H), 8.45 (s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 8.11 (t, J = 7.6 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.76 (s, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.36 (s, 1H), 6.52 (s, 1H), 3.49 - 3.37 (m, 2H), 2.82 (s, 3H), 2.71 - 2.65 (m, 1H), 2.29 - 2.22 (m, 1H).

[0684] Example 19: (R,S)-2-(3-(4-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-imidazol-1-yl)phenyl)quinazoline-4-carboxamide.

[0685]

Chemical formula

[0686] Step A: (R,S)-Ethyl 2-(3-(4-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-imidazol-1-yl)phenyl)quinazoline-4-carboxylate. A solution of (R,S)-3-Hydroxy-1-methyl-3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-4-yl)pyrrolidin-2-one (Intermediate 9, 180 mg, 0.47 mmol) in 1,4-dioxane (2 mL) and H 2 O (0.2 mL) was added with ethyl 2-chloroquinazoline-4-carboxylate (222 mg, 0.94 mmol), followed by Pd(t-Bu 3 P) 2 (24.0 mg, 0.05 mmol) and KF (82 mg, 1.41 mmol). The mixture was heated at 85 °C overnight under N 2 atmosphere. The mixture was concentrated and purified using preparative TLC (DCM / MeOH = 15 / 1) to obtain ethyl (R,S)-2-(3-(4-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-imidazol-1-yl)phenyl)quinazoline-4-carboxylate (150 mg, 69.8%) as a yellow solid. MS (ESI): C 25 H 23 N 5 O 4 Calculated mass for, 457.5, m / z, found, 458.0 [M+H] + .

[0687] Project B: (R,S)-2-(3-(4-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-imidazol-1-yl)phenyl)quinazoline-4-carboxamide. NH in MeOH 3 (R,S)-Ethyl 2-(3-(4-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-imidazol-1-yl)phenyl)quinazoline-4-carboxylate (140 mg, 0.31 mmol) in a solution of (7N, 5 mL) was heated at 75 °C for 16 h. The reaction mixture was concentrated and the residue was purified by HPLC using an Xtimate 10 mm 150 Å, 21.2×250 mm column and a 15 - 45% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) to give (R,S)-2-(3-(4-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1H-imidazol-1-yl)phenyl)quinazoline-4-carboxamide (40 mg, 31%) as a white solid. MS (ESI): C 23 H 20 N 6 O 3 Calculated mass for, 428.4, m / z, Found, 429.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.91 (d, J = 8.4 Hz, 1H), 8.79 (s, 2H), 8.64 (d, J = 8.4 Hz, 1H), 8.31 (s, 1H), 8.10 - 8.30 (m, 3H), 8.00 - 7.70 (m, 4H), 5.89 (s, 1H), 3.50 - 3.30 (m, 2H), 2.80 (s, 3H), 2.70 - 2.50 (m, 1H), 2.20 - 2.10 (m, 1H).

[0688] Example 20: (R)-3-(3-(2-(8-Amino-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)pyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0689]

Chem.

[0690] A solution of (R)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 7, 560 mg, 1.66 mmol) and 5,6,7,8-tetrahydro-2,7-naphthyridin-1-amine (247 mg, 1.66 mmol) in DMF (9 mL) was added with Pd 2 (dba) 3 (75.8 mg, 0.08 mmol), followed by BINAP (155 mg, 0.25 mmol) and t-BuONa (477 mg, 4.97 mmol). The reaction mixture was heated at 85 °C for 16 h under an Ar atmosphere, then diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic solvent extracts were concentrated to dryness and then purified by preparative TLC (DCM:MeOH 10:1) and reverse-phase HPLC to give (R)-3-(5-(3-(8-amino-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (2.5 mg, 0.4%) as a pale yellow solid. MS (ESI): C 21 H 22 N 6 O 3 Calculated mass for, 406.2, m / z, Found, 407.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.27 (d, J = 5.2 Hz, 1H), 7.75 (d, J = 5.2 Hz, 1H), 7.35 (s, 1H), 7.18 (s, 1H), 7.11 (d, J = 5.2 Hz, 1H), 6.78 (s, 1H), 6.41 (d, J = 5.2 Hz, 1H), 5.92 (s, 2H), 4.31 (s, 2H), 3.94 (t, J = 5.2 Hz, 2H), 3.50 - 3.40 (m, 2H), 2.85 (s, 3H), 2.75 (t, J = 5.2 Hz, 2H), 2.60 - 2.54 (m, 1H), 2.33 - 2.25 (m, 1H).

[0691] Example 21: (R)-4'-(5-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)-4-methoxy-[2,2'-bipyridine]-6-carboxamide.

[0692]

Chemical formula

[0693] Step A: 4-Methoxy-6-(tributylstannyl)picolylamide. To a solution of 6-bromo-4-methoxypicolylamide (400.0 mg, 1.730 mmol) in toluene (10 mL) was added bis(tributyltin) (2 g, 3.5 mmol), followed by Pd(Ph 3 P) 4 (100 mg, 0.09 mmol), and the reaction mixture was heated at 90 °C for 16 h under a N 2 atmosphere. Saturated aqueous KF solution (20 mL) was added, and stirring was continued at room temperature for 2 h. The mixture was extracted with EtOAc (3 × 20 mL), and then the combined organic solvent extracts were washed with brine (3 × 20 mL) and concentrated to dryness. The residue was purified by FCC (DCM:MeOH, 20:1) to give 4-methoxy-6-(tributylstannyl)picolylamide (185 mg, 18%) as a yellow solid. MS(ESI): C 19 H 34 N 2 O 2 Calculated mass for Sn, 442.2, m / z, found, 443.1 [M+H] + .

[0694] Project B: (R)-4'-(3-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)-4-methoxy-[2,2'-bipyridine]-6-carboxamide. A solution of 4-methoxy-6-(tributylstannyl)picolylamide (185 mg, 0.42 mmol), (R)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 7, 212 mg, 0.06 mmol), and Pd(Ph 3 P) 4 (48.5 mg, 0.04 mmol) in DMF (3 mL) was heated at 125 °C under N 2 for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL), and washed with brine (3 × 15 mL). The organic layer was concentrated to dryness and purified by reverse-phase HPLC using an Xtimate 10 mm 150 Å, 21.2 × 250 mm column with a 5% to 36% gradient of CH 3 CN / H 2 O (10 mM NH 4 HCO 3 and 0.025% NH 4 OH) to give (R)-4'-(5-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)-4-methoxy-[2,2'-bipyridine]-6-carboxamide (12 mg, 7%) as a white solid. MS (ESI): Calculated mass for C 20 H 19 N 5 O 5 , 409.2, m / z, found 410.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.63 (s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 8.41 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.78 (s, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.30 (s, 1H), 4.00 (s, 3H), 3.60 - 3.40 (m, 2H), 2.85 (s, 3H), 2.62 - 2.52 (m, 1H), 2.36 - 2.23 (m, 1H).

[0695] Example 22: (R)-1-(4-(5-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)pyridin-2-yl)-1H-indazole-3-carboxamide.

[0696]

Chemical formula

[0697] Step A: Methyl (R)-1-(4-(5-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)pyridin-2-yl)-1H-indazole-3-carboxylate. To a solution of methyl 1H-indazole-3-carboxylate (65 mg, 0.67 mmol) in toluene (5 mL) was added (R)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 7, 124 mg, 0.37 mmol), followed by (1S,2S)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (10.5 mg, 0.074 mmol), CuI (3.5 mg, 0.02 mmol), and K 3 PO 4 (165 mg, 0.78 mmol). The reaction mixture was heated at 100 °C for 16 h under N 2 atmosphere and then concentrated to dryness and purified by FCC (DCM:MeOH, 20:1) to give methyl (R)-1-(4-(5-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)pyridin-2-yl)-1H-indazole-3-carboxylate (60 mg, 77%) as a yellow solid. MS (ESI): Calculated mass for C 22 H 19 N 5 O 5 is 433.1, m / z, found 434.1 [M+H] + .

[0698] Project B: (R)-1-(4-(3-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)pyridin-2-yl)-1H-indazole-3-carboxamide. NH 3 A solution of methyl (R)-1-(4-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)pyridin-2-yl)-1H-indazole-3-carboxylate (60 mg, 0.14 mmol) in (7N, 5 mL, 35 mmol) MeOH was heated at 75 °C for 16 h. The mixture was cooled to room temperature, concentrated in vacuo, and purified by reverse-phase HPLC using an Xtimate 10 mm 150 Å, 21.2×250 mm column with a 40-45% gradient of CH 3 CN / (10 mM NH 4 HCO 3 and H 2 O with 0.025% NH 4 OH) to give (R)-1-(4-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)pyridin-2-yl)-1H-indazole-3-carboxamide (33 mg, 55%) as a white solid. MS (ESI): C 21 H 18 N 6 O 4 Calculated mass for, 418.1, m / z, Found, 419.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.84 (d, J = 8.8 Hz, 1H), 8.76 (d, J = 5.2 Hz, 1H), 8.69 (s, 1H), 8.35 - 8.32 (m, 2H), 7.88 - 7.86 (m, 1H), 7.74 (s, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.30 (s, 1H), 6.85 (s, 1H), 3.52 - 3.45 (m, 2H), 2.86 (s, 3H), 2.62 - 2.57 (m, 1H), 2.35 - 2.30 (m, 1H).

[0699] Example 23: (R)-1-(3-(5-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide.

[0700]

Chemical formula

[0701] In a large vial, (R)-3-Hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 200 mg, 0.52 mmol), 1-Bromoimidazo[1,5-a]pyridine-3-carboxamide (190 mg, 0.79 mmol), and Pd(PPh 3 ) 4 (61 mg, 0.05 mmol) were added. Then, a mixture of 1,4-dioxane (20 mL) and 2M K 2 CO 3 (1.2 mL, 2.4 mmol) was degassed with N 2 for 20 minutes and added to the reaction mixture. The vial was sealed, evacuated / purged with nitrogen three times, and then placed in an aluminum heating mantle at 100 °C. After 2 hours, the mixture was heated at 80 °C overnight. After 18 hours, the reaction mixture was filtered through a pad of diatomaceous earth (while still warm), rinsed further with EtOAc and THF, and the eluent was concentrated to give a yellowish-brown viscous oil. The material was redissolved in CHCl 3 and purified by FCC with a gradient of 0 - 90% EtOAc in DCM to give (R)-1-(3-(5-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide (151 mg, 70%) as a fluffy off-white solid. MS(ESI): Calculated mass for C 19 H 16 N 6 O 2 , 417.4, m / z, found, 418.1 [M+H] + . 11H NMR (500 MHz, CD 3 OD) δ 9.48 (dt, J = 7.2, 1.1 Hz, 1H), 8.46 - 8.32 (m, 1H), 8.11 - 7.99 (m, 2H), 7.81 - 7.77 (m, 1H), 7.67 - 7.51 (m, 1H), 7.21 - 7.18 (m, 1H), 7.01 - 6.91 (m, 2H), 3.65 - 3.47 (m, 2H), 2.96 (s, 3H), 2.78 - 2.72 (m, 1H), 2.43 - 2.37 (m, 1H).

[0702] Example 24: (R)-3-(3-(3-(1H-Pyrrolo[2,3-b]pyridin-3-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0703]

Chem.

[0704] Step A: tert-Butyl (R)-3-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. To a solution of (R)-3-hydroxy-3-(3-(3-iodophenyl)isoxazol-5-yl)-1-methylpyrrolidin-2-one (Intermediate 23, 90 mg, 0.234 mmol) in 1,4-dioxane (10 mL) and water (1.5 mL) were added tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Intermediate 24, 604 mg, 0.70 mmol), bis(tri-tert-butylphosphine)palladium(0) (12 mg, 0.02 mmol) and K 3 PO 4 (149 mg, 0.70 mmol). The mixture was heated at 75 °C for 16 h, then diluted with H 2 O (20 mL) and extracted with EtOAc (3 × 15 mL). The combined organic solvent extracts were washed with brine (20 mL) and Na 2 SO 4It was dried, filtered, and concentrated to dryness. The residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to obtain tert-butyl (R)-3-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (50 mg, 0.086 mmol) as a yellow solid. MS (ESI): C 26 H 26 N 4 O 5 Calculated mass for, 474.2, m / z, found, 475.2 [M+H] + .

[0705] Step B: (R)-3-(3-(3-(1H-Pyrrolo[2,3-b]pyridin-3-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. A solution of tert-butyl (R)-3-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (50.0 mg, 0.11 mmol) in HCl solution (8 mL, 7 M in 1,4-dioxane) was stirred at 25 °C for 2 h and then concentrated to dryness. The residue was dissolved in H 2 O (10 mL) and the pH of the solution was adjusted to pH > 7 with saturated NaHCO 3 aqueous solution. The solution was then extracted with DCM / i-PrOH (3 × 20 mL). The combined organic extracts were dried over Na 2 SO 4 and filtered and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 20 / 1, R f = 0.35) to obtain (R)-3-(3-(3-(1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (9 mg, 22%) as a white solid. MS (ESI): C 21 H 18 N 4 O 3 Calculated mass for, 374.1, m / z, found, 375.1 [M+H] + .1 1H NMR (400 MHz, DMSO-d 6 ) δ 12.01 (s, 1H), 8.29 - 8.33 (m, 2H), 8.16 (s, 1H), 8.04 (s, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.20 - 7.17 (m, 1H), 7.13 (s, 1H), 6.71 (s, 1H), 3.49 - 3.40 (m, 2H), 2.84 (s, 3H), 2.60 - 2.54 (m, 1H), 2.32 - 2.25 (m, 1H).

[0706] Example 25: (R)-3-Hydroxy-1-methyl-3-(3-(3-(4-methylpyrido[3,2-d]pyrimidin-6-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one.

[0707]

Chem.

[0708] Step A: 6-Chloro-4-methylpyrido[3,2-d]pyrimidine. Trimethylaluminum (1.25 mL, 2 M in THF, 3.00 mmol) was added to a mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (500 mg, 2.50 mmol) and THF (20 mL) cooled to 0 °C. The mixture was purged with N 2 for 5 minutes, treated with Pd(PPh 3 ) 4 (144 mg, 0.13 mmol), purged with N 2 for an additional 5 minutes, and then heated at 80 °C for 8 hours under a N 2 atmosphere. The mixture was then cooled to room temperature, diluted with saturated NH 4 Cl aqueous solution (20 mL), and extracted with ethyl acetate (100 mL). The organic phase was washed with brine (50 mL) and dried over anhydrous Na 2 SO 4It was dried, filtered, and concentrated under reduced pressure. The obtained residue was purified by FCC on silica gel (eluent: petroleum ether: ethyl acetate = 1:0 - 3:1) to obtain 6-chloro-4-methylpyrido[3,2-d]pyrimidine (270 mg, 60%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 9.24 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 3.06 (s, 3H).

[0709] Step B: (R)-3-Hydroxy-1-methyl-3-(3-(3-(4-methylpyrido[3,2-d]pyrimidin-6-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. A mixture of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 360 mg, 0.94 mmol), 6-chloro-4-methylpyrido[3,2-d]pyrimidine (168 mg, 0.935 mmol), K 3 PO 4 (597 mg, 2.81 mmol), 1,4-dioxane (4 mL), and H 2 O (1 mL) was purged with Ar for 5 minutes, then treated with 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (61 mg, 0.09 mmol) and purged with Ar for another 5 minutes. The obtained mixture was irradiated with microwave at 90 °C for 1 hour. Then, the mixture was cooled to room temperature and concentrated under reduced pressure. The product was purified on a Phenomenex Gemini-NX, 150 mm × 30 mm × 5 μm column (eluent: 27% - 51%, water (0.04% NH 4 OH + 10 mM NH 4 HCO 3 )-CH 3Purified by preparative HPLC using an HPLC column such as CN). The product was suspended in water (10 mL), the mixture was frozen by inserting it into a bath at -78 °C, and then lyophilized to dryness to obtain (R)-3-hydroxy-1-methyl-3-(3-(3-(4-methylpyrido[3,2-d]pyrimidin-6-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (99 mg, 26%) as a red solid. MS (ESI): C 22 H 19 N 5 O 3 Calculated mass for, 401.2, m / z, found, 402.0 [M+H] + 。 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.21 (s, 1H), 8.83 - 8.69 (m, 2H), 8.54 - 8.44 (m, 2H), 8.11 - 8.03 (m, 1H), 7.79 - 7.69 (m, 1H), 7.22 (s, 1H), 6.78 (s, 1H), 3.52 - 3.44 (m, 2H), 3.09 (s, 3H), 2.86 (s, 3H), 2.64 - 2.57 (m, 1H), 2.37 - 2.26 (m, 1H).

[0710] Example 26: (R)-3-(3-(3-(4-Amino-8-methylpyrido[3,2-d]pyrimidin-6-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one.

[0711]

Chemical formula

[0712] Step A: 3-Amino-4-bromo-6-chloropicolinonitrile. N-Succinimide (3.4 g, 19 mmol) was added to a solution of 3-amino-6-chloropicolinonitrile (2.7 g, 18 mmol) and DMF (50 mL). The resulting mixture was heated at 90 °C for 2 hours. Then, the mixture was cooled to room temperature and treated with saturated Na 2 SO 3 aqueous solution (100 mL) and stirred for 1 hour. The resulting mixture was saturated with NaHCO3 It was treated with an aqueous solution (100 mL), and extracted with ethyl acetate (40 mL × 3). The combined organic extracts were washed with brine (10 mL), and dried over anhydrous Na 2 SO 4 and filtered, and concentrated to dryness under reduced pressure. The obtained residue was purified by FCC (eluent: petroleum ether: ethyl acetate = 1:0 to 1:1) to obtain 3-amino-4-bromo-6-chloropicolinonitrile (1.3 g, 30%) as a yellow solid. MS (ESI): C 6 H 3 BrClN 3 Calculated mass for, 230.9, measured m / z value, 233.7 [M+H] + .

[0713] Step B: 3-amino-6-chloro-4-methylpicolinonitrile. 3-Amino-4-bromo-6-chloropicolinonitrile (1.2 g, 5.2 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatri borinane (0.8 mL, 5.7 mmol), K 2 CO 3 (13 mL, 2.0 M in water, 26 mmol), and 1,4-dioxane (30 mL) were added to a 100 mL round-bottom flask. The mixture was sparged with Ar for 5 minutes, then treated with PdCl 2 (dppf)·CH 2 Cl 2 (0.5 g, 0.5 mmol). The mixture was sparged with Ar for a further 5 minutes, and the resulting mixture was heated at 80 °C for 2 hours. Then, the mixture was cooled to room temperature, diluted with H 2 O (100 mL), and extracted with ethyl acetate (60 mL × 3). The combined organic extracts were washed with brine (10 mL), and dried over anhydrous Na 2 SO 4 and filtered, and concentrated to dryness under reduced pressure. The obtained residue was purified by FCC (eluent: petroleum ether / ethyl acetate = 5:1 to 1:1) to obtain 3-amino-6-chloro-4-methylpicolinonitrile (600 mg, 69%) as a yellow solid.

[0714] Process C: 6-chloro-8-methylpyrido[3,2-d]pyrimidin-4-amine. 3-Amino-6-chloro-4-methylpicolinonitrile (1.05 g, 6.27 mmol), formimidamide acetate (5.22 g, 50.1 mmol), K 3 PO 4 (13.3 g, 62.7 mmol), and 1,4-dioxane (30 mL) were added to a 100 mL round-bottom flask. The reaction mixture was heated at 90 °C for 2 h. Then, the mixture was cooled to room temperature, diluted with H 2 O (100 mL), and extracted with ethyl acetate (60 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to dryness under reduced pressure to obtain the product, which was purified by FCC (eluent: petroleum ether:ethyl acetate = 1:0 to 1:1) to give 6-chloro-8-methylpyrido[3,2-d]pyrimidin-4-amine (1.0 g, 82%) as a yellow solid. MS (ESI): C 8 H 7 ClN 4 for mass calculated value, 194.0, m / z, found value, 195.1 [M+H] + .

[0715] Process D: (R)-3-(3-(3-(4-amino-8-methylpyrido[3,2-d]pyrimidin-6-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. (R)-3-Hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 250 mg, 0.651 mmol), 6-chloro-8-methyl...

Claims

1. A compound of formula I: 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein A is -C （１～４） alkyl and -C （１～４） a 5-membered heteroaryl optionally substituted with 1 to 3 groups selected from haloalkyl, B is furanyl, piperidinyl, or a group having the following structure, [Chemical 2] W is CH ２ , CHF, or CF ２ and V is N, C-H, or C-R Ｖ wherein X is N, C-H, or C-R Ｘ wherein Y is N, C-H, or C-R Ｙ wherein Z is N, C—H, or C—R Ｚ wherein R Ｖ 、R Ｘ 、R Ｙ 、and R Ｚ each independently is halo, -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 -N(H)(5- to 10-membered heteroaryl), -C （６～１０） aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or 5- to 10-membered heteroaryl, wherein the -N(H)(5- to 10-membered heteroaryl), the -C （６～１０） aryl, the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, and the 5- to 10-membered heteroaryl are each optionally substituted with 1 to 5 R ３ groups, Each R ３ is, independently, halo, -OH, -N(R Ｎ１ )(R Ｎ２ ), -CN, -C （１～６） alkyl, -C （１～６） haloalkyl, -C （３～１０） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, -OC （３～１０） cycloalkyl, -C （１～３） alkyl-N(R Ｎ１ )(R Ｎ３ ), -C(O)OH, -C(O)N(R Ｎ１ )(R Ｎ４ ), -C （１～３） alkyl(3- to 8-membered heterocyclyl), -C （１～３） alkyl(phenyl), a 3- to 8-membered heterocyclyl, or a 5- to 6-membered heteroaryl, where the -C （１～６） alkyl, -C （１～６） haloalkyl, -C （３～１０） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, -OC （３～１０） cycloalkyl, -C （１～３） alkyl(3- to 8-membered heterocyclyl), -C （１～３） alkyl(phenyl), the 3- to 8-membered heterocyclyl, and the 5- to 6-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -C （１～４） alkyl, -C （１～４） haloalkyl, -C （３～６） cycloalkyl, -OC （１～４） alkyl, -OC （１～４） haloalkyl, and -C （１～４） alkylOC （１～４） alkyl, R Ｎ１ is hydrogen or -C （１～４） alkyl, R Ｎ２ , R Ｎ３ , and R Ｎ４ is, each time it appears, independently of one another, hydrogen, -C （１～４） alkyl, -C （３～６） cycloalkyl, -C(O)C （１～４） alkyl, -C （１～４） alkyl(4-6 membered heterocyclyl), 4-6 membered heterolocyclyl, 5-6 membered heteroaryl, where the said 4-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally further substituted with 1-3 groups selected from -CN, -C （１～４） alkyl, -C （１～４） haloalkyl, -OC （１～４） alkyl, -OC （１～４） haloalkyl, and -C(O)C （１～４） alkyl, but are optionally further substituted provided that at least two of V, X, Y, and Z are C-H, and R ２ When R is pyrimidinyl, the pyrimidinyl is substituted with one group selected from -OC （１～６） alkyl and -C(O)N(R Ｎ１ )(R Ｎ４ ), and is optionally further substituted with 1 to 2 R ３ groups, a compound of formula I, or a pharmaceutically acceptable salt thereof.

2. A is -C （１～４） alkyl and -C （１～４） a 5-membered heteroaryl optionally substituted with 1 to 3 groups selected from haloalkyl B is furanyl, piperidinyl, or a group having the following structure, [Chemical 3] W is CH ２ or CF ２ and V is N, C-H, or C-R Ｖ and X is N, C-H, or C-R Ｘ wherein Y is N, C-H, or C-R Ｙ wherein Z is N, C-H, or C-R Ｚ wherein R Ｖ 、R Ｘ 、R Ｙ 、and R Ｚ are each independently halo, -C （１～４） alkyl, -C （１～４） haloalkyl, or -OC （１～４） alkyl, R １ is hydrogen, -C （１～４） alkyl, or -C （１～４） haloalkyl, and R ２ is -N(H)(5 - 10 membered heteroaryl), -C （６～１０） aryl, a 5 - 12 membered bicyclic or tricyclic ring system containing one or more heteroatoms, or 5 - 10 membered heteroaryl, wherein said -N(H)(5 - 10 membered heteroaryl) is optionally substituted with 1 - 5 R ３ａ groups, said -C （６～１０） aryl is optionally substituted with 1 - 5 R ３ｂ groups, said 5 - 12 membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 - 5 R ３ｃ groups, and said 5 - 10 membered heteroaryl is optionally substituted with 1 - 5 R ３ｄ groups. R ３ａ and R ３ｂ is, each time it appears, independently of each other, halo, -N(R Ｎ１ )(R Ｎ２ ), -C （１～６） alkyl, -C （１～６） haloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, -C （１～３） alkyl-N(R Ｎ１ )(R Ｎ３ ), or -C(O)N(R Ｎ１ )(R Ｎ４ ), and R ３ｃ 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 （３～１０） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, -OC （３～１０） cycloalkyl, -C （１～３） alkyl-N(R Ｎ１ )(R Ｎ３ ), -C(O)OH, -C(O)N(R Ｎ１ )(R Ｎ４ ), -C （１～３） alkyl(3- to 8-membered heterocyclyl), -C （１～３） alkyl(phenyl), a 3- to 8-membered heterocyclyl, or a 5- to 6-membered heteroaryl, where the -C （１～６） alkyl, -C （１～６） haloalkyl, -C （３～１０） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, -OC （３～１０） cycloalkyl, -C （１～３） alkyl(3- to 8-membered heterocyclyl), -C （１～３） alkyl(phenyl), the 3- to 8-membered heterocyclyl, and the 5- to 6-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -C （１～４） alkyl, -C （１～４） haloalkyl, -C （３～６） cycloalkyl, -OC （１～４） alkyl, -OC （１～４） haloalkyl, and -C （１～４） alkylOC （１～４） alkyl, R Ｎ１ is hydrogen or C （１～４） alkyl, and R Ｎ２ 、 R Ｎ３ 、 and R Ｎ４ are, each time they appear, each independently hydrogen, -C （１～４） alkyl, -C （３～６） cycloalkyl, -C(O)C （１～４） alkyl, -C （１～４） alkyl(4-6 membered heterocyclyl), 4-6 membered heterocyclyl, 5-6 membered heteroaryl, where the 4-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally further substituted with 1-3 groups selected from -CN, -C （１～４） alkyl, -C （１～４） haloalkyl, -OC （１～４） alkyl, -OC （１～４） haloalkyl, and -C(O)C （１～４） alkyl, but provided that at least two of V, X, Y, and Z are C-H, and R ２ When R is pyrimidinyl, the pyrimidinyl is substituted with one group selected from -OC （１～６） alkyl and -C(O)N(R Ｎ１ )(R Ｎ４ ), and is optionally further substituted with 1 to 2 R ３ｄ groups, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. A is -C （１～４） alkyl and -C （１～４） a 5-membered heteroaryl optionally substituted with 1 to 3 groups selected from haloalkyl B is furanyl, piperidinyl, or a group having the following structure, [Chemical Formula 4] W is CH ２ or CF ２ and V is N, C-H, or C-R Ｖ wherein X is N, C-H, or C-R Ｘ wherein Y is N, C-H, or C-R Ｙ wherein Z is N, C-H, or C-R Ｚ wherein R Ｖ is a halo, and R Ｘ 、 R Ｙ 、 and R Ｚ are each independently halo-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 -N(H)(5- to 10-membered heteroaryl), -C （６～１０） aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or 5- to 10-membered heteroaryl, wherein the -N(H)(5- to 10-membered heteroaryl) is optionally substituted with 1 to 5 R ３ａ groups, the -C （６～１０） aryl is optionally substituted with 1 to 5 R ３ｂ groups, the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R ３ｃ groups, and the 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R ３ｄ groups. R ３ａ and R ３ｂ each independently represents, upon each occurrence, -N(R Ｎ１ )(R Ｎ２ ) or -C(O)N(R Ｎ１ )(R Ｎ４ ), and Each R ３ｃ is, each time it appears, independently, halo, -N(R Ｎ１ )(R Ｎ２ ), -C （１～６） alkyl, -C （１～６） haloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, -C （１～３） alkyl-N(R Ｎ１ )(R Ｎ３ ), -C(O)OH, -C(O)N(R Ｎ１ )(R Ｎ４ ), or -C （１～３） alkyl(phenyl), Each R ３ｄ is, upon each occurrence, independently, halo, -N(R Ｎ１ )(R Ｎ２ ), -C （１～６） alkyl, -C （１～６） haloalkyl, -C （３～１０） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, -OC （３～１０） cycloalkyl, -C （１～３） alkyl-N(R Ｎ１ )(R Ｎ３ ), -C(O)N(R Ｎ１ )(R Ｎ４ ), -C （１～３） alkyl(3- to 8-membered heterocyclyl), 3- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl, where the -C （１～６） alkyl, -C （１～６） haloalkyl, -C （３～１０） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, -OC （３～１０） cycloalkyl, -C （１～３） alkyl(3- to 8-membered heterocyclyl), 3- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -C （１～４） alkyl, -C （１～４） haloalkyl, -C （３～６） cycloalkyl, -OC （１～４） alkyl, -OC （１～４） haloalkyl, and -C （１～４） alkylOC （１～４） alkyl, R Ｎ１ is hydrogen or -C （１～４） alkyl, R Ｎ２ is hydrogen, -C （１～４） alkyl, -C （３～６） cycloalkyl, -C(O)C （１～４） alkyl, -C （１～４） alkyl(4- to 6-membered heterocyclyl), 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, where the 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with 1 to 3 groups selected from -CN, -C （１～４） alkyl, -C （１～４） haloalkyl, -OC （１～４） alkyl, -OC （１～４） haloalkyl, and -C(O)C （１～４） alkyl R Ｎ３ is hydrogen, -C （３～６） cycloalkyl, or a 5- or 6-membered heteroaryl, where the 5- or 6-membered heteroaryl is optionally further substituted with 1 to 3 -C （１～４） alkyl groups, R Ｎ４ is hydrogen, -C （１～４） alkyl, or 4- to 6-membered heterocyclyl, provided that provided that at least two of V, X, Y, and Z are C-H, and R ２ When R is pyrimidinyl, the pyrimidinyl is substituted with one group selected from -OC （１～６） alkyl and -C(O)N(R Ｎ１ )(R Ｎ４ ), and is optionally further substituted with 1 to 2 R ３ｄ groups, the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. A is a 5-membered heteroaryl optionally substituted with 1 to 3 -C （１～４） alkyl groups, B is furanyl, piperidinyl, or a group having the following structure, 【Chemical Formula 5】 W is CH ２ or CF ２ and V is N, C-H, or C-R Ｖ wherein X is N, C-H, or C-R Ｘ wherein Y is N, C-H, or C-R Ｙ wherein Z is N, C-H, or C-R Ｚ wherein R Ｖ is a halo, and R Ｘ 、R Ｙ 、and R Ｚ are each independently halo, -C （１～４） alkyl, -C （１～４） haloalkyl, or -OC （１～４） alkyl, R １ is hydrogen, -C （１～４） alkyl, or -C （１～４） haloalkyl, and R ２ is -N(H)(5- to 10-membered heteroaryl), -C （６～１０） aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or 5- to 10-membered heteroaryl, wherein said -N(H)(5- to 10-membered heteroaryl) is optionally substituted with one -N(R Ｎ１ )(R Ｎ２ ) group, said -C （６～１０） aryl is optionally substituted with one -C(O)N(R Ｎ１ )(R Ｎ４ ) group, said 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R ３ｃ groups, and said 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R ３ｄ groups. Each R ３ｃ is, independently for each occurrence, -N(R Ｎ１ )(R Ｎ２ ), -C （１～６） alkyl, -C （１～６） haloalkyl, -OC （１～６） alkyl, -C(O)OH, -C(O)N(R Ｎ１ )(R Ｎ４ ), or -C （１～３） alkyl(phenyl), Each R ３ｄ is, each time it appears, independently, halo, -N(R Ｎ１ )(R Ｎ２ ), -C （１～６） alkyl, -C （１～６） haloalkyl, -C （３～１０） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, -C （１～３） alkyl-N(R Ｎ１ )(R Ｎ３ ), -C(O)N(R Ｎ１ )(R Ｎ４ ), -C （１～３） alkyl(3- to 8-membered heterocyclyl), a 3- to 8-membered heterocyclyl, or a 5- to 6-membered heteroaryl, where the 3- to 8-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -C （１～４） alkyl, -C （１～４） haloalkyl, -C （３～６） cycloalkyl, -OC （１～４） alkyl, -OC （１～４） haloalkyl, and -C （１～４） alkylOC （１～４） alkyl R Ｎ１ is hydrogen or C （１～４） alkyl, and R Ｎ２ is hydrogen, -C （１～４） alkyl, -C （３～６） cycloalkyl, -C(O)C （１～４） alkyl, -C （１～４） alkyl(4-6 membered heterocyclyl), a 4-6 membered heterocyclyl, a 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally further substituted with 1 to 3 groups selected from -CN, -C （１～４） alkyl, -C （１～４） haloalkyl, -OC （１～４） alkyl, -OC （１～４） haloalkyl, and -C(O)C （１～４） alkyl R Ｎ３ is hydrogen, -C （３～６） cycloalkyl, or 5- to 6-membered heteroaryl, where the 5- to 6-membered heteroaryl is optionally further substituted with 1 to 3 -C （１～４） alkyl groups, R Ｎ４ is hydrogen, -C （１～４） alkyl, or 4- to 6-membered heterocyclyl, provided that provided that at least two of V, X, Y, and Z are C-H, and R ２ When R is pyrimidinyl, the pyrimidinyl is substituted with one group selected from -OC （１～６） alkyl and -C(O)N(R Ｎ１ )(R Ｎ４ ), and is optionally further substituted with 1 to 2 R ３ｄ groups, the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

5. A is a 5-membered heteroaryl optionally substituted with one -C （１～４） alkyl group, B is 【Chemical Formula 6】 wherein W is CH ２ , or CF ２ and V is N, C-H, or C-F, X is N, C-H, or C-R Ｘ wherein Y is N, C-H, or C-R Ｙ wherein Z is N, C-H, or C-R Ｚ wherein R Ｘ 、R Ｙ 、and R Ｚ are each independently fluorine, -CH ３ , or -OCH ３ and R １ is hydrogen or -CF ３ and R ２ is -N(H)(5- to 10-membered heteroaryl), -C （６～１０） aryl, a 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, or 5- to 10-membered heteroaryl, wherein the -N(H)(5- to 10-membered heteroaryl) is optionally substituted with one -NH ２ group, the -C （６～１０） aryl is optionally substituted with one -C(O)NH ２ group, the 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms is optionally substituted with 1 to 5 R ３ｃ groups, and the 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R ３ｄ groups. Each R ３ｃ is, independently for each occurrence, -NH ２ , -C （１～６） alkyl, -C （１～６） haloalkyl, -OC （１～６） alkyl, -C(O)OH, -C(O)NH ２ , or -C （１～３） alkyl(phenyl), and Each R ３ｄ is, each time it appears, independently, halo, -N(R Ｎ１ )(R Ｎ２ ), -C （１～６） alkyl, -C （１～６） haloalkyl, -C （３～１０） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, -C （１～３） alkyl-N(R Ｎ１ )(R Ｎ３ ), -C(O)N(R Ｎ１ )(R Ｎ４ ), -C （１～３） alkyl(3- to 8-membered heterocyclyl), a 3- to 8-membered heterocyclyl, or a 5- to 6-membered heteroaryl, where the 3- to 8-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -C （１～４） alkyl, -C （１～４） haloalkyl, -C （３～６） cycloalkyl, -OC （１～４） alkyl, -OC （１～４） haloalkyl, and -C （１～４） alkylOC （１～４） alkyl, R Ｎ１ is hydrogen, and R Ｎ２ is hydrogen, -C （１～４） alkyl, -C （３～６） cycloalkyl, -C(O)C （１～４） alkyl, -C （１～４） alkyl(4-6 membered heterocyclyl), 4-6 membered heterocyclyl, 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally further substituted with 1-3 groups selected from -CN, -C （１～４） alkyl, -C （１～４） haloalkyl, -OC （１～４） alkyl, -OC （１～４） haloalkyl, and -C(O)C （１～４） alkyl R Ｎ３ is hydrogen, -C （３～６） cycloalkyl, or 5- to 6-membered heteroaryl, where the 5- to 6-membered heteroaryl is optionally further substituted with 1 to 3 -C （１～４） alkyl groups, R Ｎ４ is hydrogen, -C （１～４） alkyl, or 4- to 6-membered heterocyclyl, provided that provided that at least two of V, X, Y, and Z are C-H, and R ２ When R is pyrimidinyl, the pyrimidinyl is substituted with one group selected from -OC （１～６） alkyl and -C(O)N(R Ｎ１ )(R Ｎ４ ), and is optionally further substituted with 1 to 2 R ３ｄ groups, the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

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

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

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

9. A is [Chemical Formula 7] wherein, the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

10. A is 【Chemical 8】 wherein, the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

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

12. B is 【Chemical Formula 9】 wherein, the compound according to any one of claims 1 to 4 or 6 to 11, or a pharmaceutically acceptable salt thereof.

13. B is 【Chemical 10】 wherein, the compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

14. R Ｖ 、 R Ｘ 、 R Ｙ 、 and R Ｚ are each independently fluorine, -CH ３ , or -OCH ３ and the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

15. V is N, C-H, or C-F, X is N, C-H, C-F, or C-CH ３ wherein Y is N, C-H, C-F, C-CH ３ , or C-OCH ３ and Z is N, C-H, C-F, or C-CH ３ The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein Z is as defined above.

16. B is 【Chemical 11】 wherein, the compound according to any one of claims 1 to 12, 14 or 15, or a pharmaceutically acceptable salt thereof.

17. B is 【Chemical Formula 12】 wherein, the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.

18. R １ is hydrogen or -CF ３ and is a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof.

19. The compound according to any one of claims 1 to 18, which is any one of the compounds of Formula Id-1 to Formula Id-5, or a pharmaceutically acceptable salt thereof. 【Chemical 13】

20. The compound according to any one of claims 1 to 18, which is any one of the compounds of Formula Ie-1 to Formula Ie-6, or a pharmaceutically acceptable salt thereof. 【Chemical 14】

21. R ２ is -N(H)(5- to 10-membered heteroaryl), which is optionally substituted with 1 to 5 R ３ａ groups, a compound according to any one of claims 2 to 20, or a pharmaceutically acceptable salt thereof.

22. R ２ is -N(H)(9- to 10-membered heteroaryl), which is optionally substituted with 1 to 5 R ３ａ groups, a compound according to any one of claims 2 to 21, or a pharmaceutically acceptable salt thereof.

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

24. R ３ａ is -NH ２ and is a compound according to any one of claims 2 to 23, or a pharmaceutically acceptable salt thereof.

25. R ２ is 【Chemical Formula 15】 The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof.

26. R ２ is -C （６～１０） aryl, which is optionally substituted with 1 to 5 R ３ｂ groups, the compound according to any one of claims 2 to 20, or a pharmaceutically acceptable salt thereof.

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

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

29. R ２ is 【Chemical 16】 The compound according to any one of claims 1 to 20 or 26 to 28, or a pharmaceutically acceptable salt thereof.

30. R ２ 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 ３ｃ groups, a compound according to any one of claims 2 to 20, or a pharmaceutically acceptable salt thereof.

31. R ２ is 【Chemical 17】 The compound according to any one of claims 2 to 20 or 30, or a pharmaceutically acceptable salt thereof.

32. R ２ is 【Chemical Formula 18】 The compound according to any one of claims 2 to 20, 30, or 31, or a pharmaceutically acceptable salt thereof.

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

34. R ３ｃ is, independently for each occurrence, -NH ２ , -C （１～６） alkyl, -C （１～６） haloalkyl, -OC （１～６） alkyl, -C(O)OH, -C(O)NH ２ , or -C （１～３） alkyl(phenyl), a compound according to any one of claims 2 to 20 or 30 to 33, or a pharmaceutically acceptable salt thereof.

35. R ２ is 【Chemical 19】 The compound according to any one of claims 1 to 20 or 30 to 34, or a pharmaceutically acceptable salt thereof.

36. R ２ is 【Chemical 20】 The compound according to any one of claims 1 to 20 or 30 to 34, or a pharmaceutically acceptable salt thereof.

37. R ２ is a 5- to 10-membered heteroaryl, which is optionally substituted with 1 to 5 R ３ｄ groups, a compound according to any one of claims 2 to 20, or a pharmaceutically acceptable salt thereof.

38. R ２ is a 5- or 6-membered monocyclic heteroaryl or a 9- or 10-membered bicyclic heteroaryl, each of which is optionally substituted with 1 to 5 R ３ｄ groups, the compound according to any one of claims 2 to 20 or 37, or a pharmaceutically acceptable salt thereof.

39. R ２ is pyrazolyl, imidazolyl, furanyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, indazolyl, benzimidazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolopyridazinyl, pyrrolotriazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, triazolopyridinyl, quinazolinyl, isoquinolinonyl, quinazolinonyl, pyridopyrimidinyl, pyridopyrimidinonyl, pyrimidopyrimidinyl, benzoxazolyl, thiazolopyrimidinyl, furopyridinyl, or thienopyrimidinyl, each of which is optionally substituted with 1 to 3 R ３ｄ groups, a compound according to any one of claims 2 to 20, 37, or 38, or a pharmaceutically acceptable salt thereof.

40. R ２ is thiazolyl, pyridinyl, pyrimidinyl, indazolyl, pyrazolopyridinyl, or imidazopyridinyl, each of which is optionally substituted with 1 to 3 R ３ｄ groups, a compound according to any one of claims 2 to 20 or 37 to 39, or a pharmaceutically acceptable salt thereof.

41. R ２ is 【Chemical 21】 【Chemical 22】 The compound according to any one of claims 2 to 20 or 37 to 39, or a pharmaceutically acceptable salt thereof.

42. R ３ｄ is, independently for each occurrence, halo, -N(R Ｎ１ )(R Ｎ２ ), -C （１～６） alkyl, -C （１～６） haloalkyl, -C （３～１０） cycloalkyl, -OC （１～６） alkyl, -OC （１～６） haloalkyl, -C （１～３） alkyl-N(R Ｎ１ )(R Ｎ３ ), -C(O)N(R Ｎ１ )(R Ｎ４ ), -C （１～３） alkyl(3- to 8-membered heterocyclyl), a 3- to 8-membered heterocyclyl, or a 5- to 6-membered heteroaryl, where the 3- to 8-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with 1 to 5 groups selected from halo, -C （１～４） alkyl, -C （１～４） haloalkyl, -C （３～６） cycloalkyl, -OC （１～４） alkyl, -OC （１～４） haloalkyl, and -C （１～４） alkylOC （１～４） alkyl, the compound according to any one of claims 2 to 20 or 37 to 41, or a pharmaceutically acceptable salt thereof.

43. Each R ３ｄ is, independently at each occurrence, -N(R Ｎ１ )(R Ｎ２ ), -C （１～６） alkyl, -C （１～６） haloalkyl, -C （３～１０） cycloalkyl, -C(O)N(R Ｎ１ )(R Ｎ４ ), or 5- to 6-membered heteroaryl, where the 5- to 6-membered heteroaryl is optionally further substituted with 1 to 3 -C （１～４） alkyl groups, a compound according to any one of claims 2 to 20 or 37 to 42, or a pharmaceutically acceptable salt thereof.

44. R ２ is 【Chemical 23】 【Chemical 24】 【Chemical Formula 25】 【Chemical 26】 The compound according to any one of claims 1 to 20, 37 to 39, 41, or 42, or a pharmaceutically acceptable salt thereof.

45. R ２ is 【Chemical 27】 ​ 【Chemical 29】 The compound according to any one of claims 1 to 20, 37 to 39, 41, 42, or 44, or a pharmaceutically acceptable salt thereof.

46. R ２ is 【Chemical Formula 30】 The compound according to any one of claims 1 to 20 or 37 to 44, or a pharmaceutically acceptable salt thereof.

47. R ２ is 【Chemical 31】 The compound according to any one of claims 1 to 20 or 37 to 46, or a pharmaceutically acceptable salt thereof.

48. R Ｎ１ The compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

49. R Ｎ２ is hydrogen, a 4- to 6-membered heterocyclyl, or a 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally further substituted with 1 to 3 groups -C （１～４） alkyl group, the compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof.

50. R Ｎ４ is hydrogen, the compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof.

51. A compound of Formula If, 【Chemical 32】 wherein, A is isoxazolyl, Z is N or C-H, R ２ is a 5- to 10-membered heteroaryl, which is optionally substituted with 1 to 3 R ３ｄ groups, Each R ３ｄ is, independently at each occurrence, -N(R Ｎ１ )(R Ｎ２ ), -C （１～６） alkyl, -C （１～６） haloalkyl, -C （３～１０） cycloalkyl, -C(O)N(R Ｎ１ )(R Ｎ４ ), or a 5- to 6-membered heteroaryl, where the 5- to 6-membered heteroaryl is optionally further substituted with 1 to 3 -C （１～４） alkyl groups, R Ｎ１ is hydrogen, and R Ｎ２ is hydrogen, a 4- to 6-membered heterocyclyl, or a 5- to 6-membered heteroaryl, where the 5- to 6-membered heteroaryl is optionally further substituted with 1 to 3 -C （１～４） alkyl groups, R Ｎ４ is hydrogen, but However, when R ２ is pyrimidinyl, the pyrimidinyl is substituted with one -C(O)N(R Ｎ１ )(R Ｎ４ ) group and optionally further substituted with 1 to 2 R ３ｄ groups, the compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

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

53. 【Fig. 33】 The compound according to claim 52, or a pharmaceutically acceptable salt thereof, having a structure selected from the group consisting of.

54. The following structure: 【Chemical Formula 34】 The compound according to claim 53, or a pharmaceutically acceptable salt thereof, having.

55. The following structure: 【Chemical 35】 The compound according to claim 53, or a pharmaceutically acceptable salt thereof, having.

56. The following structure: 【Chemical Formula 36】 The compound according to claim 53, or a pharmaceutically acceptable salt thereof, having.

57. The following structure: 【Chemical 37】 The compound according to claim 53, or a pharmaceutically acceptable salt thereof, having.

58. The following structure: 【Chemical Formula 38】 The compound according to claim 53, or a pharmaceutically acceptable salt thereof, having.

59. The following structure: 【Chemical Formula 39】 The compound according to claim 53, or a pharmaceutically acceptable salt thereof, having.

60. The following structure: 【Chemical 40】 The compound according to claim 53, or a pharmaceutically acceptable salt thereof, having.

61. The following structure: 【Chemical 41】 The compound according to claim 53, or a pharmaceutically acceptable salt thereof, having.

62. The following structure: 【Chemical 42】 The compound according to claim 53, or a pharmaceutically acceptable salt thereof, having.

63. The following structure: 【Chemical 43】 The compound according to claim 53, or a pharmaceutically acceptable salt thereof, having.

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

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

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

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

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

69. The method according to claim 68, wherein the disease, disorder, or medical condition mediated by said NIK activity is selected from the group consisting of systemic lupus erythematosus ("SLE"), rheumatoid arthritis ("RA"), Sjögren's syndrome, lupus nephritis, inflammatory bowel disease ("IBD"), ANCA-associated vasculitis, myositis, IgG4-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.

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