Fluoroalkyl-oxadiazoles and uses thereof

Abstract

Provided herein are compounds identified as inhibitors of HDAC6 activity that can be used to treat a variety of diseases and disorders.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 064,516, filed August 12, 2020, U.S. Provisional Application No. 63 / 027,602, filed May 20, 2020, and U.S. Provisional Application No. 62 / 951,853, filed December 20, 2019, the contents of each of which are incorporated herein by reference in their entirety for all purposes. [Background technology]

[0002] Histone deacetylases (HDACs) are a class of enzymes that possess deacetylase activity with a wide range of genomic and non-genomic substrates. There are 11 zinc-dependent HDAC enzymes, classified based on sequence identity and catalytic activity.

[0003] Histone deacetylase inhibitors have been described and used in a variety of therapeutic applications, including oncology, neurodegeneration, autoimmune diseases, chemotherapy-induced peripheral neuropathy, and cardiac indications. However, many HDAC inhibitors are nonspecific (i.e., they inhibit the activity of multiple HDACs with more or less the same affinity). When administered to humans, these so-called pan-HDAC inhibitors (e.g., SAHA and Panabinostat) exhibit significant adverse effects, such as fatigue, nausea, diarrhea, and thrombocytopenia. Therefore, HDAC inhibitors that selectively target specific HDACs, such as HDAC6, are needed. Summary of the Invention [Means for solving the problem]

[0004] The present disclosure is directed to compounds that selectively inhibit HDAC6 activity and their use in the treatment of various diseases and disorders.For example, the present disclosure provides small molecules and compositions, as well as therapeutic compositions and the use of certain small molecule compounds.

[0005] In one aspect, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] , in the formula, R 1 is selected from the group consisting of: [Table 1] R a But, H, Halo, C 1~3 selected from the group consisting of alkyl, cycloalkyl, haloalkyl, and alkoxy; R 2 and R 3 are independently selected from the group consisting of H, halogen, alkoxy, haloalkyl, aryl, heteroaryl, alkyl, and cycloalkyl, each of which is optionally substituted, or R 2 and R 3 together with the atom to which they are attached form a cycloalkyl or heterocyclyl; R 4 and R 5 are independently H, -(SO2)R 2 , -(SO2)NR 2 R 3 , -(CO)R 2 , -(CONR 2 R 3 ), aryl, arylheteroaryl, alkylenearyl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, haloalkyl, and alkoxy, each of which is optionally substituted, or R 4 and R 5 together with the atom to which they are attached form a cycloalkyl or heterocyclyl, each of which is optionally substituted; and X 1 S, O, NH, and NR 6 and R 6is selected from the group consisting of C1-C6 alkyl, alkoxy, haloalkyl, cycloalkyl, and heterocyclyl; R 9 is selected from the group consisting of H, C1-C6 alkyl, haloalkyl, cycloalkyl, and heterocyclyl; Y is CR 2 , O, N, S, SO, and SO2, and when Y is O, S, SO, or SO2, R 5 does not exist, and R 4 and R 5 together with the atom to which they are attached form a cycloalkyl or heterocyclyl, Y is CR 2 or N, n is selected from 0, 1, and 2.

[0006] In some embodiments, the present disclosure provides a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof: [ka]

[0007] In some embodiments, the present disclosure provides a compound of formula (Ib) or a pharmaceutically acceptable salt thereof: [ka]

[0008] In some embodiments, the present disclosure provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof: [ka]

[0009] In another aspect, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: [ka] , in the formula, R1 is selected from the group consisting of: [Table 2] R a But, H, Halo, C 1~3 selected from the group consisting of alkyl, cycloalkyl, haloalkyl, and alkoxy; R 2 is H, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, haloalkyl, alkoxy, -(CH2) m Aryl, -(CH2) m N(R 3 ) aryl, -(CH2) m Oaryl, -(CH2) m (SO2)aryl, -(CH2) m Heteroaryl, -(CH2) m N(R 3 ) heteroaryl, -(CH2) m Heteroaryl, -(CH2) m Cycloalkyl, -(CH2) m Heterocyclyl, -(CH2) m (COOH), -(CH2) m (COOR 3 ), -(CH2) m (CONR 3 R 4 ), -(CH2) m (NR 3 SO2NR 3 R 4 ), and -(CH2) m (SO2R 3 ), each of which is optionally substituted; and m is selected from 1, 2, or 3; R 3 and R 4 are independently selected from the group consisting of H, aryl, heteroaryl, cycloalkyl, heterocyclyl, and alkyl, each of which is optionally substituted, or R 3 and R 4together with the atom to which they are attached form an optionally substituted heterocyclyl; X 1 , X 2 and X 3 are independently selected from C and N, with the proviso that X 1 and X 2 Both of these cannot be N.

[0010] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof: [ka] , in the formula, R 1 is selected from the group consisting of: [Table 3] R a But, H, Halo, C 1~3 selected from the group consisting of alkyl, cycloalkyl, haloalkyl, and alkoxy; R 2 and R 3 are independently selected from the group consisting of H, halogen, alkoxy, haloalkyl, aryl, heteroaryl, alkyl, and cycloalkyl, or R 2 and R 3 together with the atom to which they are attached form a cycloalkyl or heterocyclyl; R 4 and R 5 But H, -(SO2)R 2 , -(SO2)NR 2 R 3 , -(CO)R 2 , -(CONR 2 R 3 ), aryl, arylheteroaryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, haloalkyl, and alkoxy, or R 4 and R 5together with the atom to which they are attached form a cycloalkyl or heterocyclyl; X 1 , X 2 , and X 3 is (1)X 1 But, CR a and X 2 is N and X 3 But, CR a (2)X 1 is N and X 2 But, CR a and X 3 But, CR a (3)X 1 But, CR a and X 2 But, CR a and X 3 (4) X is N 1 is N and X 2 But, CR a and X 3 (5)X is N 1 But, CR a and X 2 is N and X 3 (6)X is N 1 is N and X 2 is N and X 3 But, CR a is selected from the group consisting of Y is CR 2 , O, N, S, SO, and SO2, and when Y is O, S, SO, or SO2, R 5 does not exist, and R 4 and R 5 together with the atom to which they are attached form a cycloalkyl or heterocyclyl, Y is CR 2 or N, n is 1 or 2.

[0011] In some embodiments, the present disclosure provides a compound of formula (IV) or a pharmaceutically acceptable salt thereof: [ka] , in the formula, R 1 is selected from the group consisting of: [Table 4] R a But, H, Halo, C 1~3 selected from the group consisting of alkyl, cycloalkyl, haloalkyl, and alkoxy; R 2 and R 3 are independently selected from the group consisting of H, halogen, alkoxy, haloalkyl, aryl, heteroaryl, alkyl, and cycloalkyl, each of which is optionally substituted, or R 2 and R 3 together with the atom to which they are attached form a cycloalkyl or heterocyclyl; R 4 and R 5 are independently H, -(SO2)R 2 , -(SO2)NR 2 R 3 , -(CO)R 2 , -(CONR 2 R 3 ), aryl, arylheteroaryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, haloalkyl, and alkoxy, each of which is optionally substituted, or R 4 and R 5 together with the atom to which they are attached form a cycloalkyl or heterocyclyl; X 1 O, S, NH, and NR 6 and R 6 is selected from the group consisting of C1-C6 alkyl, alkoxy, haloalkyl, cycloalkyl, and heterocyclyl; Y is CR 2 , O, N, S, SO, and SO2, and when Y is O, S, SO, or SO2, R 5does not exist, and R 4 and R 5 together with the atom to which they are attached form a cycloalkyl or heterocyclyl, Y is CR 2 or N, n is selected from 0, 1, or 2.

[0012] In some embodiments, the present disclosure provides a therapeutic approach for the treatment of diseases including, but not limited to, abnormal cell proliferative disorders, amyloid protein aggregation, polyglutamine protein aggregation, neurodegeneration, stroke, psychiatric disorders, depression, autoimmune diseases, inflammatory diseases (e.g., inflammatory bowel disorder or inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis (UC), glaucoma, psoriasis, pyoderma gangrenosum, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, osteoarthritis, sepsis, acute kidney injury, lung injury, solid organ ischemia-reperfusion injury), heart failure with preserved systolic function (HFpEF), inflammasome formation leading to cell death and inflammation, chemotherapy-induced neuropathy, Charcot-Marie-Tooth disease, idiopathic Methods of treatment are provided that include the use of the compounds disclosed herein (i.e., Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Id-1), Formula (Id-2), Formula (Id-3), Formula (Id-4), Formula (Ie), Formula (Ie-1), Formula (If), Formula (If-1), Formula (Ig), Formula (Ig-1), Formula (Ih), Formula (Ih-1), Formula (Ii), Formula (Ii-1), Formula (Ij), Formula (Ij-1), Formula (Ik), Formula (Ik-1), Formula (Ik-2), Formula (Ik-3), Formula (II), Formula (III), Formula (IVa), and Formula (IVb)) in the treatment of patients suffering from indications including pulmonary fibrosis, erectile dysfunction, hypertension, muscular dystrophy, and / or heart disease or disorders, and the like. Proliferative diseases include, but are not limited to, malignant glioma, breast cancer, basal cell carcinoma, medulloblastoma, neuroectodermal tumor, and ependymoma.The cardiac diseases or disorders that can be treated with the compounds of the present disclosure include, but are not limited to, coronary heart disease, cardiomyopathy, endocarditis, congenital cardiovascular abnormalities, congestive heart failure, dilated cardiomyopathy, hypertrophic cardiomyopathy, valvular heart disease, myocardial infarction, congestive heart failure, long QT syndrome, atrial arrhythmia, ventricular arrhythmia, diastolic heart failure, systolic heart failure, cardiac valve disease, cardiac valve calcification, left ventricular noncompaction, ventricular septal defect, and ischemia.

[0013] definition Although the following terms are believed to be well understood by those of ordinary skill in the art, the following definitions are provided to facilitate description of the subject matter of the present disclosure.

[0014] The term "a" or "an" refers to one or more of the entity, for example, "HDAC6 inhibitor" refers to one or more HDAC6 inhibitors or at least one HDAC6 inhibitor. Thus, the terms "a" (or "an"), "one or more" and "at least one" are used interchangeably herein. Furthermore, the reference to "inhibitor" by the indefinite article "a" or "an" does not exclude the possibility that two or more of the inhibitors may be present, unless the context clearly requires that only one of the inhibitor is present.

[0015] The term "pharmaceutically acceptable salts" includes those obtained by reacting an active compound that functions as a base with an inorganic or organic acid to form a salt, including, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts can be prepared by reacting a compound with the appropriate inorganic or organic acid via any of several known methods.

[0016] "Alkyl" or "alkyl group" refers to a fully saturated, straight or branched hydrocarbon chain having from 1 to 12 carbon atoms and attached to the rest of the molecule by a single bond. Alkyl groups containing any number of carbon atoms from 1 to 12 are included. Alkyl groups containing up to 12 carbon atoms include C1-C 12 Alkyl, containing up to 10 carbon atoms, is C1-C 10 An alkyl having up to 6 carbon atoms is a C1-C6 alkyl, and an alkyl having up to 5 carbon atoms is a C1-C5 alkyl. C1-C5 alkyl includes C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl includes all of the moieties described above for C1-C5 alkyl, but also includes C6 alkyl. C1-C 10Alkyl includes all of the moieties described above for C1-C5 alkyl and C1-C6 alkyl, but also includes C7, C8, C9 and C 10 Also includes alkyl. Similarly, C1-C 12 Alkyl includes all of the above moieties, but C 11 and C 12 Including alkyl. C1~C 12 Non-limiting examples of alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise in the specification, an alkyl group can be optionally substituted.

[0017] "Alkylene" or "alkylene chain" refers to a fully saturated, straight or branched divalent hydrocarbon chain radical having from 1 to 12 carbon atoms. 12 Non-limiting examples of alkylene include methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group (e.g., one described herein) through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise in the specification, an alkylene chain can be optionally substituted.

[0018] "Alkenyl" or "alkenyl group" refers to a straight or branched hydrocarbon chain having 2 to 12 carbon atoms and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl groups containing any number of carbon atoms from 2 to 12 are included. Alkenyl groups containing up to 12 carbon atoms include C2-C 12 Alkenyl, containing up to 10 carbon atoms, is C2-C 10An alkenyl group containing up to 6 carbon atoms is a C2-C6 alkenyl, and an alkenyl containing up to 5 carbon atoms is a C2-C5 alkenyl. C2-C5 alkenyl includes C5 alkenyl, C4 alkenyl, C3 alkenyl, and C2 alkenyl. C2-C6 alkenyl includes all of the moieties listed above for C2-C5 alkenyl, but also includes C6 alkenyl. C2-C 10 Alkenyl includes all of the moieties listed above for C2-C5 alkenyl and C2-C6 alkenyl, but also includes C7, C8, C9 and C 10 Alkenyl is also included. Similarly, C2-C 12 Alkenyl includes all of the above moieties, but C 11 and C 12 Includes alkenyl. C2-C 12 Non-limiting examples of alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, Examples include 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Unless stated otherwise in the specification, an alkyl group may be optionally substituted.

[0019] "Alkenylene" or "alkenylene chain" refers to an unsaturated, linear or branched divalent hydrocarbon chain radical having one or more olefins and having 2 to 12 carbon atoms. 12 Non-limiting examples of alkenylene include ethenylene, propenylene, n-butenylene, etc. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group (e.g., one described herein) through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise herein, an alkenylene chain can be optionally substituted.

[0020] "Alkynyl" or "alkynyl group" refers to a straight or branched hydrocarbon chain having from 2 to 12 carbon atoms and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl groups containing any number of carbon atoms from 2 to 12 are included. Alkynyl groups containing up to 12 carbon atoms include C2-C 12 Alkynyl, containing up to 10 carbon atoms, is C2-C 10 An alkynyl group containing up to 6 carbon atoms is C2-C6 alkynyl, and an alkynyl containing up to 5 carbon atoms is C2-C5 alkynyl. C2-C5 alkynyl includes C5 alkynyl, C4 alkynyl, C3 alkynyl, and C2 alkynyl. C2-C6 alkynyl includes all of the moieties listed above for C2-C5 alkynyl, but also includes C6 alkynyl. C2-C 10 Alkynyl includes all of the moieties listed above for C2-C5 alkynyl and C2-C6 alkynyl, but also includes C7, C8, C9 and C 10 Alkynyl is also included. Similarly, C2-C 12 Alkynyl includes all of the above moieties, but C 11 and C 12 Alkynyl is included. C2-C 12Non-limiting examples of alkenyl include ethynyl, propynyl, butynyl, pentynyl, etc. Unless stated otherwise in the specification, an alkyl group can be optionally substituted.

[0021] "Alkynylene" or "alkynylene chain" refers to an unsaturated, linear or branched divalent hydrocarbon chain radical having one or more alkynes and having 2 to 12 carbon atoms. 12 Non-limiting examples of alkynylene include ethynylene, propynylene, n-butynylene, etc. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group (e.g., one described herein) through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through any two carbons in the chain having suitable valences. Unless stated otherwise herein, the alkynylene chain can be optionally substituted.

[0022] "Alkoxy" means a group of the formula -OR a where R a is an alkyl, alkenyl, or alkynyl, as defined above, containing 1 to 12 carbon atoms. Unless stated otherwise in the specification, an alkoxy group can be optionally substituted.

[0023] "Aryl" refers to a hydrocarbon ring system containing hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring, attached to the rest of the molecule by a single bond. For purposes of this disclosure, aryl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, including fused or bridged ring systems. Aryls include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified herein, aryl may be optionally substituted.

[0024] "Carbocyclyl," "carbocyclic ring," or "carbocycle" refers to a ring structure in which each atom forming the ring is carbon and is attached to the rest of the molecule by a single bond. A carbocyclic ring can contain from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryl and cycloalkyl, cycloalkenyl, and cycloalkynyl as defined herein. Unless otherwise stated in the specification, a carbocyclyl group can be optionally substituted.

[0025] A "carbocyclylalkyl" is a group of the formula -R b -R d where R b is an alkylene, alkenylene, or alkynylene group as defined above, and R d is a carbocyclyl radical as defined above. Unless stated otherwise in the specification, a carbocyclylalkyl group may be optionally substituted.

[0026] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon (which may include fused or bridged ring systems) composed solely of carbon and hydrogen atoms, having 3 to 20 carbon atoms (e.g., 3 to 10 carbon atoms), and attached to the rest of the molecule by a single bond. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise specified in the specification, cycloalkyl groups can be optionally substituted.

[0027] "Cycloalkenyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon (which may include fused or bridged ring systems) composed solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, and having 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, attached to the remainder of the molecule by a single bond. Monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like. Polycyclic cycloalkenyls include, for example, bicyclo[2.2.1]hept-2-enyl, and the like. Unless otherwise specified in the specification, cycloalkenyl groups can be optionally substituted.

[0028] "Cycloalkynyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon (which may include fused or bridged ring systems) composed solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, and having 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, attached to the rest of the molecule by a single bond. Monocyclic cycloalkynyls include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise specified in the specification, cycloalkynyl groups can be optionally substituted.

[0029] "Haloalkyl" refers to alkyl, as defined above, substituted by one or more halo radicals, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise in the specification, a haloalkyl group can be optionally substituted.

[0030] "Heterocyclyl," "heterocyclic ring," or "heterocycle" refers to a stable saturated, unsaturated, or aromatic 3- to 20-membered ring, composed of 2 to 19 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, which is attached to the remainder of the molecule by a single bond. Heterocyclyl or heterocyclic ring includes heteroaryl, heterocyclylalkyl, heterocyclylalkenyl, and heterocyclylalkynyl. Unless otherwise stated in the specification, a heterocyclyl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems, and in which the nitrogen, carbon, or sulfur atoms in the heterocyclyl can be optionally oxidized, the nitrogen atom can be optionally quaternized, and the heterocyclyl can be partially or fully saturated. Examples of such heterocyclyls include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise in the specification, heterocyclyl groups may be optionally substituted.

[0031] "Heteroaryl" refers to a 5- to 20-membered ring system containing a hydrogen atom, 1 to 19 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, at least one aromatic ring, and attached to the remainder of the molecule by a single bond. For purposes of this disclosure, heteroaryl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems, and in which the nitrogen, carbon, or sulfur atoms in the heteroaryl may be optionally oxidized, and the nitrogen atom may be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indole, benzo[4,6]imidazo[1,2-a]pyridinyl ... including dazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise in the specification, a heteroaryl group may be optionally substituted.

[0032] "Heterocyclylalkyl" refers to a group of the formula -R b -R e where R b is an alkylene, alkenylene, or alkynylene group as defined above, and R e is a heterocyclyl radical as defined above. Unless stated otherwise in the specification, a heterocyclylalkyl group may be optionally substituted.

[0033] The term "substituted," as used herein, refers to any group described herein (e.g., alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, heterocyclyl, and / or heteroaryl) in which at least one hydrogen atom has been replaced by a bond to a non-hydrogen atom, for example, but not limited to, a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl, alkoxy, and ester groups; a sulfur atom in groups such as thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups; a nitrogen atom in groups such as amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide, and enamine; a silicon atom in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups, and other heteroatoms in various other groups. "Substituted" also refers to any of the above groups in which one or more hydrogen atoms are replaced by a higher order bond (e.g., a double or triple bond) to a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups, and nitrogen in groups such as imine, oxime, hydrazone, and nitrile. For example, "substituted" refers to any group in which one or more hydrogen atoms are replaced by a heteroatom such as -NR g R h , -NR g C(=O)R h , -NRg C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h , -OC(=O)NR g R h , -OR g , -SR g , -SOR g , -SO2R g , -OSO2R g , -SO2OR g , =NSO2R g , and -SO2NR g R h "Substituted" also includes any of the above groups substituted by -C(=O)R g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , -CH2SO2NR g R h In the above, R g and R hare the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substituted" further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl group. In addition, each of the foregoing substituents may be optionally substituted with one or more of the above substituents.

[0034] As used herein, the symbols [ka] (hereinafter may be referred to as a "point of attachment bond") refers to a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond. For example, [ka] indicates that a chemical entity "XY" is attached to another chemical entity via a point-of-attachment bond. Furthermore, specific points of attachment to undepicted chemical entities can be identified by inference. For example, R 3 is H or [ka] The compound CH3-R 3is R 3 If is "XY", the attachment point bond is R 3 is assumed to be the same bond depicted as being attached to CH3. DETAILED DESCRIPTION OF THE INVENTION

[0035] Histone deacetylases ("HDACs") are a class of enzymes that possess deacetylase activity with a wide range of genomic and non-genomic substrates. There are 11 zinc-dependent HDAC enzymes, classified based on sequence identity and catalytic activity (Haberland et al., 2009).

[0036] Histone deacetylase inhibitors have been described as therapeutic agents in oncology (Yoon and Eom, 2016), neurodegenerative (Butler et al., 2010), autoimmune diseases (Choi et al., 2018), chemotherapy-induced peripheral neuropathy (Krukowski et al., 2017), and cardiac indications (Zhang et al., 2002). Given the role of nuclear HDACs in regulating gene transcription, inhibition of these target classes is known to have pleiotropic effects in various cell types, most notably resulting in cytotoxicity. Therefore, limiting the toxicity of pan-HDAC inhibitors represents a major obstacle to the widespread use of this compound class. Furthermore, significant adverse effects of pan-HDAC inhibitors (e.g., SAHA and Panabinostat) have been observed in the clinic, including fatigue, nausea, diarrhea, and thrombocytopenia (Subramanian et al., 2010).

[0037] In cardiac indications, most studies have utilized pan-HDAC inhibitors (e.g., SAHA, TSA, and givinostat) to treat pressure overload rodent models, including transcatheter aortic arch coarctation (TAC) (Cao et al., 2011), hypertension in Dahl salt-sensitive rats (Jeong et al., 2018), and myocardial infarction (Nagata et al., 2019). Additionally, HDAC6-selective inhibitors have been used to ameliorate the effects of pressure overload in rodent models (Demos-Davies et al., 2014) and provide protection against proteotoxicity in a transgenic mouse model of cardiomyopathy (McLendon et al., 2014).

[0038] HDAC6 belongs to the class IIb enzymes and contains two catalytic domains, a ubiquitin-binding domain, and a cytoplasmic retention domain (Haberland et al., 2009). HDAC6 is primarily a cytoplasmic enzyme, and its best-characterized substrates include tubulin, HSP90, and cortactin (Brindisi et al., 2019).

[0039] Pharmacological inhibition of HDAC6 blocks its deacetylase activity, resulting in hyperacetylation of its substrates, particularly tubulin (Hubbert et al., 2002).

[0040] HDAC6-selective inhibitors are known to have reduced cytotoxicity due to the cytoplasmic nature of HDAC6 substrates, and reduced effects on nuclear targets (including H3K9 and c-MYC) and global transcription ( Nebbioso et al., 2017 ).

[0041] Hydroxamic acids are zinc chelators that have been widely used in the development of pan- and selective HDAC inhibitors. However, most hydroxamic acid-based HDAC inhibitors lack the desired selectivity or exhibit poor pharmacokinetic profiles and poor bioavailability (Butler et al., 2010; Santo et al., 2012).

[0042] In some embodiments, the present disclosure provides compounds that selectively inhibit HDAC6. In some embodiments, the selectivity ratio of HDAC6 over HDAC1 is about 5 to about 30,0000, e.g., about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 1000, about 2000, about 3000, about 4000, about 5000, about 6000, about 7000, about 8000, about 9000, about 10,000, about 15,000, about 20,000, about 25,000, or about 30,000, including all values ​​and ranges therebetween.

[0043] Compounds of the Disclosure In one aspect, the disclosure provides a compound of formula (A) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, [ka] is selected from the group consisting of: [Table 5] R 1 is selected from the group consisting of: [Table 6] R 2 and R 3 are independently selected from the group consisting of H, halogen, alkoxy, haloalkyl, aryl, heteroaryl, alkyl, and cycloalkyl, each of which is optionally substituted, or R 2 and R 3 together with the atom to which they are attached form a cycloalkyl or heterocyclyl; R 4 and R 5 are independently H, -(SO2)R 2 , -(SO2)NR2 R 3 , -(CO)R 2 , -(CONR 2 R 3 ), aryl, arylheteroaryl, alkylenearyl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, haloalkyl, and alkoxy, each of which is optionally substituted, or R 4 and R 5 together with the atom to which they are attached form a cycloalkyl or heterocyclyl, each of which is optionally substituted; R 9 is selected from the group consisting of H, C1-C6 alkyl, haloalkyl, cycloalkyl, and heterocyclyl; [ka] but, [ka] If X 1 are S, O, NH, and NR 6 and R 6 is selected from the group consisting of C1-C6 alkyl, alkoxy, haloalkyl, cycloalkyl, and heterocyclyl; [ka] but, [ka] If X 1 , X 2 and X 3 are independently selected from C and N, with the proviso that X 1 and X 2 Both of these cannot be N, [ka] but, [ka] If X 1 , X 2 , and X 3 is (1)X 1 is CH and X 2 is N and X 3 is CH, (2)X 1 is N and X 2 is CH and X 3 is CH, (3)X 1 is CH and X 2 is CH and X 3 (4) X is N 1 is N and X 2 is CH and X 3 (5)X is N 1 is CH and X 2 is N and X 3 (6)X is N 1 is N and X 2 is N and X 3 is CH; R a But, H, Halo, C 1~3 selected from the group consisting of alkyl, cycloalkyl, haloalkyl, and alkoxy; Y is CR 2 , O, N, S, SO, and SO2, and when Y is O, S, SO, or SO2, R 5 does not exist, and R 4 and R 5 together with the atom to which they are attached form a cycloalkyl or heterocyclyl, Y is CR 2 or N, n is selected from 0, 1, and 2.

[0044] In some embodiments, the compound of Formula (A) is selected from the group consisting of: [Table 7]

[0045] Compounds of formula (I) In one aspect, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] , in the formula, R 1 is selected from the group consisting of: [Table 8] R a But, H, Halo, C 1~3 selected from the group consisting of alkyl, cycloalkyl, haloalkyl, and alkoxy; R 2 and R 3 are independently selected from the group consisting of H, halogen, alkoxy, haloalkyl, aryl, heteroaryl, alkyl, and cycloalkyl, each of which is optionally substituted, or R 2 and R 3 together with the atom to which they are attached form a cycloalkyl or heterocyclyl; R 4 and R 5 are independently H, -(SO2)R 2 , -(SO2)NR 2 R 3 , -(CO)R 2 , -(CONR 2 R 3 ), aryl, arylheteroaryl, heteroaryl, alkylenearyl, cycloalkyl, heterocyclyl, alkyl, haloalkyl, and alkoxy, each of which is optionally substituted, or R 4 and R 5 together with the atom to which they are attached form a cycloalkyl or heterocyclyl, each of which is optionally substituted; R 9 is selected from the group consisting of H, C1-C6 alkyl, haloalkyl, cycloalkyl, and heterocyclyl; X 1 S, O, NH, and NR 6 and R 6 is selected from the group consisting of C1-C6 alkyl, alkoxy, haloalkyl, cycloalkyl, and heterocyclyl; Y is CR 2 , O, N, S, SO, and SO2, and when Y is O, S, SO, or SO2, R 5 does not exist, and R 4 and R 5 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl, Y is 2 or N, n is selected from 0, 1, and 2.

[0046] In some embodiments of Formula (I), n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 0 or 2.

[0047] In some embodiments of Formula (I), X 1 is O. In some embodiments, X 1 is S. In some embodiments, X 1 is NH. In some embodiments, X 1 But NR 6 In some embodiments, X 1 S, O, and NR 6 In some embodiments, X is selected from the group consisting of 1 is selected from the group consisting of S, O, and NCH3. 1 is S or O, and in some embodiments, X 1 But S or NR 6 In some embodiments, R 6is a C1-C6 alkyl.

[0048] In some embodiments of Formula (I), R 2 and R 3 But it's H.

[0049] In some embodiments of Formula (I), Y is N, CR 2 In some embodiments, Y is N or O. In some embodiments, Y is N. In some embodiments, Y is CR 2 In some embodiments, Y is O.

[0050] In some embodiments, R 4 and R 5 are independently H, -(SO2)R 2 , -(SO2)NR 2 R 3 , -(CO)R 2 , -(CONR 2 R 3 ), aryl, arylheteroaryl, heteroaryl, alkylenearyl, cycloalkyl, alkylenecycloalkyl, heterocyclyl, alkyleneheterocyclyl, alkyl, haloalkyl, and alkoxy, each of which is optionally substituted, or R 4 and R 5 together with the atom to which they are attached form a cycloalkyl or heterocyclyl, each of which is optionally substituted

[0051] In some embodiments of Formula (I), R 4 is -C(O)-alkyl, -C(O)-cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -(SO2)NR 2 R 3 , —SO2-alkyl, and —SO2-cycloalkyl, each of which is optionally substituted. In some embodiments, R 4is -C(O)-alkyl, -C(O)-cycloalkyl, -SO2-alkyl, -SO2-haloalkyl, -SO2-cycloalkyl, and -(SO2)NR 2 R 3 and R is selected from the group consisting of: 4 is selected from the group consisting of -SO2 alkyl, -SO2 haloalkyl, or -SO2 cycloalkyl. In some embodiments of Formula (I), R 4 is selected from the group consisting of -SOMe, -SOEt, and -SO-cPr. In some embodiments of Formula (I), R 4 is -SOMe or -SOEt. In some embodiments, R 2 and R 3 are each independently, -C 1~5 In some embodiments, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl. In some embodiments, the optionally substituted heterocyclyl is morpholine, thiomorpholine, or thiomorpholine 1,1-dioxide.

[0052] In some embodiments of Formula (I), R 5 is aryl, heteroaryl, or cycloalkyl, each of which is optionally substituted.

[0053] In some embodiments, R 5 is aryl. In some embodiments, aryl is [ka] and R bis one or more selected from the group consisting of halogen, haloalkyl, alkyl, Oalkyl, Ohaloalkyl, alkylene-Ohaloalkyl, cycloalkyl, heterocyclyl aryl, heteroaryl, alkylnitrile, or CN. In some embodiments, haloalkyl is selected from CF, CFCH, CHF, or CHF. In some embodiments, alkyl is selected from -C 1~5 In some embodiments, -C is alkyl. 1~5 In some embodiments, the alkyl is methyl, ethyl, propyl, i-propyl, butyl, or t-butyl. In some embodiments, the methyl, ethyl, propyl, i-propyl, butyl, or t-butyl is optionally substituted with OH. In some embodiments, the cycloalkyl is C 3~6 In some embodiments, the O-haloalkyl is selected from OCF3, OCHF2, or OCH2F. In some embodiments, the O-alkyl is O-methyl, O-ethyl, O-propyl, Oi-propyl, O-butyl, or Ot-butyl.

[0054] In some embodiments, R 5is heteroaryl. In some embodiments, the heteroaryl is an optionally substituted 5-14 membered heteroaryl. In some embodiments, the heteroaryl is an optionally substituted 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, the optionally substituted 5-14 membered heteroaryl is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, indolizinyl, azaindolyl, indolyl, azaindolyl, benzoxazolyl, benzthiazolyl, benzfuranyl, benzthiophenyl, imidazopyridinyl, imidazopyrazinyl, and benzimidazolyl. In some embodiments, the optionally substituted 5-14 membered heteroaryl is selected from the group consisting of pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, imidazopyridinyl, and imidazopyrazinyl. 5 but, [ka] where R b is one or more selected from the group consisting of halogen, haloalkyl, alkyl, Oalkyl, Ohaloalkyl, alkylene-Ohaloalkyl, cycloalkyl, heterocyclyl aryl, heteroaryl, alkylnitrile, or CN. In some embodiments, haloalkyl is selected from CF, CFCH, CHF, or CHF. In some embodiments, alkyl is selected from -C 1~5 In some embodiments, -C is alkyl. 1~5 In some embodiments, the alkyl is methyl, ethyl, propyl, i-propyl, butyl, or t-butyl. In some embodiments, the methyl, ethyl, propyl, i-propyl, butyl, or t-butyl is optionally substituted with OH. In some embodiments, the cycloalkyl is C 3~6In some embodiments, the O-haloalkyl is selected from OCF3, OCHF2, or OCH2F. In some embodiments, the O-alkyl is O-methyl, O-ethyl, O-propyl, Oi-propyl, O-butyl, or Ot-butyl.

[0055] In some embodiments, R 5 is cycloalkyl. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted. In some embodiments, optionally substituted cycloalkyl is [ka] is.

[0056] In some embodiments, R 5 is selected from the group consisting of phenyl, 3-chlorophenyl, 3-chloro-4-fluorophenyl, 3-trifluoromethylphenyl, 3,4-difluorophenyl, and 2,6-difluorophenyl. 5 is cyclopropyl. In some embodiments, R 5 is selected from the group consisting of pyridin-3-yl and 1-methylindazol-6-yl. 5is selected from the group consisting of H, phenyl, 3-chlorophenyl, 3-chloro-4-fluorophenyl, 3-trifluoromethylphenyl, 3,4-difluorophenyl, cyclopropyl, pyridin-3-yl, 1-methylindazol-6-yl, 3,3-difluorocyclobutyl, and 4,4-difluorocyclohexyl. 5 is 3-chlorophenyl. In some embodiments, R 5 is H. In some embodiments, R 5 but, [ka] In some embodiments, R 5 is -CH2CH2Ph. In some embodiments, R 5 is selected from the group consisting of H, aryl, heteroaryl, alkylenearyl, cycloalkyl, heterocyclyl, alkyl, and haloalkyl, each of which is optionally substituted, or R 4 and R 5 together with the atom to which they are attached form an optionally substituted heterocyclyl.

[0057] In some embodiments of Formula (I), R 5 is optionally substituted with one or more halogen, haloalkyl, alkyl, Oalkyl, Ohaloalkyl, cycloalkyl, heterocyclyl aryl, or heteroaryl. In some embodiments, haloalkyl is selected from CF, CHF, or CHF. In some embodiments, alkyl is selected from -C 1~5 In some embodiments, -C is alkyl. 1~5 In some embodiments, the alkyl is methyl, ethyl, propyl, i-propyl, butyl, or t-butyl. 3~6In some embodiments, the O-haloalkyl is selected from OCF3, OCHF2, or OCH2F. In some embodiments, the O-alkyl is O-methyl, O-ethyl, O-propyl, Oi-propyl, O-butyl, or Ot-butyl.

[0058] In some embodiments of Formula (I), R 4 But H or -C 1~5 alkyl, and R 5 is aryl. In some embodiments, R 4 But H or -C 1~5 alkyl, and R 5 is heteroaryl. In some embodiments, R 4 But H or -C 1~5 alkyl, and R 5 is cycloalkyl. In some embodiments, -C 1~5 In some embodiments, the alkyl is methyl, ethyl, or propyl. 1~5The alkyl is methyl. In some embodiments, the aryl is an optionally substituted phenyl. In some embodiments, the heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, the optionally substituted 5-14 membered heteroaryl is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, indolizinyl, azaindolyl, indolyl, azaindolyl, benzoxazolyl, benzthiazolyl, benzfuranyl, benzthiophenyl, imidazopyridinyl, imidazopyrazinyl, and benzimidazolyl. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl ring. In some embodiments, the 5-membered heteroaryl is an optionally substituted pyrazolyl, imidazolyl, or oxazolyl. In some embodiments, the 6-membered heteroaryl is an optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, the cycloalkyl is an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the aryl is selected from the group consisting of halogen, C 1~6 Haloalkyl, C 1~6 Alkyl, OC 1~6 Alkyl, OC 1~6 In some embodiments, heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, or C cycloalkyl. 1~6 Haloalkyl, C 1~6 Alkyl, OC 1~6 Alkyl, OC 1~6 Optionally substituted with one or more substituents selected from the group consisting of haloalkyl, or C3-6 cycloalkyl.

[0059] In some embodiments of Formula (I), R 4 But -(CO)R2 and R 5 is aryl. In some embodiments, R 4 But -(CO)R 2 and R 5 is heteroaryl. In some embodiments, R 4 But -(CO)R 2 and R 5 is cycloalkyl. In some embodiments, aryl is optionally substituted phenyl. In some embodiments, aryl is optionally substituted phenyl. In some embodiments, heteroaryl is 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, the optionally substituted 5-14 membered heteroaryl is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, indolizinyl, azaindolyl, indolyl, azaindolyl, benzoxazolyl, benzthiazolyl, benzfuranyl, benzthiophenyl, imidazopyridinyl, imidazopyrazinyl, and benzimidazolyl. In some embodiments, heteroaryl is a 5-6 membered heteroaryl ring. In some embodiments, the 5-membered heteroaryl is an optionally substituted pyrazolyl, imidazolyl, or oxazolyl; in some embodiments, the 6-membered heteroaryl is an optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, the cycloalkyl is an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the aryl is selected from the group consisting of halogen, C 1~6 Haloalkyl, C 1~6 Alkyl, OC 1~6 Alkyl, OC 1~6 In some embodiments, heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, or C cycloalkyl.1~6 Haloalkyl, C 1~6 Alkyl, OC 1~6 Alkyl, OC 1~6 Optionally substituted with one or more substituents selected from the group consisting of haloalkyl, or C3-6 cycloalkyl.

[0060] In some embodiments of Formula (I), R 4 But -(SO2)R 2 and R 5 is aryl. In some embodiments, R 4 But -(SO2)R 2 and R 5 is heteroaryl. In some embodiments, R 4 But -(SO2)R 2 and R 5is cycloalkyl. In some embodiments, aryl is optionally substituted phenyl. In some embodiments, heteroaryl is 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, the optionally substituted 5-14 membered heteroaryl is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, indolizinyl, azaindolizinyl, indolyl, azaindolyl, benzoxazolyl, benzthiazolyl, benzfuranyl, benzthiophenyl, imidazopyridinyl, imidazopyrazinyl, and benzimidazolyl. In some embodiments, heteroaryl is a 5-6 membered heteroaryl ring. In some embodiments, the 5-membered heteroaryl is an optionally substituted pyrazolyl, imidazolyl, or oxazolyl. In some embodiments, the 6-membered heteroaryl is an optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, the cycloalkyl is an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the aryl is selected from the group consisting of halogen, C 1~6 Haloalkyl, C 1~6 Alkyl, OC 1~6 Alkyl, OC 1~6 In some embodiments, heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, or C cycloalkyl. 1~6 Haloalkyl, C 1~6 Alkyl, OC 1~6 Alkyl, OC 1~6 and optionally substituted with one or more substituents selected from the group consisting of haloalkyl, C3-6 cycloalkyl, and C6 cycloalkyl. 1~6 Haloalkyl is CF, CHF, or CHF. In some embodiments, OC 1~6In some embodiments, the cycloalkyl is selected from the group consisting of halogen, C 1~6 Alkyl, or OC 1~6 Optionally substituted with alkyl.

[0061] In some embodiments of Formula (I), R 4 and R 5 together with the atom to which they are attached form a cycloalkyl or heterocyclyl. In some embodiments, R 4 and R 5 taken together with the atom to which they are attached form a cycloalkyl or heterocyclyl, each of which is optionally substituted. In some embodiments, the cycloalkyl or heterocyclyl is optionally substituted with -NS(O2)(alkyl)(aryl). In some embodiments, the alkyl is C 1~5 In some embodiments, the heterocyclyl is a 4- to 10-membered heterocyclyl, and in some embodiments, the heterocyclyl is a saturated 4- to 7-membered heterocyclyl.

[0062] In some embodiments of Formula (I), n is 0 and R 4 and R 5 together with the atoms to which they are bonded, [ka] In some embodiments, the optionally substituted heterocyclyl is selected from the group consisting of: [ka] In some embodiments, the optionally substituted heterocyclyl is [ka] In some embodiments, the optionally substituted heterocyclyl is [ka] In some embodiments, the optionally substituted heterocyclyl is [ka] wherein U is O or CH. In some embodiments, the optional substituent is an alkyl group. In some embodiments, the optional substituent is an aryl group.

[0063] In some embodiments of Formula (I), R 1 but, [ka] is selected from the group consisting of:

[0064] In some embodiments of Formula (I), R 1 but, [ka] In some embodiments, R 1 but, [ka] In some embodiments, R 1 but, [ka] In some embodiments, R 1 but, [ka] .

[0065] In some embodiments of Formula (I), R a But, H, Halo, C 1~3alkyl, or haloalkyl. In some embodiments, R a is H. In some embodiments, R a But C 1~3 In some embodiments, R a is haloalkyl. In some embodiments, halo is F. In some embodiments, C 1~3 Alkyl Alkyl is methyl, ethyl, or isopropyl. In some embodiments, haloalkyl is CF, CHF, or CHF.

[0066] In some embodiments of Formula (I), Y is CH and R 4 and R 5 But it's H.

[0067] In some embodiments of Formula (I), Y is N and R 4 is H and R 5 is ethyl optionally substituted with —N(S(O2)alkyl)(aryl) or —N(S(O2)cycloalkyl)(aryl). In some embodiments, alkyl is 1~5 alkyl and cycloalkyl is C 3~6 cycloalkyl and aryl is phenyl optionally substituted with one or more halogen atoms.

[0068] In some embodiments of Formula (I), n is 1 and X 1 is O or N, Y is N, and R 1 but, [ka] and R 2 and R 3 is H and R 4 But, H, -C 1~5 Alkyl, -C(O)alkyl, -C(O)cycloalkyl, -(SO2)NR 2 R 3, -SO2 alkyl, -SO2 haloalkyl, and -SO2 cycloalkyl, each of which is optionally substituted; R 5 is aryl, heteroaryl, or cycloalkyl, each of which is optionally substituted.

[0069] In some embodiments of Formula (I), n is 1 and X 1 is O or N, Y is O, and R 1 but, [ka] and R 2 and R 3 is H and R 5 is aryl, heteroaryl, cycloalkyl, or alkylenecycloalkyl, each of which is optionally substituted.

[0070] In some embodiments of Formula (I), n is 0 and X 1 is O or N, Y is N, and R 1 but, [ka] and R 4 and R 5 together with the atom to which they are attached form a cycloalkyl or heterocyclyl, each of which is optionally substituted.

[0071] In some embodiments, the present disclosure provides a compound of formula (Ia) or a pharmaceutically acceptable salt thereof: [ka] , in the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R a , X 1, n, and Y are as defined above for formula (I).

[0072] In some embodiments of Formula (Ia), R 1 but, [ka] where n is 1, Y is N, and X 1 is S or O, and the variable R 2 , R 3 , R 4 , R 5 , and R a is as defined above for formula (I).

[0073] In some embodiments of Formula (Ia), n is 1 and X 1 is S, Y is N, and R 1 but, [ka] and R 2 and R 3 is H and R 4 is -SO2 alkyl, -SO2 haloalkyl, or -SO2 cycloalkyl, each of which is optionally substituted; R 5 is heteroaryl, each of which is optionally substituted; R a is H or F. In some further embodiments, R 4 But, -SO2C 1~5 alkyl, -SO2cyclopropyl, -SO2CF3, or -SO2CHF2, and the heteroaryl is optionally substituted pyridine or pyrazine. In some embodiments, the heteroaryl is optionally substituted pyridine.

[0074] In some embodiments of Formula (Ia), n is 1 and X 1 is S, Y is N, and R 1 but, [ka] and R 2 and R 3 is H and R 4 is -SOMe, -SOEt, or -SOcyclopropyl, each of which is optionally substituted; R 5 is pyridine or pyrazine, each of which is optionally substituted; R a is H. In some embodiments, R 5 is an optionally substituted pyridine.

[0075] In some embodiments of Formula (Ia), n is 1 and X 1 is S, Y is N, and R 1 but, [ka] and R 2 and R 3 is H and R 4 is -SO2 alkyl or -SO2 cycloalkyl, each of which is optionally substituted; R 5 but, [ka] and R b But halogen, -C 1~5 Alkyl, haloalkyl, -OC 1~5 is selected from the group consisting of alkyl, -OHaloalkyl, -CHOHaloalkyl, cyclopropyl, and CN; a is H. In some embodiments, halogen is F or Cl. In some embodiments, haloalkyl is CF3, CHF2, CH2CF3, or CF2CH3. In some embodiments, -C 1~5 The alkyl is methyl.

[0076] In some embodiments of Formula (Ia), n is 1 and X 1 is S, Y is N, and R 1but, [ka] and R 2 and R 3 is H and R 4 is -SOMe, -SOEt, or -SOcyclopropyl, each of which is optionally substituted; R 5 but, [ka] and R b But halogen, -C 1~5 Alkyl, haloalkyl, -OC 1~5 is selected from the group consisting of alkyl, -OHaloalkyl, -CHOHaloalkyl, cyclopropyl, or CN; a is H. In some embodiments, halogen is F or Cl. In some embodiments, haloalkyl is CF3, CHF2, CH2CF3, or CF2CH3. In some embodiments, -C 1~5 The alkyl is methyl.

[0077] In some embodiments of Formula (Ia), n is 1 and X 1 is S, Y is N, and R 1 but, [ka] and R 2 and R 3 is H and R 4 is -SOMe, -SOEt, or -SOcyclopropyl, each of which is optionally substituted; R 5 but, [ka] and R b is selected from the group consisting of Cl, F, Me, cyclopropyl, CF, CHF, CFCH, OCF, OCHF, OCHCFH, and CN; R aBut it's H.

[0078] In some embodiments, the present disclosure provides a compound of formula (Ib) or a pharmaceutically acceptable salt thereof: [ka] , in the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R a , X 1 , n, and Y are as defined above for formula (I).

[0079] In some embodiments of Formula (I)-(Ib), each optionally substituted alkyl independently represents an optionally substituted C 1~6 In some embodiments, C 1~6 Alkyl is Me or Et.

[0080] In some embodiments of Formulas (I)-(Ib), each optionally substituted haloalkyl independently represents an optionally substituted C 1~6 In some embodiments, C is haloalkyl. 1~6 Haloalkyl is CF, CHF, or CHF. In some embodiments, C 1~6 Haloalkyl is CF3 or CHF2.

[0081] In some embodiments of Formula (I)-(Ib), each optionally substituted cycloalkyl independently represents an optionally substituted C 3~12 In some embodiments, cycloalkyl is C 3~6 In some embodiments, cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0082] In some embodiments of Formulas (I)-(Ib), each optionally substituted heterocyclyl is independently an optionally substituted 3- to 12-membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, each optionally substituted heterocyclyl is independently an optionally substituted 3- to 6-membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, and S. In further embodiments, the heterocycloalkyl is an optionally substituted 5- or 6-membered heterocycle having 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, the heterocyclyl is selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl and thiomorpholinyl.

[0083] In some embodiments of Formula (I)-(Ib), each optionally substituted aryl is independently C 6~12 In a further embodiment, C 6~12 Aryl is optionally substituted phenyl.

[0084] In some embodiments of Formulas (I)-(Ib), each optionally substituted heteroaryl is independently a 5-12 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, each optionally substituted heteroaryl is independently a 5-12 membered heteroaryl having 3 heteroatoms independently selected from N, O, and S. In some embodiments, each optionally substituted heteroaryl is independently a 5-12 membered heteroaryl having 2 heteroatoms independently selected from N, O, and S. In some embodiments, each optionally substituted heteroaryl is independently a 5-12 membered heteroaryl having 1 heteroatom independently selected from N, O, and S. In further embodiments, each optionally substituted heteroaryl is an optionally substituted 5- or 6-membered heteroaryl having 1 heteroatom independently selected from N, O, and S. In some embodiments, each heteroaryl is independently selected from the group consisting of tetrazole, oxadiazole, thiadiazole, imidazole, pyrazole, thiazole, or oxazole, each of which is optionally substituted.

[0085] In some embodiments, the compound of formula (I) is a compound of Table 1. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] Table 9-6 Table 9-7 Table 9-8 Table 9-9 Table 9-10 Table 9-11 Table 9-12 Table 9-13 Table 9-14 Table 9-15 Table 9-16 Table 9-17 Table 9-18 Table 9-19 Table 9-20 Table 9-21 Table 9-22 Table 9-23 Table 9-24 Table 9-25 Table 9-26 Table 9-27 Table 9-28 Table 9-29 Table 9-30 Table 9-31 Table 9-32 Table 9-33 [Table 9-34] [Table 9-35] [Table 9-36] [Table 9-37]

[0086] In some embodiments, the present disclosure provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R a is H, Me, or F, R 4 and R 5 is as defined above in formula (I).

[0087] In some embodiments of Formula (Ic), R a is H. In some embodiments, R a is F. In some embodiments, R a But it's Me.

[0088] In some embodiments of Formula (Ic), R 4 is selected from the group consisting of alkylenealkoxy, alkyleneheterocyclyl, -S(O)alkyl, -S(O)cycloalkyl, -S(O)alkylenecycloalkyl, -S(O)alkyleneheterocyclyl, -S(O)N(H)alkyleneheterocyclyl, -C(O)alkyl, -C(O)cycloalkyl, -C(O)alkylenecycloalkyl, -C(O)alkyleneheterocyclyl, and -C(O)N(H)alkyleneheterocyclyl.4 is selected from the group consisting of alkyleneheterocyclyl, —S(O)2 alkyl, —S(O)2 cycloalkyl, —S(O)2 alkyleneheterocyclyl, —C(O)alkyleneheterocyclyl, and —C(O)N(H)alkyleneheterocyclyl. 4 is selected from the group consisting of -S(O)2 alkyl, -S(O)2 cycloalkyl, and -S(O)2 alkyleneheterocyclyl. 4 is —S(O)alkyl. In some embodiments, R 4 is —S(O)cycloalkyl. In some embodiments, R 4 In some embodiments, alkylene is -S(O)N(H)alkyleneheterocyclyl. 1~5 In some embodiments, the alkylene is an optionally substituted 4-10 membered heterocyclyl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the alkylene is an optionally substituted 4-10 membered heterocyclyl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S. 1~5 In some embodiments, the alkylene is an optionally substituted 4-7 membered heterocyclyl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the alkylene is an optionally substituted 4-7 membered heterocyclyl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S. 2~4 and alkylene, wherein the heterocyclyl is an optionally substituted 6-membered heterocyclyl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the heterocyclyl is selected from the group consisting of piperidine, morpholine, thiomorpholine, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide, and piperizine, each of which is optionally substituted. In some embodiments, the optional substituents are selected from the group consisting of alkyl, haloalkyl, alkoxy, acyl, sulfonyl, heteroaryl, and heterocyclyl.

[0089] In some embodiments of Formula (Ic), R 5 teeth, [ka] In some embodiments, R 5 but, [ka] In some embodiments, R 5 but, [ka] In some embodiments, R 5 but, [ka] In some embodiments, R 5 but, [ka] In some embodiments, R b is selected from the group consisting of halogen, haloalkyl, alkyl, Oalkyl, Ohaloalkyl, alkylene-Ohaloalkyl, cycloalkyl, heterocyclyl aryl, heteroaryl, alkylnitrile, or CN. b is selected from the group consisting of halo, alkyl, haloalkyl, alkoxy, haloalkoxy, acyl, sulfonyl, cycloalkyl, heteroaryl, and heterocyclyl. In some embodiments, haloalkyl is selected from CF, CFCH, CHF, or CHF. In some embodiments, alkyl is selected from -C 1~5 In some embodiments, -C is alkyl. 1~5 In some embodiments, the alkyl is methyl, ethyl, propyl, i-propyl, butyl, or t-butyl. In some embodiments, the methyl, ethyl, propyl, i-propyl, butyl, or t-butyl is optionally substituted with OH. In some embodiments, the cycloalkyl is C 3~6In some embodiments, the O-haloalkyl is selected from OCF3, OCHF2, or OCH2F. In some embodiments, the O-alkyl is O-methyl, O-ethyl, O-propyl, Oi-propyl, O-butyl, or Ot-butyl. In some embodiments, R b is selected from the group consisting of F, Cl, -CH3, -CH2CH3, -CF3, -CHF2, -CF2CH3, -CN, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCH2CF2H, and cyclopropyl. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0090] In some embodiments, R 4 and R 5 together with the atom to which they are attached form a cycloalkyl or heterocyclyl.

[0091] In some embodiments, the present disclosure provides a compound of formula (Id) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, U is NR d , O, S, S(O), S(O)2, CH2, CHF, or CF2; R a is H, Me, or F, R bare each independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)R e , -C(O)OR e , -C(O)N(R e )(R e’ ), -S(O2)R e , cycloalkyl, heteroaryl, or heterocyclyl; R c are each independently F, alkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)R e , -C(O)OR e , -C(O)N(R e )(R e’ ), -S(O2)R e , heteroaryl, or heterocyclyl, and / or two R c The C groups, together with the carbon atoms to which they are attached, are bridged or fused together. 3~7 forming a cycloalkyl, a bridged or fused 4- to 7-membered heterocyclyl, or a 5- or 6-membered heteroaryl, each of which is optionally substituted; R d is H, alkyl, acyl, sulfonyl, cycloalkyl, aryl, or heteroaryl; R e and R e’ are each independently H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CHcycloalkyl, —CHheterocyclyl, —CHaryl, or —CHheteroaryl; m is 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, or 2; r is 1, 2, 3, or 4.

[0092] In some embodiments, the present disclosure provides a compound of formula (Ie) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, U is NR d , O, S, S(O), S(O)2, CH2, CHF, or CF2; R a is H, Me, or F, R b are each independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)R e , -C(O)OR e , -C(O)N(R e )(R e’ ), sulfonyl, cycloalkyl, heteroaryl, or heterocyclyl; R c are each independently F, alkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)R e , -C(O)OR e , -C(O)N(R e )(R e’ ), -S(O2)R e , heteroaryl, or heterocyclyl, and / or two R c The C groups, together with the carbon atoms to which they are attached, are bridged or fused together. 3~7 forming a cycloalkyl, a bridged or fused 4- to 6-membered heterocyclyl, or a 5- or 6-membered heteroaryl, each of which is optionally substituted; R d is H, alkyl, acyl, sulfonyl, cycloalkyl, aryl, or heteroaryl; R e and R e’ are each independently H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CHcycloalkyl, -CHheterocyclyl, -CHaryl, or -CHheteroaryl; m is 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, or 2; r is 1, 2, 3, or 4.

[0093] In some embodiments, the present disclosure provides a compound of formula (If) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, U is NR d , O, S, S(O), S(O)2, CH2, CHF, or CF2; R a is H, Me, or F, R b are each independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)R e , -C(O)OR e , -C(O)N(R e )(R e’ ), sulfonyl, cycloalkyl, heteroaryl, or heterocyclyl; R c are each independently F, alkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)R e , -C(O)OR e , -C(O)N(R e )(R e’ ), -S(O2)R e , heteroaryl, or heterocyclyl, and / or two R c The C groups, together with the carbon atoms to which they are attached, are bridged or fused together. 3~7 forming a cycloalkyl, a bridged or fused 4- to 7-membered heterocyclyl, or a 5- or 6-membered heteroaryl, each of which is optionally substituted; R d is H, alkyl, acyl, sulfonyl, cycloalkyl, aryl, or heteroaryl; R e and R e’ are each independently H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CHcycloalkyl, —CHheterocyclyl, —CHaryl, or —CHheteroaryl; m is 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, or 2; r is 1, 2, 3, or 4.

[0094] In some embodiments, the present disclosure provides a compound of formula (Ig) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, U is NR d , O, S, S(O), S(O)2, CH2, CHF, or CF2; R a is H, Me, or F, R b are each independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)R e , -C(O)OR e , -C(O)N(R e )(R e’ ), sulfonyl, cycloalkyl, heteroaryl, or heterocyclyl; R c are each independently F, alkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)R e , -C(O)OR e , -C(O)N(R e )(R e’ ), -S(O2)R e , heteroaryl, or heterocyclyl, and / or two R c The C groups, together with the carbon atoms to which they are attached, are bridged or fused together. 3~7 forming a cycloalkyl, a bridged or fused 4- to 7-membered heterocyclyl, or a 5- or 6-membered heteroaryl, each of which is optionally substituted; R d is H, alkyl, acyl, sulfonyl, cycloalkyl, aryl, or heteroaryl; R e and R e’are each independently H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CHcycloalkyl, —CHheterocyclyl, —CHaryl, or —CHheteroaryl; m is 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, or 2; r is 1, 2, 3, or 4.

[0095] In some embodiments, the present disclosure provides a compound of formula (Id-1), (Ie-1), (If-1), or (Ig-1) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, U, R a , R b , m, and r are as defined above in formulas (Id), (Ie), (If), and (Ig); V is O or NR d is.

[0096] In some embodiments, the present disclosure provides a compound of formula (Id-2), (Id-3), or (Id-4) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, U, R a , R b , m, and r are as defined above in formulas (Id), (Ie), (If), and (Ig); V is O or NR d is.

[0097] In some embodiments of Formulas (Id)-(Ig) and (Id-1)-(Ig-1), U is NR d , O, or S, and V is O. In some embodiments, U is N, O, or S, and V is NR dIn some embodiments, U is NR d and V is NR d In some embodiments, U is O and V is NR d In some embodiments, U is S and V is NR d In some embodiments, U is NR d and V is O. In some embodiments, U is O and V is O. In some embodiments, U is S and V is O.

[0098] In some embodiments of Formulas (Id)-(Ig) and (Id-1)-(Ig-1), U is O, S, S(O)2, CH2, or NR d In some embodiments, U is O, S, CH, or NR d In some embodiments, U is O, S, or NR d In some embodiments, U is O or CH. In some embodiments, U is O. In some embodiments, U is S. In some embodiments, U is NR d In some embodiments, U is S(O).

[0099] In some embodiments of Formulas (Id)-(Ig) and (Id-1)-(Ig-1), R a is H. In some embodiments, R a is F. In some embodiments, R a But it's Me.

[0100] In some embodiments of Formulas (Id)-(Ig) and (Id-1)-(Ig-1), R b is halo, alkyl, haloalkyl, alkyl, haloalkoxy, cycloalkyl, heterocyclyl, heteroaryl, or nitrile. bis halo, alkyl, haloalkyl, alkyl, haloalkoxy, cycloalkyl, or nitrile. In some embodiments, haloalkyl is selected from CF, CFCH, CHF, or CHF. In some embodiments, alkyl is -C 1~5 In some embodiments, -C is alkyl. 1~5 In some embodiments, the alkyl is methyl, ethyl, propyl, i-propyl, butyl, or t-butyl. 3~6 In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, the heterocyclyl is a 4- to 7-membered heterocyclyl having 1 or 2 heteroatoms selected from N, O, and S. In some embodiments, the haloalkoxy is selected from OCF3, OCHF2, or OCH2F. In some embodiments, the alkoxy is O-methyl, O-ethyl, O-propyl, Oi-propyl, O-butyl, or Ot-butyl. In some embodiments, R b But -C(O)R e , -C(O)OR e , -C(O)N(R e )(R e’ )

[0101] In some embodiments of Formulas (Id)-(Ig), R c But F, C 1~5 Alkyl, haloalkyl, C 1~5 Alkoxy, haloalkoxy, acyl, sulfonyl, 5- or 6-membered heteroaryl, or C 3~6 In some embodiments, R is heterocyclyl. c But -C(O)R e , -C(O)OR e , -C(O)N(R e )(R e’ In some embodiments, two R c The C groups, together with the carbon atoms to which they are attached, are bridged or fused together. 3~7In some embodiments, two R c Bridged or fused C groups, where the C groups, together with the carbon atoms to which they are attached, are optionally substituted 3~7 In some embodiments, two R c In some embodiments, two R groups, taken together with the carbon atoms to which they are attached, form an optionally substituted bridged or fused 5- or 6-membered heterocyclyl. c In some embodiments, the optional substituents are one or more R groups, together with the carbon atoms to which they are attached, to form an alkoxy or aminoalkyl bridge. b In some embodiments, the optional substituents are F, C 1~5 Alkyl, C 1~5 Alkoxy, CF3, CF2H, CFH2, -OCF3, -OCF2H, -OCFH2, -C(O)R e , -C(O)OR e , -C(O)N(R e )(R e’ ), and -SO2R e In some embodiments, the optional substituents are selected from the group consisting of F, C 1~5 Alkyl, C 1~5 In some embodiments, the optional substituents are selected from the group consisting of F or C. 1~5 In some embodiments, the optional substituent is F. In some embodiments, the optional substituent is C 1~5 In some embodiments, C 1~5 In some embodiments, the alkyl is methyl. 1~5 In some embodiments, C alkyl is ethyl. 1~5 In some embodiments, the alkyl is propyl. 1~5The alkyl is isopropyl.

[0102] In some embodiments of Formulas (Id)-(Ig) and (Id-1)-(Ig-1), R e and R e’ are each independently H, alkyl, cycloalkyl, or —CHcycloalkyl. In some embodiments, alkyl is —C 1~5 In some embodiments, -C is alkyl. 1~5 In some embodiments, the alkyl is methyl, ethyl, propyl, i-propyl, butyl, or t-butyl. 3~6 In some embodiments, R is cycloalkyl. In some embodiments, R is cyclopropyl. e and R e’ But it's H.

[0103] In some embodiments of Formulas (Id)-(Ig) and (Id-1)-(Ig-1), m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0104] In some embodiments of Formulas (Id)-(Ig), p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0105] In some embodiments of Formulas (Id)-(Ig) and (Id-1)-(Ig-1), r is 1, 2, or 3. In some embodiments, r is 1 or 2. In some embodiments, r is 2 or 3. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4.

[0106] In some embodiments of Formulas (Id)-(Ig), q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2.

[0107] In some embodiments of Formulas (Id)-(Ig), r is 1 and p is 1. In some embodiments, r is 2 and p is 1. In some embodiments, r is 3 and p is 1.

[0108] In some embodiments, the present disclosure provides a compound of formula (Ih) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, U is NR d , O, S, S(O), S(O)2, CH2, CHF, or CF2; X 1 , X 2 , X 3 , and X 4 are each independently CH or N; R a is H, Me, or F, R b are each independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)R e , -C(O)OR e , -C(O)N(R e )(R e’ ), -SO2R e , cycloalkyl, heteroaryl, or heterocyclyl; R c are each independently F, alkyl, haloalkyl, alkoxy, or haloalkoxy, and / or two R c C groups, together with the atoms to which they are attached, are optionally substituted 3~7 forming a cycloalkyl, R dis H, alkyl, acyl, sulfonyl, cycloalkyl, aryl, or heteroaryl; R e and R e’ are each independently H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CHcycloalkyl, —CHheterocyclyl, —CHaryl, or —CHheteroaryl; m is 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, or 2.

[0109] In some embodiments, the present disclosure provides a compound of formula (Ii) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, U is NR d , O, S, S(O), S(O)2, CH2, CHF, or CF2; X 1 , X 2 , X 3 , and X 4 are each independently CH or N; R a is H, Me, or F, R b are each independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)R e , -C(O)OR e , -C(O)N(R e )(R e’ ), -SO2R e , cycloalkyl, heteroaryl, or heterocyclyl; R c are each independently F, alkyl, haloalkyl, alkoxy, or haloalkoxy, and / or two R c C groups, together with the atoms to which they are attached, are optionally substituted 3~7 forming a cycloalkyl, Rd H, alkyl, -C(O)R e , sulfonyl, cycloalkyl, aryl, or heteroaryl; R e and R e’ are each independently H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CHcycloalkyl, —CHheterocyclyl, —CHaryl, or —CHheteroaryl; m is 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, or 2.

[0110] In some embodiments, the present disclosure provides a compound of formula (Ij) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, U is NR d , O, S, S(O), S(O)2, CH2, CHF, or CF2; X 1 , X 2 , X 3 , and X 4 are each independently CH or N; R a is H, Me, or F, R b are each independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)R e , -C(O)OR e , -C(O)N(R e )(R e’ ), -SO2R e , cycloalkyl, heteroaryl, or heterocyclyl; R c are each independently F, alkyl, haloalkyl, alkoxy, or haloalkoxy, and / or two R c C groups, together with the atoms to which they are attached, are optionally substituted 3~7forming a cycloalkyl, R d H, alkyl, -C(O)R e , sulfonyl, cycloalkyl, aryl, or heteroaryl; R e and R e’ are each independently H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CHcycloalkyl, —CHheterocyclyl, —CHaryl, or —CHheteroaryl; m is 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, or 2.

[0111] In some embodiments of Formulas (Ih)-(Ij), NR d , O, S, S(O)2, or CH2. In some embodiments, U is NR d , O, S, or CH2. In some embodiments, U is O or CH2. In some embodiments, U is O. In some embodiments, U is CH2. In some embodiments, U is S. In some embodiments, U is S(O)2. In some embodiments, U is NR d is.

[0112] In some embodiments of Formulas (Ih)-(Ij), X 1 , X 2 , X 3 , and X 4 Each of X is CH. 1 , X 2 , X 3 , and X 4 is N. In some embodiments, one of X 1 , X 2 , X 3 , and X 4 and two of X are N. In some embodiments, 1 is N and X 2 , X 3 , and X4 Each of X is CH. 2 is N and X 1 , X 3 , and X 4 Each of X is CH. 3 is N and X 1 , X 2 , and X 4 Each of X is CH. 4 is N and X 1 , X 2 , and X 3 Each of the is CH.

[0113] In some embodiments of Formulas (Ih)-(Ij), U is CH and X 1 , X 2 , X 3 , and X 4 and one of X is N. In some embodiments, U is CH and X 1 is N and X 2 , X 3 , and X 4 In some embodiments, U is CH and X 2 is N and X 1 , X 3 , and X 4 In some embodiments, U is CH and X 3 is N and X 1 , X 2 , and X 4 In some embodiments, U is CH and X 4 is N and X 1 , X 2 , and X 3 In some embodiments, p is 0. In some embodiments, p is 1.

[0114] In some embodiments of Formulas (Ih)-(Ij), U is O and X 1 , X 2 , X 3, and X 4 In some embodiments, U is O and one of X 1 is N and X 2 , X 3 , and X 4 In some embodiments, U is O and X 2 But N 、X 1. X 3 , and X 4 In some embodiments, U is O and X 3 is N and X 1 , X 2 , and X 4 In some embodiments, U is O and X 4 is N and X 1 , X 2 , and X 3 Each of the is CH.

[0115] In some embodiments of Formulas (Ih)-(Ij), R a is H. In some embodiments, R a is F. In some embodiments, R a But it's Me.

[0116] In some embodiments of Formulas (Ih)-(Ij), R b is halo, alkyl, haloalkyl, alkyl, haloalkoxy, cycloalkyl, heterocyclyl, heteroaryl, or nitrile. b is halo, alkyl, haloalkyl, alkyl, haloalkoxy, cycloalkyl, or nitrile. In some embodiments, haloalkyl is selected from CF, CFCH, CHF, or CHF. In some embodiments, alkyl is -C 1~5 In some embodiments, -C is alkyl. 1~5 In some embodiments, the alkyl is methyl, ethyl, propyl, i-propyl, butyl, or t-butyl. 3~6In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, the heterocyclyl is a 4- to 7-membered heterocyclyl having 1 or 2 heteroatoms selected from N, O, and S. In some embodiments, the haloalkoxy is selected from OCF3, OCHF2, or OCH2F. In some embodiments, the alkoxy is O-methyl, O-ethyl, O-propyl, Oi-propyl, O-butyl, or Ot-butyl.

[0117] In some embodiments of Formulas (Ih)-(Ij), R c But F, C 1~5 Alkyl, haloalkyl, C 1~5 Alkoxy, haloalkoxy, acyl, sulfonyl, 5- or 6-membered heteroaryl, or C 3~6 In some embodiments, R is heterocyclyl. c But F, C 1~5 Alkyl, haloalkyl, C 1~5 In some embodiments, R c But F or C 1~5 In some embodiments, R c is F or methyl. In some embodiments, R c is F. In some embodiments, R c is methyl. In some embodiments, two R c In some embodiments, two R groups are attached to the same carbon atom, which can also be referred to as a germinal substitution. c C groups, together with the atoms to which they are attached, are optionally substituted 3~6 In some embodiments, two R cIn some embodiments, the optional substituents are one or more R , ... b In some embodiments, the optional substituents are F, C 1~5 Alkyl, C 1~5 Alkoxy, CF3, CF2H, CFH2, -OCF3, -OCF2H, -OCFH2, -C(O)R e , -C(O)OR e , -C(O)N(R e )(R e’ ), and -SO2R e In some embodiments, the optional substituents are selected from the group consisting of F, C 1~5 Alkyl, C 1~5 In some embodiments, the optional substituents are selected from the group consisting of F or C. 1~5 In some embodiments, the optional substituent is F. In some embodiments, the optional substituent is C 1~5 In some embodiments, C 1~5 In some embodiments, the alkyl is methyl. 1~5 In some embodiments, C alkyl is ethyl. 1~5 In some embodiments, the alkyl is propyl. 1~5 Alkyl is isopropyl. In some embodiments, two optional substituents are attached to the same carbon atom, which may also be referred to as germinal substitution.

[0118] In some embodiments of Formulas (Ih)-(Ij), U is NR d When R d and R c together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl. d and R ctogether with the atom to which they are attached form a 6-membered heterocyclyl. In some embodiments, the heterocyclyl contains 1 or 2 heteroatoms selected from N, O, and S.

[0119] In some embodiments, the present disclosure provides a compound of Formula (Ih-1), Formula (Ii-1), or Formula (Ij-1): [ka] In the formula, R a , R b , R c , X 1 , X 2 , X 3 , X 4 , U, and m are as defined above in formula (Ih), formula (Ii), and formula (Ij).

[0120] In some embodiments of Formula (Ih-1), Formula (Ii-1), and Formula (Ij-1), each R c is F. In some embodiments, each R c is Me. In some embodiments, two R c groups, together with the carbon atoms to which they are attached, are optionally substituted C 3~6 In some embodiments, two R c In some embodiments, two R groups, taken together with the carbon atom to which they are attached, form a cyclopropyl or cyclobutyl, each of which is optionally substituted. c In some embodiments, the optional substituents are F or C. 1~5 In some embodiments, the optional substituent is F. In some embodiments, the optional substituent is C 1~5 In some embodiments, C 1~5 In some embodiments, the alkyl is methyl. 1~5In some embodiments, C alkyl is ethyl. 1~5 In some embodiments, the alkyl is propyl. 1~5 Alkyl is isopropyl. In some embodiments, two optional substituents are attached to the same carbon atom, which may also be referred to as germinal substitution.

[0121] In some embodiments, R d is H, alkyl, or cycloalkyl. In some embodiments, R d is H. In some embodiments, R d is alkyl. In some embodiments, R d is cycloalkyl. In some embodiments, alkyl is methyl, ethyl, propyl, i-propyl, or t-butyl. In some embodiments, cycloalkyl is cyclopropyl, cyclopentyl, or cyclohexyl.

[0122] In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0123] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0124] In some embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2.

[0125] In some embodiments, the present disclosure provides a compound of formula (Ik) or a pharmaceutically acceptable salt thereof: [ka] , in the formula, R b is haloalkoxy; R 4 is an alkyl.

[0126] In some embodiments, the present disclosure provides a compound of formula (Ik-1) or a pharmaceutically acceptable salt thereof: [ka] , in the formula, R b is haloalkoxy; R 4 is an alkyl.

[0127] In some embodiments, the present disclosure provides a compound of formula (Ik-2) or a pharmaceutically acceptable salt thereof: [ka] , in the formula, R b is haloalkoxy; R 4 is an alkyl.

[0128] In some embodiments, the present disclosure provides a compound of formula (Ik-3) or a pharmaceutically acceptable salt thereof: [ka] , in the formula, R b is haloalkoxy; R 4 is an alkyl.

[0129] In some embodiments of formulas (Ik) to (Ik-3), R b is H, —OCF, —OCHF, —OCHF, —OCHCF. In some embodiments, R bis H, -OCF3, or -OCHF 2である In some embodiments, R b is H or —OCHF. In some embodiments, R b is H or -OCF. In some embodiments, R b is H or -OCHF. In some embodiments, R b is -OCF3. In some embodiments, R b is -OCHF. In some embodiments, R b is -OCH2F.

[0130] In some embodiments of formulas (Ik) to (Ik-3), R 4 But C 1~5 In some embodiments, R 4 is methyl, ethyl, or propyl. In some embodiments, R 4 is methyl or ethyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is propyl.

[0131] In some embodiments of formulas (Ik) to (Ik-3), R b is H, -OCF3, -OCHF2, or -OCH2F, and R 4 But C 1~5 In some embodiments, R b is H or -OCHF2, and R 4 But C 1~5 In some embodiments, R b is H or -OCH2F, and R 4 But C 1~5 In some embodiments, R b is H or -OCF3, and R 4 But C 1~5 In some embodiments, R b is H or -OCH2F, and R4 But C 1~5 In some embodiments, C 1~5 Alkyl is methyl, ethyl, or propyl. In some embodiments, C 1~5 In some embodiments, the alkyl is methyl. 1~5 In some embodiments, C alkyl is ethyl. 1~5 The alkyl is propyl.

[0132] Compound of formula (II) In one aspect, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: [ka] , in the formula, R 1 is selected from the group consisting of: [Table 10] R a But, H, Halo, C 1~3 selected from the group consisting of alkyl, cycloalkyl, haloalkyl, and alkoxy; R 2 is H, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, haloalkyl, alkoxy, -(CH2) m Aryl, -(CH2) m N(R 3 ) aryl, -(CH2) m Oaryl, -(CH2) m (SO2)aryl, -(CH2) m Heteroaryl, -(CH2) m N(R 3 ) heteroaryl, -(CH2) m Heteroaryl, -(CH2) m Cycloalkyl, -(CH2) m Heterocyclyl, -(CH2) m (COOH), -(CH2) m (COOR 3 ), -(CH2)m (CONR 3 R 4 ), -(CH2) m (NR 3 SO2NR 3 R 4 ), and -(CH2) m (SO2R 3 ), each of which is optionally substituted; and m is selected from 1, 2, or 3; R 3 and R 4 is independently selected from the group consisting of H, aryl, heteroaryl, cycloalkyl, heterocyclyl, and alkyl, each of which is optionally substituted, or R 3 and R 4 together with the atom to which they are attached form an optionally substituted heterocyclyl; X 1 , X 2 and X 3 are independently selected from C and N, with the proviso that X 1 and X 2 Both of these cannot be N.

[0133] In some embodiments of Formula (II), X 1 , X 2 and X 3 is C. In some embodiments, X 1 is N and X 2 and X 3 is C. In some embodiments, X 1 and X 3 But C and X 2 But it is N.

[0134] In some embodiments of Formula (II), R a But, H, Halo, C 1~3 alkyl, or haloalkyl. In some embodiments, R a is H. In some embodiments, R a But C 1~3 In some embodiments, Ra is haloalkyl. In some embodiments, halo is F. In some embodiments, C 1~3 Alkyl Alkyl is methyl, ethyl, or isopropyl. In some embodiments, haloalkyl is CF, CHF, or CHF.

[0135] In some embodiments of Formula (II), R 2 But -(CH2) m Cycloalkyl, -(CH2) m Heterocyclyl, -(CH2) m Aryl, -(CH2) m N(R 3 ) aryl, -(CH2) m Oaryl, -(CH2) m Heteroaryl, -(CH2) m N(R 3 ) heteroaryl, or -(CH2) m O is heteroaryl and m is 1, 2, or 3.

[0136] In some embodiments of Formula (II), R 2 is optionally substituted -(CH2) m cycloalkyl, and m is 1, 2, or 3. In some embodiments, cycloalkyl is C 3~6 In some embodiments, the cycloalkyl is cyclopropyl. In some embodiments, the cycloalkyl is cyclobutyl. In some embodiments, the cycloalkyl is cyclopentyl. In some embodiments, the cycloalkyl is cyclohexyl.

[0137] In some embodiments, R 2 is heterocyclyl or -(CH2) mheterocyclyl, each of which is optionally substituted, and m is 1, 2, or 3. In some embodiments, the heterocyclyl is selected from the group consisting of azetidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, thiomorpholin-1,1-dioxide, tetrahydropyranyl, piperidinyl, or piperizinyl, each of which is optionally substituted. In some embodiments, the heterocyclyl is 2-oxa-5-azabicyclo[2.2.1]heptane, 8-azabicyclo[3.2.1]octane, or 9-azabicyclo[3.3.1]nonane.

[0138] In some embodiments, R 2 But -(CH2) m Aryl, -(CH2) m N(R 3 ) aryl, or -(CH2) m and m is 1, 2, or 3. In some embodiments, aryl is optionally substituted phenyl or naphthalenyl. In some embodiments, aryl is optionally substituted phenyl.

[0139] In some embodiments, R 2 But -(CH2) m Heteroaryl, -(CH2) m N(R 3 ) aryl, or -(CH2) mand m is 1, 2, or 3. In some embodiments, heteroaryl is an optionally substituted 5-14 membered heteroaryl. In some embodiments, heteroaryl is an optionally substituted 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, the optionally substituted 5-14 membered heteroaryl is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, indolizinyl, azaindolyl, indolyl, azaindolyl, benzoxazolyl, benzthiazolyl, benzfuranyl, benzthiophenyl, imidazopyridinyl, imidazopyrazinyl, and benzimidazolyl. In some embodiments, the optionally substituted 5-14 membered heteroaryl is selected from the group consisting of pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, imidazopyridinyl, and imidazopyrazinyl. In some embodiments, the heteroaryl is quinolinyl, pyridinyl, pyrimidinyl, oxazolyl, imidazolyl, pyrazolyl, or pyrazinyl.

[0140] In some embodiments of Formula (II), R 2 is selected from the group consisting of H, CH, CH-C6H5, CHCH-C6H5, CH(COOt-Bu), CH(COOH), CH(CO-N-morpholine), and CH(CO-N-pyrrolidine). 2 but one or more halogen atoms and / or one or more C 1~5 It is optionally substituted with an alkyl group.

[0141] In some embodiments of Formula (II), R 2 But unsubstituted C 1~6 In some embodiments, R 2 But C1~6 In some embodiments, the substituted C 1~6 The alkyl is 2,2-dimethylpropylnitrile (i.e., —CH2C(CH3)2—CN).

[0142] In some embodiments of Formula (II), R 2 is —C(H)(CH)—CH. In some embodiments, R 2 is alkylene-O-alkyl, or alkylene-O-aryl. In some embodiments, R 2 is alkylene-CN. In some embodiments of Formula (II), R 2 But -(CH2) m In some embodiments of Formula (II), R 2 But -(CH2) m In some embodiments, R 2 is optionally substituted -(CH2) m In some embodiments, R 2 is optionally substituted cycloalkyl. In some embodiments, R 2 But -(CH2) m (COOR 3 In some embodiments, R 2 But -(CH2) m (CONR 3 R 4 In some embodiments, m is selected from 1, 2, or 3. In some embodiments of Formula (II), R 2 but one or more halogen atoms and / or one or more C 1~5 In some embodiments, R 2 is optionally substituted -(CH2) m It is a heterocyclyl.

[0143] In some embodiments of formula (II), R as defined above 2 The group is oxo, halo, C 1~6 Alkyl, haloalkyl, OC1~6 Alkyl, haloalkyl, C 3~6 Optionally substituted on any available carbon or heteroatom by one or more substituents independently selected from the group consisting of cycloalkyl, 4- to 6-membered heteroaryl, phenyl, SO2alkyl, SO2aryl, C(O)alkyl, C(O)aryl, CO2alkyl, CO2aryl, and CN.

[0144] In some embodiments of Formula (II), alkyl, aryl, cycloalkyl, or heterocyclyl can each be halo, -OR 7 , alkyl, phenyl, heteroaryl, CN, COOR 7 , C(O)R 7 , SO2R 7 , and CONR 7 R 8 , where R 7 , and R 8 is independently for each occurrence selected from the group consisting of H, alkyl, and aryl, wherein said alkyl and aryl are optionally substituted with one or more halogens and / or one or more alkyl groups.

[0145] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 1 or 2. In some embodiments of Formula (II), R 3 and R 4 are independently selected from the group consisting of H, aryl, heteroaryl, cycloalkyl, heterocyclyl, and alkyl, each of which is optionally substituted. In some embodiments, the aryl, heteroaryl, cycloalkyl, heterocyclyl, and alkyl are optionally substituted with one or more halogen atoms and / or one or more C 1~5 It is optionally substituted with an alkyl group.

[0146] In some embodiments of Formula (II), R 3 and R 4together with the atom to which they are attached form a heterocyclyl. In some embodiments, the heterocyclyl is 1~5 It is optionally substituted with an alkyl group.

[0147] In some embodiments of Formula (II), R 1 but, [ka] In some embodiments, R 1 but, [ka] is.

[0148] In some embodiments of Formula (II), R 1 but, [ka] and 、 X 1 , X 2 and X 3 is C and R 2 is aryl, C-linked heteroaryl, cycloalkyl, C-linked heterocyclyl, alkyl, haloalkyl, -(CH2) m Aryl, -(CH2) m Heteroaryl, -(CH2) m Cycloalkyl, -(CH2) m Heterocyclyl, -(CH2) m (COOH), -(CH2) m (COOR 3 ), -(CH2) m (CONR 3 R 4 ), -(CH2) m (NR 3 SO3NR 3 R 4 ), and -(CH2) m (SO2R 3 ), each optionally substituted, m is selected from 1, 2, or 3, and the variable R a , R3 and R 4 is as defined above for formula (II).

[0149] In some embodiments of Formula (II), R 1 but, [ka] and 、 X 1 , X 2 and X 3 is C and R 2 is aryl, C-linked heteroaryl, cycloalkyl, C-linked heterocyclyl, alkyl, haloalkyl, -(CH2) m Aryl, -(CH2) m (NR 3 ) aryl, -(CH2) m Oaryl, -(CH2) m Heteroaryl, -(CH2) m (NR 3 ) heteroaryl, -(CH2) m Heteroaryl, -(CH2) m Cycloalkyl, -(CH2) m Heterocyclyl, -(CH2) m (COOH), -(CH2) m (COOR 3 ), -(CH2) m (CONR 3 R 4 ), -(CH2) m (NR 3 SO2NR 3 R 4 ), and -(CH2) m (SO2R 3 ), each optionally substituted; m is selected from 1, 2, or 3; and the variable R a , R 3 and R 4 is as defined above for formula (II).

[0150] In some embodiments of Formula (II), R 1 but, [ka] and 、 X 1 is N and X 2 and X 3 is C and R 2 is aryl, C-linked heteroaryl, cycloalkyl, C-linked heterocyclyl, alkyl, haloalkyl, -(CH2) m Aryl, -(CH2) m (NR 3 ) aryl, -(CH2) m Oaryl, -(CH2) m Heteroaryl, -(CH2) m (NR 3 ) heteroaryl, -(CH2) m Heteroaryl, -(CH2) m Cycloalkyl, -(CH2) m Heterocyclyl, -(CH2) m (COOH), -(CH2) m (COOR 3 ), -(CH2) m (CONR 3 R 4 ), -(CH2) m (NR 3 SO2NR 3 R 4 ), and -(CH2) m (SO2R 3 ), each optionally substituted; m is selected from 1, 2, or 3; and the variable R a , R 3 and R 4 is as defined above for formula (II).

[0151] In some embodiments of Formula (II), each optionally substituted alkyl independently represents an optionally substituted C 1~6 In a further embodiment, C 1~6In a further embodiment, C is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, amyl, and isoamyl. 1~6 Alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, amyl, and isoamyl. 1~6 Alkyl is Me or Et.

[0152] In some embodiments of Formula (II), each optionally substituted cycloalkyl independently represents an optionally substituted C 3~12 In some embodiments, cycloalkyl is C 3~6 In some embodiments, cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0153] In some embodiments of Formula (II), each optionally substituted heterocyclyl is independently an optionally substituted 3- to 12-membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, each optionally substituted heterocyclyl is independently an optionally substituted 3- to 6-membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, and S. In further embodiments, the heterocycloalkyl is an optionally substituted 5- or 6-membered heterocycle having 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, the heterocyclyl is selected from N, NR 6 In some embodiments, R is a saturated 4-7 membered heterocyclyl having 1 or 2 heteroatoms independently selected from O and SO. 6is selected from the group consisting of C1-C6 alkyl, —COO-alkyl, and C(O)-alkyl. In some embodiments, heterocyclyl is selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and thiomorpholinyl.

[0154] In some embodiments of Formula (II), each optionally substituted aryl is independently C 6~12 In a further embodiment, C 6~12 Aryl is optionally substituted phenyl.

[0155] In some embodiments of Formula (II), each optionally substituted heteroaryl is independently a 5-12 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, each optionally substituted heteroaryl is independently a 5-12 membered heteroaryl having 3 heteroatoms independently selected from N, O, and S. In some embodiments, each optionally substituted heteroaryl is independently a 5-12 membered heteroaryl having 2 heteroatoms independently selected from N, O, and S. In some embodiments, each optionally substituted heteroaryl is independently a 5-12 membered heteroaryl having 1 heteroatom independently selected from N, O, and S. In further embodiments, each optionally substituted heteroaryl is an optionally substituted 5- or 6-membered heteroaryl having 1 heteroatom independently selected from N, O, and S. In further embodiments, each optionally substituted heteroaryl is an optionally substituted 5- or 6-membered heteroaryl having 1 or 2 N atoms. In some embodiments, each heteroaryl is independently selected from the group consisting of tetrazole, oxadiazole, thiadiazole, imidazole, pyrazole, thiazole, or oxazole, each of which is optionally substituted. In some embodiments, the heteroaryl is tetrazole. In some embodiments, the heteroaryl is oxadiazole.

[0156] In some embodiments, the compound of formula (I) is a compound of Table 2. [Table 11-1] [Table 11-2] [Table 11-3] Table 11-4 Table 11-5 Table 11-6 Table 11-7 Table 11-8 Table 11-9 Table 11-10 Table 11-11 Table 11-12 Table 11-13 Table 11-14 Table 11-15 Table 11-16 Table 11-17 [Table 11-18] [Table 11-19] [Table 11-20]

[0157] Compound of formula (III) In another aspect, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof: [ka] , in the formula, R 1 is selected from the group consisting of: [Table 12] R a But, H, Halo, C 1~3 selected from the group consisting of alkyl, cycloalkyl, haloalkyl, and alkoxy; R 2 and R 3 are independently selected from the group consisting of H, halogen, alkoxy, haloalkyl, aryl, heteroaryl, alkyl, and cycloalkyl, or R 2 and R 3 together with the atom to which they are attached form a cycloalkyl or heterocyclyl; R 4 and R 5 But H, -(SO2)R 2 , -(SO2)NR 2 R 3 , -(CO)R 2 , -(CONR 2 R 3), aryl, arylheteroaryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, haloalkyl, and alkoxy, each of which is optionally substituted, or R 4 and R 5 together with the atom to which they are attached form a cycloalkyl or heterocyclyl; X 1 , X 2 , and X 3 is (1)X 1 But, CR a and X 2 is N and X 3 But, CR a (2)X 1 is N and X 2 But, CR a and X 3 But, CR a (3)X 1 But, CR a and X 2 But, CR a and X 3 (4) X is N 1 is N and X 2 But, CR a and X 3 (5)X is N 1 But, CR a and X 2 is N and X 3 (6)X is N 1 is N and X 2 is N and X 3 But, CR a is selected from the group consisting of Y is CR 2 , O, N, S, SO, and SO2, and when Y is O, S, SO, or SO2, R 5 does not exist, and R 4 and R 5 together with the atom to which they are attached form a cycloalkyl or heterocyclyl, Y is CR 2 or N, n is 1 or 2.

[0158] In some embodiments, n is 1. In some embodiments, n is 2.

[0159] In some embodiments of Formula (III), X 1 But, CR a and X 2 is N and X 3 But, CR a In some embodiments, X 1 is N and X 2 But, CR a and X 3 But, CR a In some embodiments, R a But it's H.

[0160] In some embodiments of Formula (III), R 2 and R 3 But it's H.

[0161] In some embodiments of Formula (III), Y is -CR 2 and R 2 But it's H.

[0162] In some embodiments of Formula (III), Y is N. In some embodiments of Formula (III), R 4 But -(SO2)R 2 and R 5 is aryl. In some embodiments, R 4 But -(SO2)R 2 and R 5 is heteroaryl. In some embodiments, R 4 But -(SO2)R 2 and R 5 is cycloalkyl. In some embodiments, R 4 But -(CO)R 2 and R 5 is an aryl.

[0163] In some embodiments of Formula (III), R4 But -(CO)R 2 and R 5 But it's H.

[0164] In some embodiments of Formula (III), R 4 is selected from the group consisting of ethylsulfonyl, methylsulfonyl, and cyclopropylsulfonyl. 4 is ethylsulfonyl. In some embodiments, R 4 is methylsulfonyl. In some embodiments, R 4 is selected from the group consisting of -(SO2)-alkyl and -(CO)-aryl. In some embodiments, alkyl or aryl is optionally substituted with one or more halogens.

[0165] In some embodiments of Formula (III), R 5 is selected from the group consisting of phenyl, 3-chlorophenyl, 3-chloro-4-fluorophenyl, 3-trifluoromethylphenyl, 3,4-difluorophenyl, and 2,6-difluorophenyl. 5 is cyclopropyl. In some embodiments, R 5 is selected from the group consisting of pyridin-3-yl and 1-methylindazol-6-yl. 5 is selected from the group consisting of H, pyridin-2-yl, 3-chlorophenyl, and phenyl.

[0166] In some embodiments of Formula (III), R 1 but, [ka] and 、 X 1 is CH and X 2 is N and X 3 is CH and Y is CR 2 or N and R 4 and R 5together with the atoms to which they are attached form a cycloalkyl or heterocyclyl, and the variable R 2 , R 3 and n is as defined above for formula (III).

[0167] In some embodiments of Formula (III), R 1 but, [ka] In some embodiments, R 1 but, [ka] is.

[0168] In some embodiments, R a But, H, Halo, C 1~3 alkyl, or haloalkyl. In some embodiments, R a is H. In some embodiments, R a But C 1~3 In some embodiments, R a is haloalkyl. In some embodiments, halo is F. In some embodiments, C 1~3 Alkyl Alkyl is methyl, ethyl, or isopropyl. In some embodiments, haloalkyl is CF, CHF, or CHF.

[0169] In some embodiments, the compound of formula (III) is selected from the group consisting of: [Table 13]

[0170] Compound of formula (IV) In some embodiments, the present disclosure provides a compound of formula (IV) or a pharmaceutically acceptable salt thereof: [ka] , in the formula, R 1 is selected from the group consisting of: [Table 14] R a But, H, Halo, C 1~3 selected from the group consisting of alkyl, cycloalkyl, haloalkyl, and alkoxy; R 2 and R 3 are independently selected from the group consisting of H, halogen, alkoxy, haloalkyl, aryl, heteroaryl, alkyl, and cycloalkyl, each of which is optionally substituted, or R 2 and R 3 together with the atom to which they are attached form a cycloalkyl or heterocyclyl; R 4 and R 5 are independently H, -(SO2)R 2 , -(SO2)NR 2 R 3 , -(CO)R 2 , -(CONR 2 R 3 ), aryl, arylheteroaryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, haloalkyl, and alkoxy, each of which is optionally substituted, or R 4 and R 5 together with the atom to which they are attached form a cycloalkyl or heterocyclyl; X 1 O, S, NH, and NR 6 and R 6 is selected from the group consisting of C1-C6 alkyl, alkoxy, haloalkyl, cycloalkyl, and heterocyclyl; Y is CR 2 , O, N, S, SO, and SO2, and when Y is O, S, SO, or SO2, R 5does not exist, and R 4 and R 5 together with the atom to which they are attached form a cycloalkyl or heterocyclyl, Y is CR 2 or N, n is selected from 0, 1, or 2.

[0171] In some embodiments of Formula (IVa) and (IVb), n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 1 or 2.

[0172] In some embodiments, in formulas (IVa) and (IVb), X 1 is O. In some embodiments, X 1 is NH. In some embodiments, X 1 But NR 6 In some embodiments, X 1 is NCH3. In some embodiments, X 1 is O or NCH3.

[0173] In some embodiments of formula (IVa) and (IVb), R 2 and R 3 But it's H.

[0174] In some embodiments of formula (IVa) and (IVb), Y is N.

[0175] In some embodiments of formula (IVa) and (IVb), R 4 But -(SO2)R 2 and R 5 is aryl. In some embodiments, R 4 But -(SO2)R 2 and R 5 is heteroaryl. In some embodiments, R 4 But -(SO2)R 2 and R 5is cycloalkyl. In some embodiments, R 4 But -(CO)R 2 and R 5 is aryl. In some embodiments, R 4 But -(CO)R 2 and R 5 But it's H.

[0176] In some embodiments of formula (IVa) and (IVb), R 4 is selected from the group consisting of ethylsulfonyl, methylsulfonyl, and cyclopropylsulfonyl. 4 is selected from the group consisting of -(SO)-alkyl, -(SO)-cycloalkyl, -(CO)-alkyl, -(CO)-aryl, and -(CO)-cycloalkyl. In some embodiments, the alkyl, cycloalkyl, or aryl is optionally substituted with one or more halogens.

[0177] In some embodiments of formula (IVa) and (IVb), R 5 is selected from the group consisting of phenyl, 3-chlorophenyl, 3-chloro-4-fluorophenyl, 3-trifluoromethylphenyl, 3,4-difluorophenyl, and 2,6-difluorophenyl. 5 is cyclopropyl. In some embodiments, R 5 is selected from the group consisting of pyridin-3-yl and 1-methylindazol-6-yl. 5 is 3-chlorophenyl.

[0178] In some embodiments of formula (IVa) and (IVb), R 1 but, [ka] is.

[0179] In some embodiments of formula (IVa) and (IVb), Ra But, H, Halo, C 1~3 alkyl, or haloalkyl. In some embodiments, R a is H. In some embodiments, R a But C 1~3 In some embodiments, R a is haloalkyl. In some embodiments, halo is F. In some embodiments, C 1~3 Alkyl Alkyl is methyl, ethyl, or isopropyl. In some embodiments, haloalkyl is CF, CHF, or CHF.

[0180] In some embodiments, the compound of Formula (IVa) or Formula (IVb) is selected from the group consisting of: [Table 15-1] [Table 15-2]

[0181] In some embodiments, the compound of the disclosure is a compound of Table 3. In some embodiments, the compound of the disclosure is a compound of Table 4.

[0182] In some embodiments, the compounds of the present disclosure include any isotopically labeled (or radiolabeled) derivatives of the compounds described herein. Such derivatives are derivatives of compounds having the formulas described herein, in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of radionuclides that can be incorporated include: 2H (also written as "D" for deuterium). Thus, in one embodiment, there is provided a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Id-1), formula (Id-2), formula (Id-3), formula (Id-4), formula (Ie), formula (Ie-1), formula (If), formula (If-1), formula (Ig), formula (Ig-1), formula (Ih), formula (Ih-1), formula (Ii), formula (Ii-1), formula (Ij), formula (Ij-1), formula (Ik), formula (Ik-1), formula (Ik-2), formula (Ik-3), formula (II), formula (III), formula (IVa), or formula (IVb), wherein one or more hydrogen atoms are replaced with one or more deuterium atoms.

[0183] Pharmaceutical Composition In various embodiments of the present disclosure, one or more compounds disclosed herein, e.g., Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Id-1), Formula (Id-2), Formula (Id-3), Formula (Id-4), Formula (Ie), Formula (1e-1), Formula (If), Formula (If-1), Formula (Ig), Formula (Ig-1), Formula (Ih), Formula (Ih-1), Formula (Ii), Formula (I Pharmaceutical compositions are provided comprising a compound of Formula (I-1), Formula (Ij), Formula (Ij-1), Formula (Ik), Formula (Ik-1), Formula (Ik-2), Formula (Ik-3), Formula (II), Formula (III), Formula (IVa), or Formula (IVb), or a pharmaceutically acceptable solvate, hydrate, tautomer, N-oxide, or salt thereof, and a pharmaceutically acceptable excipient or adjuvant. Pharmaceutically acceptable excipients and adjuvants are added to compositions or formulations for various purposes. In some embodiments, pharmaceutical compositions comprising one or more compounds disclosed herein, or a pharmaceutically acceptable solvate, hydrate, tautomer, N-oxide, or salt thereof, further comprise a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable excipient, binder, and / or diluent. In some embodiments, suitable pharmaceutically acceptable excipients include, but are not limited to, water, saline, alcohol, polyethylene glycol, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, and polyvinylpyrrolidone. [Example]

[0184] The present invention is further illustrated by the following examples, which are non-limiting and merely representative of various aspects of the present invention. Solid and dotted wedges in the structures disclosed herein indicate relative stereochemistry; absolute stereochemistry is indicated only where specifically stated or depicted.

[0185] General method

[0186] All reagents whose synthesis is not described in the experimental section are commercially available, are known compounds, or can be formed from known compounds by known methods by one skilled in the art.

[0187] The compounds and intermediates produced according to the methods of the present invention may require purification. Purification of organic compounds is well known to those skilled in the art, and there may be several ways to purify the same compound. In some cases, purification may not be necessary. In some cases, the compound may be purified by crystallization. In some cases, impurities may be stirred out using an appropriate solvent. In some cases, the compound may be purified by chromatography, particularly flash column chromatography, for example, on a prepacked silica gel cartridge, such as RediSep®. f and may be purified using eluents such as a gradient of 0-100% EtOAc in hexanes, or a gradient of 0-100% 10% MeOH in CH2Cl2.

[0188] The purification methods described herein can provide compounds of the present invention having sufficiently basic or acidic functional groups in the form of a salt, such as a trifluoroacetate or formate salt for sufficiently basic compounds of the present invention, or an ammonium salt for sufficiently acidic compounds of the present invention. This type of salt can be converted to its free base or free acid form, respectively, by various methods known to those skilled in the art, or can be used as a salt in subsequent biological assays. It should be understood that the specific form of the compound of the present invention isolated and described herein is not necessarily the only form in which the compound can be applied to a biological assay to quantify a specific biological activity.

[0189] All starting materials and reagents were commercially available and used as received. 1H nuclear magnetic resonance (NMR) spectroscopy was performed near room temperature using a Bruker Avance III instrument operating at 400 MHz with the solvents indicated unless otherwise noted. In all cases, the NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts per million using conventional abbreviations for the following major peak designations: s, singlet; d, doublet; t, triplet; q, quartet; dd, double doublet; dt, double triplet; m, multiplet; br, broad. Preparative HPLC purification was performed using an Agilent Technologies 1200 Infinity series or Teledyne ISCO CombiFlash® R f The results were analyzed by reverse phase HPLC using an equivalent HPLC system such as

[0190] Chemical names were generated using ChemDraw naming software (version 17.0.0.206) from PerkinElmer Informatics, Inc. In some cases, commonly accepted names of commercially available reagents were used instead of names generated by the naming software.

[0191] Abbreviation In the examples, the following abbreviations are used, other abbreviations have their customary meaning in the art: [Table 16]

[0192] Analytical LC-MS method

[0193] Column: Eclipse Plus C18 4.6 × 3.5 μm, eluent A: 0.1% TFA in H2O, eluent B: 0.1% TFA in CH3CN, gradient: 20–100% over 4 min, flow rate: 1.5 mL / min, injection volume: 1–5 μL, temperature: 23 °C, UV scan: 220 nm and 250 nm, signal settings—scan positive mode.

[0194] Analytical HPLC method

[0195] Column: Eclipse Plus C18 4.6 x 110 mm, Eluent A: 0.1% TFA in HO, Eluent B: 0.1% TFA in CH3CN, Gradient: 10–100% Eluent B over 10 min, Flow rate: 1 mL / min, Injection volume: 1–5 μL, Temperature: 23 °C, UV scan: 220, 254, and 280 nm (Method 1); 20–100% Eluent B over 10 min, Flow rate: 1 mL / min, Injection volume: 1–5 μL, Temperature: 23 °C, UV scan: 220, 254, and 280 nm (Method 2).

[0196] Preparative HPLC

[0197] Instrument: Agilent Technologies 1200 Infinity Series Column: Gemini 5 μm NX-C18 110 Å, 250 × 21.2 mm, Eluent A: 0.1% TFA in H2O, Eluent B: 0.1% TFA in CH3CN; Gradient: 10–100%; Flow rate: 20 mL / min; Injection volume: 0.5–2 mL; Temperature: 23 °C, UV scan: 254 and 220 nm.

[0198] Compound synthesis Example 1: General scheme for the synthesis of compounds of formula (I) via intermediates 4 and 6 [ka]

[0199] Step 1: Preparation of tert-butyl 2-(2-methylthiazole-5-carbonyl)hydrazine-1-carboxylate (2a). [ka]

[0200] (tert-Butoxy)carbohydrazide (21 g, 161 mmol) was taken up in DMF (300 ml), and EDCI (31 g, 161 mmol) and benzotriazole (13 g, 94 mmol) were added. 2-Methyl-1,3-thiazole-5-carboxylic acid (1a, 20 g, 140 mmol) was then added, and the resulting solution was cooled in an ice bath. Diisopropylethylamine (53 ml, 307 mmol) was then slowly added to the solution, and the reaction was stirred for 36 hours. TLC indicated the reaction was complete. The solution was quenched by adding water and then extracted with EtOAc (×2). The combined organic layers were filtered through MgSO4 and concentrated. The residue was purified by Combiflash® (DCM / methanol) to give the product as a yellow foam. 1 H NMR (400MHz, DMSO-d6) δ 10.33 (s, 1H), 9.01 (s, 1H), 8.23 ​​(s, 1H) 2.69 (s, 3H) 1.43 (s, 9H). LC-MS: tR (min) 3.15 (20~100%ACN 6 min with 0.1% TFA), m / z[M+H]+C 10 H 16 N3O3S required value: 258.3, actual value 258.0

[0201] Step 2: Preparation of 2-(difluoromethyl)-5-(2-methylthiazol-5-yl)-1,3,4-oxadiazole (3a). [ka]

[0202] tert-Butyl 2-(2-methylthiazole-5-carbonyl)hydrazine-1-carboxylate (2.7 g, 10.5 mmol) was taken up in DCM (100 mL) and cooled in an ice bath. Trifluoroacetic acid (8.0 mL, 105 mmol) was added dropwise to the solution, and the reaction solution was stirred at room temperature for 18 hours. TLC indicated the reaction was complete. The solution was concentrated to give the hydrazide salt as a yellow oil. The resulting oil was dissolved in DMF (100 mL), and triethylamine (11.7 mL, 84 mmol) was added. Difluoroacetic anhydride (2.6 mL, 21 mmol) was then added, and the solution was heated at 80°C for 16 hours. After cooling to room temperature, the solution was diluted with EtOAc and washed with water. The organic layer was filtered through MgSO4 and concentrated. The resulting residue was purified by Combiflash® (hexane / EtOAc gradient) to afford the title compound (1.0 g, 44%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H) 6.90 (t, J = 51.6 Hz, 1H) 2.83 (s, 3H). LC-MS: tR (min) 3.65 (20-100% ACN with 0.1% TFA, 6 min), m / z [M+H]+C7H6N3F2OS required: 217.2, found: 218.0. HPLC Rt 5.35 min, 97.2% (10-100% ACN with 0.1% TFA, 10 min).

[0203] Step 3: Preparation of 2-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a) [ka]

[0204] 2-(Difluoromethyl)-5-(2-methylthiazol-5-yl)-1,3,4-oxadiazole (1.2 g, 5.5 mmol) was taken up in 1,2-dichloroethane (200 ml) along with N-bromosuccinimide (1.7 g, 9.9 mmol), and 2-[(1E)-2-(1-cyano-1-methylethyl)diazen-1-yl]-2-methylpropanenitrile (91 mg, 0.55 mmol) was added. The resulting solution was heated to reflux for 5 hours. The solution was cooled to room temperature and concentrated. The residue was purified by Combiflash® (hexane / EtOAc) gradient to give the title product (1.0 g, 63%) as a white solid. 1 H NMR (400MHz, CDCl3) δ8.43(s,1H)6.20(t,J=51.6Hz,1H)4.78(s,2H). LC-MS: tR (min) 4.44 (20-100% ACN with 0.1% TFA, 6 min), m / z[M+H] + C7H5BrF2N3OS required value: 296.1, found values ​​295.9, 297.9.

[0205] Example 2. Synthesis of amide compounds of formula (I) - nucleophilic substitution [ka]

[0206] Preparation of 4-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one: [ka] 2,2-Dimethyl-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-3-one (40 mg, 0.22 mmol) was taken up in DMF (0.7 mL) in an ice bath. Sodium hydride (10 mg, 60 wt%, 0.22 mmol) was added, and the solution was stirred at 0 °C for 20 min. Then, a solution of 2-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 50 mg, 0.17 mmol) in DMF (0.5 mL) was added dropwise at 0 °C. The solution was stirred at room temperature for 4 h. TLC indicated the reaction was complete (all bromide was consumed). The reaction was quenched by adding water, and the separated aqueous phase was extracted with EtOAc. The organic layer was collected, washed with brine, and then filtered through MgSO. The filtrate was concentrated and the residue was purified by Combiflash® (DCM / methanol gradient) to give the title compound (42 mg, 63%) as a white powder.

[0207] Preparation of N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-3-(morpholin-4-yl)-N-(pyridin-3-yl)propenamide (I-185) [ka]

[0208] Step 1: 3-Morpholino-N-(3-pyridyl)propanamide [ka]

[0209] A mixture of 3-chloropyridine (359 mg, 3.16 mmol), 3-morpholinopropanamide (500 mg, 3.16 mmol), tris(dibenzylideneacetone)dipalladium(0) (145 mg, 0.16 mmol), ditert-butyl-[2,3,4,5-tetramethyl-6-(2,4,6-triisopropylphenyl)phenyl]phosphane (38 mg, 0.08 mmol), and potassium phosphate (1.0 g, 4.74 mmol) in tert-butanol (10 mL) was heated at 110° C. under nitrogen for 16 hours and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0-7% methanol in dichloromethane) to give 3-morpholino-N-(3-pyridyl)propanamide (675 mg, 84%) as a brown oil.

[0210] Step 2: N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-3-(morpholin-4-yl)-N-(pyridin-3-yl)propanamide [ka]

[0211] To a solution of 3-morpholino-N-(3-pyridyl)propanamide (286 mg, 1.22 mmol) in tetrahydrofuran (5 mL) was added sodium hydride (60%, 41 mg, 1.01 mmol). After stirring at 0° C. for 30 minutes, 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 300 mg, 1.01 mmol) was added. The mixture was stirred at 20° C. for 1 hour and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by RP-HPLC (0–20% acetonitrile and 0.225% formic acid in water) to give N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-3-(morpholino-4-yl)-N-(pyridin-3-yl)propanamide (3.4 mg, 3.7%) as a colorless oil.

[0212] Preparation of 1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-1H,2H,3H,4H,5H-pyrido[4,3-b]azepin-2-one (I-200) [ka]

[0213] Step 1: tert-Butyl (E)-4-(4-amino-3-pyridyl)but-3-enoate [ka]

[0214] A mixture of 3-bromopyridin-4-amine (1.0 g, 5.78 mmol), tert-butyl but-3-enoate (3.3 g, 23.12 mmol), triethylamine (2.3 g, 23.12 mmol), palladium(II) acetate (130 mg, 0.58 mmol), and tris-o-tolylphosphane (352 mg, 1.16 mmol) in N,N-dimethylformamide (50 mL) was heated at 120 °C for 16 h and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0-10% methanol in dichloromethane) to give tert-butyl (E)-4-(4-amino-3-pyridyl)but-3-enoate (431 mg, 30%) as a brown oil.

[0215] Step 2: tert-Butyl 4-(4-amino-3-pyridyl)butanoate [ka]

[0216] A mixture of tert-butyl (E)-4-(4-amino-3-pyridyl)but-3-enoate (331 mg, 1.41 mmol) and palladium (10% carbon, 33 mg, 0.03 mmol) in methanol (30 mL) was hydrogenated (15 psi) at 20 °C for 16 hours and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0-7% methanol in dichloromethane) to give tert-butyl 4-(4-amino-3-pyridyl)butanoate (354 mg, 78%) as a yellow oil.

[0217] Step 3: 1,3,4,5-Tetrahydropyrido[4,3-b]azepin-2-one [ka]

[0218] To a solution of tert-butyl 4-(4-amino-3-pyridyl)butanoate (284 mg, 1.20 mmol) in tetrahydrofuran (3 mL) was added potassium tert-butoxide (674 mg, 6.01 mmol). After stirring at 20° C. for 1 h, the reaction mixture was diluted with ethyl acetate (20 mL), washed with brine (20 mL), dried over sodium sulfate, and concentrated to dryness under reduced pressure to give crude 1,3,4,5-tetrahydropyrido[4,3-b]azepin-2-one (77 mg, crude) as a yellow solid.

[0219] Step 4: 1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-1H,2H,3H,4H,5H-pyrido[4,3-b]azepin-2-one [ka]

[0220] To a solution of 1,3,4,5-tetrahydropyrido[4,3-b]azepin-2-one (33 mg, 0.20 mmol) in N,N-dimethylformamide (1 mL) was added sodium hydride (60%, 7 mg, 0.19 mmol). After stirring at 0° C. for 0.5 h, 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 50 mg, 0.17 mmol) was added. The mixture was stirred for an additional 0.5 h at 20° C. and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by RP-HPLC (0–40% acetonitrile and 0.225% formic acid in water) to give 1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-1H,2H,3H,4H,5H-pyrido[4,3-b]azepin-2-one (13.3 mg, 20%) as a yellow oil.

[0221] Preparation of 1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-3,3-dimethyl-4,5-dihydropyrido[3,4-b]azepin-2-one (I-253) [ka]

[0222] Step 1: Benzyl 2,2-dimethylbut-3-enoate [ka]

[0223] To a solution of 2,2-dimethylbut-3-enoic acid (1.0 g, 8.76 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (2.4 g, 17.52 mmol). The mixture was stirred at 20 °C for 5 minutes, and then benzyl bromide (1.7 g, 9.64 mmol) was added. After stirring at 20 °C for 16 hours, the reaction mixture was filtered. The filtrate was diluted with ethyl acetate (100 mL) and washed with brine (3 × 100 mL). The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum ether) to give benzyl 2,2-dimethylbut-3-enoate (1.20 g, 67%) as a colorless oil.

[0224] Step 2: Benzyl (E)-4-(3-amino-4-pyridyl)-2,2-dimethyl-but-3-enoate [ka]

[0225] To a solution of benzyl 2,2-dimethylbut-3-enoate (1.1 g, 5.39 mmol) and 4-bromopyridin-3-amine (466 mg, 2.69 mmol) in 1,4-dioxane (15 mL) was added N-cyclohexyl-N-methyl-cyclohexanamine (1.47 g, 7.54 mmol), Pd(dba) (123 mg, 0.13 mmol), and P(t-Bu) (138 mg, 0.27 mmol). After stirring at 110 °C under a nitrogen atmosphere for 16 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-70% ethyl acetate in petroleum ether) to give benzyl (E)-4-(3-amino-4-pyridyl)-2,2-dimethyl-but-3-enoate (712 mg, 81%) as a pale yellow oil.

[0226] Step 3: 4-(3-amino-4-pyridyl)-2,2-dimethyl-butanoic acid [ka]

[0227] To a solution of benzyl (E)-4-(3-amino-4-pyridyl)-2,2-dimethyl-but-3-enoate (612 mg, 2.07 mmol) in methanol (30 mL) was added palladium (220 mg, 0.21 mmol, 10% carbon). After stirring under hydrogen (15 psi) at 20 °C for 16 h, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% methanol in dichloromethane) to give 4-(3-amino-4-pyridyl)-2,2-dimethyl-butanoic acid (250 mg, 58%) as a pale yellow solid.

[0228] Step 4: 3,3-Dimethyl-4,5-dihydro-1H-pyrido[3,4-b]azepin-2-one [ka]

[0229] To a solution of 4-(3-amino-4-pyridyl)-2,2-dimethyl-butanoic acid (250 mg, 1.20 mmol) in N,N-dimethylformamide (3 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (479 mg, 1.26 mmol) and N-ethyl-N-isopropylpropan-2-amine (310 mg, 2.40 mmol) at 0 °C. After stirring at 20 °C for 2 h, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with brine (3 × 50 mL). The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% methanol in dichloromethane) to give 3,3-dimethyl-4,5-dihydro-1H-pyrido[3,4-b]azepin-2-one (340 mg, crude) as a pale yellow solid.

[0230] Step 5: 1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-3,3-dimethyl-4,5-dihydropyrido[3,4-b]azepin-2-one [ka]

[0231] To a solution of 3,3-dimethyl-4,5-dihydro-1H-pyrido[3,4-b]azepin-2-one (50 mg, 0.26 mmol) in N,N-dimethylformamide (1 mL) was added sodium hydride (60%, 8 mg, 0.20 mmol). After stirring at 0°C for 30 minutes, 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (60 mg, 0.20 mmol) was added and stirred for an additional 0.5 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (25–55% acetonitrile in water and 0.225% formic acid) to give 1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-3,3-dimethyl-4,5-dihydropyrido[3,4-b]azepin-2-one (28 mg, 32%) as a pale yellow solid.

[0232] 1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-4,5-dihydro-1H-pyrido[3,4-b]azepin-2(3H)-one (I-252), (S)-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl Preparation of (R)-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-4,5-dihydro-1H-pyrido[3,4-b]azepin-2(3H)-one (I-246), (R)-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-4,5-dihydro-1H-pyrido[3,4-b]azepin-2(3H)-one (I-245) [ka]

[0233] Step 1: Benzyl 2-methylbut-3-enoate [ka]

[0234] To a solution of 2-methylbut-3-enoic acid (1.0 g, 9.99 mmol) in dichloromethane (1 mL) was added benzyl alcohol (1.1 g, 9.99 mmol), N,N-dicyclohexylcarbodiimide (2.1 g, 9.99 mmol), and dimethylaminopyridine (122 mg, 1.00 mmol). After stirring at 20 °C for 16 h, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum ether) to give benzyl 2-methylbut-3-enoate (1.8 g, 95%) as a colorless oil.

[0235] Step 2: Benzyl 4-(3-aminopyridin-4-yl)-2-methylbut-3-enoate [ka]

[0236] To a solution of 4-bromopyridin-3-amine (1.1 g, 6.36 mmol) in 1,4-dioxane (20 mL) was added benzyl 2-methylbut-3-enoate (1.7 g, 8.90 mmol), Pd(dba) (291 mg, 0.32 mmol), tritert-butylphosphane palladium (325 mg, 0.64 mmol), and N-cyclohexyl-N-methyl-cyclohexanamine (3.7 g, 19.07 mmol). After stirring at 110 °C under a nitrogen atmosphere for 16 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (10-40% acetonitrile and 0.225% formic acid in water) to give benzyl 4-(3-amino-4-pyridyl)-2-methyl-but-3-enoate (900 mg, 47%) as a yellow oil.

[0237] Step 3: 4-(3-aminopyridin-4-yl)-2-methylbutanoic acid [ka]

[0238] To a solution of benzyl 4-(3-amino-4-pyridyl)-2-methyl-but-3-enoate (800 mg, 2.83 mmol) in methanol (10 mL) was added palladium (302 mg, 0.28 mmol, 10% carbon). After stirring under a hydrogen atmosphere (15 psi) at 20° C. for 16 hours, the reaction mixture was filtered. The filtrate was concentrated to dryness under reduced pressure to give crude 4-(3-amino-4-pyridyl)-2-methyl-butanoic acid (500 mg, 91%) as a yellow oil.

[0239] Step 4: 3-Methyl-4,5-dihydro-1H-pyrido[3,4-b]azepin-2(3H)-one [ka]

[0240] To a mixture of 4-(3-amino-4-pyridyl)-2-methyl-butanoic acid (500 mg, 2.57 mmol) in N,N-dimethylformamide (0.5 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (979 mg, 2.57 mmol) and N-ethyl-N-isopropylpropan-2-amine (998 mg, 7.72 mmol). After stirring at 20 °C for 16 h, the reaction mixture was diluted with ethyl acetate (60 mL) and washed with brine (3 × 30 mL). The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% methanol in dichloromethane) to give 3-methyl-1,3,4,5-tetrahydropyrido[3,4-b]azepin-2-one (800 mg, crude) as a yellow oil.

[0241] Step 5: 1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-4,5-dihydro-1H-pyrido[3,4-b]azepin-2(3H)-one, (S)-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-4,5-dihydro-1H-pyrido[3,4-b]azepin-2(3H)-one, (R)-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-4,5-dihydro-1H-pyrido[3,4-b]azepin-2(3H)-one [ka]

[0242] To a solution of 3-methyl-1,3,4,5-tetrahydropyrido[3,4-b]azepin-2-one (45 mg, 0.25 mmol) in N,N-dimethylformamide (1 mL) was added sodium hydride (60%, 7 mg, 0.17 mmol, 60%) at 0° C. After stirring for 30 minutes at 0° C., 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (50 mg, 0.17 mmol) was added to the reaction. After stirring for an additional 30 minutes at 20° C., the reaction mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by RP-HPLC (15–45% acetonitrile in water and 0.225% formic acid) to give 1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-3-methyl-4,5-dihydro-3H-pyrido[3,4-b]azepin-2-one (3.5 mg, 5%) as a white solid.

[0243] Another batch of racemic material (100 mg, 0.26 mmol) was further separated by SFC to give the following arbitrarily assigned:

[0244] (3S)-1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-3-methyl-4,5-dihydro-3H-pyrido[3,4-b]azepin-2-one (peak 1, retention time = 3.001 min) as a pale yellow solid (49.5 mg, 49%).

[0245] LCMS (0–60% in 4 min, 0.018% TFA in acetonitrile + 0.037% TFA in water)

[0246] Retention time 1.251 min, ESI + observed value [M+H] + =392.3.

[0247] (3R)-1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-3-methyl-4,5-dihydro-3H-pyrido[3,4-b]azepin-2-one (peak 2, retention time = 3.310 min) as a pale yellow solid (49.8 mg, 49%).

[0248] LCMS (0–60% in 4 min, 0.018% TFA in acetonitrile + 0.037% TFA in water)

[0249] Retention time 1.250 min, ESI + observed value [M+H] + =392.3.

[0250] SFC conditions: Column: Chiral ND-3 100 x 4.6 mm i.d., 3 μm; Mobile phase: A: CO2; B: Isopropanol (0.05% DEA); Gradient: 5% to 40% B in 4.5 min, hold at 40% for 2.5 min, then 5% B for 1 min; Flow rate: 2.8 mL / min; Column temperature: 40 °C.

[0251] 1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one (I-255), (R)-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one (I-250), (S)-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one (I-251). [ka]

[0252] Step 1: Methyl 3-(3-aminopyridin-4-yl)-2-methylacrylate [ka]

[0253] To a solution of 4-bromopyridin-3-amine (2.0 g, 11.56 mmol) in N,N-dimethylacetamide (2 mL) was added 2-methylprop-2-enoate methyl (2.3 g, 23.12 mmol), tetrabutylammonium chloride (321 mg, 1.16 mmol), N-cyclohexyl-N-methyl-cyclohexanamine (3.6 g, 18.50 mmol), and di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; and iron (753 mg, 1.16 mmol). After stirring at 80 °C for 16 h, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL) and washed with brine (3 × 100 mL). The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to give 3-(3-aminopyridin-4-yl)-2-methylacrylate (1.8 g, 81%) as a colorless oil.

[0254] Step 2: 3-Methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one [ka]

[0255] To a solution of methyl 3-(3-aminopyridin-4-yl)-2-methylacrylate (1.5 g, 7.80 mmol) in methanol (2 mL) was added palladium (1.6 g, 1.56 mmol, 10% carbon). After stirring at 50° C. under hydrogen (45 psi) for 16 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to give 3-methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one (300 mg, 23%) as a white solid.

[0256] Step 3: 1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one, (R)-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one, (S)-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one

[0257] To a solution of 3-methyl-3,4-dihydro-1H-1,7-naphthyridin-2-one (150 mg, 0.92 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (60%, 33 mg, 0.84 mmol) at 0° C. After stirring at 0° C. for 0.5 h, 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 248 mg, 0.84 mmol) was added to the reaction. After stirring at 20° C. for an additional 0.5 h, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (8–48% acetonitrile in water and 0.225% formic acid) to give 1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one (120 mg, 36%) as a white solid.

[0258] The above racemic material (100 mg, 0.26 mmol) was further separated by SFC to give the following arbitrarily assigned:

[0259] (R)-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one (peak 1, retention time = 1.984 min) as a colorless oil (24.7 mg, 24%).

[0260] (S)-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one (peak 2, retention time = 2.744 min) as a colorless oil (31.4 mg, 29%).

[0261] SFC conditions: Column: Chiral NS-3 100 x 4.6 mm i.d., 3 μm. Mobile phase: A:CO2, B:ethanol (0.05% DEA). Gradient: 5% to 40% B in 4 min, hold at 40% for 2.5 min, then 5% B for 1.5 min. Flow rate: 2.8 mL / min. Column temperature: 40°C.

[0262] Preparation of 1'-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'-one (I-247) [ka]

[0263] Step 1: Ethyl 2-(3-bromo-4-pyridyl)acetate [ka]

[0264] To a mixture of 3-bromo-4-methyl-pyridine (5.0 g, 29.07 mmol) and diethyl carbonate (4.0 g, 34.30 mmol) in tetrahydrofuran (50 mL) was added lithium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 46.0 mL, 46.0 mmol) at 0 °C. After stirring for 3 h at 0 °C under a nitrogen atmosphere, the mixture was carefully poured into saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (3 × 100 mL). The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-6% ethyl acetate in petroleum ether) to give ethyl 2-(3-bromo-4-pyridyl)acetate (5.68 g, 75%) as a colorless oil.

[0265] Step 2: Ethyl 1-(3-bromo-4-pyridyl)cyclopropanecarboxylate [ka]

[0266] To a solution of ethyl 2-(3-bromo-4-pyridyl)acetate (500 mg, 2.05 mmol) in N,N-dimethylformamide (35 mL) was added sodium hydride (60%, 180 mg, 4.51 mmol) at 0° C. After stirring for 15 minutes at 0° C., 1,2-dibromoethane (385 mg, 2.05 mmol) was added to the reaction. The mixture was stirred at 30° C. for 30 minutes, and then another batch of sodium hydride (60%, 41 mg, 1.02 mmol) was added. After completion of the reaction as monitored by TLC, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-3% ethyl acetate in petroleum ether) to give ethyl 1-(3-bromo-4-pyridyl)cyclopropanecarboxylate (390 mg, 47%) as a colorless oil.

[0267] Step 3: Ethyl 1-[3-(benzhydrylideneamino)-4-pyridyl]cyclopropanecarboxylate [ka]

[0268] A mixture of ethyl 1-(3-bromo-4-pyridyl)cyclopropanecarboxylate (1.1 g, 4.00 mmol), diphenylmethanimine (797 mg, 4.40 mmol), Pd(dba) (183 mg, 0.2 mmol), BINAP (249 mg, 0.4 mmol), and sodium tert-butoxide (576 mg, 6.00 mmol) in toluene (10 mL) was stirred at 80 °C for 16 h under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give ethyl 1-[3-(benzhydrylideneamino)-4-pyridyl]cyclopropanecarboxylate (836 mg, 50%) as a yellow solid.

[0269] Step 4: Ethyl 1-(3-amino-4-pyridyl)cyclopropanecarboxylate [ka]

[0270] To a solution of ethyl 1-[3-(benzhydrylideneamino)-4-pyridyl]cyclopropanecarboxylate (736 mg, 1.99 mmol) in tetrahydrofuran (7 mL) was added hydrochloric acid (1.0 M in water, 22.0 mL, 22.00 mmol). After stirring at 20 °C for 1 h, the mixture was diluted with water (30 mL) and washed with ethyl acetate (2 × 20 mL). The aqueous phase was adjusted to pH = 8 with sodium carbonate and extracted with dichloromethane (3 × 20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude ethyl 1-(3-amino-4-pyridyl)cyclopropanecarboxylate (300 mg) as a yellow oil.

[0271] Step 5: Spiro[1H-pyrrolo[2,3-c]pyridine-3,1'-cyclopropan]-2-one [ka]

[0272] To a solution of ethyl 1-(3-amino-4-pyridyl)cyclopropanecarboxylate (250 mg, 1.21 mmol) in tetrahydrofuran (5 mL) was added potassium tert-butoxide (272 mg, 2.42 mmol). The mixture was stirred at 20 °C for 1 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% methanol in dichloromethane) to give spiro[1H-pyrrolo[2,3-c]pyridin-3,1'-cyclopropan]-2-one (185 mg, 64%) as a colorless oil.

[0273] Step 6: 1'-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'-one [ka]

[0274] To a solution of spiro[1H-pyrrolo[2,3-c]pyridin-3,1'-cyclopropan]-2-one (19 mg, 0.13 mmol) in N,N-dimethylformamide (1 mL) was added sodium hydride (60%, 4 mg, 0.11 mmol) at 0° C. After stirring for 30 minutes at 0° C., 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 30 mg, 0.11 mmol) was added to the reaction. After stirring for 1 hour at 20° C., the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (0–30% acetonitrile and 0.225% formic acid in water) to give 1′-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′-one (10.8 mg, 17%) as a yellow solid.

[0275] Preparation of 1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-1H,2H,3H-pyrido[3,4-b][1,4]oxazin-2-one (I-176) [ka]

[0276] Step 1: 2-Chloro-N-(3-hydroxy-4-pyridyl)acetamide [ka]

[0277] A mixture of 4-aminopyridin-3-ol (200 mg, 1.82 mmol) and 2-chloroacetyl chloride (2 mL) was stirred at 80° C. for 2 hours and concentrated under reduced pressure. The residue was diluted with water (10 mL) and neutralized by the addition of saturated aqueous sodium bicarbonate solution. The solid precipitate was collected by filtration and dried under reduced pressure to give 2-chloro-N-(3-hydroxy-4-pyridyl)acetamide (324 mg, 93%) as a white solid.

[0278] Step 2: 1H-pyrido[3,4-b][1,4]oxazin-2-one [ka]

[0279] To a solution of 2-chloro-N-(3-hydroxy-4-pyridyl)acetamide (324 mg, 1.74 mmol) in water (8 mL) was added potassium carbonate (324 mg, 2.34 mmol). The mixture was stirred at 20° C. for 16 hours and concentrated to dryness under reduced pressure. The residue was washed with methanol (2 mL) and hot ethyl acetate (2 mL). The solid was collected by filtration and dried under reduced pressure to give crude 1H-pyrrolid[3,4-b][1,4]oxazin-2-one (370 mg) as a white solid.

[0280] Step 3: 1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-1H,2H,3H-pyrido[3,4-b][1,4]oxazin-2-one [ka]

[0281] To a solution of 1H-pyrido[3,4-b][1,4]oxazin-2-one (101 mg, 0.68 mmol) in tetrahydrofuran (2 mL) was added sodium hydride (60%, 15 mg, 0.37 mmol, 60% purity) under a nitrogen atmosphere at 0° C. After stirring at 0° C. for 0.5 h, a solution of 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 100 mg, 0.34 mmol) in tetrahydrofuran (1 mL) was added. The mixture was stirred at 25° C. for 16 h and quenched by the addition of saturated aqueous ammonium chloride solution (6 mL). The resulting solution was extracted with ethyl acetate (3×6 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (0–30% acetonitrile and 0.225% formic acid in water) to give 1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-1H,2H,3H-pyrido[3,4-b][1,4]oxazin-2-one (4.6 mg, 4%) as a pale yellow oil.

[0282] The method described in Example 2 was also used to prepare the following compounds: I-171, I-172, I-173, I-186, I-195, I-198, I-199, I-200, I-209, I-210, I-248, I-249, I-254, I-256, I-269, and I-270.

[0283] Example 3. Synthesis of amide compound of formula (I) - by Pd coupling

[0284] Preparation of (R)-3-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-4-phenyloxazolidin-2-one (compound I-43) and (S)-3-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-4-phenyloxazolidin-2-one (compound I-44). [ka]

[0285] A solution of methyl 2-bromo-1,3-thiazole-5-carboxylate (2 g, 9.01 mmol) in 3:2:1 THF / water / methanol (24 mL:16 mL:8 mL) was treated with LiOH (2 equiv., 431 mg, 18 mmol). After 5 min at room temperature, LCMS indicated complete conversion. The mixture was neutralized to pH 7 and concentrated. The remaining aqueous layer was acidified to pH 1 with 6 N HCl. The precipitate was filtered and washed with water and a small amount of hexane (the desired product was partially dissolved in hexane). The solid was dried under high vacuum for 2 h, transferred to a pear-shaped flask, rinsed with toluene 3x (to azeotropically remove water), and dried again under high vacuum to give 1.80 g (96%) of 2-bromothiazole-5-carboxylic acid as a white solid.

[0286] To a cooled (0° C.) solution of the amine (1.25 g, 6 mmol), ({[3-(dimethylamino)propyl]imino}-methylidene)(ethyl)amine hydrochloride (1.1 equiv., 1.27 g, 6.61 mmol), (tert-butoxy)carbohydrazide (1.3 equiv., 1.03 g, 7.81 mmol), and 1H-1,2,3,benzotriazol-1-ol (1.3 equiv., 1.06 g, 7.81 mmol) in DMF (20 mL) was added DIPEA (4 equiv., 3.11 g, 4.19 mmol, 24 mmol) dropwise. After 90 min, LCMS indicated complete conversion. The mixture was poured into water and brine (1:1, 300 mL) and extracted with EtOAc (3×). The combined organics were washed with brine (3×) and dried (Na 2 S04) and concentration gave 3.5 g of a yellow oil. The crude material was purified by column chromatography (80 g of SiO2, 0-50% EA in hexanes). Yield: 1.39 g (72%) of 2-bromo-N'-[(tert-butoxy)carbonyl]-1,3-thiazole-5-carbohydrazide was obtained as a white solid.

[0287] To a cooled (0° C.) solution of 2-bromo-N′-[(tert-butoxy)carbonyl]-1,3-thiazole-5-carbohydrazide (819 mg, 2.54 mmol) in anhydrous DCM (7 mL) was added dropwise 4 M HCl in dioxane (15 equiv., 38.1 mmol, 9.53 mL). The mixture was stirred at room temperature for 16 h. LCMS showed complete conversion. The mixture was treated with a 1:3 mixture of MTBE:hexane (50 mL). The precipitate was filtered, washed with hexane, and dried under high vacuum. Yield: 529.7 mg (80%) of 2-bromothiazole-5-carbohydrazide hydrochloride as an off-white solid.

[0288] A suspension of 2-bromo-1,3-thiazole-5-carbohydrazide HCl (250 mg, 0.968 mmol) in anhydrous THF (5 mL) was treated with triethylamine (6 equiv., 588 mg, 0.81 mL, 5.81 mmol), followed by difluoroacetic anhydride (2 equiv., 344 mg, 0.215 mL, 1.94 mmol). The mixture was stirred at 70 °C for 21 h. LCMS indicated total consumption of starting material but not the desired mass or specific amount of bromide. However, when a small sample was reacted with phenethylamine, the reaction afforded the desired Sn-Ar product, confirming that the bromide was intact. The mixture was quenched with water (0.3 mL) and concentrated. The residue was rinsed with dichloromethane and evaporated. The process was repeated four times. 1.28 g of residue was obtained and purified by column chromatography (40 g SiO, 0-10% MeOH in dichloromethane). Yield: 238.3 mg (82%) of 2-bromo-N'-(2,2-difluoroacetyl)thiazole-5-carbohydrazide as a yellow solid.

[0289] A mixture of 2-bromo-N'-(2,2-difluoroacetyl)-1,3-thiazole-5-carbohydrazide (154 mg, 0.513 mmol) and Burgess reagent (5 equiv., 619 mg, 2.57 mmol) in anhydrous THF (5 mL) was heated in a microwave at 150 °C for 90 min. LCMS showed complete conversion. The desired product was not fully ionized, [M+H]+ No 282 / 284 was observed (although the previous step demonstrated that the bromide was intact). THF was removed on a rotary evaporator. The mixture was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2x). The combined organics were washed with brine, dried (Na2SO4), and concentrated to give 146 mg of crude material, which was purified by column chromatography (12 g SiO2, 0-15% EA in hexanes). Yield: 59.9 mg (41%) of 2-(2-bromothiazol-5-yl)-5-(difluoromethyl)-1,3,4-oxadiazole as a white solid.

[0290] A mixture of 2-(2-bromo-1,3-thiazol-5-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (33.4 mg, 0.118 mmol), (4R)-4-phenyl-1,3-oxazolidin-2-one (1.3 equiv., 25 mg, 0.149 mmol), and cesium carbonate (1.5 equiv., 34.3 mg, 0.177 mmol) in dioxane (2 mL) was flushed with nitrogen for 5 minutes. Xantphos (0.09 equiv., 6.14 mg, 0.01062 mmol) and tetrakis(triphenylphosphine)-palladium (0.1 equiv., 13.6 mg, 0.0118 mmol) were added. The mixture was flushed with nitrogen for 10 minutes, sealed, and heated in a microwave at 125 °C for 2 hours. LCMS showed complete conversion. The mixture was poured into water and extracted with ethyl acetate (3x). The combined organics were washed with water (3x), brine, dried (Na2SO4), and concentrated to give 101 mg of a yellow solid. The crude material was purified by column chromatography (4 g SiO2, 0-50% EA in hexanes). Yield: 15.6 mg (54%) of (R)-3-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-4-phenyloxazolidin-2-one (I-43) as a yellow solid.

[0291] A mixture of 2-(2-bromo-1,3-thiazol-5-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (22.2 mg, 0.079 mmol), (4S)-4-phenyl-1,3-oxazolidin-2-one (1.3 equiv., 15.4 mg, 0.0944 mmol), and cesium carbonate (1.5 equiv., 22.9 mg, 0.118 mmol) in dioxane (2 mL) was flushed with nitrogen for 5 minutes. Xantphos (0.09 equiv., 4.10 mg, 0.0071 mmol) and tetrakis(triphenylphosphine)-palladium (0.1 equiv., 9.10 mg, 0.0079 mmol) were added. The mixture was flushed with nitrogen for 10 minutes, sealed, and heated in a microwave at 125 °C for 2 hours. LCMS showed complete conversion. The mixture was poured into water and extracted with ethyl acetate (3x). The combined organics were washed with water (3x), brine, dried (Na2SO4), and concentrated to give 60 mg of a yellow solid. The crude material was purified by column chromatography (4 g SiO2, 0-50% EA in hexanes). Yield: 14.6 mg (51%) of (S)-3-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-4-phenyloxazolidin-2-one (I-44) as a yellow solid.

[0292] The method described in Example 3 was also used to prepare compound I-101.

[0293] Example 4. Synthesis of sulfonamide compounds of formula (I) [ka]

[0294] Preparation of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(pyridin-3-yl)ethanesulfonamide (compound I-6). [ka]

[0295] Step 1: Preparation of N-(pyridin-3-yl)ethanesulfonamide. [ka]

[0296] 3-Aminopyridine (370 mg, 3.9 mmol) was taken up in DCM (15 mL) and cooled in an ice bath. Pyridine (0.35 mL, 4.3 mmol) and ethanesulfonyl chloride (0.4 mL, 0.43 mmol) were added, and the resulting solution was stirred at room temperature for 16 hours. The reaction was quenched by adding saturated brine and then extracted with DCM. The separated organic layer was filtered through MgSO4 and then concentrated. The residue was purified by Combiflash® (hexane / EtOAc gradient) to give the title compound (120 mg, 17%) as a white powder.

[0297] Step 2: Preparation of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(pyridin-3-yl)ethanesulfonamide. [ka]

[0298] N-(pyridin-3-yl)ethane-1-sulfonamide (31 mg, 0.17 mmol) was taken up in DMF (0.4 ml) in an ice bath. Sodium hydride (7 mg, 60% wt, 0.17 mmol) was then added, and the solution was stirred in an ice bath for 30 minutes. A solution of 2-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 31 mg, 0.17 mmol) in DMF (0.5 ml) was then added, and the reaction was stirred at room temperature for 16 hours. TLC showed the reaction was complete. The reaction was quenched by adding saturated NH4Cl solution and then extracted with EtOAc. The organic layer was filtered through MgSO4 and then concentrated. The residue was purified by Combiflash® (DCM / methanol gradient) to give the title compound.

[0299] Preparation of N-[5-(difluoromethoxy)-3-pyridyl]-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]ethanesulfonamide (compound I-96). [ka]

[0300] Step 1: 3-(Difluoromethoxy)-5-nitropyridine [ka]

[0301] To a solution of 5-nitropyridin-3-ol (500 mg, 3.57 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (1.48 g, 10.71 mmol). The mixture was stirred at 20°C for 30 minutes, and then 2-chloro-2,2-difluoroacetate (1.4 g, 8.92 mmol) was added. The reaction mixture was stirred at 100°C for 4 hours and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 10-30% ethyl acetate in petroleum ether) to give 3-(difluoromethoxy)-5-nitro-pyridine (200 mg, 29%) as a yellow oil.

[0302] Step 2: 5-(Difluoromethoxy)pyridin-3-amine [ka]

[0303] To a solution of 3-(difluoromethoxy)-5-nitro-pyridine (150 mg, 0.80 mmol) in ethanol (2 mL) was added palladium (10% on carbon, 84 mg). The reaction mixture was stirred under a hydrogen atmosphere at 15 psi for 2 hours and filtered. The filtrate was concentrated under reduced pressure to give 5-(difluoromethoxy)pyridin-3-amine (150 mg, crude) as a yellow solid.

[0304] Step 3: N-(5-(difluoromethoxy)pyridin-3-yl)ethanesulfonamide [ka]

[0305] To a solution of 5-(difluoromethoxy)pyridin-3-amine (130 mg, 0.8 mmol) in pyridine (2 mL) was added ethanesulfonyl chloride (125 mg, 0.97 mmol). The reaction mixture was stirred at 20° C. for 16 hours and concentrated under reduced pressure. The residue was purified by RP-TLC (dichloromethane:methanol=10:1) to give N-[5-(difluoromethoxy)-3-pyridyl]ethanesulfonamide (200 mg, 98%) as a white solid.

[0306] Step 4: N-[5-(difluoromethoxy)-3-pyridyl]-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]ethanesulfonamide (compound I-96) [ka]

[0307] Prepared from 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole according to the method described in I-6. The crude product was purified by RP-HPLC (50–80% acetonitrile in water and 0.225% formic acid) to give N-[5-(difluoromethoxy)-3-pyridyl]-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]ethanesulfonamide (19.7 mg, 30%) as a white solid.

[0308] Preparation of N-[5-(difluoromethoxy)pyridin-3-yl]-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)methanesulfonamide (I-147) [ka]

[0309] Prepared from 5-(difluoromethoxy)pyridin-3-amine and methanesulfonyl chloride according to the method described in I-6. The crude product was purified by RP-HPLC (35–65% acetonitrile in water and 0.225% formic acid) to give N-[5-(difluoromethoxy)pyridin-3-yl]-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)methanesulfonamide (12 mg, 16%) as a pale yellow solid.

[0310] Preparation of N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[5-(2,2-difluoropropoxy)pyridin-3-yl]methanesulfonamide (I-224) [ka]

[0311] Step 1: 1-((5-bromopyridin-3-yl)oxy)propan-2-one [ka]

[0312] To a mixture of 5-bromopyridin-3-ol (2.0 g, 11.49 mmol) and 1-chloropropan-2-one (1.3 g, 13.79 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.8 g, 12.64 mmol). After stirring at 20 °C for 16 h, the reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (3 × 50 mL), dried, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0-15% ethyl acetate in petroleum ether) to give 1-[(5-bromo-3-pyridyl)oxy]propan-2-one (2.6 g, 93%) as a brown solid.

[0313] Step 2: 3-Bromo-5-(2,2-difluoropropoxy)pyridine [ka]

[0314] To a solution of 1-[(5-bromo-3-pyridyl)oxy]propan-2-one (2.4 g, 10.43 mmol) in dichloromethane (20 mL) was added diethylaminosulfur trifluoride (3.4 g, 20.86 mmol) at 0 °C. The mixture was then stirred at 20 °C for 2 h and carefully poured into ice-water (100 mL). The solution was extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were dried and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100–200 mesh, 0–13% ethyl acetate in petroleum ether) to give 3-bromo-5-(2,2-difluoropropoxy)pyridine (1.85 g, 70%) as a yellow oil.

[0315] Step 3: 5-(2,2-difluoropropoxy)-N-(diphenylmethylene)pyridin-3-amine [ka]

[0316] To a solution of 3-bromo-5-(2,2-difluoropropoxy)pyridine (1.9 g, 7.34 mmol) and diphenylmethanimine (1.5 g, 8.07 mmol) in toluene (20 mL) was added sodium tert-butoxide (1.1 g), (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthalene (457 mg, 0.73 mmol), and tris(dibenzylideneacetone)dipalladium(0) (336 mg, 0.37 mmol). The mixture was heated at 80° C. under a nitrogen atmosphere for 16 hours and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give N-[5-(2,2-difluoropropoxy)-3-pyridyl]-1,1-diphenyl-methanimine (2.64 g, 77%) as a yellow oil.

[0317] Step 3: 5-(2,2-difluoropropoxy)pyridin-3-amine [ka]

[0318] To a solution of N-[5-(2,2-difluoropropoxy)-3-pyridyl]-1,1-diphenyl-methanimine (2.3 g, 6.64 mmol) in tetrahydrofuran (23 mL) was added hydrochloric acid (2 M, 6.0 mL, 12.0 mmol). The mixture was stirred at 20 °C for 2 hours and diluted with water (50 mL). The resulting solution was washed with ethyl acetate (3 × 50 mL). The separated aqueous layer was adjusted to pH = 8 by the addition of aqueous sodium hydroxide (1 M) and extracted with dichloromethane (3 × 20 mL). The combined organic extracts were dried and concentrated under reduced pressure to give crude 5-(2,2-difluoropropoxy)pyridin-3-amine (1.32 g, crude) as a yellow solid.

[0319] Step 4: N-[5-(2,2-difluoropropoxy)-3-pyridyl]methanesulfonamide [ka]

[0320] To a solution of 5-(2,2-difluoropropoxy)pyridin-3-amine (100 mg, 0.53 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (73 mg, 0.64 mmol). The mixture was stirred at 20° C. for 16 h and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to give N-[5-(2,2-difluoropropoxy)-3-pyridyl]methanesulfonamide (112 mg, 77%) as a yellow solid.

[0321] Step 5: N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[5-(2,2-difluoropropoxy)pyridin-3-yl]methanesulfonamide [ka]

[0322] To a solution of 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 50 mg, 0.17 mmol) and N-[5-(2,2-difluoropropoxy)-3-pyridyl]methanesulfonamide (49 mg, 0.19 mmol) in N,N-dimethylformamide (1 mL) was added sodium bicarbonate (35 mg, 0.42 mmol). The mixture was stirred at 20° C. for 16 hours and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by RP-HPLC (35–65% acetonitrile in water and 0.225% formic acid) to give N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[5-(2,2-difluoropropoxy)pyridin-3-yl]methanesulfonamide (26 mg, 32%) as a yellow oil.

[0323] N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[5-(1-fluoroethyl)pyridin-3-yl]ethane-1-sulfonamide (I-227), N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-{5-[(1S)-1-fluoroethyl]pyridin-3-yl}ethane-1-sulfonamide (I-207), and N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-{5-[(1R)-1-fluoroethyl]pyridin-3-yl}ethane-1-sulfonamide (I-208). [ka]

[0324] Step 1: 1-(5-bromo-3-pyridyl)ethanol [ka]

[0325] To a solution of 1-(5-bromo-3-pyridyl)ethanone (3.0 g, 15.00 mmol) in methanol (30 mL) was added sodium borohydride (1.1 g, 30.00 mmol) in small portions. The mixture was stirred at 20 °C for 16 hours and concentrated under reduced pressure. The residue was diluted with saturated aqueous ammonium chloride (10 mL) and water (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were dried and concentrated. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give 1-(5-bromo-3-pyridyl)ethanol (2.80 g, 92%) as a colorless oil.

[0326] Step 2: 3-Bromo-5-(1-fluoroethyl)pyridine [ka]

[0327] To a solution of 1-(5-bromo-3-pyridyl)ethanol (2.6 g, 12.87 mmol) in dichloromethane (2 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (2.9 g, 13.06 mmol) dropwise at 0 °C under a nitrogen atmosphere. The mixture was stirred at 20 °C for 0.5 h and quenched by the addition of saturated aqueous sodium bicarbonate (40 mL). The mixture was then extracted with ethyl acetate (3 × 40 mL). The combined organic extracts were dried and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum ether) to give 3-bromo-5-(1-fluoroethyl)pyridine (1.78 g, 65%) as a pale yellow oil.

[0328] Step 3: N-[5-(1-fluoroethyl)-3-pyridyl]-1,1-diphenyl-methanimine [ka]

[0329] To a solution of 3-bromo-5-(1-fluoroethyl)pyridine (1.8 g, 8.72 mmol) and diphenylmethanimine (1.7 g, 9.60 mmol) in toluene (30 mL) was added (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthalene (543 mg, 0.87 mmol), sodium tert-butoxide (838 mg, 8.72 mmol), and tris(dibenzylideneacetone)dipalladium (399 mg, 0.44 mmol) under nitrogen at 20° C. The mixture was stirred at 80° C. for 16 hours and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give N-[5-(1-fluoroethyl)-3-pyridyl]-1,1-diphenyl-methanimine (2.19 g, 73%) as a pale yellow oil.

[0330] Step 4: 5-(1-fluoroethyl)pyridin-3-amine [ka]

[0331] To a solution of N-[5-(1-fluoroethyl)-3-pyridyl]-1,1-diphenyl-methanimine (500 mg, 1.64 mmol) in tetrahydrofuran (6 mL) was added hydrochloric acid (1 M, 2.0 mL, 2.0 mmol) at 20 °C. The mixture was stirred at 20 °C for 2 hours and diluted with water (10 mL). The solution was washed with ethyl acetate (3 × 10 mL). The aqueous layer was adjusted to pH = 8 by adding aqueous sodium hydroxide (1 M) and extracted with dichloromethane (3 × 10 mL). The combined organic extracts were dried and concentrated under reduced pressure to give crude 5-(1-fluoroethyl)pyridin-3-amine (200 mg, 86%) as a pale yellow oil.

[0332] Step 5: N-[5-(1-fluoroethyl)-3-pyridyl]ethanesulfonamide [ka]

[0333] To a solution of 5-(1-fluoroethyl)pyridin-3-amine (200 mg, 1.43 mmol) in pyridine (5 mL) was added ethanesulfonyl chloride (220 mg, 1.71 mmol) at 20° C. The mixture was stirred at 20° C. for 16 hours and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to give N-[5-(1-fluoroethyl)-3-pyridyl]ethanesulfonamide (236 mg, 71%) as a white solid.

[0334] Step 6: N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[5-(1-fluoroethyl)pyridin-3-yl]ethane-1-sulfonamide and N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-{5-[(1S)-1-fluoroethyl]pyridin-3-yl}ethane-1-sulfonamide and N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-{5-[(1R)-1-fluoroethyl]pyridin-3-yl}ethane-1-sulfonamide

[0335] To a solution of N-[5-(1-fluoroethyl)-3-pyridyl]ethanesulfonamide (206 mg, 0.89 mmol) in N,N-dimethylformamide (4.5 mL) were added 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (263 mg, 0.89 mmol) and sodium bicarbonate (224 mg, 2.66 mmol) at 20° C. The mixture was stirred at 20° C. for 16 hours and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (0–40% acetonitrile and 0.225% formic acid in water) to give N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[5-(1-fluoroethyl)pyridin-3-yl]ethane-1-sulfonamide (101.2 mg, 25%) as a brown oil.

[0336] The above racemate (98 mg, 0.22 mmol) was further separated by SFC to give the following arbitrarily assigned:

[0337] N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-{5-[(1R)-1-fluoroethyl]pyridin-3-yl}ethane-1-sulfonamide (peak 1, retention time = 2.597 min) (11.1 mg, 11%) as a pale yellow oil.

[0338] N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-{5-[(1S)-1-fluoroethyl]pyridin-3-yl}ethane-1-sulfonamide (peak 2, retention time = 2.689 min) (15.2 mg, 15%) as a pale yellow oil.

[0339] SFC conditions: Column: (S,S)-Whelk-0-3 50iA 4.6 mm id 1.8 μm, Mobile phase: A:CO2, B:ethanol (0.05% DEA), Gradient: 5% to 40% B in 4.5 min, 40% B for 2.5 min, then 5% B for 1.5 min, Flow rate: 2.8 mL / min, Column temperature: 40 °C.

[0340] Preparation of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(1-phenylcyclopropyl)ethanesulfonamide (compound I-20). [ka]

[0341] Step 1: Preparation of N-(1-phenylcyclopropyl)ethanesulfonamide. [ka]

[0342] To a vial containing commercially available 1-phenylcyclopropan-1-amine (200 mg, 1.50 mmol) in DCM (1 mL) at ambient temperature was added pyridine (143 mg, 1.80 mmol), followed by ethanesulfonyl chloride (232 mg, 1.80 mmol). The mixture was stirred at ambient temperature for 18 h. Quenched with 1N HCl, the reaction mixture was extracted with EtOAc. The organic layer was washed with water, dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by chromatography (silica gel, EtOAc / hexane, 0:1 to 1:1) to afford 95 mg (28.1%) of the title compound as an oil.

[0343] Step 2: N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(1-phenylcyclopropyl)ethanesulfonamide [ka]

[0344] To a vial containing NaH (7.29 mg, 60 wt% in mineral oil, 0.18 mmol) in DMF at 0 °C was added dropwise a solution of N-(1-phenylcyclopropyl)ethanesulfonamide from Step 1 in DMF (45 mg, 0.20 mmol). After stirring the reaction at ambient temperature for 10 minutes, the mixture was added dropwise to a cooled solution of 2-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 40 mg, 0.14 mmol) in DMF in an ice bath. The reaction mixture was then stirred and warmed to ambient temperature for 4 hours, then quenched with saturated aqueous NH4Cl, EtOAc was added, and the organic layer was dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by chromatography (silica gel, EtOAc / hexane, 0:1 to 3:2) to give 22 mg (37%) of a light brow solid.

[0345] Preparation of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(1-(difluoromethyl)-1H-pyrazol-4-yl)ethanesulfonamide (compound I-48). [ka]

[0346] Step 1: N-[1-(difluoromethyl)pyrazol-4-yl]ethanesulfonamide [ka]

[0347] To a solution of 1-(difluoromethyl)pyrazol-4-amine (100 mg, 0.75 mmol) in pyridine (2 mL) was added ethanesulfonyl chloride (116 mg, 0.90 mmol). The mixture was stirred at 20° C. for 16 hours and concentrated under reduced pressure. The residue was purified by RP-TLC (dichloromethane:methanol=20:1) to give N-[1-(difluoromethyl)pyrazol-4-yl]ethanesulfonamide (100 mg, 59%) as a red solid.

[0348] Step 2: N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(1-(difluoromethyl)-1H-pyrazol-4-yl)ethanesulfonamide (compound I-48) [ka]

[0349] To a solution of 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 17 mg, 0.06 mmol) in N,N-dimethylformamide (0.2 mL) was added sodium bicarbonate (15 mg, 0.17 mmol) and N-[1-(difluoromethyl)pyrazol-4-yl]ethanesulfonamide (19 mg, 0.08 mmol). The mixture was stirred at 20° C. for 16 hours and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by RP-HPLC (22–55% acetonitrile in water and 0.225% formic acid) to give N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-[1-(difluoromethyl)pyrazol-4-yl]ethanesulfonamide (14.1 mg, 56%) as a yellow solid.

[0350] Preparation of N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(1H-imidazol-5-yl)ethane-1-sulfonamide (I-235) [ka]

[0351] Step 1: Trimethyl-[2-[(5-nitroimidazol-1-yl)methoxy]ethyl]silane [ka]

[0352] To a solution of 5-nitro-1H-imidazole (2.0 g, 18 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (60%, 1.1 g, 28 mmol) at 0 °C under a nitrogen atmosphere. The mixture was stirred at 20 °C for 1 h, and then 2-(chloromethoxy)ethyl-trimethyl-silane (3.5 g, 21 mmol) was added. The resulting mixture was stirred at 20 °C for 16 h and quenched by the addition of water (5 mL). The solution was extracted with ethyl acetate (100 mL). The organic extract was washed with brine (100 mL), dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give trimethyl-[2-[(5-nitroimidazol-1-yl)methoxy]ethyl]silane (3.75 g, 83%) as a yellow solid.

[0353] Step 2: 3-(2-trimethylsilylethoxymethyl)imidazol-4-amine [ka]

[0354] To a solution of trimethyl-[2-[(5-nitroimidazol-1-yl)methoxy]ethyl]silane (1.0 g, 4 mmol) in tetrahydrofuran (10 mL) was added palladium (10% carbon, 437 mg, 0.41 mmol). The mixture was hydrogenated (15 psi) at 20° C. for 1 hour and filtered. The filtrate was concentrated to dryness under reduced pressure to give crude 3-(2-trimethylsilylethoxymethyl)imidazol-4-amine (800 mg, crude) as a brown-black oil, which was used directly in the next step.

[0355] Step 3: N-[3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]ethanesulfonamide [ka]

[0356] To a solution of 3-(2-trimethylsilylethoxymethyl)imidazol-4-amine (800 mg, 3.75 mmol) in tetrahydrofuran (15 mL) was added ethanesulfonyl chloride (579 mg, 4.50 mmol) and pyridine (890 mg, 11.25 mmol). The mixture was stirred at 20° C. for 2 hours and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to give N-[3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]ethanesulfonamide (53 mg, 4%) as a pale yellow solid.

[0357] Step 4: N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-[3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]ethanesulfonamide [ka]

[0358] To a solution of N-[3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]ethanesulfonamide (50 mg, 0.16 mmol) in N,N-dimethylformamide (2 mL) was added 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 80 mg, 0.27 mmol) and sodium bicarbonate (34 mg, 0.41 mmol). The mixture was stirred at 20° C. for 2 hours and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol=20:1) to give N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-[3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]ethanesulfonamide (65 mg, 46%) as a yellow solid.

[0359] Step 5: N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(1H-imidazol-5-yl)ethane-1-sulfonamide [ka]

[0360] To a solution of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-[3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]ethanesulfonamide (59 mg, 0.11 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (6 mL) was added trifluoroacetic acid (129 mg, 1.13 mmol). The mixture was stirred at 20° C. for 16 hours and concentrated to dryness under reduced pressure. The residue was purified by RP-HPLC (20–50% acetonitrile in water and 0.225% formic acid) to give N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(1H-imidazol-5-yl)ethane-1-sulfonamide (9.7 mg, 22%) as a pale yellow solid.

[0361] Preparation of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-(difluoromethyl)pyridin-3-yl)ethanesulfonamide (compound I-60). [ka]

[0362] Step 1: 3-Bromo-5-(difluoromethyl)pyridine [ka]

[0363] To a solution of 5-bromopyridine-3-carbaldehyde (500 mg, 2.7 mmol) in dichloromethane (4 mL) was added diethylaminosulfur trifluoride (867 mg, 5.38 mmol) at 0 °C under a nitrogen atmosphere. The mixture was then warmed to 20 °C and stirred for 2 h. After quenching by careful addition of water (50 mL), the reaction was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give 3-bromo-5-(difluoromethyl)pyridine (370 mg, 66%) as a yellow solid.

[0364] Step 2: N-[5-(difluoromethyl)-3-pyridyl]-1,1-diphenyl-methanimine [ka]

[0365] A mixture of 3-bromo-5-(difluoromethyl)pyridine (300 mg, 1.44 mmol), diphenylmethanimine (262 mg, 1.44 mmol), BINAP (90 mg, 0.14 mmol), Pd(dba) (66 mg, 0.07 mmol), and sodium tert-butoxide (139 mg, 1.44 mmol) in toluene (2 mL) was stirred at 80 °C for 16 h under nitrogen protection. The reaction was quenched by the addition of water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give N-[5-(difluoromethyl)-3-pyridyl]-1,1-diphenyl-methanimine (300 mg, 68%) as a yellow solid.

[0366] Step 3: 5-(Difluoromethyl)pyridin-3-amine [ka]

[0367] A solution of N-[5-(difluoromethyl)-3-pyridyl]-1,1-diphenyl-methanimine (300 mg, 0.97 mmol) and hydrochloric acid (1 M in water, 2 mL) in tetrahydrofuran (5 mL) was stirred at 20° C. for 2 hours. The reaction mixture was diluted with water (50 mL) and then washed with ethyl acetate (50 mL×2). The aqueous layer was adjusted to pH=11 by adding aqueous sodium hydroxide (1.0 M) and extracted with dichloromethane (50 mL×2). The combined organic layers were dried over sodium sulfate and concentrated to dryness under reduced pressure to give crude 5-(difluoromethyl)pyridin-3-amine (112 mg, 80%) as a yellow solid.

[0368] Step 4: N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-(difluoromethyl)pyridin-3-yl)ethanesulfonamide (compound I-60) [ka]

[0369] Prepared from 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole as described above for I-6. The crude product was purified by RP-HPLC (30–60% acetonitrile in water and 0.05% ammonia hydroxide) to give N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-[5-(difluoromethyl)-3-pyridyl]ethanesulfonamide (4.9 mg, 16%) as a white solid.

[0370] Preparation of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)ethanesulfonamide (compound I-81). [ka]

[0371] Step 1: N-(5-fluoropyrimidin-2-yl)ethanesulfonamide [ka]

[0372] A mixture of 2-chloro-5-fluoro-pyrimidine (150 mg, 1.13 mmol), ethanesulfonamide (148 mg, 1.36 mmol), and cesium carbonate (922 mg, 2.83 mmol) in dimethyl sulfoxide (3 mL) was stirred at 100 °C for 16 h and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by RP-HPLC (10-40% acetonitrile in water and 0.225% formic acid) to give N-(5-fluoropyrimidin-2-yl)ethanesulfonamide (63 mg, 27%) as a white solid.

[0373] Step 2: N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)ethanesulfonamide (compound I-81) [ka]

[0374] A mixture of N-(5-fluoropyrimidin-2-yl)ethanesulfonamide (12 mg, 0.06 mmol), 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 15 mg, 0.05 mmol), and potassium carbonate (21 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL) was stirred at 20 °C for 1 h and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by RP-HPLC (44-74% acetonitrile in water and 0.225% formic acid) to give N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-(5-fluoropyrimidin-2-yl)ethanesulfonamide (9.9 mg, 46%) as a yellow solid.

[0375] Preparation of N-(pyridin-3-yl)-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)ethane-1-sulfonamide (I-119) [ka]

[0376] Step 1: 2-(2-methylthiazol-5-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole [ka]

[0377] To a solution of 2-methylthiazole-5-carbohydrazide (3.5 g, 22.27 mmol) in N,N-dimethylformamide (50 mL) was added trifluoroacetic anhydride (18.7 g, 89.06 mmol) and triethylamine (22.5 g, 222.66 mmol). After stirring at 70 °C for 2 h, the reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (3 × 50 mL), dried, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0-15% ethyl acetate in petroleum ether) to give 2-(2-methylthiazol-5-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole (2.2 g, 39%) as a yellow solid.

[0378] Step 2: 2-(2-(bromomethyl)thiazol-5-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole [ka]

[0379] To a solution of 2-(2-methylthiazol-5-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole (2.3 g, 9.78 mmol) in 1,2-dichloroethane (100 mL) was added N-bromosuccinimide (2.6 g, 14.67 mmol) and azodiisobutyronitrile (azobisisobutyronitrile) (161 mg, 0.98 mmol). The mixture was stirred at 80 °C for 12 h and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give 2-[2-(bromomethyl)thiazol-5-yl]-5-(trifluoromethyl)-1,3,4-oxadiazole (1.11 g, 35%) as a yellow solid.

[0380] Step 3: N-(pyridin-3-yl)-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)ethane-1-sulfonamide [ka]

[0381] To a solution of N-(3-pyridyl)ethanesulfonamide (28 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL) was added sodium bicarbonate (32 mg, 0.38 mmol) and 2-[2-(bromomethyl)thiazol-5-yl]-5-(trifluoromethyl)-1,3,4-oxadiazole (4b, 40 mg, 0.13 mmol). The mixture was stirred at 20 °C for 2 h and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by RP-HPLC (45–75% acetonitrile in water and 0.225% formic acid) to give N-(pyridin-3-yl)-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)ethane-1-sulfonamide (7.0 mg, 13%) as a yellow solid.

[0382] Preparation of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)ethanesulfonamide (Compound I-102) [ka]

[0383] Step 1: [1-(6-bromo-3-pyridyl)-1-methyl-ethoxy]-tert-butyl-dimethyl-silane [ka]

[0384] To a solution of 2-(6-bromo-3-pyridyl)propan-2-ol (70 mg, 0.32 mmol) in dichloromethane (1 mL) was added 2,6-lutidine (69 mg, 0.65 mmol) and [tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (128 mg, 0.49 mmol). After stirring at 20 °C for 2 h, the reaction was quenched by the addition of water (10 mL) and ethyl acetate (30 mL). The separated organic layer was dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give [1-(6-bromo-3-pyridyl)-1-methyl-ethoxy]-tert-butyl-dimethyl-silane (70 mg, 65%) as a colorless oil.

[0385] Step 2: N-[5-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-2-pyridyl]ethanesulfonamide [ka]

[0386] To a solution of [1-(6-bromo-3-pyridyl)-1-methyl-ethoxy]-tert-butyl-dimethyl-silane (160 mg, 0.48 mmol) in 1,4-dioxane (6 mL) was added ethanesulfonamide (159 mg, 1.45 mmol), cesium carbonate (789 mg, 2.42 mmol), Xantphos (56 mg, 0.10 mmol), and Pd(dba) (44 mg, 0.05 mmol). The reaction mixture was stirred at 110 °C under a nitrogen atmosphere for 16 h and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100–200 mesh, 0–10% methanol in dichloromethane) to give N-[5-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-2-pyridyl]ethanesulfonamide (71 mg, 38%) as a yellow solid.

[0387] Step 3: N-[5-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-2-pyridyl]-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]ethanesulfonamide [ka]

[0388] To a solution of N-[5-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-2-pyridyl]ethanesulfonamide (68 mg, 0.19 mmol) in N,N-dimethylformamide (2 mL) was added 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 73 mg, 0.25 mmol) and sodium bicarbonate (48 mg, 0.57 mmol). The reaction mixture was stirred at 20° C. for 6 hours and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100–200 mesh, 0–25% ethyl acetate in petroleum ether) to give N-[5-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-2-pyridyl]-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]ethanesulfonamide (13 mg, 11%) as a yellow oil.

[0389] Step 4: N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)ethanesulfonamide (compound I-102) [ka]

[0390] To a solution of N-[5-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-2-pyridyl]-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]ethanesulfonamide (10 mg, 0.02 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (2 mL) was added trifluoroacetic acid (154 mg, 1.35 mmol). The reaction mixture was stirred at 20° C. for 2 hours and concentrated under reduced pressure. The residue was purified by RP-HPLC (35–65% acetonitrile in water and 0.225% formic acid) to give N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-[5-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]ethanesulfonamide (5.8 mg, 72%) as a white solid.

[0391] Preparation of 2-cyano-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-methylpyridin-3-yl)ethane-1-sulfonamide (I-219) [ka]

[0392] Step 1: Methyl 3-[(5-methyl-3-pyridyl)sulfamoyl]propanoate [ka]

[0393] To a solution of 5-methylpyridin-3-amine (400 mg, 3.70 mmol) in pyridine (6 mL) was added methyl 3-chlorosulfonylpropanoate (966 mg, 5.18 mmol). The mixture was stirred at 20° C. for 16 hours and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to give methyl 3-[(5-methyl-3-pyridyl)sulfamoyl]propanoate (440 mg, 40%) as a pale yellow solid.

[0394] Step 2: 3-[(5-methyl-3-pyridyl)sulfamoyl]propanoic acid [ka]

[0395] To a solution of methyl 3-[(5-methyl-3-pyridyl)sulfamoyl]propanoate (390 mg, 1.51 mmol) in methanol (6 mL) was added sodium hydroxide (181 mg, 4.53 mmol) in water (2 mL). The mixture was stirred at 20° C. for 3 hours and concentrated under reduced pressure. The residue was adjusted to pH=3 by the addition of hydrochloric acid (1 M) and filtered to give crude 3-[(5-methyl-3-pyridyl)sulfamoyl]propanoic acid (213 mg, crude) as a pale yellow solid.

[0396] Step 3: 3-[(5-methyl-3-pyridyl)sulfamoyl]propanamide [ka]

[0397] To a solution of 3-[(5-methyl-3-pyridyl)sulfamoyl]propanoic acid (203 mg, 0.83 mmol) in N,N-dimethylformamide (6 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (V) (632 mg, 1.66 mmol), ammonium chloride (178 mg, 3.32 mmol), and N-ethyl-N-isopropylpropan-2-amine (1.1 g, 8.31 mmol). The mixture was stirred at 20° C. for 16 hours and concentrated under reduced pressure. The residue was purified by RP-HPLC (0-15% acetonitrile and 0.05% NH3H2O ​​in water + 10 mM NH4HCO3) to give 3-[(5-methyl-3-pyridyl)sulfamoyl]propanoic acid (213 mg, crude) as a pale yellow solid.

[0398] Step 4: 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl-(5-methyl-3-pyridyl)sulfamoyl]propanamide [ka]

[0399] To a solution of 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 43 mg, 0.14 mmol) in N,N-dimethylformamide (2 mL) was added 3-[(5-methyl-3-pyridyl)sulfamoyl]propanamide (42 mg, 0.17 mmol) and sodium bicarbonate (36 mg, 0.43 mmol). The mixture was stirred at 20 °C for 16 hours and filtered. The filtrate was concentrated, and the residue was purified by preparative TLC (dichloromethane:methanol = 10:1) to give 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl-(5-methyl-3-pyridyl)sulfamoyl]propanamide (12 mg, 15%) as a yellow solid.

[0400] Step 5: 2-cyano-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-methylpyridin-3-yl)ethane-1-sulfonamide [ka]

[0401] To a solution of 3-(N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-methylpyridin-3-yl)sulfamoyl)propanamide (12 mg, 0.03 mmol) in dichloromethane (2 mL) was added Burgess reagent (37 mg, 0.16 mmol) at 0° C. The mixture was stirred at 20° C. for 2 hours and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by RP-HPLC (16–56% acetonitrile in water and 0.225% formic acid) to give 2-cyano-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-methylpyridin-3-yl)ethane-1-sulfonamide (1.4 mg, 12%) as a pale yellow solid.

[0402] Preparation of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(pyridin-3-yl)-2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethane-1-sulfonamide (I-174) [ka]

[0403] Step 1: N-(3-pyridyl)ethenesulfonamide [ka]

[0404] To a solution of ethenesulfonyl chloride (70 mg, 0.55 mmol) and pyridin-3-amine (52 mg, 0.55 mmol) in dichloromethane (2 mL) was added triethylamine (62 mg, 0.61 mmol) at −78° C. under a nitrogen atmosphere. The mixture was stirred at −78° C. for 0.5 h and then at 0° C. for 2 h. The reaction mixture was used directly in the next step without purification.

[0405] Step 2: 2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-N-(3-pyridyl)ethanesulfonamide [ka]

[0406] To the above solution of N-(3-pyridyl)ethenesulfonamide in dichloromethane (2 mL) was added 3,3a,4,5,6,6a-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride (69 mg, 0.46 mmol) and triethylamine (71 mg, 0.71 mmol) under a nitrogen atmosphere at 25 °C. The mixture was stirred at 25 °C for 16 hours and then concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol = 10:1) to give 2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-N-(3-pyridyl)ethanesulfonamide (30 mg, 29%) as a pale yellow oil.

[0407] Step 3: N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(pyridin-3-yl)-2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethane-1-sulfonamide [ka]

[0408] To a solution of 2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-N-(3-pyridyl)ethanesulfonamide (25 mg, 0.08 mmol) and 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 25 mg, 0.08 mmol) in N,N-dimethylformamide (0.3 mL) was added sodium bicarbonate (21 mg, 0.25 mmol). The mixture was stirred at 35° C. for 3 hours and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by RP-HPLC (0–40% acetonitrile in water and 0.225% formic acid) to give N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(pyridin-3-yl)-2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethane-1-sulfonamide (3.1 mg, 7%) as a pale yellow oil.

[0409] Preparation of N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-fluoropyridin-3-yl)-2-(1,4-oxazepan-4-yl)ethane-1-sulfonamide (I-186) [ka]

[0410] Step 1: N-(5-fluoro-3-pyridyl)ethenesulfonamide [ka]

[0411] To a solution of ethenesulfonyl chloride (100 mg, 0.79 mmol) in dichloromethane (1 mL) was added 5-fluoropyridin-3-amine (88 mg, 0.79 mmol) and triethylamine (159 mg, 1.58 mmol) at −78° C. The mixture was warmed to 20° C. and stirred for 30 minutes. The reaction mixture was used directly in the next step without further treatment.

[0412] Step 2: N-(5-fluoro-3-pyridyl)-2-(1,4-oxazepan-4-yl)ethanesulfonamide [ka]

[0413] To the above solution, 1,4-oxazepane (60 mg, 0.59 mmol) and triethylamine (50 mg, 0.49 mmol) were added at 0° C. The mixture was stirred at 20° C. for 2 hours and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol=20:1) to give N-(5-fluoro-3-pyridyl)-2-(1,4-oxazepan-4-yl)ethanesulfonamide (57 mg, 37%) as a colorless oil.

[0414] Step 3: N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-fluoropyridin-3-yl)-2-(1,4-oxazepan-4-yl)ethane-1-sulfonamide [ka]

[0415] To a solution of N-(5-fluoro-3-pyridyl)-2-(1,4-oxazepan-4-yl)ethanesulfonamide (57 mg, 0.18 mmol) in N,N-dimethylformamide (1 mL) was added 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 55 mg, 0.19 mmol) and sodium bicarbonate (47 mg, 0.56 mmol). The mixture was stirred at 20° C. for 2 hours and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by RP-HPLC (0–40% acetonitrile and formic acid 0.225% in water) to give N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-fluoropyridin-3-yl)-2-(1,4-oxazepan-4-yl)ethane-1-sulfonamide (12.6 mg, 12%) as a yellow oil.

[0416] Preparation of N-[5-(difluoromethoxy)pyridin-3-yl]-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)butane-2-sulfonamide (I-177) [ka]

[0417] Step 1: sec-Butylsulfonyloxysodium [ka]

[0418] To a solution of 2-bromobutane (5.0 g, 36.49 mmol) in water (50 mL) was added sodium sulfate (5.1 g, 40.14 mmol). The mixture was stirred at 100° C. for 16 hours and filtered. The filtrate was concentrated under reduced pressure. The residue was triturated with chloroform and filtered to give crude sec-butylsulfonyloxysodium (8.8 g, crude) as a white solid, which was used directly in the next step.

[0419] Step 2: Butane-2-sulfonyl chloride [ka]

[0420] To a solution of sec-butylsulfonyloxysodium (8 g, 49.95 mmol) in thionyl chloride (25 mL) was added N,N-dimethylformamide (233 mg, 3.19 mmol). The mixture was heated at 100° C. for 3 h and concentrated under reduced pressure. The residue was triturated with chloroform and filtered. The filtrate was concentrated under reduced pressure to give butane-2-sulfonyl chloride (3 g, crude) as a yellow oil, which was used directly in the next step.

[0421] Step 3: N-[5-(difluoromethoxy)-3-pyridyl]butane-2-sulfonamide [ka]

[0422] To a solution of 5-(difluoromethoxy)pyridin-3-amine (2 g, 12.49 mmol) in dichloromethane (20 mL) was added butane-2-sulfonyl chloride (2.74 g, 17.49 mmol) and pyridine (2.96 g, 37.47 mmol). After stirring at 25 °C for 3 h, the mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC (25-70% acetonitrile in water and 0.225% formic acid) to give N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-[2-(trifluoromethyl)-4-pyridyl]ethanesulfonamide (790 mg, 20%) as a white solid.

[0423] Step 4: N-[5-(difluoromethoxy)pyridin-3-yl]-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)butane-2-sulfonamide [ka]

[0424] To a solution of 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 349 mg, 1.18 mmol) in acetone (3 mL) was added N-[5-(difluoromethoxy)-3-pyridyl]butane-2-sulfonamide (300 mg, 1.07 mmol) and potassium carbonate (444 mg, 3.21 mmol). The mixture was stirred at 25° C. for 1.5 hours and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (40–70% acetonitrile in water and 0.1% trifluoroacetic acid) to give N-[5-(difluoromethoxy)pyridin-3-yl]-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)butane-2-sulfonamide 318 (268.4 mg, 51%) as a yellow solid.

[0425] Preparation of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-[5-(trifluoromethoxy)-3-pyridyl]ethanesulfonamide (I-267) [ka]

[0426] Step 1: 5-Bromo-3-(trifluoromethoxy)pyridin-2-amine [ka]

[0427] To a solution of 3-(trifluoromethoxy)pyridin-2-amine (900 mg, 5.05 mmol) in dichloromethane (10 mL) was added N-bromosuccinimide (1.4 g, 7.58 mmol). After stirring at 25 °C for 0.5 h, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-6% ethyl acetate in petroleum ether) to give 5-bromo-3-(trifluoromethoxy)pyridin-2-amine (1.14 g, 84%) as a brown solid.

[0428] Step 2: 5-Bromo-2-chloro-3-(trifluoromethoxy)pyridine [ka]

[0429] To a solution of 5-bromo-3-(trifluoromethoxy)pyridin-2-amine (1.1 g, 4.44 mmol) in dichloromethane (4 mL) was added chlorotrimethylsilane (4.3 g, 39.92 mmol). After stirring at 25 °C for 0.5 h, isopentyl nitrite (1.6 g, 13.31 mmol) was added dropwise. After stirring at 25 °C for 2 h, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-2% ethyl acetate in petroleum ether) to give 5-bromo-2-chloro-3-(trifluoromethoxy)pyridine (955 mg, 71%) as a colorless oil.

[0430] Step 3: N-[6-chloro-5-(trifluoromethoxy)-3-pyridyl]ethanesulfonamide [ka]

[0431] To a solution of ethanesulfonamide (79 mg, 0.72 mmol) and 5-bromo-2-chloro-3-(trifluoromethoxy)pyridine (200 mg, 0.72 mmol) in 1,4-dioxane (5 mL) was added Xantphos Pd G3 (69 mg, 0.07 mmol) and cesium carbonate (589 mg, 1.81 mmol). After stirring at 110 °C for 16 h under a nitrogen atmosphere, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-15% methanol in dichloromethane) to give N-[6-chloro-5-(trifluoromethoxy)-3-pyridyl]ethanesulfonamide (38 mg, 16%) as a yellow oil.

[0432] Step 4: N-[5-(trifluoromethoxy)-3-pyridyl]ethanesulfonamide [ka]

[0433] To a solution of N-[6-chloro-5-(trifluoromethoxy)-3-pyridyl]ethanesulfonamide (38 mg, 0.12 mmol) in methanol (1 mL) was added palladium (13 mg, 0.01 mmol, 10% carbon). After stirring at 25° C. under a hydrogen atmosphere (15 psi) for 2 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give crude N-[5-(trifluoromethoxy)-3-pyridyl]ethanesulfonamide (30 mg, crude) as a yellow solid.

[0434] Step 5: N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-[5-(trifluoromethoxy)-3-pyridyl]ethanesulfonamide [ka]

[0435] To a solution of N-[5-(trifluoromethoxy)-3-pyridyl]ethanesulfonamide (20 mg, 0.07 mmol) and 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 20 mg, 0.07 mmol) in acetone (1 mL) was added potassium carbonate (28 mg, 0.20 mmol). After stirring at 25 °C for 1 h, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (35–65% acetonitrile in water and 0.225% formic acid) to give N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-[5-(trifluoromethoxy)-3-pyridyl]ethanesulfonamide (8.5 mg, 25%) as a yellow solid.

[0436] Preparation of N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-yl}ethane-1-sulfonamide (I-231) [ka]

[0437] Step 1: Methyl 5-nitro-2-(2-tetrahydropyran-2-yloxyethyl)pyrazole-3-carboxylate [ka]

[0438] To a solution of methyl 3-nitro-1H-pyrazole-5-carboxylate (2.0 g, 11.69 mmol) in N-methyl-2-pyrrolidone (10 mL) was added 2-(2-bromoethoxy)tetrahydropyran (2.0 g, 9.35 mmol) and potassium carbonate (1.6 g, 11.69 mmol). After stirring at 80 °C for 16 h, the reaction mixture was diluted with water (30 mL) and ethyl acetate (50 mL). The separated organic layer was dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0-25% ethyl acetate in petroleum ether) to give methyl 5-nitro-2-(2-tetrahydropyran-2-yloxyethyl)pyrazole-3-carboxylate (2.2 g, 63%) as a yellow oil. Step 2: [5-nitro-2-(2-tetrahydropyran-2-yloxyethyl)pyrazol-3-yl]methanol [ka]

[0439] To a solution of methyl 5-nitro-2-(2-tetrahydropyran-2-yloxyethyl)pyrazole-3-carboxylate (2.2 g, 7.35 mmol) in tetrahydrofuran (30 mL) was added lithium borohydride (240 mg, 11.03 mmol) at 0 °C. After stirring at 20 °C for 3 h, the reaction was quenched by the addition of methanol (10 mL). The mixture was diluted with ethyl acetate (40 mL), washed with brine (40 mL), dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give [5-nitro-2-(2-tetrahydropyran-2-yloxyethyl)pyrazol-3-yl]methanol (1.4 g, 70%) as a yellow oil.

[0440] Step 3: 2-[5-(bromomethyl)-3-nitro-pyrazol-1-yl]ethanol [ka]

[0441] To a solution of [5-nitro-2-(2-tetrahydropyran-2-yloxyethyl)pyrazol-3-yl]methanol (1.4 g, 5.16 mmol) in tetrahydrofuran (10 mL) was added pyridine (408 mg, 5.16 mmol), tetrabromomethane (3.4 g, 10.32 mmol), and triphenylphosphine (2.7 g, 10.32 mmol) at 0 °C. The mixture was stirred at 20 °C for 17 h and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) followed by preparative TLC (petroleum ether:ethyl acetate = 1:1) to give 2-[5-(bromomethyl)-3-nitro-pyrazol-1-yl]ethanol (180 mg, 14%) as a white solid.

[0442] Step 4: 2-Nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine [ka]

[0443] To a solution of 2-[5-(bromomethyl)-3-nitro-pyrazol-1-yl]ethanol (140 mg, 0.56 mmol) in tetrahydrofuran (5 mL) was added sodium hydride (60%, 25 mg, 0.62 mmol) under a nitrogen atmosphere. After stirring at 20 °C for 4 hours, the reaction mixture was quenched by the addition of water (10 mL) and extracted with ethyl acetate (30 mL). The organic extract was dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) to give 2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (34 mg, 33%) as a white solid.

[0444] Step 5: 6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine [ka]

[0445] To a solution of 2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (24 mg, 0.1 mmol) in ethanol (2.5 mL) and water (1 mL) was added iron (48 mg, 0.85 mmol) and ammonium chloride (91 mg, 1.70 mmol). The mixture was stirred at 80° C. for 4 hours and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was diluted with dichloromethane (15 mL), washed with brine (20 mL), dried over sodium sulfate, and concentrated to dryness under reduced pressure to give 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine (13 mg, 66%) as a yellow solid.

[0446] Step 6: N-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)ethanesulfonamide [ka]

[0447] To a solution of 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine (22 mg, 0.16 mmol) in pyridine (0.5 mL) was added ethanesulfonyl chloride (24 mg, 0.19 mmol) at 0° C. The mixture was stirred at 20° C. for 2 hours and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to give N-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)ethanesulfonamide (24 mg, 53%) as a white solid.

[0448] Step 7: N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-yl}ethane-1-sulfonamide [ka]

[0449] To a solution of 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 25 mg, 0.08 mmol) in N,N-dimethylformamide (0.5 mL) was added N-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)ethanesulfonamide (21 mg, 0.09 mmol) and sodium bicarbonate (21 mg, 0.25 mmol). The mixture was stirred at 25° C. for 2 hours and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by RP-HPLC (30–60% acetonitrile in water and 0.225% formic acid) to give N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-yl}ethane-1-sulfonamide (10.9 mg, 28%) as a yellow oil.

[0450] Preparation of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-fluoropyridin-3-yl)-1′-benzyl-1′-methylamino-sulfonamide (compound I-29). [ka]

[0451] Step 1: N-benzyl-N-methylsulfamoyl chloride

[0452] To a solution of sulfuryl chloride (1.11 g, 8.25 mmol) in dichloromethane (10 mL) at -10 °C, N-methyl-N-benzylamine (1.00 g, 8.25 mmol) was added. After 30 min, the cooling bath was removed and the reaction mixture was stirred for 5 h. After washing with water, the organic layer was dried (Na2SO4), filtered, and concentrated. The crude residue obtained was used directly in the next step.

[0453] Step 2: N-benzyl-N-methyl-[(5-fluoropyridin-3-yl)amino]sulfonamide

[0454] Half of the crude material was mixed with 5-fluoro-3-pyridin-amine (196 mg, 0.89 mmol) and pyridine (106 mg, 1.34 mmol) in dichloromethane at ambient temperature. After stirring for 2 h, the reaction was quenched with saturated NH4Cl. The organic residue was purified by chromatography (silica gel, DCM / EtOAc, 1:0 to 1:1) to give a white solid (25 mg, 9.5%). LC-MS: m / z [M+H] + 296

[0455] Step 3: N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-fluoropyridin-3-yl)-1'-benzyl-1'-methylamino-sulfonamide

[0456] The title compound was synthesized following the same experimental procedure as described above for the preparation of N-((5-(5-difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl-N-(1-phenylcyclopropoyl)ethanesulfonamide (I-20), using instead N-benzyl-N-methyl-[(5-fluoropyridin-3-yl)amino]sulfonamide (36% yield).

[0457] The method disclosed in Example 4 above was also used to prepare the following compounds: I-2, I-3, I-4, I-5, I-9, I-10, I-13, I-14, I-15, I-16, I-17, I-22, I-23, I-24, I-25, I-27, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-46, I-47, I-49, I-50, I-51, I-52, I-53, I-54, I-55, I-56, I-57, I-58, I-59, I-61, I-62, I-63, I-64, I-65, I-66, I-67, I-68, I-69, I-70, I-74, I-75, I-76, I-77, I-78, I-79, I-80, I-87, I-88, I-89, I-90, I-91, I-92, I-93, I-94, I-95, I-97, I-98, I-99, I-100, I-103, I-104, I-105, I-106, I-107, I-108, I-109, I-110, I-111, I-112, I-113, I-114, I-115, I-116, I-117, I-118, I-120, I-121, I-122, I-123, I-125, I-126, I-127, I-128, I-129, I-130, I-131, I-132, I-133, I-134, I-136, I-137, I-138, I-139, I-140, I-141, I-145, I-146, I-148, I-149, I-150, I-151, I-152, I-153, I-155, I-156, I-157, I-158, I-159, I-160, I-161, I-162, I-163, I-164, I-165, I-166, I-167, I-168, I-169, I-170, I-178, I-179, I-180, I-181, I-182, I-183, I-184, I-187, I-188, I-189, I-190, I-191, I-192, I-193, I-194, I-196, I-197, I-201, I-202, I-203, I-204, I-205, I-206, I-211, I-212, I-213, I-214, I-215, I-216, I-217, I-218, I-220, I-221, I-222, I-223, I-225, I-226, I-228, I-229, I-230, I-232, I-233,I-234, I-236, I-237, I-238, I-239, I-240, I-241, I-242, I-243, I-244, I-265, I-266, and I-268. ,

[0458] Example 5. Synthesis of amine / aniline compounds of formula (I) [ka]

[0459] Preparation of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-(trifluoromethyl)aniline (compound I-7). [ka]

[0460] 2-[2-(Bromomethyl)-1,3-thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 150 mg, 0.51 mmol) was taken up in DMF (1 mL) with cesium carbonate (330 mg, 0.20 mmol), and then 3-trifluoromethylaniline (75 μL, 0.60 mmol) was added to it. The solution immediately turned dark and was stirred at room temperature for 16 hours. TLC showed that the reaction was complete. The solution was diluted with EtOAc and then washed with water. The organic layer was filtered through MgSO4 and then concentrated. The residue was purified by Combiflash® (hexane / EtOAc gradient) to give the title compound (75 mg, 39%) as an oil.

[0461] Preparation of 3-chloro-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(2-methoxyethyl)aniline (I-142) [ka]

[0462] Step 1: 3-chloro-N-(2-methoxyethyl)aniline [ka]

[0463] To a solution of 3-chloroaniline (500 mg, 3.92 mmol) in tetrahydrofuran (3 mL) was added sodium hydride (60%, 220 mg, 5.49 mmol) and 1-bromo-2-methoxyethane (817 mg, 5.88 mmol). The mixture was stirred at 70 °C for 2 h and quenched by adding water (10 mL). The resulting solution was extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (45–75% acetonitrile in water with 0.05% ammonium hydroxide and 10 mM ammonium bicarbonate) to give 3-chloro-N-(2-methoxyethyl)aniline (264 mg, 36%) as a colorless oil.

[0464] Step 2: 3-chloro-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(2-methoxyethyl)aniline [ka]

[0465] To a solution of 3-chloro-N-(2-methoxyethyl)aniline (19 mg, 0.1 mmol) in N,N-dimethylformamide (0.5 mL) was added 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 60 mg, 0.2 mmol) and sodium bicarbonate (26 mg, 0.3 mmol). The mixture was stirred at 20 °C for 2 h and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (20–70% acetonitrile in water and 10 mM ammonium bicarbonate) to give 3-chloro-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(2-methoxyethyl)aniline (13.7 mg, 33%) as a white solid.

[0466] The method disclosed in Example 5 was also used to prepare the following compounds: I-7, I-45, I-72, I-73, I-124, and I-135.

[0467] Preparation of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)pyridin-3-amine (compound I-28). [ka]

[0468] To a 5 mL microwave reaction vial was added 2-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 60 mg, 0.20 mmol), 3-aminopyridine (57 mg, 0.61 mmol), potassium iodide (3 mg, 0.02 mmol), potassium carbonate (31 mg, 0.22 mmol), and acetonitrile (0.68 mL). The reaction mixture was stirred at 110 °C for 15 min under microwave irradiation. The crude reaction mixture was filtered through a plug of Celite, the Celite plug was washed with acetonitrile, and the filtrate was concentrated. The residue was adsorbed onto silica with methanol and purified by column chromatography (0–20% MeOH / DCM) to afford the title compound (54 mg, 86%) as a light brown solid.

[0469] Example 6. Synthesis of tertiary amide compounds of formula (I) from the amines of Example 5 [ka]

[0470] Preparation of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(3-(trifluoromethyl)phenyl)nicotinamide (compound I-8). [ka]

[0471] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-(trifluoromethyl)aniline (I-7, 26 mg, 0.07 mmol) was taken up in DMF (1 ml) with nicotinoyl chloride hydrochloride (15 mg, 0.80 mmol), and then diisopropylethylamine (0.04 mL, 0.21 mmol) was added to it. The solution was stirred at room temperature for 18 hours and then at 40° C. for 16 hours. TLC showed that the reaction was complete. The reaction was cooled to room temperature, diluted with EtOAc, and then washed with water. The organic layer was collected, filtered through MgSO4, and concentrated. The residue was purified by Combiflash® (DCM / methanol gradient) to give the title compound (21 mg, 63%) as a white solid.

[0472] The method disclosed in Example 4 was also used to prepare compound I-175.

[0473] Preparation of 1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3,3-dimethyl-1-(pyridin-3-yl)urea (compound I-21). [ka]

[0474] To a 2-dram vial was added N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)pyridin-3-amine (I-28, 30 mg, 0.097 mmol), potassium carbonate (40 mg, 0.15 mmol), and acetonitrile (1 mL). To the reaction mixture was added 4-nitrophenyl chloroformate (29.3 mg, 0.15 mmol). The reaction mixture was stirred at 45 °C for 4 h. To the crude reaction mixture was added a 2 M solution of dimethylamine in THF (0.24 mL, 0.49 mmol), and the reaction was stirred at 45 °C for 30 min. The reaction mixture was then filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (0-20% MeOH / DCM) to afford the title compound (11.4 mg, 31%) as an amorphous brown solid.

[0475] Preparation of methyl ((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)(pyridin-3-yl)carbamate (compound I-26). [ka]

[0476] To a 2-dram vial was added N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)pyridin-3-amine (I-28, 20 mg, 0.065 mmol), potassium carbonate (18 mg, 0.13 mmol), and acetonitrile (0.6 mL). To the reaction mixture was added 4-nitrophenyl chloroformate (19.6 mg, 0.097 mmol). The reaction mixture was stirred at 40 °C for 4 h. The reaction mixture was cooled to ambient temperature, and MeOH (1 mL) was added to the reaction mixture. After stirring the reaction mixture for 15 min, the crude reaction mixture was then filtered through Celite, and the Celite was washed with MeOH. The combined filtrate was concentrated under reduced pressure, adsorbed onto silica, and purified by column chromatography (0–20% EtOAc / hexanes) to afford the title compound (12.6 mg, 53%) as an off-white solid.

[0477] Example 7. Synthesis of amine / aniline compounds of formula (I)

[0478] Preparation of 5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,6-difluorophenyl)cyclopropyl)thiazol-2-amine (compound I-18). [ka]

[0479] Step 1: Preparation of 1-(2,6-difluorophenyl)cyclopropan-1-amine [ka]

[0480] To an oven-dried 200 mL round-bottom flask containing a 1.5-inch egg-shaped stir bar under a N atmosphere was added 2,6-difluorobenzonitrile (2.78 g, 20 mmol), followed by methyl tert-butyl ether (MTBE) (100 mL). The pale yellow solution was cooled to -78 °C and tetraisopropoxide titanium (7.3 mL, 24 mmol, 1.2 equiv.) was added in one portion. Ethyl magnesium bromide (3 M in ether, 16.7 mL, 50 mmol, 2.5 equiv.) was added dropwise with vigorous stirring over 5 min to give a pale yellow homogeneous solution (CAUTION: exotherm and possible gas evolution). No gas evolution was observed in this case. The dry ice bath was allowed to slowly expire over 4 h while the solution was vigorously stirred (1500 RPM). Upon warming to room temperature, a viscous, opaque brown solution formed. This solution was cooled to 0 °C in an ice bath. BF3·OEt2 (4.9 mL, 40 mmol, 2 equiv.) was then added dropwise over 5 min (CAUTION: exothermic, gas evolution). The ice bath was removed, and the opaque brown suspension was allowed to warm to room temperature overnight. The next day, the reaction was quenched by first adding 1 M NaOH (100 mL, 5 equiv.) in portions, followed by EtOAc (50 mL), and then vigorously stirred at room temperature for 2 h to give a biphasic mixture consisting of an upper colorless organic layer and a lower dark blue aqueous emulsion. This biphasic mixture was filtered directly through water-wetted Celite and washed once with water (50 mL) and once with EtOAc (50 mL). The filtrate was collected, and the layers were separated. The aqueous layer was extracted twice more with EtOAc (50 mL). The combined organic layers were washed twice with water (50 mL) and once with brine (25 mL), then dried over MgSO4, filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography (silica gel, 0-50% EtOAc in hexanes) to give the title compound.

[0481] Step 2: Preparation of methyl 2-((1-(2,6-difluorophenyl)cyclopropyl)amino)-thiazole-5-carboxylate. [ka]

[0482] To a tall, silicon-capped scintillation vial under a N atmosphere (balloon) was added 1-(2,6-difluorophenyl)cyclopropan-1-amine (169 mg, 1.0 mmol, 1 equiv.), methyl 2-chlorothiazole-5-carboxylate (195 mg, 1.1 mmol, 1.1 equiv.), DIPEA (0.87 mL, 5 mmol, 5 equiv.), and DMSO (3 mL). The orange, biphasic, clear mixture was heated to 110 °C overnight (12 h), where it became a monophasic, brown solution. The next day, LCMS and TLC analysis indicated complete conversion of the cyclopropylamine to a complex mixture. The reaction was allowed to cool to room temperature and then poured into water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organics were washed with water, then brine, then dried over MgSO, filtered, and concentrated by rotary evaporation. The crude dark brown oil was dry-loaded onto silica gel and purified by flash column chromatography (gradient of 0 to 50% EtOAc in hexanes) to afford 47.9 mg (15% yield) of the title compound as a brown oil.

[0483] Step 3: Preparation of 2-((1-(2,6-difluorophenyl)cyclopropyl)amino)thiazole-5-carbohydrazide. [ka]

[0484] To a red PTFE-capped tall scintillation vial under a N atmosphere (balloon) was added methyl 2-((1-(2,6-difluorophenyl)cyclopropyl)amino)thiazole-5-carboxylate (30.0 mg, 0.97 mmol, 1 equiv.), 1,4-dioxane (1 mL), and finally hydrazine monohydrate (0.05 mL, 1 mmol, 10 equiv.). The homogeneous orange solution was heated to 100 °C for 64 h, after which LCMS analysis indicated complete conversion to the desired acyl hydrazide. The mixture was allowed to cool to room temperature and then poured into water (50 mL) and extracted three times with EtOAc (50 mL). The combined organic layers were washed with water, then brine, then dried over MgSO, filtered, and concentrated by rotary evaporation to give the title compound, 25.1 mg (84% yield), as a brown oil of sufficient purity to proceed directly to the next step.

[0485] Step 4: Preparation of N'-(2,2-difluoroacetyl)-2-((1-(2,6-difluorophenyl)-cyclopropyl)amino)thiazole-5-carbohydrazide. [ka]

[0486] To the vial was added 2-((1-(2,6-difluorophenyl)cyclopropyl)amino)thiazole-5-carbohydrazide (25.1 mg, 0.081 mmol, 1 equiv.) and DCM (1 mL). The heterogeneous orange suspension was cooled to 0 °C in an ice bath. Finally, difluoroacetic anhydride (DFAA, 0.02 mL, 0.16 mmol, 2 equiv.) was added dropwise over 30 seconds. The resulting homogeneous orange solution was allowed to warm to room temperature. After 30 minutes, LCMS analysis indicated complete conversion to the desired diacylhydrazide. The reaction was quenched by the addition of 1 mL of saturated aqueous NaHCO3 and 1 mL of methanol and stirred at room temperature for 1 hour. The reaction was poured into 50 mL of half-saturated NaHCO3 and then extracted three times with EtOAc (50 mL). The combined organic layers were washed with water, then brine, then dried over MgSO.sub.4, filtered, and concentrated by rotary evaporation to give 22.9 mg (73% yield) of the title compound as an orange waxy solid.

[0487] Step 5: Preparation of 5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,6-difluorophenyl)cyclopropyl)thiazol-2-amine. [ka]

[0488] To a 0.5-2 mL microwave vial, stirring free, was added N'-(2,2-difluoroacetyl)-2-((1-(2,6-difluorophenyl)cyclopropyl)amino)thiazole-5-carbohydrazide (22.9 mg, 0.06 mmol, 1 equiv.) as a solution in THF (1 mL), and finally Burgess reagent (70.6 mg, 0.3 mmol, 5 equiv.). The mixture was pre-stirred for 2 min and then heated to 150 °C for 2 h at approximately 8 bar pressure in a microwave. After reaction, the reaction was an orange float with a brown oil precipitating. LCMS analysis of the orange float indicated complete conversion of the diacylhydrazide to the desired oxadiazole. The reaction mixture was poured into water (50 mL) and extracted three times with EtOAc (50 mL). The combined organics were washed with water, then brine, then dried over MgSO, filtered, and concentrated by rotary evaporation to give the crude material as a yellow solid. The crude material was dry-loaded onto silica gel and purified by flash column chromatography (gradient of 0 to 50% EtOAc in hexanes) to give 16.6 mg of the title compound as a still impure pale yellow solid. The material was subjected to preparative HPLC purification (10 to 100% MeCN in water with 0.1% TFA), and the product-containing fractions were frozen at -78 °C and lyophilized to give 4.1 mg (19% yield) of the purified title compound as a fluffy white solid.

[0489] Preparation of 5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-phenethylthiazol-2-amine (compound I-19). [ka]

[0490] Step 1: Preparation of methyl 2-(phenethylamino)thiazole-5-carboxylate. [ka]

[0491] To a tall, PTFE-capped scintillation vial under a N atmosphere (balloon) was added methyl 2-bromothiazole-5-carboxylate (444 mg, 2.0 mmol, 1 equiv.), 2-phenethylamine (0.30 mL, 2.4 mmol, 1.2 equiv.), DMSO (6 mL), and DIPEA (1.7 mL, 10 mmol, 5 equiv.). The pale yellow-orange, biphasic, clear mixture was heated to 110 °C for 2 h, after which LCMS analysis showed clean, complete conversion to the desired product. The reaction was cooled to room temperature and then poured into half-saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organics were washed with water, then brine, then dried over MgSO4, filtered, and concentrated by rotary evaporation to give a crude red solid, which was dry-loaded onto silica gel and purified by flash column chromatography (gradient of 0 to 50% EtOAc in hexanes) to give 395.5 mg (75% yield) of the title compound as a pale pink solid.

[0492] Step 2: Preparation of 2-(phenethylamino)thiazole-5-carbohydrazide. [ka]

[0493] To a tall PTFE-capped scintillation vial under a N atmosphere (balloon) was added methyl 2-(phenethylamino)thiazole-5-carboxylate (131 mg, 0.5 mmol, 1 equiv.), followed by 1,4-dioxane (2 mL), and finally hydrazine hydrate (0.24 mL, 5 mmol, 10 equiv.). The pale yellow, biphasic, clear mixture was heated to 100 °C overnight, after which LCMS analysis indicated complete conversion to the desired acyl hydrazide. The reaction was poured into water (50 mL) and then extracted three times with EtOAc (50 mL). The combined organic layers were washed with water, then brine, then dried over MgSO, filtered, and concentrated by rotary evaporation to give 105.1 mg (80% yield) of crude product as a pale orange solid of sufficient purity to carry forward directly.

[0494] Step 3: Preparation of N'-(2,2-difluoroacetyl)-2-(phenethylamino)thiazole-5-carbohydrazide. [ka]

[0495] To a scintillation vial, 2-(phenethylamino)thiazole-5-carbohydrazide (52.5 mg, 0.2 mmol) was added, followed by DCM (1 mL). The heterogeneous white suspension was cooled to 0 °C in an ice bath. Difluoroacetic anhydride (DFAA, 0.05 mL, 0.4 mmol, 2 equiv.) was then added dropwise over 30 seconds. The now completely homogeneous pale yellow solution was allowed to warm to room temperature for 30 minutes, after which LCMS analysis indicated complete conversion to a mixture of the desired product and by-product, with the aminothiazole NH also acylated (the latter being favored). The acylated aminothiazole was chemoselectively deprotected in situ by adding 1 mL of methanol followed by 1 mL of saturated aqueous Na2CO3, and the heterogeneous biphasic mixture was stirred at room temperature for 1 hour. The mixture was then poured into 50 mL of water (50 mL) and then extracted three times with 50 mL of EtOAc. The combined organic layers were washed with water, then brine, then dried over MgSO, filtered, and concentrated by rotary evaporation to give the crude product, 23.2 mg (34%), as a pale yellow-orange solid that was pure enough to carry on directly to the next step.

[0496] Step 4: Preparation of 5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-phenethylthiazol-2-amine. [ka]

[0497] To a small microwave vial (0.5-2 mL) containing a magnetic stirrer, N'-(2,2-difluoroacetyl)-2-(phenethylamino)thiazole-5-carbohydrazide (23.2 mg, 0.068 mmol, 1 equiv.) was added as a solution in THF (1 mL). Burgess reagent (81.6 mg, 0.34 mmol, 5 equiv.) was then added, and the vial was crimped and microwaved at 150 °C and approximately 8 bar for 2 h. After cooling to room temperature, the reaction contained a precipitated brown oil with a clear yellow precipitate. LCMS analysis of the yellow precipitate showed complete conversion of the diacylhydrazide starting material to the desired oxadiazole, along with several minor impurities. The mixture was then poured into 50 mL of water (50 mL) and then extracted three times with EtOAc (50 mL). The combined organic layers were washed with water, then brine, then dried over MgSO, filtered, and concentrated by rotary evaporation to give a crude pale yellow oil. The material was dry-loaded onto silica gel and purified by flash column chromatography (0-50% EtOAc / hexanes gradient) to give the title compound, 13.8 mg (63% yield) as a waxy white solid.

[0498] Example 8. Preparation of 2-(2-((3-chlorophenoxy)methyl)thiazol-5-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (compound I-71). [ka] To a solution of 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (30 mg, 0.1 mmol) and 3-chlorophenol (16 mg, 0.12 mmol) in N,N-dimethylformamide (1 mL) was added potassium carbonate (42 mg, 0.3 mmol). The mixture was stirred at 20 °C for 1 h and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by RP-HPLC (55-85% acetonitrile and 0.225% formic acid in water) to give 2-[2-[(3-chlorophenoxy)methyl]thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (9.7 mg, 28%) as a yellow solid.

[0499] Example 9. Synthesis of regioisomeric thiazole / oxazole compounds-amides of formula (I)

[0500] Preparation of N-(3-chlorophenyl)-N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)cyclopropanecarboxamide (compound I-84). [ka]

[0501] N-(3-chlorophenyl)-N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)cyclopropanecarboxamide

[0502] Step 1: 2-Methylthiazole-4-carbohydrazide [ka]

[0503] To a solution of ethyl 2-methylthiazole-4-carboxylate (5.0 g, 29.2 mmol) in ethanol (50 mL) was added hydrazine hydrate (16.5 g, 280.4 mmol) at 20° C. The reaction was then stirred at 90° C. for 16 hours and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% methanol in dichloromethane) to give 2-methylthiazole-4-carbohydrazide (2.2 g, 48%) as a yellow solid. LCMS R T =0.483min, m / z=158.2[M+H] + .

[0504] Step 2: N'-(2,2-difluoroacetyl)-2-methyl-thiazole-4-carbohydrazide [ka]

[0505] To a solution of 2-methylthiazole-4-carbohydrazide (2.0 g, 12.7 mmol) and N,N-diisopropylethylamine (1.6 g, 12.7 mmol) in tetrahydrofuran (20 mL) was added (2,2-difluoroacetyl) 2,2-difluoroacetate (2.7 g, 15.3 mmol). The reaction was stirred at 20 °C for 16 h and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% methanol in dichloromethane) to give N'-(2,2-difluoroacetyl)-2-methyl-thiazole-4-carbohydrazide (2.8 g, 94%) as a white solid.

[0506] Step 3: 2-(Difluoromethyl)-5-(2-methylthiazol-4-yl)-1,3,4-oxadiazole [ka]

[0507] To a solution of N'-(2,2-difluoroacetyl)-2-methyl-thiazole-4-carbohydrazide (2.8 g, 11.9 mmol) in tetrahydrofuran (30 mL) was added Burgess's reagent (7.1 g, 29.8 mmol). The mixture was stirred at 90 °C for 3 h under microwave irradiation. The mixture was cooled and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-25% ethyl acetate in petroleum ether) to give 2-(difluoromethyl)-5-(2-methylthiazol-4-yl)-1,3,4-oxadiazole (1.4 g, 54%) as a white solid.

[0508] Step 4: 2-[2-(bromomethyl)thiazol-4-yl]-5-(difluoromethyl)-1,3,4-oxadiazole [ka]

[0509] To a solution of 2-(difluoromethyl)-5-(2-methylthiazol-4-yl)-1,3,4-oxadiazole (150 mg, 0.69 mmol) in carbon tetrachloride (5 mL) was added N-bromosuccinimide (135 mg, 0.76 mmol) and azodiisobutyronitrile (11 mg, 0.07 mmol). The mixture was stirred at 80° C. for 16 hours and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by RP-TLC (petroleum ether:ethyl acetate=3:1) to give 2-[2-(bromomethyl)thiazol-4-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (70 mg, 34%) as a colorless oil. LCMS R T =1.048 min, m / z=297.7[M+H] + .

[0510] Step 5: N-(3-chlorophenyl)cyclopropanecarboxamide [ka]

[0511] To a mixture of 3-chloroaniline (1.0 g, 7.84 mmol) and triethylamine (1.6 g, 15.68 mmol) in tetrahydrofuran (16 mL) was added cyclopropanecarbonyl chloride (901 mg, 8.62 mmol) at 0 °C. After stirring at 20 °C for 16 h, the reaction was quenched by the addition of water (100 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-25% ethyl acetate in petroleum ether) to give N-(3-chlorophenyl)cyclopropanecarboxamide (1.45 g, 95% yield) as a white solid.

[0512] Step 6: N-(3-chlorophenyl)-N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)cyclopropanecarboxamide (I-84) [ka]

[0513] To a solution of N-(3-chlorophenyl)cyclopropanecarboxamide (66 mg, 0.34 mmol) in tetrahydrofuran (3 mL) was added sodium hydride (12 mg, 0.30 mmol, 60% purity) under a nitrogen atmosphere at 0° C. After stirring at 0° C. for 30 minutes, 2-[2-(bromomethyl)thiazol-4-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (50 mg, 0.17 mmol) was added to the reaction mixture and stirred at 25° C. for 30 minutes. The reaction was quenched by the addition of water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by RP-HPLC (53–83% acetonitrile in water and 0.225% formic acid) to give N-(3-chlorophenyl)-N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]cyclopropanecarboxamide (11.3 mg, 16%) as a white solid.

[0514] The method used in Example 9 was also used to prepare compound I-82.

[0515] Example 10. Synthesis of regioisomeric thiazole / oxazole compounds-sulfonamides of formula (I)

[0516] Preparation of N-(3-chlorophenyl)-N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)cyclopropanesulfonamide (Compound I-83) [ka]

[0517] Step 1: N-(3-chlorophenyl)cyclopropanesulfonamide [ka]

[0518] To a mixture of cyclopropanesulfonyl chloride (1.33 g, 9.43 mmol) and pyridine (930 mg, 11.76 mmol) in dichloromethane (10 mL) was added 3-chloroaniline (1.00 g, 7.84 mmol) at 0 °C. After stirring at 20 °C for 16 h, the reaction was quenched by the addition of water (70 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give N-(3-chlorophenyl)cyclopropanesulfonamide (1.70 g, 94% yield) as a yellow solid.

[0519] Step 2: N-(3-chlorophenyl)-N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)cyclopropanesulfonamide (compound I-83) [ka]

[0520] A mixture of 2-[2-(bromomethyl)thiazol-4-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (35.0 mg, 0.12 mmol), N-(3-chlorophenyl)cyclopropanesulfonamide (33.0 mg, 0.14 mmol), and potassium carbonate (49 mg, 0.35 mmol) in N,N-dimethylformamide (1 mL) was stirred at 30 °C for 1 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (45-75% acetonitrile in water and 0.225% formic acid) to give N-(3-chlorophenyl)-N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]cyclopropanesulfonamide (25.2 mg, 47.2% yield) as a white solid.

[0521] Preparation of N-(3-chlorophenyl)-N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)oxazol-2-yl)methyl)cyclopropanesulfonamide (compound I-86). [ka]

[0522] Step 1: 2-Methyloxazole-4-carbohydrazide [ka]

[0523] To a solution of ethyl 2-methyloxazole-4-carboxylate (4.5 g, 29.00 mmol) in ethyl alcohol (80 mL) was added hydrazine hydrate (15.8 g, 316.62 mmol). After stirring at 90 °C for 16 h, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% methanol in dichloromethane) to give 2-methyloxazole-4-carbohydrazide (3.5 g, 86%) as an orange solid.

[0524] Step 2: N'-(2,2-difluoroacetyl)-2-methyl-oxazole-4-carbohydrazide [ka]

[0525] To a solution of 2-methyloxazole-4-carbohydrazide (3.5 g, 24.94 mmol) and N-ethyl-N-isopropylpropan-2-amine (3.87 g, 29.93 mmol) in tetrahydrofuran (38 mL) was added (2,2-difluoroacetyl) 2,2-difluoroacetate (5.21 g, 29.93 mmol). After stirring at 20 °C for 3 h, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% methanol in dichloromethane) to give N'-(2,2-difluoroacetyl)-2-methyl-oxazole-4-carbohydrazide (5.0 g, 91%) as a yellow solid.

[0526] Step 3: 2-(Difluoromethyl)-5-(2-methyloxazol-4-yl)-1,3,4-oxadiazole [ka]

[0527] To a solution of N'-(2,2-difluoroacetyl)-2-methyl-oxazole-4-carbohydrazide (3.0 g, 13.69 mmol) in tetrahydrofuran (8 mL) was added Burgess reagent (8.16 g, 34.22 mmol). The mixture was stirred at 90 °C for 3 hours in a microwave oven and then quenched by adding water (30 mL). The mixture was extracted with ethyl acetate (50 mL × 3). The organic extract was dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-80% ethyl acetate in petroleum ether) to give 2-(difluoromethyl)-5-(2-methyloxazol-4-yl)-1,3,4-oxadiazole (1.14 g, 41%) as a yellow solid.

[0528] Step 4: 2-[2-(bromomethyl)oxazol-4-yl]-5-(difluoromethyl)-1,3,4-oxadiazole [ka]

[0529] To a solution of 2-(difluoromethyl)-5-(2-methyloxazol-4-yl)-1,3,4-oxadiazole (1.14 g, 5.65 mmol) in tetrachloromethane (20 mL) was added 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile (93 mg, 0.56 mmol) and N-bromosuccinimide (2.52 g, 14.13 mmol). After stirring at 90° C. for 16 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by RP-TLC (petroleum ether:ethyl acetate=2:1) ​​to give 2-[2-(bromomethyl)oxazol-4-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (200 mg, 10%) as a white solid. LCMS R T =1.222 min, m / z=279.8[M+H] + .

[0530] Step 5: N-(3-chlorophenyl)-N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)oxazol-2-yl)methyl)cyclopropanesulfonamide (compound I-86) [ka]

[0531] A mixture of 2-[2-(bromomethyl)oxazol-4-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (30 mg, 0.11 mmol), N-(3-chlorophenyl)cyclopropanesulfonamide (25 mg, 0.11 mmol), and potassium carbonate (30 mg, 0.22 mmol) in N,N-dimethylformamide (1 mL) was stirred at 20 °C for 1 h and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (40–70% acetonitrile in water with 0.04% ammonium hydroxide and 10 mM ammonium bicarbonate) to give N-(3-chlorophenyl)-N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]oxazol-2-yl]methyl]cyclopropanesulfonamide (17.2 mg, 37%) as a white solid.

[0532] The method described in Example 10 was also used to prepare compound I-85.

[0533] Example 11. Preparation of N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(1,5-dimethyl-1H-pyrazol-4-yl)ethane-1-sulfonamide (I-144) [ka]

[0534] Step 1: N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-1,5-dimethyl-pyrazol-4-amine [ka]

[0535] To a solution of 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (30 mg, 0.1 mmol) in N,N-dimethylformamide (0.5 mL) was added sodium bicarbonate (26 mg, 0.3 mmol) and 1,5-dimethylpyrazol-4-amine (14 mg, 0.12 mmol). After stirring at 20° C. for 16 hours, the mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=1:1) to give N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-1,5-dimethyl-pyrazol-4-amine (30 mg, 74%) as a yellow oil.

[0536] Step 2: N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(1,5-dimethyl-1H-pyrazol-4-yl)ethane-1-sulfonamide [ka] To a solution of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-1,5-dimethyl-pyrazol-4-amine (27 mg, 0.08 mmol) in dichloromethane (0.5 mL) was added pyridine (20 mg, 0.25 mmol) and ethanesulfonyl chloride (13 mg, 0.1 mmol). After stirring at 20 °C for 16 h, the mixture was concentrated to dryness under reduced pressure. The residue was purified by RP-HPLC (0–40% acetonitrile in water and 0.2% formic acid) to give N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(1,5-dimethyl-1H-pyrazol-4-yl)ethane-1-sulfonamide (13 mg, 36%) as a white solid.

[0537] Example 12. Preparation of 3-(2-methylthiazol-5-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (Compound I-11) [ka]

[0538] Step 1: Preparation of methyl 2-methylthiazole-5-carboxylate.

[0539] To a 1 L round-bottom flask was added 2-methyl-1,3-thiazole-5-carboxylic acid (10.0 g, 70 mmol) and MeOH (100 mL). The reaction mixture was then cooled to 0° C., and thionyl chloride (13 mL, 180 mmol) was added dropwise. The reaction mixture was stirred under reflux for 16 hours. The reaction mixture was partially concentrated and then diluted with EtOAc. The organic layer was washed with water, brine, dried over MgSO4, and then concentrated to give the title compound as a white solid, which was used without further purification (11.0 g, 100%).

[0540] Step 2: 2-Methylthiazole-5-carboxamide.

[0541] To a 250 mL round-bottom flask was added methyl 2-methyl-1,3-thiazole-5-carboxylate (11.0 g, 70 mmol) and aqueous ammonium hydroxide (28% NH in HO, 140 mL). The reaction mixture was stirred for 3 h, during which time a white precipitate formed. The crude reaction mixture was diluted with water, and the product was extracted with EtOAc (15x). The combined organic layers were dried over MgSO and then concentrated to give the title compound (8.11 g, 81%) as a white solid.

[0542] Step 3: 2-Methylthiazole-5-carbonitrile.

[0543] To a 100 mL round-bottom flask was added 2-methyl-1,3-thiazole-5-carboxamide (4.00 g, 28.1 mmol), tosyl chloride (13.4 mg, 70.3 mmol), and pyridine (20 mL). The reaction mixture was stirred at 50° C. for 3 hours. The reaction mixture was diluted with EtOAc and washed with approximately 1 M HCl (aq), water, saturated NaHCO (aq), and then brine. The organic layer was dried over MgSO and then concentrated to give the title compound as a brown solid (2.30 g, 66%).

[0544] Step 4: N'-hydroxy-2-methylthiazole-5-carboximidamide.

[0545] To a 500 mL round-bottom flask were added 2-methyl-1,3-thiazole-5-carbonitrile (2.30 g, 18.5 mmol), 8-hydroxyquinoline (13.4 mg, 0.093 mmol), and ethanol (180 mL). To the reaction mixture was sequentially added a solution of hydroxylamine hydrochloride (5.15 g, 74.1 mmol) in water (26 mL) and a solution of sodium carbonate (6.4 g, 59.3 mmol) in water (53 mL). The mixture was then stirred at 78 °C for 16 h. The reaction mixture was then concentrated to remove ethanol, diluted with water, and then acidified to pH 5 with 2 M HCl (aq). The product was extracted with EtOAc (6x), dried over MgSO4, and then concentrated to give the title compound as a brown solid (2.91 g, 89%).

[0546] Step 5: 3-(2-Methylthiazol-5-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole.

[0547] To a 20 mL vial was added (Z)-N'-hydroxy-2-methylthiazole-5-carboximidamide (247 mg, 0.54 mmol) and pyridine (3.8 mL). The reaction mixture was cooled to 0 °C, and TFAA (0.66 mL, 4.7 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 15 minutes, then stirred while warming to ambient temperature for 45 minutes. The crude reaction mixture was diluted with EtOAc and then washed with 1 M HCl (aq), water, and then brine. The organic layer was then dried over MgSO and concentrated. The resulting residue was adsorbed onto Celite and purified by column chromatography (0-15% EtOAc / hexanes) to afford the title compound as a yellow oil (369 mg, 58%). 1 H NMR (400 MHz, chloroform-d) δ ppm 8.38 (s, 1H) 2.82 (s, 3H). LCMS: tR (min): 4.90 (20 to 100% ACN with 0.1% TFA, 6 min), m / z [M+H] + Required: 236.0, Found: 236.0. HPLC tR (min) 6.34, 99% (10–100% ACN with 0.1% TFA, 10 min).

[0548] Example 13. Preparation of N-(3-chlorophenyl)-N-((5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)thiazol-2-yl)methyl)cyclopropanesulfonamide (Compound I-12) [ka]

[0549] Step 1: 3-(2-(bromomethyl)thiazol-5-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole.

[0550] To a 20 mL vial was added 3-(2-methylthiazol-5-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (208 mg, 0.88 mmol), NBS (283 mg, 1.59 mmol), AIBN (7.3 mg, 0.044 mmol), and DCE (9.0 mL). The reaction mixture was stirred at 84 °C for 16 h. The crude reaction mixture was diluted with EtOAc, washed with water, washed with brine, dried over MgSO4, and then concentrated. To the resulting residue was added THF (9.0 mL). The reaction mixture was cooled to 0 °C, and then DIPEA (0.13 mL, 0.88 mmol) and diethyl phosphite (0.09 mL, 0.9 mmol) were added dropwise, successively. The reaction mixture was stirred for 2 h while warming to ambient temperature. The reaction mixture was concentrated, then diluted with EtOAc, washed with water, washed with brine, dried over MgSO4, and then concentrated. The crude product was adsorbed onto Celite and then purified by column chromatography (0-10% EtOAc / hexanes) to afford the title compound as a white solid (174 mg, 62%).

[0551] Step 2: N-(3-chlorophenyl)-N((5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)thiazol-2-yl)methyl)cyclopropanesulfonamide.

[0552] To a 2-dram vial was added 60 wt% NaH in mineral oil (8.3 mg, 0.21 mmol) and DMF (0.5 mL). The reaction mixture was cooled to 0° C., and then a solution of N-(3-chlorophenyl)cyclopropanesulfonamide (40.6 mg, 0.18 mmol) in DMF (0.5 mL) was added dropwise. The reaction mixture was stirred for 20 minutes while warming to ambient temperature. The reaction mixture was then cooled to 0° C., and then a solution of 3-(2-(bromomethyl)thiazol-5-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (50.0 mg, 0.16 mmol) in DMF (1.0 mL) was added dropwise. After 4 hours, the reaction mixture was quenched with water and diluted with brine. The product was extracted with EtOAc (3×). The combined organic layers were washed with water (4×), brine, dried over MgSO4, and concentrated. The resulting residue was adsorbed onto Celite and purified by column chromatography (0-70% EtOAc / hexanes) to afford the title compound as an orange solid (16.6 mg, 22%).

[0553] Example 14. Preparation of N-[[2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-5-yl]methyl]-N-(5-fluoro-3-pyridyl)ethanesulfonamide (I-264) [ka]

[0554] Step 1: tert-butyl N-[(5-methylthiazole-2-carbonyl)amino]carbamate [ka]

[0555] To a mixture of 5-methylthiazole-2-carboxylic acid (3.0 g, 20.95 mmol) in dichloromethane (50 mL) was added N-(3-dimethylaminopropyl)-n-ethylcarbodiimide hydrochloride (4.8 g, 25.15 mmol) and 1-hydroxybenzotriazole (1.42 g, 10.48 mmol). After stirring at 20° C. for 15 minutes, the reaction was added with tert-butyl N-aminocarbamate (3.3 g, 25.15 mmol). After stirring at 20° C. for 16 hours, the reaction was quenched by the addition of water (100 mL) and extracted with dichloromethane (2×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give tert-butyl N-[(5-methylthiazole-2-carbonyl)amino]carbamate (4.16 g, 75%) as a colorless oil.

[0556] Step 2: 5-Methylthiazole-2-carbohydrazide [ka]

[0557] A solution of tert-butyl N-[(5-methylthiazole-2-carbonyl)amino]carbamate (4.07 g, 15.82 mmol) in hydrochloric acid (4.0 M in ethyl acetate, 40.0 mL, 160.00 mmol) was stirred at 20° C. for 2 hours and filtered. The collected solid was dried under reduced pressure to give 5-methylthiazole-2-carbohydrazide hydrochloride (3.2 g, crude) as a white solid.

[0558] Step 3: N'-(2,2-difluoroacetyl)-5-methyl-thiazole-2-carbohydrazide [ka]

[0559] To a solution of 5-methylthiazole-2-carbohydrazide hydrochloride (3.0 g, crude) in tetrahydrofuran (30 mL) was added N-ethyl-N-isopropylpropan-2-amine (4.0 g, 30.98 mmol) and (2,2-difluoroacetyl) 2,2-difluoroacetate (3.2 g, 18.59 mmol) at 0 °C. After stirring at 20 °C for 1 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% methanol in dichloromethane) to give N'-(2,2-difluoroacetyl)-5-methyl-thiazole-2-carbohydrazide (2.0 g, 54%) as a white solid.

[0560] Step 4: 2-(Difluoromethyl)-5-(5-methylthiazol-2-yl)-1,3,4-oxadiazole [ka]

[0561] A mixture of N'-(2,2-difluoroacetyl)-5-methyl-thiazole-2-carbohydrazide (1.0 g, 4.25 mmol) and Burgess reagent (3.0 g, 12.75 mmol) in tetrahydrofuran (15 mL) was heated at 90 °C for 3 h under microwave irradiation. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-15% ethyl acetate in petroleum ether) to give 2-(difluoromethyl)-5-(5-methylthiazol-2-yl)-1,3,4-oxadiazole (712 mg, 32%) as a white solid.

[0562] Step 5: 2-[5-(bromomethyl)thiazol-2-yl]-5-(difluoromethyl)-1,3,4-oxadiazole [ka]

[0563] To a solution of 2-(difluoromethyl)-5-(5-methylthiazol-2-yl)-1,3,4-oxadiazole (610 mg, 2.81 mmol) in 1,2-dichloroethane (20 mL) was added N-bromosuccinimide (550 mg, 3.09 mmol) and azodiisobutyronitrile (azobisisobutyronitrile) (23 mg, 0.14 mmol). After stirring at 80 °C for 3 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give 2-[5-(bromomethyl)thiazol-2-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (743 mg, 73%) as a white solid.

[0564] Step 6: N-[[2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-5-yl]methyl]-N-(5-fluoro-3-pyridyl)ethanesulfonamide [ka]

[0565] To a solution of 2-[5-(bromomethyl)thiazol-2-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (50 mg, 0.7 mmol) in N,N-dimethylformamide (1 mL) was added sodium bicarbonate (43 mg, 0.51 mol) and N-(5-fluoro-3-pyridyl)ethanesulfonamide (41 mg, 0.2 mmol). After stirring at 20 °C for 1 h, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (35–65% acetonitrile in water and 0.225% formic acid) to give N-[[2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-5-yl]methyl]-N-(5-fluoro-3-pyridyl)ethanesulfonamide (37 mg, 51%) as a colorless oil.

[0566] The method described in Example 14 was also used to prepare the following compounds: I-257, I-259, I-260, I-261, I-262, and I-263.

[0567] Example 15. Preparation of 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-2-ol (I-258) [ka]

[0568] To a solution of 1,3-dihydropyrrolo[2,3-c]pyridin-2-one (25 mg, 0.19 mmol) in N,N-dimethylformamide (0.5 mL) was added sodium hydride (60%, 7 mg, 0.17 mmol). After stirring at 0° C. for 0.5 hours, 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (50 mg, 0.17 mmol) was added to the reaction. After stirring at 20° C. for an additional 0.5 hours, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (10–40% acetonitrile in water and 0.225% formic acid) to give 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-1H-pyrrolo[2,3-c]pyridin-2-ol (10.3 mg, 17%) as a red solid.

[0569] Example 16. Synthesis of N-alkylamidopyridinone compounds of formula (I)

[0570] Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2(1H)-one (II-12), tert-butyl 2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-oxopyridin-1(2H)-yl)acetate (Compound II-11), 2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-oxopyridin-1(2H)-yl)acetic acid (Compound II-10), and 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-1-(2-morpholino-2-oxoethyl)pyridin-2(1H)-one (Compound II-1) [ka]

[0571] Step 1: Preparation of 4-(2H-tetrazol-5-yl)pyridin-2(1H)-one, HCl salt. [ka]

[0572] To a 100 mL round-bottom flask containing a 1-inch egg-shaped stir bar equipped with an air condenser and under a N2 atmosphere (balloon), 2-oxo-1,2-dihydropyridine-4-carbonitrile (1.00 g, 8.33 mmol, 1 equiv.) was added, followed by sodium azide (1.62 g, 25.0 mmol, 3 equiv.), ammonium chloride (1.34 g, 25.0 mmol, 3 equiv.), and lithium chloride (529 mg, 12.5 mmol, 1.5 equiv.). Finally, DMF (20 mL) was added, and the pink heterogeneous suspension was vigorously stirred at 110 °C for 16 h, after which LCMS analysis indicated clean, complete conversion to the desired tetrazole product. The reaction mixture was cooled to room temperature, and then 50 mL of water was added to form a pale orange, homogeneous solution (pH = 6). With vigorous stirring, concentrated aqueous HCl (approximately 2 mL) was added dropwise over 2 minutes until the pH reached 1. Upon acidification, the desired tetrazole HCl salt precipitated as a pale beige solid. The suspension was filtered, and the pale beige solid was washed with water (20 mL) followed by hexane (20 mL) and then air-dried on the filter for 10 minutes. (Caution: The filtrate contains hydrazoic acid, which is volatile, toxic, and explosive. The acidic aqueous solution of hydrazoic acid can be safely quenched by adding sodium nitrite until spotting on starch-iodide paper yields dark blue spots, indicating complete decomposition of the hydrazoic acid.) The resulting wet solid was dried overnight in vacuo to remove residual water, yielding 1.21 g (73%) of the title compound HCl salt as a free-flowing beige solid.

[0573] Step 2: Preparation of 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2(1H)-one (compound II-12). [ka]

[0574] To a 100 mL round-bottom flask containing a 1-inch egg-shaped stir bar equipped with an air condenser and under a N atmosphere (balloon) was added 4-(2H-tetrazol-5-yl)pyridin-2(1H)-one (HCl salt, 600 mg, 3.01 mmol, 1 equiv.), followed by 1,4-dioxane (20 mL) and potassium carbonate (1.69 g, 12.0 mmol, 4 equiv.). The beige heterogeneous suspension was vigorously stirred at room temperature for 5 minutes, after which difluoroacetic anhydride (DFAA, 0.70 mL, 6.0 mmol, 2 equiv.) was added dropwise over 2 minutes, with no immediate visible change in the reaction. The reaction was heated to 90 °C overnight (16 hours) with vigorous stirring, after which LCMS analysis indicated approximately 80% clean conversion to the desired oxadiazole. Deemed sufficient, the reaction was cooled to room temperature and then poured into 30 mL of water to give a dark yellow-orange homogeneous solution (pH = 10). The basic aqueous layer was extracted three times with 50 mL of EtOAc, and the organic layer was washed with minimal saturated aqueous NaHCO (10 mL), then brine (10 mL), then dried over MgSO, filtered, and concentrated by rotary evaporation. The resulting yellow solid was taken up in MTBE (10 mL), sonicated to form a fine suspension, and then filtered to give the title compound, 477 mg (74% yield), as a white solid.

[0575] The method used to prepare compound II-12 was also used to prepare compound II-6.

[0576] Step 3: Preparation of tert-butyl 2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-oxopyridin-1(2H)-yl)acetate (compound II-11). [ka]

[0577] To a scintillation vial containing a magnetic stirrer, 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2(1H)-one (140 mg, 0.66 mmol, 1 equiv.) and DMF (2 mL) were added. The resulting orange homogeneous solution was cooled to 0 °C in an ice bath. Potassium carbonate (461 mg, 3.3 mmol, 5 equiv.) was added. Finally, tert-butyl bromoacetate (0.29 mL, 2.0 mmol, 3 equiv.) was added in one portion. After 1 h, LCMS analysis of the fine orange suspension showed complete conversion to a >10:1 mixture of N- and O-alkylated pyridones. The N-alkylated pyridone is much more polar than the O-alkylated pyridone by both LCMS and TLC. Additionally, the N-alkylated pyridone exhibits bright blue fluorescence by TLC at 254 nm excitation. The reaction was worked up by pouring into 50 mL of water and then extracting the aqueous layer three times with 50 mL of EtOAc. The combined organic layers were washed with water, then brine, then dried over MgSO, filtered, and concentrated by rotary evaporation. The crude pale yellow oil was dry-loaded onto silica gel and purified by flash column chromatography (0 to 50% EtOAc in hexanes gradient) to afford 188.0 mg (87% yield) of the title compound as a white solid. Connectivity was assigned by NOESY (NOE crosspeaks were observed between the alpha CH at 4.61 ppm and the most downfield pyridone doublet at 7.40 ppm).

[0578] The method used to prepare compound II-11 was also used to prepare compound II-7.

[0579] Step 4: Preparation of 2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-oxopyridin-1(2H)-yl)acetic acid (compound II-10). [ka]

[0580] To a scintillation vial containing a magnetic stirrer, tert-butyl 2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-oxopyridin-1(2H)-yl)acetate (188 mg, 0.57 mmol, 1 equiv.) was added dropwise with stirring at room temperature for 1 min, followed by DCM (2 mL), and finally trifluoroacetic acid (TFA, 0.5 mL). The pale yellow homogeneous solution was stirred open to air at room temperature for 6 h, after which LCMS analysis showed approximately 96% clean conversion of the tert-butyl ester to the free carboxylic acid. Deemed sufficient, the reaction mixture was directly concentrated by rotary evaporation to give the crude material as a colorless viscous oil containing residual TFA. The material was dissolved in 3 mL of 1:1 acetonitrile:water, then frozen in a 78° C. tri-ice acetone bath, and then lyophilized overnight to give 165 mg (103% yield) of the title compound as a pale yellow, brittle solid of sufficient purity.

[0581] Step 5: Preparation of 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-1-(2-morpholino-2-oxoethyl)pyridin-2(1H)-one. [ka]

[0582] To a scintillation vial was added 2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-oxopyridin-1(2H)-yl)acetic acid (II-10, 27.1 mg, 0.10 mmol, 1 equiv.), followed by EtOAc (1 mL) and HATU (76.0 mg, 0.20 mmol, 2 equiv.). The heterogeneous white suspension was stirred at room temperature for 5 minutes, after which morpholine (0.025 mL, 0.30 mmol, 3 equiv.) was added, followed by triethylamine (0.07 mL, 0.5 mmol, 5 equiv.), each dropwise with vigorous stirring at room temperature. The heterogeneous white suspension was stirred at room temperature for 1 hour, after which LCMS analysis showed complete conversion to the desired amide. The reaction was poured into water (50 mL), and the aqueous layer was then extracted three times with EtOAc (50 mL). The combined organic layers were washed with minimal water, then brine, then dried over MgSO, filtered, and concentrated by rotary evaporation to give the crude product as a yellow oil. The material was dry-loaded onto silica gel and purified by flash column chromatography (gradient of 0 to 10% methanol in DCM) to give the title compound, 7.8 mg (23% yield), as a colorless oil.

[0583] Any suitable amide coupling procedure known in the art can be used to prepare the compounds of the present disclosure, including, but not limited to, EDC / 1-hydroxybenzotriazole (HOBT) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDAC) / HOBT / EtN(iPr2).

[0584] The method disclosed in Example 16 was also used to prepare the following compounds: II-2 and II-18.

[0585] Example 17. Synthesis of N-alkylpyridinone compounds of formula (I)

[0586] Preparation of 1-benzyl-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2(1H)-one (compound II-4). [ka]

[0587] To a 1-dram vial containing a magnetic stirrer was added 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2(1H)-one (II-12, 20.0 mg, 0.094 mmol, 1 equiv.) and DMF (1 mL). The orange homogeneous solution was cooled to 0 °C in an ice bath. Potassium carbonate (69 mg, 0.5 mmol, 5 equiv.) was added, followed by the dropwise addition of benzyl bromide (0.05 mL, 0.5 mmol, 5 equiv.). The reaction was allowed to warm to room temperature. After 2 h, LCMS analysis indicated complete conversion to a >10:1 mixture of N- and O-alkylated pyridones. The reaction was worked up by pouring into 50 mL of water and then extracting the aqueous layer three times with EtOAc (50 mL). The combined organic layers were washed with water, then brine, then dried over MgSO4, filtered, and concentrated by rotary evaporation. The crude pale yellow film was dry-loaded onto silica gel and purified by flash column chromatography (gradient of 0 to 50% EtOAc in hexanes) to afford the title compound, 25.3 mg (85% yield), as a colorless oil that solidified to a waxy white solid at room temperature.

[0588] Preparation of 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-1-phenethylpyridin-2(1H)-one (compound II-5). [ka]

[0589] To a 1-dram vial containing a magnetic stirrer was added 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2(1H)-one (II-12, 21.0 mg, 0.099 mmol, 1 equiv.) and DMF (1 mL). The orange homogeneous solution was cooled to 0 °C in an ice bath. Potassium carbonate (69 mg, 0.5 mmol, 5 equiv.) was added, followed by the dropwise addition of phenethyl bromide (0.07 mL, 0.5 mmol, 5 equiv.). The reaction was allowed to warm to room temperature. After 2 h, LCMS analysis indicated complete conversion of the N-linked pyridone to the O-linked pyridone in an approximately 2:1 ratio (selectivity is usually much greater in favor of the N-linked pyridone than in this case). The reaction was worked up by pouring into 50 mL of water and then extracting the aqueous layer three times with EtOAc (50 mL). The combined organic layers were washed with water, then brine, then dried over MgSO, filtered, and concentrated by rotary evaporation. The crude pale yellow oil was dry-loaded onto silica gel and purified by flash column chromatography (0-50% EtOAc in hexanes gradient) to afford each of the two isomeric title compounds in high purity (connectivity was unambiguously confirmed by NOESY for both isomers).

[0590] N-linked 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-1-phenethylpyridin-2(1H)-one. White solid, 18.3 mg (58% yield). LC-MS: tR (min) 4.39 (20-100% ACN with 0.1% TFA, 6 min), m / z [M+H] + C 16 H 13 F2N3O2 required: 317.1, found: 318.1. HPLC tR (min) 5.89, 97.9% (10 to 100% ACN with 0.1% TFA, 10 min).

[0591] O-linked 2-(difluoromethyl)-5-(2-phenethoxypyridin-4-yl)-1,3,4-oxadiazole. Pale yellow oil that solidified to a waxy solid at room temperature, 10.5 mg (33% yield). 1H NMR (400MHz, chloroform-d) δppm 8.35 (br d,J=3.67Hz,1H)7.18-7.59(m,7H)6.73-7.12(m,1H)4.60(br t,J=6.85Hz,2H)3.13(br d,J=6.60Hz,2H). LC-MS: tR (min) 5.66 (20-100% ACN with 0.1% TFA, 6 min), m / z[M+H] + C 16 H 13 F2N3O2 required: 317.1, found: 318.1. HPLC tR (min) 6.89, 98.1% (10 to 100% ACN with 0.1% TFA, 10 min).

[0592] The method described in Example 17 was also used to prepare II-3, II-8, and II-9:

[0593] Example 18. Preparation of 1-((2-cyclopropylpyridin-4-yl)methyl)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2(1H)-one (Compound II-15). [ka]

[0594] Step 1: Methyl 2-cyclopropylpyridine-4-carboxylate [ka]

[0595] A mixture of methyl 2-bromopyridine-4-carboxylate (5.0 g, 23.14 mmol), tricyclohexylphosphine (649 mg, 2.31 mmol), cyclopropylboronic acid (3.0 g, 34.72 mmol), potassium phosphate (17 g, 81.01 mmol), and palladium acetate (260 mg, 1.16 mmol) in toluene (140 mL) and water (28 mL) was stirred at 100 °C for 16 h under a nitrogen atmosphere. After cooling, the reaction mixture was diluted with water (100 mL) and ethyl acetate (100 mL). The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give methyl 2-cyclopropylpyridine-4-carboxylate (1.33 g, 30%) as a pale yellow oil.

[0596] Step 2: (2-Cyclopropyl-4-pyridyl)methanol [ka]

[0597] To a solution of methyl 2-cyclopropylpyridine-4-carboxylate (1.3 g, 7.48 mmol) and sodium methoxide (20 mg, 0.37 mmol) in methanol (20 mL) was added sodium borohydride (851 mg, 22.49 mmol) at 0 °C. After stirring at 80 °C for 16 h, the reaction mixture was diluted with water (50 mL) and ethyl acetate (50 mL). The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give (2-cyclopropyl-4-pyridyl)methanol (690 mg, 62%) as a colorless oil.

[0598] Step 3: 1-((2-cyclopropylpyridin-4-yl)methyl)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2(1H)-one (Compound II-15) [ka]

[0599] To a solution of (2-cyclopropyl-4-pyridyl)methanol (42 mg, 0.28 mmol), 4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1H-pyridin-2-one (II-12, 50 mg, 0.23 mmol), and triphenylphosphine (123 mg, 0.47 mmol) in tetrahydrofuran (3 mL) was added diisopropyl azodicarboxylate (95 mg, 0.47 mmol) at 0° C. After stirring at 20° C. for 16 hours, the reaction mixture was diluted with water (30 mL) and ethyl acetate (30 mL). The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (10–40% acetonitrile in water and 0.04% ammonium hydroxide and 10 mM ammonium bicarbonate) to give 1-[(2-cyclopropyl-4-pyridyl)methyl]-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-one (11 mg, 13%) as a yellow solid.

[0600] Example 19. Synthesis of N-alkyl ether pyridinone compounds of formula (I)

[0601] Preparation of 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-1-(2-(3,5-difluorophenoxy)ethyl)pyridin-2(1H)-one (Compound II-14) [ka]

[0602] Step 1: 1-(2-bromoethoxy)-3,5-difluoro-benzene [ka]

[0603] To a solution of 3,5-difluorophenol (500 mg, 3.84 mmol) and 1,2-dibromoethane (4.4 g, 23.54 mmol) in acetonitrile (10 mL) was added potassium carbonate (712 mg, 5.15 mmol). The mixture was stirred at 75 °C for 16 h and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum ether) to give 1-(2-bromoethoxy)-3,5-difluorobenzene (174 mg, 19%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ6.58-6.34 (m, 3H), 4.26 (t, J = 6.40Hz, 2H), 3.64 (t, J = 6.0Hz, 2H).

[0604] Step 2: 4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-[2-(3,5-difluorophenoxy)ethyl]pyridin-2-one (Compound II-14) [ka]

[0605] To a solution of 4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1H-pyridin-2-one (II-12, 40 mg, 0.19 mmol) and 1-(2-bromoethoxy)-3,5-difluorobenzene (53 mg, 0.23 mmol) in N,N-dimethylformamide (1 mL) was added potassium carbonate (78 mg, 0.56 mmol). The mixture was stirred at 25 °C for 16 h and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (49-79% acetonitrile in water and 0.225% formic acid) to give 4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-[2-(3,5-difluorophenoxy)ethyl]pyridin-2-one (23.4 mg, 34%) as a white solid.

[0606] The method disclosed in Example 19 was also used to prepare compounds II-13 and II-16.

[0607] Example 20. Preparation of 5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-(2-(3-fluorophenoxy)ethyl)pyridazin-3(2H)-one (Compound II-17). [ka]

[0608] Step 1: Ethyl 6-oxo-1H-pyridazine-4-carboxylate [ka]

[0609] To a solution of 6-oxo-1H-pyridazine-4-carboxylic acid (5.5 g, 39.26 mmol) in ethyl alcohol (50 mL) was added concentrated sulfuric acid (98%, 10.1 g, 101.12 mmol). After stirring at 80 °C for 48 h under a nitrogen atmosphere, the mixture was concentrated under reduced pressure. The residue was adjusted to pH = 8 by adding saturated aqueous sodium carbonate solution and extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated to dryness under reduced pressure to give crude ethyl 6-oxo-1H-pyridazine-4-carboxylate (3 g, 45%) as a brown solid.

[0610] Step 2: Ethyl 6-oxo-1-(2-trimethylsilylethoxymethyl)pyridazine-4-carboxylate [ka]

[0611] To a solution of ethyl 6-oxo-1-(2-trimethylsilylethoxymethyl)pyridazine-4-carboxylate (3.0 g, 17.84 mmol) in N,N-dimethylformamide (20 mL) was added N,N-diisopropylethylamine (3.7 g, 28.55 mmol) and (2-(chloromethoxy)ethyl)trimethylsilane (5.9 g, 35.68 mmol). After stirring at 20 °C for 32 h, the reaction mixture was diluted with water (30 mL) and ethyl acetate (100 mL). The separated organic extract was washed with brine (50 mL × 3), dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give ethyl 6-oxo-1-(2-trimethylsilylethoxymethyl)pyridazine-4-carboxylate (2.9 g, 42%) as a yellow oil.

[0612] Step 3: 6-oxo-1-(2-trimethylsilylethoxymethyl)pyridazine-4-carbohydrazide [ka]

[0613] To a solution of ethyl 6-oxo-1-(2-trimethylsilylethoxymethyl)pyridazine-4-carboxylate (2.9 g, 9.72 mmol) in ethyl alcohol (50 mL) was added hydrazine hydrate (85%, 6.2 g, 105.10 mmol). After stirring at 80 °C for 3 h, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% dichloromethane in methanol) to give 6-oxo-1-(2-trimethylsilylethoxymethyl)pyridazine-4-carbohydrazide (2.5 g, 90%) as a yellow solid.

[0614] Step 4: 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one [ka]

[0615] To a solution of 6-oxo-1-(2-trimethylsilylethoxymethyl)pyridazine-4-carbohydrazide (2.5 g, 8.79 mmol) and N,N-diisopropylethylamine (9.1 g, 70.33 mmol) in tetrahydrofuran (30 mL) was added dropwise (2,2-difluoroacetyl)2,2-difluoroacetate (6.1 g, 35.16 mmol) at 0 °C. After stirring at 20 °C for 1 hour, the mixture was warmed to 70 °C and stirred for 1 hour. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100–200 mesh, 0–5% methanol in dichloromethane) to give 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one (1.27 g, 40%) as a brown solid.

[0616] Step 5: 4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1H-pyridazin-6-one [ka]

[0617] To a solution of 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one (1.3 g, 3.69 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (10 mL) was added trifluoroacetic acid (4.2 g, 36.88 mmol). After stirring at 20 °C for 1 hour, the mixture was concentrated under reduced pressure. The residue was diluted with water (50 mL) and adjusted to pH = 8 by the addition of saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (50 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% methanol in dichloromethane) to give 4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1H-pyridazin-6-one (571 mg, 59%) as a yellow solid.

[0618] Step 6: 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[2-(3-fluorophenoxy)ethyl]pyridazin-3-one (Compound II-17) [ka]

[0619] To a solution of 1-(2-bromoethoxy)-3-fluorobenzene (56 mg, 0.26 mmol) in N,N-dimethylformamide (1 mL) was added sodium carbonate (49 mg, 0.47 mmol) and 4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1H-pyridazin-6-one (50 mg, 0.23 mmol). The mixture was stirred at 20 °C for 1 h and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (30–60% acetonitrile in water and 0.225% formic acid) to give 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[2-(3-fluorophenoxy)ethyl]pyridazin-3-one (19.2 mg, 23%) as a white solid.

[0620] Example 21. Preparation of 4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-[[(1R,2R)-2-phenylcyclopropyl]methyl]pyridin-2-one (Compound II-19). [ka]

[0621] Step 1: [(1R,2R)-2-phenylcyclopropyl]methanol [ka]

[0622] To a solution of ethyl (1R,2R)-2-phenylcyclopropanecarboxylate (500 mg, 2.63 mmol) in tetrahydrofuran (25 mL) was added diisobutylaluminum hydride (1 M in tetrahydrofuran, 5.3 mL, 5.3 mmol) at 0 °C. After the addition, the reaction mixture was warmed to 20 °C and stirred for 16 h. The reaction was quenched by the addition of saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic extracts were dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to give [(1R,2R)-2-phenylcyclopropyl]methanol (301 mg, 77%) as a colorless oil.

[0623] Step 2: [(1R,2R)-2-(iodomethyl)cyclopropyl]benzene [ka]

[0624] To a solution of [(1R,2R)-2-phenylcyclopropyl]methanol (160 mg, 1.08 mmol) in tetrahydrofuran (5 mL) was added iodine (411 mg, 1.62 mmol), imidazole (220 mg, 3.24 mmol), and triphenylphosphane (850 mg, 3.24 mmol). The reaction mixture was stirred at 25° C. for 0.5 h and concentrated to dryness under reduced pressure. The residue was purified by RP-TLC (petroleum ether) to give [(1R,2R)-2-(iodomethyl)cyclopropyl]benzene (54 mg, 19%) as a white solid.

[0625] Step 3: 4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-[[(1R,2R)-2-phenylcyclopropyl]methyl]pyridin-2-one (Compound II-19) [ka]

[0626] To a solution of [(1R,2R)-2-(iodomethyl)cyclopropyl]benzene (54 mg, 0.21 mmol) and 4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1H-pyridin-2-one (37 mg, 0.17 mmol) in N,N-dimethylformamide (1 mL) was added potassium phosphate (72 mg, 0.52 mmol). The mixture was stirred at 25 °C for 16 h and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by RP-HPLC (50% to 80% acetonitrile in water and 0.225% formic acid) to give 4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-[[(1R,2R)-2-phenylcyclopropyl]methyl]pyridin-2-one (5.6 mg, 9%) as a yellow solid.

[0627] Example 22. Preparation of N-(3-chlorophenyl)-N((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)isoxazol-3-yl)methyl)ethanesulfonamide (Compound IVb-1). [ka]

[0628] Step 1: (1E)-2-Chloroacetaldehyde oxime [ka]

[0629] To a solution of 2-chloroacetaldehyde (14.5 g, 73.8 mmol, 40% purity) in water (50 mL) was added sodium acetate (7.3 g, 88.6 mmol) and hydroxylamine hydrochloride (6.2 g, 88.6 mmol). After stirring at 20 °C for 1 h, the reaction was quenched by the addition of saturated sodium bicarbonate (20 mL). The mixture was extracted with ethyl acetate (100 mL × 2). The combined organic extracts were dried over sodium sulfate and concentrated to dryness under reduced pressure to give (1E)-2-chloroacetaldehyde oxime (4.0 g, 58%) as a yellow solid, which was used in the next step without further purification.

[0630] Step 2: Ethyl 3-(chloromethyl)isoxazole-5-carboxylate [ka]

[0631] To a solution of (1E)-2-chloroacetaldehyde oxime (4.0 g, 42.8 mmol) in tetrahydrofuran (15 mL) was added ethyl prop-2-ynoate (4.2 g, 42.8 mmol) and sodium hypochlorite (181.5 g, 243.8 mmol, 10% purity) at 0 °C. After stirring at 20 °C for 18 h, the reaction mixture was diluted with ethyl acetate (200 mL) and brine (200 mL). The separated organic layer was dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give ethyl 3-(chloromethyl)isoxazole-5-carboxylate (2.8 g, 35%) as a white solid.

[0632] Step 3: Ethyl 3-[(3-chloro-N-ethylsulfonyl-anilino)methyl]isoxazole-5-carboxylate [ka]

[0633] To a solution of N-(3-chlorophenyl)ethanesulfonamide (461 mg, 2.10 mmol) in N,N-dimethylformamide (5 mL) was added ethyl 3-(chloromethyl)isoxazole-5-carboxylate (200 mg, 1.05 mmol) and sodium carbonate (334 mg, 3.15 mmol). After stirring at 30 °C for 16 h, the mixture was diluted with ethyl acetate (50 mL) and washed with brine (50 mL × 2). The separated organic layer was dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give ethyl 3-[(3-chloro-N-ethylsulfonyl-anilino)methyl]isoxazole-5-carboxylate (370 mg, 95%) as a white solid.

[0634] Step 4: N-(3-chlorophenyl)-N-[[5-(hydrazinecarbonyl)isoxazol-3-yl]methyl]ethanesulfonamide [ka]

[0635] To a solution of ethyl 3-[(3-chloro-N-ethylsulfonyl-anilino)methyl]isoxazole-5-carboxylate (170 mg, 0.46 mmol) in ethanol (2 mL) was added hydrazine hydrate (250 mg, 4.89 mmol). The mixture was stirred at 60 °C for 2 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% methanol in dichloromethane) to give N-(3-chlorophenyl)-N-[[5-(hydrazinecarbonyl)isoxazol-3-yl]methyl]ethanesulfonamide (100 mg, 61%) as a white solid.

[0636] Step 5: N-(3-chlorophenyl)-N-[[5-[[(2,2-difluoroacetyl)amino]carbamoyl]-isoxazol-3-yl]methyl]ethanesulfonamide [ka]

[0637] To a solution of N-(3-chlorophenyl)-N-[[5-(hydrazinecarbonyl)isoxazol-3-yl]methyl]ethanesulfonamide (100 mg, 0.28 mmol) and N,N-diisopropylethylamine (36 mg, 0.28 mmol) in tetrahydrofuran (2 mL) was added (2,2-difluoroacetyl) 2,2-difluoroacetate (49 mg, 0.28 mmol) under a nitrogen atmosphere. After stirring at 20 °C for 2 hours, the reaction was quenched by the addition of water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by RP-TLC (petroleum ether:ethyl acetate=1:1) to give N-(3-chlorophenyl)-N-[[5-[[(2,2-difluoroacetyl)amino]carbamoyl]isoxazol-3-yl]methyl]ethanesulfonamide (110 mg, 90%) as a white solid.

[0638] Step 6: N-(3-chlorophenyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)isoxazol-3-yl)methyl)ethanesulfonamide (compound IVb-1) [ka]

[0639] To a solution of N-(3-chlorophenyl)-N-[[5-[[(2,2-difluoroacetyl)amino]carbamoyl]isoxazol-3-yl]methyl]ethanesulfonamide (100 mg, 0.23 mmol) in tetrahydrofuran (2 mL) was added Burgess's reagent (136 mg, 0.57 mmol). The mixture was stirred at 90 °C under a nitrogen atmosphere for 2 h and concentrated under reduced pressure. The residue was purified by RP-HPLC (35-65% acetonitrile in water and 0.1% trifluoroacetic acid) to give N-(3-chlorophenyl)-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]isoxazol-3-yl]methyl]ethanesulfonamide (13 mg, 13%) as a white solid.

[0640] Example 23. Preparation of N-({3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,2-oxazol-5-yl}methyl)-N-(pyridin-3-yl)ethane-1-sulfonamide (IVa-2) [ka]

[0641] Step 1: Ethyl 5-[[ethylsulfonyl(3-pyridyl)amino]methyl]isoxazole-3-carboxylate [ka]

[0642] To a solution of ethyl 5-(p-tolylsulfonyloxymethyl)isoxazole-3-carboxylate (400 mg, 1.23 mmol) and N-(3-pyridyl)ethanesulfonamide (275 mg, 1.48 mmol) in N,N-dimethylformamide (8 mL) was added sodium carbonate (391 mg, 3.69 mmol) and potassium iodide (20 mg, 0.12 mmol) at 20 °C. After stirring at 20 °C for 16 h, the residue was diluted with ethyl acetate (10 mL) and washed with brine (3 × 10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100–200 mesh, 0–6% methanol in dichloromethane) to give ethyl 5-[[ethylsulfonyl(3-pyridyl)amino]methyl]isoxazole-3-carboxylate (323 mg, 75%) as a pale yellow solid.

[0643] Step 2: N-[[3-(hydrazinecarbonyl)isoxazol-5-yl]methyl]-N-(3-pyridyl)ethanesulfonamide [ka]

[0644] To a solution of ethyl 5-[[ethylsulfonyl(3-pyridyl)amino]methyl]isoxazole-3-carboxylate (273 mg, 0.80 mmol) in ethanol (3 mL) was added hydrazine hydrate (403 mg, 8.04 mmol). The mixture was stirred at 60 °C for 1 h and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0-10% methanol in dichloromethane) to give N-[[3-(hydrazinecarbonyl)isoxazol-5-yl]methyl]-N-(3-pyridyl)ethanesulfonamide (204 mg, 75%) as a pale yellow oil.

[0645] Step 3: N-[[3-[[(2,2-difluoroacetyl)amino]carbamoyl]isoxazol-5-yl]methyl]-N-(3-pyridyl)ethanesulfonamide [ka]

[0646] To a solution of N-[[3-(hydrazinecarbonyl)isoxazol-5-yl]methyl]-N-(3-pyridyl)ethanesulfonamide (184 mg, 0.56 mmol) in tetrahydrofuran (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (80 mg, 0.62 mmol) and (2,2-difluoroacetyl) 2,2-difluoroacetate (118 mg, 0.69 mmol). After stirring at 20 °C for 1 hour, the reaction mixture was quenched by the addition of water (5 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100–200 mesh, 0–10% methanol in dichloromethane) to give N-[[3-[[(2,2-difluoroacetyl)amino]carbamoyl]isoxazol-5-yl]methyl]-N-(3-pyridyl)ethanesulfonamide (200 mg, 70%) as a colorless oil.

[0647] Step 4: N-({3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,2-oxazol-5-yl}methyl)-N-(pyridin-3-yl)ethane-1-sulfonamide [ka]

[0648] To a solution of N-[[3-[[(2,2-difluoroacetyl)amino]carbamoyl]isoxazol-5-yl]methyl]-N-(3-pyridyl)ethanesulfonamide (100 mg, 0.25 mmol) in tetrahydrofuran (2 mL) was added Burgess's reagent (148 mg, 0.62 mmol). The mixture was stirred at 90° C. for 3 hours and cooled. The solution was diluted with water (4 mL) and extracted with ethyl acetate (2×10 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol=20:1) to give N-({3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,2-oxazol-5-yl}methyl)-N-(pyridin-3-yl)ethane-1-sulfonamide (20.3 mg, 21%) as a white solid.

[0649] The method disclosed in Example 23 was also used to prepare compounds IVa-3 and IVa-4.

[0650] Example 24. Preparation of 3-chloro-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)isoxazol-3-yl)methyl)-N-methylaniline (Compound IVb-2). [ka]

[0651] Step 1: Ethyl 3-[(3-chloro-N-methyl-anilino)methyl]isoxazole-5-carboxylate [ka]

[0652] To a solution of ethyl 3-(chloromethyl)isoxazole-5-carboxylate (300 mg, 1.58 mmol) in N,N-dimethylformamide (10 mL) was added 3-chloro-N-methyl-aniline (291 mg, 2.06 mmol), sodium carbonate (503 mg, 4.75 mmol), and potassium iodide (26 mg, 0.16 mmol). The reaction mixture was stirred at 25 °C for 2 hours and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-15% ethyl acetate in petroleum ether) to give ethyl 3-[(3-chloro-N-methyl-anilino)methyl]isoxazole-5-carboxylate (270 mg, 54%).

[0653] Step 2: 3-[(3-chloro-N-methyl-anilino)methyl]isoxazole-5-carbohydrazide [ka]

[0654] To a solution of ethyl 3-[(3-chloro-N-methyl-anilino)methyl]isoxazole-5-carboxylate (220 mg, 0.75 mmol) in ethyl alcohol (4 mL) was added hydrazine hydrate (440 mg, 7.46 mmol, 85% purity). The reaction mixture was stirred at 60 °C for 2 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% methanol in dichloromethane) to give 3-[(3-chloro-N-methyl-anilino)methyl]isoxazole-5-carbohydrazide (150 mg, 68%) as a yellow oil.

[0655] Step 3: 3-[(3-chloro-N-methyl-anilino)methyl]-N'-(2,2-difluoroacetyl)isoxazole-5-carbohydrazide [ka]

[0656] To a solution of 3-[(3-chloro-N-methyl-anilino)methyl]isoxazole-5-carbohydrazide (150 mg, 0.53 mmol) in tetrahydrofuran (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (69 mg, 0.53 mmol) and (2,2-difluoroacetyl) 2,2-difluoroacetate (112 mg, 0.64 mmol). The mixture was stirred at 20 °C for 2 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give 3-[(3-chloro-N-methyl-anilino)methyl]-N'-(2,2-difluoroacetyl)isoxazole-5-carbohydrazide (150 mg, 74%) as a yellow solid.

[0657] Step 4: 3-chloro-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]isoxazol-3-yl]methyl]-N-methyl-aniline (compound IVb-2) [ka]

[0658] To a solution of 3-[(3-chloro-N-methyl-anilino)methyl]-N'-(2,2-difluoroacetyl)isoxazole-5-carbohydrazide (50 mg, 0.14 mmol) in tetrahydrofuran (2 mL) was added Burgess's reagent (83 mg, 0.35 mmol). The mixture was stirred at 90 °C in a microwave reactor for 3 h and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (40–70% acetonitrile in water with 0.04% ammonium hydroxide and 10 mM ammonium bicarbonate) to give 3-chloro-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]isoxazol-3-yl]methyl]-N-methyl-aniline (7.2 mg, 15%).

[0659] The method disclosed in Example 24 was also used to prepare compound IVb-3.

[0660] Example 25. Preparation of 3-chloro-N-({3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,2-oxazol-5-yl}methyl)-N-methylaniline (IVa-1) [ka]

[0661] Step 1: Ethyl 5-(p-tolylsulfonyloxymethyl)isoxazole-3-carboxylate [ka]

[0662] To a solution of ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (2.0 g, 11.69 mmol) in dichloromethane (50 mL) was added triethylamine (1.3 g, 12.85 mmol) and 4-methylbenzenesulfonyl chloride under a nitrogen atmosphere. After stirring at 20 °C for 3 h, the reaction mixture was diluted with dichloromethane (30 mL) and washed with brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0-25% ethyl acetate in petroleum ether) to give ethyl 5-(p-tolylsulfonyloxymethyl)isoxazole-3-carboxylate (2.54 g, 64%) as a white solid.

[0663] Step 2: Ethyl 5-[(3-chloro-N-methyl-anilino)methyl]isoxazole-3-carboxylate [ka]

[0664] To a solution of ethyl 5-(p-tolylsulfonyloxymethyl)isoxazole-3-carboxylate (400 mg, 1.23 mmol) and 3-chloro-N-methyl-aniline (209 mg, 1.48 mmol) in N,N-dimethylformamide (8 mL) was added sodium carbonate (391 mg, 3.69 mmol) and potassium iodide (20 mg, 0.12 mmol). After stirring at 20 °C for 16 h, the mixture was diluted with ethyl acetate (10 mL) and washed with brine (3 × 10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100–200 mesh, 0–25% ethyl acetate in petroleum ether) to give ethyl 5-[(3-chloro-N-methyl-anilino)methyl]isoxazole-3-carboxylate (230 mg, 59%) as a white solid.

[0665] Step 3: 5-[(3-chloro-N-methyl-anilino)methyl]isoxazole-3-carbohydrazide [ka]

[0666] To a solution of ethyl 5-[(3-chloro-N-methyl-anilino)methyl]isoxazole-3-carboxylate (180 mg, 0.61 mmol) in ethanol (3 mL) was added hydrazine hydrate (360 mg, 6.11 mmol). The mixture was stirred at 60 °C for 1 h and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0-5% methanol in dichloromethane) to give 5-[(3-chloro-N-methyl-anilino)methyl]isoxazole-3-carbohydrazide (181 mg, 88%) as a pale yellow oil.

[0667] Step 4: 5-[(3-chloro-N-methyl-anilino)methyl]-N'-(2,2-difluoroacetyl)isoxazole-3-carbohydrazide [ka]

[0668] To a solution of 5-[(3-chloro-N-methyl-anilino)methyl]isoxazole-3-carbohydrazide (181 mg, 0.64 mmol) in tetrahydrofuran (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (92 mg, 0.71 mmol) and (2,2-difluoroacetyl) 2,2-difluoroacetate (135 mg, 0.77 mmol) under a nitrogen atmosphere. After stirring at 20 °C for 1 hour, the reaction mixture was quenched by the addition of water (5 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100–200 mesh, 0–50% ethyl acetate in petroleum ether) to give 5-[(3-chloro-N-methyl-anilino)methyl]-N′-(2,2-difluoroacetyl)isoxazole-3-carbohydrazide (148 mg, 62%) as a white solid.

[0669] Step 5: 3-chloro-N-({3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,2-oxazol-5-yl}methyl)-N-methylaniline [ka]

[0670] To a solution of 5-[(3-chloro-N-methyl-anilino)methyl]-N'-(2,2-difluoroacetyl)isoxazole-3-carbohydrazide (72 mg, 0.20 mmol) in tetrahydrofuran (2 mL) was added Burgess's reagent (120 mg, 0.50 mmol). The mixture was stirred at 90°C for 3 hours and cooled. The solution was diluted with water (4 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 3:1) to give 3-chloro-N-({3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,2-oxazol-5-yl}methyl)-N-methylaniline (22.2 mg, 27%) as a pale yellow oil.

[0671] Example 26. Preparation of 5-(6-((1-(2,6-difluorophenyl)cyclopropyl)amino)-5-fluoropyridin-3-yl)-1,3,4-oxadiazole-2-carbonitrile (A-1) [ka]

[0672] Step 1: 5-bromo-N-(1-(2,6-difluorophenyl)cyclopropyl)-3-fluoropyridin-2-amine

[0673] To a vial was added 1-(2,6-difluorophenyl)cyclopropan-1-amine (304 mg, 1.80 mmol), DMSO (3 mL), DIPEA (1.57 mL, 9.0 mmol, 5 equiv.), and 5-bromo-2,3-difluoropyridine (0.29 mL, 2.2 mmol, 1.2 equiv.). The biphasic homogeneous mixture was heated to 120 °C overnight under a N atmosphere (balloon). Upon reaching 120 °C, the reaction became monophasic. The next day, LCMS analysis of the dark brown mixture revealed complete conversion of the amine partner. The reaction was worked up by pouring into water (50 mL) and extracting three times with EtOAc (30 mL each). The combined organic layers were washed twice with water and once with brine, then dried over MgSO, filtered, and concentrated by rotary evaporation. The crude brown oil was dry loaded onto silica gel and purified by column chromatography (silica gel, 0-25% EtOAc / hexanes) to afford the title compound as a pale yellow oil, 400 mg (65%).

[0674] Step 2: Methyl 6-((1-(2,6-difluorophenyl)cyclopropyl)amino)-5-fluoronicotinate

[0675] 5-Bromo-N-(1-(2,6-difluorophenyl)cyclopropyl)-3-fluoropyridin-2-amine (686 mg, 2 mmol), Pd(OAc) (22 mg, 0.1 mmol), and Xantphos (115 mg, 0.2 mmol) were dissolved in a mixture of MeOH (6.5 mL) and EtN (35 mL). A balloon containing carbon monoxide was attached, and the gas was bubbled through the solution for 1 minute. The reaction mixture with the carbon monoxide balloon attached was heated at 70 °C overnight. The reaction mixture was cooled to room temperature, evaporated, diluted with MeOH, pre-adsorbed onto silica gel, and purified by column chromatography (silica gel, hexane / EtOAc gradient 1:0 to 4:1) to give 525 mg (81%) of product.

[0676] Step 3: 6-((1-(2,6-difluorophenyl)cyclopropyl)amino)-5-fluoronicotinic acid

[0677] A solution of LiOH (1.5 mmol, 1.5 mL, 1 M in water) was added to a stirred solution of methyl 6-((1-(2,6-difluorophenyl)cyclopropyl)amino)-5-fluoronicotinate (161 mg, 0.5 mmol) in THF (2 mL). The reaction mixture was stirred at 70° C. for 3 h, cooled to room temperature, and acidified with HCl solution (1 M in water). The reaction mixture was diluted with EtOAc and washed with water (2×) and brine. The organic fraction was dried over anhydrous NaSO and evaporated to give 170 mg (quantitative yield) of product.

[0678] Step 4: 2-(2-(6-((1-(2,6-difluorophenyl)cyclopropyl)amino)-5-fluoronicotinoyl)hydrazinyl)-2-oxoacetamide

[0679] HOBt (4 mg, 0.025 mmol) was added to a solution of 6-((1-(2,6-difluorophenyl)cyclopropyl)amino)-5-fluoronicotinic acid (154 mg, 0.5 mmol) and 2-hydrazinyl-2-oxoacetamide (77 mg, 0.75 mmol) in DMF (5 mL), and the reaction mixture was stirred at room temperature for 15 min. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg, 0.75 mmol) was added in one portion, and the reaction mixture was heated at 50 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3x). The combined organic fractions were dried over anhydrous NaSO. The solvent was evaporated, and the crude product was purified by column chromatography (silica gel, CHCl / MeOH, 19:1 to 3:1 gradient) to give 149 mg of DMF-contaminated product. Trituration from CHCl3 gave 81 mg (41%) of pure material.

[0680] Step 5: 5-(6-((1-(2,6-difluorophenyl)cyclopropyl)amino)-5-fluoropyridin-3-yl)-1,3,4-oxadiazole-2-carbonitrile

[0681] A solution of 2-(2-(6-((1-(2,6-difluorophenyl)cyclopropyl)amino)-5-fluoronicotinoyl)hydrazinyl)-2-oxoacetamide (61 mg, 0.16 mmol) in POCl (3 mL) was stirred at 100 °C for 6 h. The reaction mixture was cooled to room temperature, POCl was evaporated, and the residue was dissolved in EtOAc. The solution was poured into saturated NaHCO solution, and the layers were separated. The organic fraction was dried over anhydrous NaSO. The solvent was evaporated, and the crude product was purified by column chromatography (silica gel, hexane / EtOAc 1:0 to 7:3 gradient) to give 18 mg (33%) of product.

[0682] Example 27. Preparation of 1-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-5-phenylpyrrolidin-2-one (Compound A-2).

[0683] Step 1: Ethyl 2-benzylpyrazolo[1,5-a]pyrimidine-6-carboxylate [ka]

[0684] To a solution of ethyl 2-formyl-3-oxopropanoate (247 mg, 1.71 mmol) in ethanol (5 mL) was added 3-benzyl-1H-pyrazol-5-amine (300 mg, 1.73 mmol). The mixture was stirred at 80°C for 2 hours. The reaction was quenched by the addition of saturated sodium bicarbonate (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give ethyl 2-benzylpyrazolo[1,5-a]pyrimidine-6-carboxylate (205 mg, 42%) as a white solid.

[0685] Step 2: 2-Benzylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid [ka]

[0686] To a solution of ethyl 2-benzylpyrazolo[1,5-a]pyrimidine-6-carboxylate (200 mg, 0.71 mmol) in tetrahydrofuran (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (60 mg, 1.42 mmol). The mixture was stirred at 20°C for 2 hours and adjusted to pH = 4 by adding hydrochloric acid (1 M). The resulting mixture was extracted with ethyl acetate (30 mL x 3). The combined organic extracts were dried over sodium sulfate and concentrated to dryness under reduced pressure to give crude 2-benzylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (180 mg, crude) as a white solid.

[0687] Step 3: tert-Butyl N-[(2-benzylpyrazolo[1,5-a]pyrimidine-6-carbonyl)amino]carbamate [ka]

[0688] To a solution of 2-benzylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (130 mg, 0.51 mmol) in dichloromethane (5 mL) was added HATU (234 mg, 0.61 mmol) and N-ethyl-N-isopropylpropan-2-amine (100 mg, 0.77 mmol). After stirring at 0° C. for 15 minutes, tert-butyl N-aminocarbamate (75 mg, 0.56 mmol) was added. After stirring at 20° C. for 16 hours, the reaction mixture was diluted with ethyl acetate (50 mL) and brine (50 mL). The separated organic extract was dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, 100–200 mesh, 0–20% ethyl acetate in petroleum ether) to give tert-butyl N-[(2-benzylpyrazolo[1,5-a]pyrimidine-6-carbonyl)amino]carbamate (185 mg, 98%) as a white solid.

[0689] Step 4: 2-benzylpyrazolo[1,5-a]pyrimidine-6-carbohydrazide [ka]

[0690] A solution of tert-butyl N-[(2-benzylpyrazolo[1,5-a]pyrimidine-6-carbonyl)amino]carbamate (150 mg, 0.48 mmol) in hydrochloric acid (4 M in methanol, 5 mL) was stirred at 20° C. for 2 hours and concentrated to dryness under reduced pressure. The residue was diluted with ethyl acetate (50 mL), and sodium bicarbonate (200 mg) was added. The resulting mixture was stirred for 30 minutes and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by RP-TLC (dichloromethane:methanol=10:1) to give 2-benzylpyrazolo[1,5-a]pyrimidine-6-carbohydrazide (35 mg, 32%) as a white solid.

[0691] Step 5: 2-benzyl-N'-(2,2-difluoroacetyl)pyrazolo[1,5-a]pyrimidine-6-carbohydrazide [ka]

[0692] To a solution of 2-benzylpyrazolo[1,5-a]pyrimidine-6-carbohydrazide (35 mg, 0.13 mmol) in tetrahydrofuran (5 mL) was added N-ethyl-N-isopropylpropan-2-amine (17 mg, 0.13 mmol) and (2,2-difluoroacetyl) 2,2-difluoroacetate (27 mg, 0.16 mmol). After stirring at 20 °C for 1 hour, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by RP-TLC (petroleum ether:ethyl acetate=1:1) to give 2-benzyl-N'-(2,2-difluoroacetyl)pyrazolo[1,5-a]pyrimidine-6-carbohydrazide (35 mg, 77%) as a white solid.

[0693] Step 6: 2-(2-benzylpyrazolo[1,5-a]pyrimidin-6-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (compound A-2) [ka]

[0694] To a solution of 2-benzyl-N'-(2,2-difluoroacetyl)pyrazolo[1,5-a]pyrimidine-6-carbohydrazide (35 mg, 0.10 mmol) in tetrahydrofuran (2 mL) was added Burgess reagent (109 mg, 0.46 mmol). The mixture was stirred at 90 °C in a microwave reactor under a nitrogen atmosphere for 3 h. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by RP-HPLC (30-60% acetonitrile in water and 0.225% formic acid) to give 2-(2-benzylpyrazolo[1,5-a]pyrimidin-6-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (2.7 mg, 8%) as a white solid.

[0695] Biochemical Assays The compounds disclosed herein were tested for potency against HDAC6 and selectivity against HDAC1 in biochemical assays. A biochemical assay using the luminescent HDAC-Glo I / II assay (Promega) was employed to measure the relative activity of HDAC6 and HDAC1 recombinant proteins. Compounds were first incubated separately in the presence of HDAC6 or HDAC1, followed by the addition of a luminescent substrate. Data were acquired using a plate reader, and biochemical IC values ​​were calculated accordingly. 50 was calculated from the data. The data are summarized in Tables 3 and 4. From these studies, it was determined that the compounds of the present disclosure are selective inhibitors of HDAC6 over HDAC1, resulting in a selectivity ratio of about 5 to about 30,0000. [Table 17-1] [Table 17-2] Table 17-3 Table 17-4 Table 17-5 Table 17-6 Table 17-7 Table 17-8 Table 17-9 Table 17-10 Table 17-11 Table 17-12 Table 17-13 Table 17-14 Table 17-15 Table 17-16 Table 17-17 Table 17-18 Table 17-19 Table 17-20 Table 17-21 Table 17-22 Table 17-23 Table 17-24 Table 17-25 Table 17-26 Table 17-27 Table 17-28 Table 17-29 Table 17-30 Table 17-31 Table 17-32 Table 17-33 Table 17-34 Table 17-35 Table 17-36 Table 17-37 Table 17-38 Table 17-39 Table 17-40 Table 17-41 Table 17-42 Table 17-43 Table 17-44 Table 17-45 Table 17-46 Table 17-47 Table 17-48 Table 17-49 Table 17-50 Table 17-51 Table 17-52 Table 17-53 Table 17-54 Table 17-55 Table 17-56 Table 17-57 Table 17-58 Table 17-59 Table 17-60 Table 17-61 Table 17-62 Table 17-63 Table 17-64 Table 17-65 Table 17-66 Table 17-67 Table 17-68 Table 17-69 Table 17-70 Table 17-71 Table 17-72 Table 17-73 Table 17-74 Table 17-75 Table 17-76 Table 17-77 Table 17-78 Table 17-79 Table 17-80 Table 17-81 Table 17-82 Table 17-83 Table 17-84 Table 17-85 Table 17-86 Table 18-1 Table 18-2 Table 18-3 Table 18-4 Table 18-5 Table 18-6 Table 18-7 Table 18-8 Table 18-9 The present invention provides, for example, the following items. (Item 1) A compound of formula (I), or a pharmaceutically acceptable salt thereof,

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Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, 【Chemical 314】 , in the formula, R １ but, 【Chemistry 639】 and R ａ is H, R ２ and R ３ is H, R ４ But -(SO ２ ) alkyl, -(SO ２ ) haloalkyl, -(SO ２ ) alkyleneheterocyclyl, -(SO ２ ) cycloalkyl, -(SO ２ ) NH(alkyl), -(SO ２ ) N(alkyl) ２ , -(SO ２ ) selected from the group consisting of N(alkyl)(alkylenearyl), -(CO)alkyl, -(CO)alkyleneheterocyclyl, -(CO)cycloalkyl, -(CO)aryl, -(CO)heteroaryl, each of which is optionally substituted; R ５ is alkyl, aryl, heteroaryl, or cycloalkyl, each of which is optionally substituted; X １ is S, Y is N; A compound, or a pharmaceutically acceptable salt thereof, wherein n is 1.

2. Formula (Ia): 【Chemical 317】 2. The compound of claim 1 having the formula:

3. Formula (Ib): 【Chemical 318】 3. The compound of claim 1 or 2, having the formula:

4. X １ The compound according to any one of claims 1 to 3, wherein is S.

5. R １ but, 【Chemical 401】 The compound according to any one of claims 1 to 4,

6. R １ but, 【Chemical 402】 The compound according to any one of claims 1 to 4,

7. Formula (Ic): 【Chemical 319】 3. The compound of claim 1 or 2, having the formula:

8. R ４ But -(SO ２ ) alkyl, -(SO ２ ) haloalkyl, -(SO ２ ) alkyleneheterocyclyl, -(SO ２ ) cycloalkyl, -(SO ２ ) NH(alkyl), -(SO ２ ) N(alkyl) ２ , -(SO ２ 8. The compound of any one of claims 1 to 7, wherein the N-N(alkyl)(alkylenearyl), -(CO)alkyl, -(CO)alkyleneheterocyclyl, -(CO)cycloalkyl, or -(CO)aryl is N(alkyl)(alkylenearyl), -(CO)alkyl, -(CO)alkyleneheterocyclyl, -(CO)cycloalkyl, or -(CO)aryl.

9. R ４ But -(SO ２ ) alkyl, -(SO ２ ) cycloalkyl, -(SO ２ ) alkylenecycloalkyl, —(SO ２ ) alkyleneheterocyclyl, -(SO ２ 8. The compound of any one of claims 1 to 7, wherein the heterocyclyl group is selected from the group consisting of -N(H)alkyleneheterocyclyl, -(CO)alkyl, and -(CO)alkyleneheterocyclyl.

10. R ４ But -(SO ２ ) alkyl, -(SO ２ ) haloalkyl, -(SO ２ ) alkyleneheterocyclyl, -(SO ２ 8. The compound of claim 1, wherein the heterocyclyl group is -(CO)cycloalkyl, -(CO)alkyl, or -(CO)alkyleneheterocyclyl.

11. R ４ But -(SO ２ ) alkyl, -(SO ２ ) haloalkyl, -(SO ２ ) alkyleneheterocyclyl, or —(SO ２ 8. The compound according to claim 1, wherein R is 1 or 2. 9.) cycloalkyl.

12. The alkylene is C １～５ alkylene, wherein the alkyl is C １～５ alkyl, and said cycloalkyl is C ３～６ 12. The compound of any one of claims 8 to 11, wherein said heteroaryl is a 5- to 14-membered heteroaryl and said heterocyclyl is an optionally substituted 4- to 10-membered heterocyclyl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S.

13. The compound of any one of claims 8 to 11, wherein the heterocyclyl is selected from the group consisting of piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl 1-oxide, thiomorpholinyl 1,1-dioxide, and piperidinyl.

14. R ４ が、-(CO)CH ３ 、-(CO)CH ２ CH ３ 、-(CO)CH ２ CH ２ CH ３ 、-(SO ２ )CH ３ 、-(SO ２ )CH ２ CH ３ 、-(SO ２ )CH ２ CH ２ CH ３ および 【Chemical 403】 The compound according to any one of claims 1 to 7, selected from the group consisting of:

15. R ５ The compound of any one of claims 1 to 14, wherein is alkyl, cycloalkyl, aryl, or heteroaryl.

16. R ５ The compound of any one of claims 1 to 14, wherein is aryl or heteroaryl.

17. R ５ The compound of any one of claims 1 to 14, wherein is heteroaryl.

18. R ５ The compound of any one of claims 1 to 14, wherein is 5-14 membered heteroaryl.

19. R ５ is selected from the group consisting of phenyl, 3-chlorophenyl, 3-chloro-4-fluorophenyl, 3-trifluoromethylphenyl, 3,4-difluorophenyl, and 2,6-difluorophenyl.

20. R ５ The compound of any one of claims 1 to 14, wherein is selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 2-benzoxazolyl, pyrazolyl, and imidazolyl.

21. R ５ but, 【Chem.320】 and R ｂ is selected from the group consisting of halo, alkyl, haloalkyl, alkoxy, haloalkoxy, acyl, sulfonyl, cycloalkyl, heteroaryl, and heterocyclyl; and m is 0, 1, or 2.

22. R ５ but, 【Chemistry 321】 22. The compound of claim 21, wherein:

23. R ｂ is F, Cl, -CH ３ , -CH ２ CH ３ , -CF ３ , -CHF ２ , -CF ２ CH ３ , -CN, -OCH ３ , -OCH ２ CH ３ , -OCH(CH ３ ) ２ , -OCHF ２ , -OCH ２ CF ２ 23. The compound of claim 21 or 22, wherein the compound is selected from the group consisting of H and cyclopropyl.

24. The compound has the formula: 【Chemistry 322】 or a pharmaceutically acceptable salt thereof, wherein: U is NR ｄ , O, or S; R ａ is H, R ｂ is halo, alkyl, haloalkyl, alkoxy, haloalkoxy, —C(O)R ｅ , -C(O)OR ｅ , -C(O)N(R ｅ ) (R ｅ’ ), SO ２ R ｅ , cycloalkyl, heteroaryl, or heterocyclyl; R ｃ is F, alkyl, haloalkyl, alkoxy, haloalkoxy, or —C(O)N(R ｅ ) (R ｅ’ ) and / or two R ｃ The groups, together with the carbon atoms to which they are attached, are bridged or fused ３～７ forming a cycloalkyl, a bridged or fused 4- to 7-membered heterocyclyl, or a 5- or 6-membered heteroaryl, each of which is optionally substituted; R ｄ is H, alkyl, acyl, sulfonyl, or cycloalkyl; R ｅ and R ｅ’ are each independently H or alkyl; m is 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; 8. The compound of claim 1 or 7, wherein r is 1, 2, 3, or 4.

25. Two R's ｃ The groups, together with the carbon atoms to which they are attached, are fused or bridged ５～７ 25. The compound of claim 24, which forms a cycloalkyl, a fused or bridged 5- or 6-membered heterocyclyl, or a 5- or 6-membered heteroaryl.

26. 26. The compound of claim 24 or 25, wherein p is 1.

27. The compound of any one of claims 24 to 26, wherein q is 0 or 1.

28. The compound of any one of claims 24 to 26, wherein q is 0.

29. The compound has the following formula: 【Chemistry 326】 and wherein V is O or NR ｄ The compound according to any one of claims 24 to 26,

30. 30. The compound of any one of claims 24 to 29, wherein U is O.

31. Each R ｂ The compound of any one of claims 24 to 30, wherein is independently halo, alkyl, haloalkyl, alkyl, haloalkoxy, cycloalkyl, or nitrile.

32. The compound according to any one of claims 24 to 31, wherein m is 0 or 1.

33. The compound of any one of claims 24 to 32, wherein r is 1 or 2.

34. The compound is 【Chemical 640】 【Chemistry 641】 【Chemistry 642】 【Chemistry 643】 【Chemical Formula 644】 【Chemistry 645】 【Chemical 646】 【Chemical 647】 【Chemical Formula 648】 【Chemical Formula 649】 【Chemical 650】 【Chemical 651】 【Chemical 652】 【Chemical 653】 【Chemical 654】 【Chemical 655】 【Chemical 656】 【Chemical Formula 657】 【Chemical Formula 658】 【Chemistry 659】 【Chemical 660】 【Chemical 661】 【Chemical 662】 【Chemical 663】 【Chemical 664】 【Chemical Formula 665】 【Chemical 666】 【Chemical 667】 【Chemical Formula 668】 【Chemical Formula 669】 【Transformation 670】 【Chemistry 671】 or a pharmaceutically acceptable salt thereof.

35. Formula (Ik); 【Chemistry 673】 or a pharmaceutically acceptable salt thereof, wherein: R ｂ is H, halogen, alkyl, cycloalkyl, —CN, haloalkyl, or haloalkoxy; R ４ But -(SO ２ ) alkyl, -(SO ２ ) haloalkyl, or —(SO ２ 10. The compound of claim 1, 2, or 7, wherein:

36. R ｂ 36. The compound of claim 35, wherein is H, halogen, haloalkyl, or haloalkoxy.

37. R ４ is optionally substituted -(SO ２ ) alkyl or -(SO ２ ) cycloalkyl.

38. Formula (Ik-1); 【Transformation 674】 or a pharmaceutically acceptable salt thereof, wherein: R ｂ is H, halogen, alkyl, cycloalkyl, —CN, haloalkyl, or haloalkoxy; R ４ But -(SO ２ ) alkyl, -(SO ２ ) haloalkyl, or —(SO ２ 36. The compound of claim 35, wherein:

39. R ｂ 39. The compound of claim 38, wherein is H, halogen, haloalkyl, or haloalkoxy.

40. R ４ is optionally substituted -(SO ２ ) alkyl or -(SO ２ ) cycloalkyl.

41. R ４ But -(SO ２ ) alkyl.

42. Formula (a) 【Chemistry 446】 or a pharmaceutically acceptable salt thereof, (b) 【Chemistry 447】 or a pharmaceutically acceptable salt thereof, (c) 【Chemistry 448】 or a pharmaceutically acceptable salt thereof, (d) 【Chemistry 449】 or a pharmaceutically acceptable salt thereof, (e) [Chemical 450] or a pharmaceutically acceptable salt thereof, (f) 【Chemistry 451】 or a pharmaceutically acceptable salt thereof, (g) 【Chemistry 452】 or a pharmaceutically acceptable salt thereof, (h) 【Chemistry 453】 or a pharmaceutically acceptable salt thereof, (i) 【Chemical 454】 or a pharmaceutically acceptable salt thereof, or (j) 【Chemistry 455】 or a pharmaceutically acceptable salt thereof.

43. formula: 【Transformation 672】 or a pharmaceutically acceptable salt thereof.

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