5-Fluoronicotinamide Derivatives and Uses Thereof

Abstract

Provided herein are compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein R 1 , Y, X, and n are defined herein. Also provided herein are compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and methods of using a compound of formula (I) or a pharmaceutically acceptable salt thereof, for example, in the treatment of heart disease. 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 uses of certain small molecule compounds. JPEG2022550576000146.jpg3375

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 910,278, filed October 3, 2019, the contents 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, two or more 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] During the ceremony, n is 0 or 1, X is O, NR 4 , or CR 4 R 4’ and Y is a bond, CR 2 R 3 or S(O)2, R 1 is selected from the group consisting of H, amido, carbocyclyl, heterocyclyl, aryl, and heteroaryl; R 2 and R 3 is independently selected from the group consisting of H, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH)-carbocyclyl, -(CH)-heterocyclyl, -(CH)-aryl, and -(CH)-heteroaryl; or R 1 and R 2 together with the carbon atom to which they are attached form a carbocyclyl or heterocyclyl, or R 2 and R 3 together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl, R 4 and R 4’ are each independently selected from the group consisting of H, alkyl, -CO2-alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH2)-carbocyclyl, -(CH2)-heterocyclyl, -(CH2)-aryl, and -(CH2)-heteroaryl; or R 4 and R 4’ together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl, Each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, oxo, hydroxy, alkoxy, —OCH3, —CO2CH3, —C(O)NH(OH), —CH3, morpholine, and —C(O)N-cyclopropyl.

[0006] In some embodiments, the present disclosure provides a compound of formula (Ia) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n, X, and Y are as defined above for formula (I); Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are independently N and CR 5 is selected from R 5 is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —COH, —CO-alkyl, —O-alkyl, —O-haloalkyl, —O-aryl, —O-heteroaryl, —SO-alkyl, and —CN.

[0007] In some embodiments, the present disclosure provides a compound of formula (Ib) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n, X, and Y are as defined above for formula (I); R 6 , R 7 R 8 , R 9 , and R 10is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —COH, —CO-alkyl, —O-alkyl, —O-haloalkyl, —O-aryl, —O-heteroaryl, —SO-alkyl, and —CN.

[0008] In some embodiments, the present disclosure provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n, X, and Y are as defined above for formula (I); R 6 , R 7 R 8 , R 9 , and R 10 is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —COH, —CO-alkyl, —O-alkyl, —O-haloalkyl, —O-aryl, —O-heteroaryl, —SO-alkyl, and —CN.

[0009] In another aspect, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n is 0 or 1, X is NR 4 , or CR 4 R 4’ and R 1 is selected from the group consisting of carbocyclyl, heterocyclyl, aryl, and heteroaryl; R 2 and R 3is independently selected from the group consisting of H, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH)-carbocyclyl, -(CH)-heterocyclyl, -(CH)-aryl, and -(CH)-heteroaryl; or R 2 and R 3 together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl, R 4 and R 4’ is independently selected from the group consisting of H, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH)-carbocyclyl, -(CH)-heterocyclyl, -(CH)-aryl, and -(CH)-heteroaryl; or R 4 and R 4’ together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl, Each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, alkoxy, -OCH3, -CO2CH3, and -CH3.

[0010] In some embodiments, the present disclosure provides a compound of formula (IIa) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n, R 2 , R 3 , and R 4 is as defined above in formula (II), Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are independently N and CR 5 is selected from In the formula, R5 is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —COH, —CO-alkyl, —O-alkyl, —O-haloalkyl, —O-aryl, —O-heteroaryl, —SO-alkyl, and —CN.

[0011] In some embodiments, the present disclosure provides a compound of formula (IIb) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n, R 2 , R 3 , and R 4 is as defined above in formula (II), R 6 , R 7 R 8 , R 9 , and R 10 is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —COH, —CO-alkyl, —O-alkyl, —O-haloalkyl, —O-aryl, —O-heteroaryl, —SO-alkyl, and —CN.

[0012] In some embodiments, the present disclosure provides a compound of formula (IIc) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n, R 2 , R 3 , and R 4 is as defined above in formula (II), R 6 , R 7 R 8 , and R 9are independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —COH, —CO-alkyl, —O-alkyl, —O-haloalkyl, —O-aryl, —O-heteroaryl, —SO-alkyl, and —CN.

[0013] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n is 0 or 1, Y is a bond or CR 2 R 3 and R 1 is selected from the group consisting of H, amido, carbocyclyl, heterocyclyl, aryl, and heteroaryl; R 2 and R 3 is independently selected from the group consisting of H, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH)-carbocyclyl, -(CH)-heterocyclyl, -(CH)-aryl, and -(CH)-heteroaryl; or R 1 and R 2 together with the carbon atom to which they are attached form a carbocyclyl or heterocyclyl, or R 2 and R 3 together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl, Each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, alkoxy, -OCH3, -CO2CH3, and -CH3.

[0014] In some embodiments, the present disclosure provides a compound of formula (IV) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n is 0 or 1, p is 0, 1, 2, 3, or 4; each q is independently 0, 1, or 2; X is O, S(O)2, NR 12 , or CHR 12 and R 11 are each independently H, F, alkyl, or oxo; Two adjacent R 11 together with the carbon atoms to which they are attached form an aryl, heteroaryl, or heterocyclyl ring; or Two non-adjacent R 11 together with the atoms to which they are attached form a carbocyclyl or heterocyclyl ring; R 12 is selected from the group consisting of alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH)-carbocyclyl, -(CH)-heterocyclyl, -(CH)-aryl, and -(CH)-heteroaryl; or R 11 and R 12 together with the carbon atom and / or nitrogen atom to which they are attached form an aryl or heteroaryl ring; Each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, alkoxy, -OCH3, -CO2CH3, and -CH3.

[0015] In some embodiments, the present disclosure provides therapeutic methods comprising the use of the compounds disclosed herein (i.e., Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (IIa), Formula (IIb), Formula (IIc), Formula (III), and Formula (IV)) in treating patients suffering from abnormal cell proliferative disorders, amyloid beta protein aggregation, polyglutamine protein aggregation, neurodegeneration, stroke, psychiatric disorders, depression, autoimmune diseases, chemotherapy-induced neuropathy, Charcot-Marie-Tooth disease, idiopathic pulmonary fibrosis, erectile dysfunction, hypertension, muscular dystrophy, and / or cardiac diseases or disorders. Proliferative disorders include, but are not limited to, malignant glioma, breast cancer, basal cell carcinoma, medulloblastoma, neuroectodermal tumor, and ependymoma. Cardiac diseases or disorders that may 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 arrhythmias, ventricular arrhythmias, diastolic heart failure, systolic heart failure, valvular heart disease, valvular calcification, left ventricular noncompaction, ventricular septal defect, and ischemia.

[0016] 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.

[0017] 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 an "inhibitor" by the indefinite article "a" or "an" does not exclude the possibility that two or more inhibitors may be present, unless the context clearly requires that only one of the inhibitor is present.

[0018] 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.

[0019] "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 10 Alkyl 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 12Non-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.

[0020] "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.

[0021] "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 10 An 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 10Alkenyl 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.

[0022] "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. 12Non-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.

[0023] "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 12 Non-limiting examples of alkenyl include ethynyl, propynyl, butynyl, pentynyl, etc. Unless stated otherwise in the specification, an alkyl group can be optionally substituted.

[0024] "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.

[0025] "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.

[0026] "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.

[0027] "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.

[0028] 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.

[0029] "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.

[0030] "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.

[0031] "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.

[0032] "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.

[0033] "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.

[0034] "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.

[0035] "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.

[0036]

[0023] As used herein, the term "substituted" refers to a 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 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 a bond to another heteroatom 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.

[0037] 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 3 is R 3 If is "XY", the point bond is R 3 is assumed to be the same bond depicted as being attached to CH3. DETAILED DESCRIPTION OF THE INVENTION

[0038] 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).

[0039] 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).

[0040] In cardiac settings, most studies have utilized pan-HDAC inhibitors (e.g., SAHA, TSA, and givinostat) to treat pressure overload rodent models, including transaortic aortic constriction (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).

[0041] 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).

[0042] Pharmacological inhibition of HDAC6 blocks its deacetylase activity, resulting in hyperacetylation of its substrates, particularly tubulin (Hubbert et al., 2002).

[0043] 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 ).

[0044] Hydroxylic acids are zinc chelators and have been widely used in the development of pan- and selective HDAC inhibitors. However, most hydroxamic acid HDAC inhibitors lack the desired selectivity or exhibit poor pharmacokinetic profiles and poor bioavailability (Butler et al., 2010; Santo et al., 2012).

[0045] The present disclosure provides, in some embodiments, hydroxamic acid compounds that selectively inhibit HDAC6.

[0046] Compounds of formulas (I) to (III) In one aspect, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n is 0 or 1, X is O, NR 4 , or CR 4 R 4’ and Y is bond, CR 2 R 3 or S(O)2, R 1 is selected from the group consisting of H, amido, carbocyclyl, heterocyclyl, aryl, and heteroaryl; R 2 and R 3 is independently selected from the group consisting of H, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH)-carbocyclyl, -(CH)-heterocyclyl, -(CH)-aryl, and -(CH)-heteroaryl; or R 1 and R 2 together with the carbon atom to which they are attached form a carbocyclyl or heterocyclyl, or R 2 and R 3 together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl, R 4 and R 4’are each independently selected from the group consisting of H, alkyl, -CO2-alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH2)-carbocyclyl, -(CH2)-heterocyclyl, -(CH2)-aryl, and -(CH2)-heteroaryl; or R 4 and R 4’ together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl, Each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, oxo, hydroxy, alkoxy, —OCH3, —CO2CH3, —C(O)NH(OH), —CH3, morpholine, and —C(O)N-cyclopropyl.

[0047] In one aspect, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n is 0 or 1, X is O, NR 4 , or CR 4 R 4’ and Y is a bond, CR 2 R 3 or S(O)2, R 1 is selected from the group consisting of H, amido, carbocyclyl, heterocyclyl, aryl, and heteroaryl; R 2 and R 3 is independently selected from the group consisting of H, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH)-carbocyclyl, -(CH)-heterocyclyl, -(CH)-aryl, and -(CH)-heteroaryl; or R 1 and R 2together with the carbon atom to which they are attached form a carbocyclyl or heterocyclyl, or R 2 and R 3 together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl, R 4 and R 4’ are each independently selected from the group consisting of H, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH)-carbocyclyl, -(CH)-heterocyclyl, -(CH)-aryl, and -(CH)-heteroaryl; or R 4 and R 4’ together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl, Each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more halogen, haloalkyl, oxo, hydroxy, alkoxy, —OCH 3 , —CO 2 CH 3 , —C(O)NH(OH), and —CH 3 .

[0048] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided: [ka] During the ceremony, n is 0 or 1, X is NR 4 , or CR 4 R 4’ and Y is CR 2 R 3 or S(O)2, R 1 is selected from the group consisting of carbocyclyl, heterocyclyl, aryl, and heteroaryl; R 2 and R 3is independently selected from the group consisting of H, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH)-carbocyclyl, -(CH)-heterocyclyl, -(CH)-aryl, and -(CH)-heteroaryl; or R 2 and R 3 together with the carbon atom to which they are attached form a carbocyclyl or heterocyclyl, each of which is optionally substituted; R 4 and R 4’ is independently selected from the group consisting of H, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH)-carbocyclyl, -(CH)-heterocyclyl, -(CH)-aryl, and -(CH)-heteroaryl; or R 4 and R 4’ together with the carbon atom to which they are attached form a carbocyclyl or heterocyclyl, each of which is optionally substituted; Each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, alkoxy, -OCH3, -CO2CH3, and -CH3.

[0049] In some embodiments of Formula (I), n is 1. In some embodiments, n is 0.

[0050] In some embodiments of Formula (I), X is NR 4 or CR 4 R 4’ In some embodiments, X is NR 4 or O, and in some embodiments, X is NR 4 In some embodiments, X is CR 4 R 4’である In some embodiments, X is O.

[0051] In some embodiments of Formula (I), X is NR 4 and R 4 is H.

[0052] In some embodiments of Formula (I), Y is a bond or CR 2 R 3 In some embodiments, Y is S(O) or CR 2 R 3 In some embodiments, Y is a bond. In some embodiments, Y is CR 2 R 3 In some embodiments, Y is S(O).

[0053] In some embodiments of Formula (I), X is NR 4 and Y is CR 2 R 3 In some embodiments, X is NR 4 and Y is S(O). In some embodiments, X is NR 4 and Y is a bond. In some embodiments, X is CR 4 R 4’ and Y is CR 2 R 3 In some embodiments, X is CR 4 R 4’ and Y is a bond. In some embodiments, X is O and Y is CR 2 R 3 In some embodiments, X is O and Y is a bond.

[0054] In some embodiments of Formula (I), R 1 is selected from the group consisting of amido, carbocyclyl, heterocyclyl, aryl, and heteroaryl. In some embodiments, R 1 is selected from the group consisting of carbocyclyl, heterocyclyl, aryl, and heteroaryl. In some embodiments, R 1is selected from the group consisting of H, cyclopropyl, phenyl, 6-membered heterocyclyl, 8- to 10-membered fused bicyclic heterocyclyl, and 11- to 13-membered fused tricyclic heterocyclyl, each heterocyclyl being selected from the group consisting of N, O, and S(O) w (wherein w is 0, 1, or 2). Each cyclopropyl, phenyl, and heterocyclyl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, oxo, hydroxy, alkoxy, —OCH, —COCH, —C(O)NH(OH), —CH, morpholine, and —C(O)N-cyclopropyl. In some embodiments, R 1 is a heteroaryl selected from the group consisting of pyrimidinyl, pyridinyl, pyridazine, and pyrazine. 1 is pyridinyl. In some embodiments, R 1 is phenyl. In some embodiments, R 1 is H. In some embodiments, R 1 is cyclopropyl. In some embodiments, R 1 is selected from the group consisting of pyridinyl, hydrogen, cyclopropyl, and phenyl.

[0055] In some embodiments of Formula (I), X is NR 4 and Y is CR 2 R 3 and R 1 is aryl or heteroaryl. In some embodiments, X is NR 4 and Y is CR 2 R 3 and R 1 is aryl. In some embodiments, X is NR 4 and Y is CR 2 R 3 and R 1 is heteroaryl. In some embodiments, n is 0. In some embodiments, n is 1.

[0056] In some embodiments of Formula (I), X is NR 4 Y is a bond and R 1 is H. In some embodiments, X is CR 4 R 4’ Y is a bond and R 1 is H. In some embodiments, X is O and Y is CR 2 R 3 and R 1 is H. In some embodiments, n is 0. In some embodiments, n is 1.

[0057] In some embodiments of Formula (I), R 1 and R 2 together with the carbon atoms to which they are attached, form C 3~12 In some embodiments, C forms a carbocyclyl. 3~12 The carbocyclyl is a propyl ring. In some embodiments, C 3~12 The carbocyclyl is a cyclobutyl ring. 3~12 The carbocyclyl is an indane ring. In some embodiments of Formula (I), R 1 and R 2 together with the carbon atoms to which they are attached, form C 3~12 In some embodiments, C forms a heterocyclyl. 3~12 The heterocyclyl is an oxetanyl ring.

[0058] In some embodiments of Formula (I), R 2 and R 3 are independently H, F, C 1~6 Alkyl, C 3~6 Cycloalkyl, -(CH2)-C 3~6 In some embodiments, R is selected from the group consisting of cycloalkyl, 4- to 6-membered heterocyclyl, and -(CH)-(4- to 6-membered heterocyclyl). 3 is optionally alkoxy-substituted C 1~6 In some embodiments, R 3is C 1~6 In some embodiments, R 2 and R 3 together with the carbon atoms to which they are attached, form C 3~6 In some embodiments, R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, or cyclohexyl. In some embodiments, R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl. In some embodiments, R 2 and R 3 taken together with the carbon atom to which they are attached form a 4- to 6-membered heterocyclyl. In some embodiments, R 2 and R 3 taken together with the carbon atoms to which they are attached form azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, or tetrahydropyranyl. 2 and R 3 together with the carbon atom to which they are attached form oxetanyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, and piperidinyl, each of which is optionally substituted with one or more substituents selected from the group consisting of fluoro, —OCH3, —CH3, and oxo.

[0059] In some embodiments of Formula (I), R 2 is H and R 3 is C 3~6 In some embodiments, R 2 is H and R 3is cyclopropyl. In some embodiments, R 2 and R 3 is C 1~6 In some embodiments, R 2 and R 3 is methyl.

[0060] In some embodiments of Formula (I), R 1 is C 3~6 is cycloalkyl or aryl, and R 2 is H and R 3 is C 3~6 In some embodiments, R 1 is aryl and R 2 is H and R 3 is C 3~6 In some embodiments, R 1 is aryl and R 2 is H and R 3 is C 3~6 Cycloalkyl or C 1~5 In some embodiments, R 1 is aryl and R 2 is H and R 3 is C 3~6 In some embodiments, R 1 is C 3~6 is cycloalkyl, and R 2 is H and R 3 is C 3~6 In some embodiments, R 1 is C 3~6 is cycloalkyl, and R 2 is H and R 3 is C 3~6 Cycloalkyl or C 1~5 In some embodiments, R 1 is C 3~6 is cycloalkyl, and R 2 is H and R 3 is C 3~6In some embodiments, aryl is phenyl and C 3~6 Cycloalkyl is cyclopropyl.

[0061] In some embodiments of Formula (I), R 4 is selected from the group consisting of H, alkyl, carbocyclyl, heterocyclyl, -(CH)-carbocyclyl, and -(CH)-heterocyclyl. In some embodiments, R 4 is H or alkyl. In some embodiments, R 4 is H. In some embodiments, R 4 is -(CH)-heterocyclyl. In some embodiments, R 4 is —(CH)-oxetane. In some embodiments, R 4 is alkyl. In some embodiments, alkyl is C 1~5 In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is isopropyl. In some embodiments, R 4 is -C(O)(CH3).

[0062] In some embodiments of Formula (I), R 4 and R 4’ are each H. In some embodiments, R 4 and R 4’ are each alkyl. In some embodiments, R 4 and R 4’ are each methyl. In some embodiments, R 4 and R 4’ together with the carbon atoms to which they are attached, form C 3~6 In some embodiments, R 4 and R 4’ together with the carbon atom to which they are attached form cyclopropyl.

[0063] In some embodiments, the compound of formula (I) is [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, the present disclosure provides a compound of formula (Ia) or a pharmaceutically acceptable salt thereof: [ka] , During the ceremony, n, X, and Y are as defined above for formula (I); Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are independently N and CR 5 is selected from R 5is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —COH, —CO-alkyl, —O-alkyl, —O-haloalkyl, —O-aryl, —O-heteroaryl, —SO-alkyl, and —CN.

[0065] In some embodiments of Formula (Ia), Z 1 , Z 2 , Z 3 , Z 4 and Z 5 is CR 5 In some embodiments, Z 1 is N and Z 2 , Z 3 , Z 4 and Z 5 But, CR 5 In some embodiments, Z 2 is N and Z 1 , Z 3 , Z 4 and Z 5 But, CR 5 In some embodiments, Z 3 is N and Z 1 , Z 2 , Z 4 and Z 5 But, CR 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 is N. In some embodiments, one of Z 1 , Z 2 , Z 3 , Z 4 and Z 5 In some embodiments, two of Z 1 and Z 5 are N respectively.

[0066] In some embodiments of Formula (Ia), R 5is independently selected from H, halogen, alkyl, alkoxy, and haloalkyl. In some embodiments, R 5 is independently selected from H and halogen. In some embodiments, R 5 is independently selected from H and fluoro.

[0067] In some embodiments, the present disclosure provides a compound of formula (Ib) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n, X, and Y are as defined above for formula (I); R 6 , R 7 R 8 , R 9 , and R 10 is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —COH, —CO-alkyl, —O-alkyl, —O-haloalkyl, —O-aryl, —O-heteroaryl, —SO-alkyl, and —CN.

[0068] In some embodiments of Formula (Ib), R 6 , R 7 R 8 , R 9 , and R 10 is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, —COH, —CO-alkyl, —O-alkyl, —O-haloalkyl, —O-aryl, —O-heteroaryl, —SO-alkyl, and —CN. In some embodiments, R 6 , R 7 R 8 , R 9 , and R 10 is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, -O-alkyl, and -O-haloalkyl. 6 , R7 R 8 , R 9 , and R 10 is independently selected from the group consisting of H and halogen. In some embodiments, R 6 and R 10 is a halogen, and R 7 R 8 , and R 9 is H. In some embodiments, R 6 and R 10 is fluoro and R 7 R 8 , and ,R 9 But it's H.

[0069] In some embodiments, the present disclosure provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n, X, and Y are as defined above for formula (I); R 6 , R 7 R 8 , and R 9 are independently selected from the group consisting of H, halogen, alkyl, hydroxyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —COH, —CO-alkyl, —O-alkyl, —O-haloalkyl, —O-aryl, —O-heteroaryl, —SO-alkyl, and —CN.

[0070] In some embodiments of compounds of Formula (Ic), R 6 , R 7 R 8 , R 9 , and R 10 is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —COH, —CO-alkyl, —O-alkyl, —O-haloalkyl, —O-aryl, —O-heteroaryl, —SO-alkyl, and CN.

[0071] In some embodiments of Formula (Ic), R 6 , R 7 R 8 , and R 9 is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, —COH, —CO-alkyl, —O-alkyl, —O-haloalkyl, —O-aryl, —O-heteroaryl, —SO-alkyl, and —CN. In some embodiments, R 6 , R 7 R 8 , and R 9 is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, -O-alkyl, and -O-haloalkyl. 6 , R 7 R 8 , and R 9 is independently selected from the group consisting of H and halogen. In some embodiments, R 6 is a halogen, and R 7 R 8 , and R 9 is H. In some embodiments, R 6 is fluoro and R 7 R 8 , and R 9 But it's H.

[0072] In some embodiments of Formulas (I)-(Ic), each optionally substituted alkyl independently represents an optionally substituted C 1~6 In a further embodiment, C 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. In some embodiments, C 1~6 Alkyl is C 1~6 In a further embodiment, C is haloalkyl. 1~6Haloalkyl is selected from the group consisting of -CF, -CHF, -CHF, and -CHBr. In some embodiments, C 1~6 Haloalkyl is CF. In some embodiments, C 1~6 Haloalkyl is CHF2.

[0073] In some embodiments of Formulas (I)-(Ic), each optionally substituted carbocyclyl independently represents an optionally substituted C 3~12 In some embodiments, the carbocyclyl is C 3~6 In some embodiments, the cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0074] In some embodiments of Formulas (I)-(Ic), 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, morpholinyl, and thiomorpholinyl.

[0075] In some embodiments of Formulas (I)-(Ic), each optionally substituted aryl is independently C 6~12 In a further embodiment, C is aryl. 6~12 Aryl is optionally substituted phenyl.

[0076] In some embodiments of Formulas (I)-(Ic), 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. In some embodiments, the heteroaryl is tetrazole. In some embodiments, the heteroaryl is oxadiazole.

[0077] In one aspect, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n is 0 or 1, X is NR 4 or CR 4 R 4’ and R 1 is selected from the group consisting of carbocyclyl, heterocyclyl, aryl, and heteroaryl; R 2 and R 3is independently selected from the group consisting of H, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH)-carbocyclyl, -(CH)-heterocyclyl, -(CH)-aryl, and -(CH)-heteroaryl; or R 2 and R 3 together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl, R 4 and R 4’ are each independently selected from the group consisting of H, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH)-carbocyclyl, -(CH)-heterocyclyl, -(CH)-aryl, and -(CH)-heteroaryl; or R 4 and R 4’ together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl, Each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, alkoxy, -OCH3, -CO2CH3, and -CH3.

[0078] In some embodiments of Formula (II), n is 1. In some embodiments, n is 0.

[0079] In some embodiments of Formula (II), X is NR 4 In some embodiments, X is CR 4 R 4’ is.

[0080] In some embodiments of Formula (II), R 1 is selected from the group consisting of carbocyclyl, heterocyclyl, aryl, and heteroaryl. In some embodiments, R 1is a heteroaryl selected from the group consisting of pyrimidinyl, pyridinyl, pyridazine, and pyrazine. 1 is pyridinyl. In some embodiments, R 1 is phenyl.

[0081] In some embodiments of Formula (II), X is NR 4 and R 1 is aryl or heteroaryl. In some embodiments, X is NR 4 and R 1 In some embodiments, X is NR 4 and R 1 In some embodiments, X is NR 4 and R 1 In some embodiments, X is NR 4 and R 1 In some embodiments, n is 0. In some embodiments, n is 1.

[0082] In some embodiments of Formula (II), R 1 and R 2 together with the carbon atoms to which they are attached, form C 3~12 In some embodiments, C forms a carbocyclyl. 3~12 The carbocyclyl is a propyl ring. In some embodiments, C 3~12 The carbocyclyl is a cyclobutyl ring. 3~12 The carbocyclyl is an indane ring.

[0083] In some embodiments of Formula (II), R 2 and R 3 are independently H, F, C 1~6 Alkyl, C 3~6 Cycloalkyl, -(CH2)-C 3~6In some embodiments, R is selected from the group consisting of cycloalkyl, 4- to 6-membered heterocyclyl, and -(CH)-(4- to 6-membered heterocyclyl). 2 and R 3 together with the carbon atoms to which they are attached, form C 3~6 In some embodiments, R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, or cyclohexyl. In some embodiments, R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl. In some embodiments, R 2 and R 3 taken together with the carbon atom to which they are attached form a 4- to 6-membered heterocyclyl. In some embodiments, R 2 and R 3 together with the carbon atoms to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0084] In some embodiments of Formula (II), R 2 is H and R 3 But C 3~6 In some embodiments, R 2 is H and R 3 is cyclopropyl. In some embodiments, R 2 and R 3 is C 1~6 In some embodiments, R 2 and R 3 is methyl.

[0085] In some embodiments of Formula (II), R 1 But C 3~6 is cycloalkyl or aryl, and R 2 is H and R 3 is C3~6 In some embodiments, R 1 is aryl and R 2 is H and R 3 But C 3~6 In some embodiments, R 1 is aryl and R 2 is H and R 3 But C 3~6 Cycloalkyl or C 1~5 In some embodiments, R 1 is aryl and R 2 is H and R 3 But C 3~6 In some embodiments, R 1 But C 3~6 is cycloalkyl, and R 2 is H and R 3 But C 3~6 In some embodiments, R 1 But C 3~6 is cycloalkyl, and R 2 is H and R 3 But C 3~6 Cycloalkyl or C 1~5 In some embodiments, R 1 But C 3~6 is cycloalkyl, and R 2 is H and R 3 But C 3~6 In some embodiments, aryl is phenyl and C 3~6 Cycloalkyl is cyclopropyl.

[0086] In some embodiments of Formula (II), R 4 is selected from the group consisting of H, alkyl, carbocyclyl, heterocyclyl, -(CH)-carbocyclyl, and -(CH)-heterocyclyl. In some embodiments, R 4 is H or alkyl. In some embodiments, R 4is H. In some embodiments, R 4 is -(CH)-heterocyclyl. In some embodiments, R 4 is —(CH)-oxetane. In some embodiments, R 4 is alkyl. In some embodiments, alkyl is C 1~5 In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is isopropyl.

[0087] In some embodiments of Formula (II), R 4 and R 4’ are each H. In some embodiments, R 4 and R 4’ are each alkyl. In some embodiments, R 4 and R 4’ are each methyl. In some embodiments, R 4 and R 4’ together with the carbon atoms to which they are attached, form C 3~6 In some embodiments, R 4 and R 4’ together with the carbon atom to which they are attached form cyclopropyl.

[0088] In some embodiments of Formula (II), each optionally substituted alkyl independently represents an optionally substituted C 1~6 In a further embodiment, C 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. In some embodiments, C 1~6 Alkyl is C 1~6 In a further embodiment, C is haloalkyl.1~6 Haloalkyl is selected from the group consisting of -CF, -CHF, -CHF, and -CHBr. In some embodiments, C 1~6 Haloalkyl is CF. In some embodiments, C 1~6 Haloalkyl is CHF2.

[0089] In some embodiments of Formula (II), each optionally substituted carbocyclyl independently represents an optionally substituted C 3~12 In some embodiments, the carbocyclyl is C 3~6 In some embodiments, the cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0090] 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 the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and thiomorpholinyl.

[0091] In some embodiments of Formula (II), each optionally substituted aryl is independently C 6~12 In a further embodiment, C is aryl. 6~12 Aryl is optionally substituted phenyl.

[0092] 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 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.

[0093] In some embodiments, the present disclosure provides: [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments, the present disclosure provides a compound of formula (IIa) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n, R 2 , R 3 , and R 4 is as defined above in formula (II), Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are independently N and CR 5 is selected from R 5 is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —COH, —CO-alkyl, —O-alkyl, —O-haloalkyl, —O-aryl, —O-heteroaryl, —SO-alkyl, and —CN.

[0095] In some embodiments of Formula (IIa), Z 1 , Z 2 , Z 3 , Z 4 and Z 5 is CR 5 In some embodiments, Z 1 is N and Z 2 , Z 3 , Z 4 and Z 5 But, CR 5 In some embodiments, Z 2 is N and Z 1 , Z 3 , Z 4 and Z 5 But, CR 5 In some embodiments, Z 3 is N and Z 1 , Z 2 , Z 4 and Z 5 But, CR 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5is N. In some embodiments, one of Z 1 , Z 2 , Z 3 , Z 4 and Z 5 In some embodiments, two of Z 1 and Z 5 are N respectively.

[0096] In some embodiments of Formula (IIa), R 5 is independently selected from H, halogen, alkyl, alkoxy, and haloalkyl. In some embodiments, R 5 is independently selected from H and halogen. In some embodiments, R 5 is independently selected from H and fluoro.

[0097] In some embodiments, the present disclosure provides a compound of formula (IIb) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n, R 2 , R 3 , and R 4 is as defined above in formula (II), R 6 , R 7 R 8 , R 9 , and R 10 is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —COH, —CO-alkyl, —O-alkyl, —O-haloalkyl, —O-aryl, —O-heteroaryl, —SO-alkyl, and —CN.

[0098] In some embodiments of Formula (IIb), R 6 , R 7 R 8 , R 9 , and R 10is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, —COH, —CO-alkyl, —O-alkyl, —O-haloalkyl, —O-aryl, —O-heteroaryl, —SO-alkyl, and —CN. In some embodiments, R 6 , R 7 R 8 , R 9 , and R 10 is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, -O-alkyl, and -O-haloalkyl. 6 , R 7 R 8 , R 9 , and R 10 is independently selected from the group consisting of H and halogen. In some embodiments, R 6 and R 10 is a halogen, and R 7 R 8 , and R 9 is H. In some embodiments, R 6 and R 10 is fluoro and R 7 R 8 , and ,R 9 But it's H.

[0099] In some embodiments, the present disclosure provides a compound of formula (IIc) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n, R 2 , R 3 , and R 4 is as defined above in formula (II), R 6 , R 7 R 8 , and R 9are independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —COH, —CO-alkyl, —O-alkyl, —O-haloalkyl, —O-aryl, —O-heteroaryl, —SO-alkyl, and —CN.

[0100] In some embodiments of Formula (IIc), R 6 , R 7 R 8 , and R 9 is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, —COH, —CO-alkyl, —O-alkyl, —O-haloalkyl, —O-aryl, —O-heteroaryl, —SO-alkyl, and —CN. In some embodiments, R 6 , R 7 R 8 , and R 9 is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, -O-alkyl, and -O-haloalkyl. 6 , R 7 R 8 , and R 9 is independently selected from the group consisting of H and halogen. In some embodiments, R 6 is a halogen, and R 7 R 8 , and R 9 is H. In some embodiments, R 6 is fluoro and R 7 R 8 , and R 9 But it's H.

[0101] In another aspect, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n is 0 or 1, Y is a bond or CR 2 R3 and R 1 is selected from the group consisting of H, carbocyclyl, heterocyclyl, aryl, and heteroaryl; R 2 and R 3 is independently selected from the group consisting of H, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH)-carbocyclyl, -(CH)-heterocyclyl, -(CH)-aryl, and -(CH)-heteroaryl; or R 1 and R 2 when present, together with the carbon atom to which they are attached form a carbocyclyl or heterocyclyl, or R 2 and R 3 together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl, Each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, alkoxy, -OCH3, -CO2CH3, and -CH3.

[0102] In some embodiments of Formula (III), n is 1. In some embodiments, n is 0.

[0103] In some embodiments of Formula (III), Y is a bond or CR 2 R 3 In some embodiments, Y is S(O) or CR 2 R 3 In some embodiments, Y is a bond. In some embodiments, Y is CR 2 R 3 In some embodiments, Y is S(O)2.

[0104] In some embodiments of Formula (III), R 1is selected from the group consisting of amido, carbocyclyl, heterocyclyl, aryl, and heteroaryl. In some embodiments, R 1 is selected from the group consisting of carbocyclyl, heterocyclyl, aryl, and heteroaryl. In some embodiments, R 1 is a heteroaryl selected from the group consisting of pyrimidinyl, pyridinyl, pyridazine, and pyrazine. 1 is pyridinyl. In some embodiments, R 1 is phenyl.

[0105] In some embodiments of Formula (III), Y is CR 2 R 3 and R 1 is aryl or heteroaryl. In some embodiments, Y is CR 2 R 3 and R 1 In some embodiments, Y is CR 2 R 3 and R 1 is heteroaryl. In some embodiments, n is 0. In some embodiments, n is 1.

[0106] In some embodiments of Formula (III), Y is a bond and R 1 is H. In some embodiments, Y is a bond and R 1 is H. In some embodiments, Y is CR 2 R 3 and R 1 is H. In some embodiments, n is 0. In some embodiments, n is 1.

[0107] In some embodiments of Formula (III), R 1 and R 2 together with the carbon atoms to which they are attached, form C 3~12 In some embodiments, C forms a carbocyclyl. 3~12The carbocyclyl is a propyl ring. In some embodiments, C 3~12 The carbocyclyl is a cyclobutyl ring. 3~12 The carbocyclyl is an indane ring.

[0108] In some embodiments of Formula (III), R 2 and R 3 are independently H, F, C 1~6 Alkyl, C 3~6 Cycloalkyl, -(CH2)-C 3~6 In some embodiments, R is selected from the group consisting of cycloalkyl, 4- to 6-membered heterocyclyl, and -(CH)-(4- to 6-membered heterocyclyl). 2 and R 3 together with the carbon atoms to which they are attached, form C 3~6 In some embodiments, R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, or cyclohexyl. In some embodiments, R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl. In some embodiments, R 2 and R 3 taken together with the carbon atom to which they are attached form a 4- to 6-membered heterocyclyl. In some embodiments, R 2 and R 3 together with the carbon atoms to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0109] In some embodiments of Formula (III), R 2 is H and R 3 But C 3~6 In some embodiments, R 2 is H and R 3is cyclopropyl. In some embodiments, R 2 and R 3 is C 1~6 In some embodiments, R 2 and R 3 is methyl.

[0110] In some embodiments of Formula (III), R 1 But C 3~6 is cycloalkyl or aryl, and R 2 is H and R 3 But C 3~6 In some embodiments, R 1 is aryl and R 2 is H and R 3 But C 3~6 In some embodiments, R 1 is aryl and R 2 is H and R 3 But C 3~6 Cycloalkyl or C 1~5 In some embodiments, R 1 is aryl and R 2 is H and R 3 But C 3~6 In some embodiments, R 1 But C 3~6 is cycloalkyl, and R 2 is H and R 3 But C 3~6 In some embodiments, R 1 But C 3~6 is cycloalkyl, and R 2 is H and R 3 But C 3~6 Cycloalkyl or C 1~5 In some embodiments, R 1 But C 3~6 is cycloalkyl, and R 2 is H and R 3 But C 3~6In some embodiments, aryl is phenyl and C 3~6 Cycloalkyl is cyclopropyl.

[0111] In some embodiments of Formula (III), each optionally substituted alkyl independently represents an optionally substituted C 1~6 In a further embodiment, C 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. In some embodiments, C 1~6 Alkyl is C 1~6 In a further embodiment, C is haloalkyl. 1~6 Haloalkyl is selected from the group consisting of -CF, -CHF, -CHF, and -CHBr. In some embodiments, C 1~6 Haloalkyl is CF. In some embodiments, C 1~6 Haloalkyl is CHF2.

[0112] In some embodiments of Formula (III), each optionally substituted carbocyclyl independently represents an optionally substituted C 3~12 In some embodiments, the carbocyclyl is C 3~6 In some embodiments, the cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0113] In some embodiments of Formula (III), 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, morpholinyl, and thiomorpholinyl.

[0114] In some embodiments of Formula (III), each optionally substituted aryl is independently C 6~12 In a further embodiment, C is aryl. 6~12 Aryl is optionally substituted phenyl.

[0115] In some embodiments of Formula (III), 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 further 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. In some embodiments, the heteroaryl is tetrazole. In some embodiments, the heteroaryl is oxadiazole.

[0116] In some embodiments, the compound of formula (III) is [ka] or a pharmaceutically acceptable salt thereof.

[0117] Compound of formula (IV) In some embodiments, the present disclosure provides a compound of formula (IV) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n is 0 or 1, p is 0, 1, 2, 3, or 4; each q is independently 0, 1, or 2; X is O, S(O)2, NR 12 , or CHR 12 and R 11 are each independently H, F, alkyl, or oxo; Two adjacent R 11 together with the carbon atoms to which they are attached form an aryl, heteroaryl, or heterocyclyl ring; or Two non-adjacent R 11 together with the atoms to which they are attached form a carbocyclyl or heterocyclyl ring; R 12 is selected from the group consisting of alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH)-carbocyclyl, -(CH)-heterocyclyl, -(CH)-aryl, and -(CH)-heteroaryl; or R 11 and R 12 together with the carbon atom and / or nitrogen atom to which they are attached form an aryl ring, heteroaryl ring, or heterocyclyl ring; Each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, alkoxy, -OCH3, -CO2CH3, and -CH3.

[0118] In some embodiments of Formula (IV), n is 1. In some embodiments, n is 0.

[0119] In some embodiments of Formula (IV), q is 2. In some embodiments of Formula (IV), q is 1. In some embodiments, q is 0.

[0120] In some embodiments of Formula (IV), X is S(O)2, NR 12 , or CHR 12 In some embodiments, X is NR 12 or CHR 12 In some embodiments, X is O. In some embodiments, X is S(O). In some embodiments, X is NR 12 In some embodiments, X is CHR 12 is.

[0121] In some embodiments of Formula (IV), R 11 is oxo, alkyl, or -O-alkyl. In some embodiments, R 11 is oxo or alkyl. In some embodiments, R 11 is oxo.

[0122] In some embodiments of Formula (IV), two adjacent R 11 together with the carbon atoms to which they are attached form an aryl or heteroaryl ring. In some embodiments, two adjacent R 11 together with the carbon atoms to which they are attached form an aryl ring. In some embodiments, the aryl ring is a phenyl ring. In some embodiments, two adjacent R 11 together with the carbon atoms to which they are attached form a heteroaryl or heterocyclyl ring. In some embodiments, the heteroaryl or heterocyclyl ring is a pyridinyl or pyrimidinyl ring. In some embodiments, the heteroaryl ring is a pyridinyl ring.

[0123] In some embodiments of Formula (IV), two non-adjacent R 11 together with the atoms to which they are attached form a carbocyclyl or heterocyclyl ring (ie, a bridged ring).

[0124] In some embodiments of Formula (IV), R12 is H, alkyl, or aryl. In some embodiments, R 12 is H, Me, or Ph. In some embodiments, R 12 is Me. In some embodiments, R 12 is H. In some embodiments, R 12 is Ph.

[0125] In some embodiments of Formula (I), R 11 and R 12 together with the carbon and / or nitrogen atoms to which they are attached form an aryl, heteroaryl ring, or heterocyclyl ring. In some embodiments, the aryl is phenyl. In some embodiments, the heteroaryl is a 5-6 membered heteroaryl. In some embodiments, the heterocyclyl is a 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms selected from the group N, S, and O. In some embodiments, the heterocyclyl ring is [ka] is.

[0126] In some embodiments of Formula (IV), p is 1, 2, or 3, or 4. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 2, 3, or 4. In some embodiments, p is 4. In some embodiments, p is 3. In some embodiments, p is 2. In some embodiments, p is 1. In some embodiments, p is 0.

[0127] In some embodiments of Formula (IV), X is CHR 12 When R 11 and R 12 together with the carbon atoms to which they are attached form an aryl ring. In some embodiments, the aryl ring is a phenyl ring.

[0128] In some embodiments of Formula (IV), X is NR 12 When R 11 and R 12 together with the carbon atom and nitrogen atom to which they are attached form a heterocyclyl or heteroaryl ring. In some embodiments, the heteroaryl ring is a pyridinyl ring.

[0129] In some embodiments of Formula (IV), when p is 4, two adjacent R 11 form an aryl ring together with the carbon atoms to which they are attached and two adjacent R 11 together with the carbon atoms to which they are attached form a heterocyclyl ring. In some embodiments, the aryl ring is a phenyl ring. In some embodiments, the heterocyclyl ring is [ka] In some embodiments, n is 1 and q is 0.

[0130] In some embodiments, the compound of formula (IV) is [ka] or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments of Formula (IV), p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0 or 1. In particular embodiments, m is p. In another particular embodiment, p is 1. In yet another particular embodiment, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0132] In some embodiments, the disclosure provides a compound in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0133] Pharmaceutical Composition Various embodiments of the present disclosure provide pharmaceutical compositions comprising one or more compounds disclosed herein, or pharmaceutically acceptable solvates, hydrates, tautomers, N-oxides, or salts 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 pharmaceutically acceptable solvates, hydrates, tautomers, N-oxides, or salts 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, salt solution, alcohol, polyethylene glycol, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, and polyvinylpyrrolidone. [Example]

[0134] 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.

[0135] General method

[0136] 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.

[0137] The compounds and intermediates produced according to the methods of the present disclosure 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% ethyl acetate in hexanes, or a gradient of 0-100% 10% MeOH in CH2Cl2.

[0138] The purification method described herein can provide compounds of the present disclosure having sufficiently basic or acidic functional groups in the form of a salt, such as a trifluoroacetate or formate salt for compounds of the present disclosure that are sufficiently basic, or an ammonium salt for compounds of the present disclosure that are sufficiently acidic. This type of salt can be converted to its free base form 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 disclosure 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.

[0139] All commercially available starting materials and reagents were used as received. 1 H 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 major peak designations. For example, s, singlet; d, doublet; t, triplet; q, quartet; dd, double doublet; dt, double triplet; m, multiplet; and 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

[0140] 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.

[0141] In the examples, the following abbreviations are used, other abbreviations have their customary meaning in the art: BOC: tert-butoxycarbonyl protecting group DMAP: dimethylaminopyridine DIPEA: Diisopropylethylamine EDCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride EtOH: ethanol EtOC(O)Cl: Ethyl chloroformate EtOAc: ethyl acetate h: time HCl: Hydrochloric acid HOBt: Hydroxybenzotriazole KO t Bu: potassium t-butoxide L: Liter LCMS: Liquid Chromatography Mass Spectrometry M: mole MeOH: Methanol min:minutes μL: microliter mL: milliliter N: Regulation N2: Nitrogen n-BuLi n-butyllithium NMR: nuclear magnetic resonance spectroscopy ppm: parts per million PCC: Pyridinium chlorochromate PPTS: Pyridinium p-toluenesulfonate rt: room temperature Rt: retention time Sat.: Saturation Sphos: 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl TEA: Triethylamine THF: tetrahydrofuran TMS-Cl: chlorotrimethylsilane

[0142] Analytical LC-MS method

[0143] 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.

[0144] Analytical HPLC method

[0145] 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 for 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 for 10 min, Flow rate: 1 mL / min, Injection volume: 1–5 μL, Temperature: 23 °C, UV scan: 220, 254, and 280 nm (Method 2).

[0146] Preparative HPLC

[0147] 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.

[0148] Compound synthesis Example 1

[0149] Preparation of 5-fluoro-N-hydroxynicotinamide (1) [ka]

[0150] To a cold solution of commercially available methyl 5-fluoronicotinate (100 mg, 0.64 mmol) in methanol-THF (4 mL, 1:1) in an ice bath, 50% aqueous NH2OH (1.28 g, 19.2 mmol) and KOH (362 mg, 6.4 mmol) were added. The reaction mixture was stirred and allowed to warm to ambient temperature. It was monitored by LCMS. After the reaction was complete, 1 N HCl was carefully added until pH 6-7, followed by ethyl acetate. The organic layer was washed with water, dried (Na2SO4), filtered, and concentrated. The resulting white solid was triturated with ethyl acetate / hexane and filtered to give 50 mg (49.7%) of the title compound.

[0151] Analysis of 5-fluoro-N-hydroxynicotinamide: 1 H NMR (400MHz, CD3OD-d4) δ8.78 (s, 1H), 8.66 (d, J = 2.69Hz, 1H), 7.98 (br d, J = 9.05Hz, 1H), 4.64 (s, 1H).

[0152] LC-MS: tR (min) 1.21 (20–100% ACN with 0.1% TFA, 4 min), m / z [M+H] + C6H5FN2O2 requires 156.0, measured value 157.1

[0153] HPLC tR (min) 2.70, 98% (20–100% ACN with 0.1% TFA, 10 min)

[0154] Example 2

[0155] Preparation of 6-methyl-N-hydroxynicotinamide (2) [ka]

[0156] Following the same experimental procedure as described in Example 1, methyl 6-methyl-N-nicotinate was converted to the title compound, using commercially available methyl 6-methyl-N-nicotinate instead.

[0157] Analysis of 6-methyl-N-hydroxynicotinamide:

[0158] 1 H NMR (400MHz, DMSO-d6) δ11.32(brs,1H)9.15(brs,1H)8.79(d,J=1.71Hz,1H)7.99(dd,J=8.07,2.45Hz,1H)7.35(d,J=8.07Hz,1H),3.30(s,3H).

[0159] LC-MS: tR (min) 1.36 (20–100% ACN with 0.1% TFA, 4 min), m / z [M+H] + C7H8N2O2 required value: 152.1, actual value: 153.1

[0160] HPLC tR (min) 1.21, 100% (20 to 100% ACN with 0.1% TFA, 10 min)

[0161] Example 3

[0162] Preparation of 5-fluoro-6-methyl-N-hydroxynicotinamide (I-1) [ka]

[0163] Step 1: Methyl 5-fluoro-6-methylnicotinate

[0164] Commercially available methyl 6-bromo-5-fluoronicotinate (360 mg, 1.54 mmol) was mixed with trimethyl-1,3,5,2,4,6-trioxatriborinane (966 mg, 7.69 mmol), KCO (319 mg, 2.31 mmol), and Pd(PhP) (196 mg, 0.169 mmol) in 1,4-dioxane (5 mL). The mixture was sparged with N and then cooled to 100°C. 2The mixture was stirred under atmospheric pressure at 110°C in a sealed tube for 18 hours. After cooling, ethyl acetate was added to the reaction mixture and washed with water. The organic layer was dried (NaSO) and filtered through Celite. The solvent was evaporated and the resulting residue was purified by chromatography (silica gel, hexane / ethyl acetate, 1:0 to 1:1) to give 198 mg (76%) of the title compound. LC-MS: m / z [M+H] + 170.1.

[0165] Step 2: 5-Fluoro-6-methyl-N-hydroxynicotinamide

[0166] Following the same experimental procedure as described in Example 1, methyl 5-fluoronicotinate (20 mg) from Step 1 above was converted to the title compound as a white solid, 8 mg (40%).

[0167] Analysis of 5-fluoro-6-methyl-N-hydroxynicotinamide:

[0168] 1 H NMR (400MHz, CD3OD-d4) δ8.65(s,1H),7.88(d,J=9.78Hz,1H),4.64(s,2H),2.57(d,J=2.93Hz,3H).

[0169] LC-MS: tR (min) 1.26 (20–100% ACN with 0.1% TFA, 4 min), m / z [M+H] + C7H7FN2O2 required value: 170.1, actual value: 171.1

[0170] HPLC tR (min) 3.14, 98% (20–100% ACN with 0.1% TFA, 10 min)

[0171] Example 4

[0172] Preparation of 6-amino-5-fluoro-N-hydroxynicotinamide (I-2) [ka]

[0173] Step 1: Tert-butyl-(3-fluoro-5-(hydroxycarbamoyl)pyridin-2-yl)carbamate

[0174] Methyl 6-bromo-5-fluoronicotinate (300 mg, 1.28 mmol) was mixed with tert-butyl carbamate (150 mg, 1.28 mmol), sodium tert-butoxide (123 mg, 1.28 mmol), palladium acetate (7.20 mg, 0.032 mmol), and XantPhos (37.1 mg, 0.064 mmol) in 1,4-dioxane in an oven-dried sealed tube. After evacuating and refilling with N2 (X3), the mixture was stirred and heated at 75 °C for 5 h. After cooling, ethyl acetate was added to the reaction and washed with water. The organic layer was dried (Na2SO4), concentrated, and purified by chromatography (silica gel, hexane / ethyl acetate, 1:0 to 5:1) to give 250 mg (72.1%) of the title compound as a white solid. LC-MS: m / z [2M+Na] + 563.5

[0175] Step 2: Methyl 6-amino-5-fluoronicotinate hydrochloride

[0176] The tert-butyl-(3-fluoro-5-(hydroxycarbamoyl)pyridin-2-yl)carbamate obtained from Step 1 above was treated with 4N HCl in methanol (5 ml) at ambient temperature for 18 hours. The solvent was evaporated to give the title compound as a white solid, 150 mg (65%). LC-MS: m / z [M+H] + 171.1

[0177] Step 3: 6-amino-5-fluoro-N-hydroxynicotinamide

[0178] Following the same experimental procedure as described in Example 1, methyl 6-amino-5-fluoronicotinate hydrochloride from Step 2 above, which was first treated with saturated NaHCO and extracted with ethyl acetate / MeOH, was then converted to the title compound.

[0179] Analysis of 6-amino-5-fluoro-N-hydroxynicotinamide:

[0180] 1 H NMR (400 MHz, methanol-d₄) δ 8.21 (s, 1H) 7.66 (d, J = 9.78 Hz, 1H).

[0181] LC-MS: tR (min) 1.36 (20–100% ACN with 0.1% TFA, 4 min), m / z [M+H] + C6H6FN3O2 required value: 171.1, actual value: 172.1.

[0182] HPLC tR (min) 2.36, 96% (20–100% ACN with 0.1% TFA, 10 min)

[0183] Example 5

[0184] Preparation of 5-fluoro-6-methoxyl-N-hydroxynicotinamide (I-3) [ka]

[0185] Step 1: 5-Fluoro-methoxynicotinic acid methyl ester

[0186] To commercially available 5-bromo-2,3-difluoropyridine (520 mg, 2.7 mmol) in a vial was added palladium acetate (12 mg, 2.7 mmol), Xantphos (62 mg, 2.7 mmol), methanol (1.1 mL, 27 mmol), and triethylamine (20 mL). The reaction mixture was sparged with a CO balloon for 1 minute, sealed, and heated at 65 °C under a CO atmosphere. After 17 h, complete consumption of the starting material was observed by TLC. The mixture was washed with water, extracted with ethyl acetate, and concentrated. The resulting residue was purified by chromatography (silica gel, ethyl acetate / hexane, 0-5%) to give 91.7 mg (18%) of the title compound as a white solid. LC-MS: m / z [M+H] + 186.0

[0187] Step 2: 5-Fluoro-N-hydroxy-6-methoxynicotinamide

[0188] Following the same experimental procedure as described in Example 1, methyl 6-methoxy-5-fluoronicotinate (31 mg, 0.17 mmol) from Step 1 above was converted to the title compound as 24.4 mg (79%) of a tan solid.

[0189] Analysis of 5-fluoro-N-hydroxy-6-methoxynicotinamide:

[0190] 1 H NMR (400 MHz, methanol-d₄) δ 8.35 (s, 1H) 7.80 (dd, J = 10.76, 1.47 Hz, 1H) 4.05 (s, 3H).

[0191] LC-MS: m / z [M+H] + C7H7FN2O3 Required value: 186.1, Measured value: 187.0

[0192] HPLC tR (min) 3.92, 100% (20–100% ACN with 0.1% TFA, 10 min)

[0193] Example 6

[0194] Preparation of 5-fluoro-N-hydroxy-6-(((1-phenylcyclopropyl)amino)methyl)nicotinamide (I-4) [ka]

[0195] Step 1: Methyl 6-(bromomethyl)-5-fluoronicotinate

[0196] To a solution of methyl 5-fluoro-6-methylnicotinate (195 mg, 1.15 mmol) in CCl4, NBS (328 mg, 1.84 mmol) and AIBN (38 mg, 231 mmol) were added. The reaction mixture was stirred and heated at 75 °C for 48 h. After cooling, the reaction mixture was evaporated. The resulting residue was purified by chromatography (silica gel, hexane / ethyl acetate, 1:0 to 0:1) to give 131 mg (46%) of the title compound as a white solid. LC-MS: m / z [M+H] + 249.0

[0197] Step 2: Methyl 5-fluoro-6-(((1-phenylcyclopropyl)amino)methyl)nicotinate

[0198] Methyl 6-(bromomethyl)-5-fluoronicotinate (80 mg, 0.323 mmol) from Step 2 above was combined with 1-phenylcyclopropan-1-amine hydrochloride (54.8 mg, 0.323 mmol) and K2CO3 (89.1 mg, 0.323 mmol) in acetonitrile (3 mL). The reaction was stirred and heated at 77 °C under a N2 atmosphere for 18 hours. After cooling and filtering through Celite, the mixture was concentrated. The resulting residue was purified by chromatography (silica gel, hexane / ethyl acetate, 1:0 to 1:1) to afford 60 mg (62%) of the title compound as an oil. LC-MS: m / z [M+H] + 301.3

[0199] Step 3: 5-Fluoro-N-hydroxy-6-(((1-phenylcyclopropyl)amino)methyl)nicotinamide

[0200] Following the same experimental procedure as described in Example 1, methyl 5-fluoro-6-(((1-phenylcyclopropyl)amino)methyl)nicotinate from Step 2 above was converted to the title compound. LC-MS: m / z [M+H] + 302.3

[0201] Analysis of 5-fluoro-N-hydroxy-6-(((1-phenylcyclopropyl)amino)methyl)nicotinamide:

[0202] 1 H NMR (400MHz, methanol-d4) δ8.69(s,1H),7.81(d,J=10.03Hz,1H),7.42(d,J=7.83Hz,2H),7.31(t,J =7.58Hz,2H),7.19-7.24(m,1H),4.64(s,1H),3.94(s,2H),1.05-1.11(m,2H),0.96-1.04(m,2H).

[0203] LC-MS: tR (min) 1.94 (20–100% ACN with 0.1% TFA, 4 min), m / z [M+H] + C 16 H 16 Required FN3O2 value: 301.3, Actual value: 302.3

[0204] HPLC tR (min) 4.16, 99% (20–100% ACN with 0.1% TFA, 10 min)

[0205] Example 7

[0206] Preparation of 6-((2,3-dihydro-1H-inden-2-yl)amino)-5-fluoro-N-hydroxynicotinamide (I-5) [ka]

[0207] Step 1: Methyl 6-((2,3-dihydro-1H-inden-2-yl)amino-5-fluoronicotinate

[0208] To a solution of methyl 5-fluoro-6-bromonicotinate (100 mg, 0.47 mmol) in NMP (2 mL) was added 2,3-dihydro-1H-inden-2-amine (62.6 mg, 0.47 mmol) and K2CO3 (195 mg, 1.41 mmol) in a vial. The reaction mixture was stirred and heated at 120 °C under N2 for 18 h. After cooling and dilution with ethyl acetate, the organic layer was washed with water. After drying (Na2SO4), filtration, and concentration, the resulting residue was purified by chromatography (silica gel, hexane / ethyl acetate, 1:0 to 0:1) to give 38 mg (31%) of the title compound as a brown oil. LC-MS: m / z [M+H] + 287.3

[0209] Step 2: 6-((2,3-dihydro-1H-inden-2-yl)amino)-5-fluoro-N-hydroxynicotinamide

[0210] Following the same experimental procedure as described in Example 1, methyl 6-((2,3-dihydro-1H-inden-2-yl)amino-5-fluoronicotinate from Step 1 above was converted to the title compound.

[0211] Analysis of 6-((2,3-dihydro-1H-inden-2-yl)amino)-5-fluoro-N-hydroxynicotinamide

[0212] 1 H NMR(400MHz,DMSO-d6)δ11.0(br,s,1H),8.98(s,1H),8.32(s,1H),7.63(d,J=12.2Hz,1H),7.45(br,d,J=6.60Hz,1H), 7.26-7.19(m,2H),7.18-7.11(m,2H),4.84-4.75(m,1H),3.27(dd,J=15.9,7.58HZ,2H),2.96(dd,J=15.9,7.09Hz,2H).

[0213] LC-MS: m / z [M+H] + C 15 H 13Required FN3O2: 287.3, Actual: 288.3

[0214] HPLC tR (min) 5.16, 99% (20–100% ACN with 0.1% TFA, 10 min)

[0215] Example 8

[0216] Preparation of 5-fluoro-N-hydroxy-6-((1-phenylcyclopropyl)amino)nicotinamide (I-6) [ka]

[0217] Step 1: Methyl 5-fluoro-6-((1-phenylcyclopropyl)amino)nicotinate

[0218] The title compound was synthesized according to the same experimental procedure described in Step 1 of Example 7, using instead methyl 5-fluoro-6-bromonicotinate and 1-phenylcyclopropan-1-amine hydrochloride. LC-MS: m / z [M+H] + 287.3

[0219] Step 2: 5-Fluoro-N-hydroxy-6-((1-phenylcyclopropyl)amino)nicotinamide

[0220] Following the same experimental procedure as described in Example 1, methyl 5-fluoro-6-((1-phenylcyclopropyl)amino)nicotinate from Step 1 above was converted to the title compound as a solid.

[0221] Analysis of 5-fluoro-N-hydroxy-6-((1-phenylcyclopropyl)amino)nicotinamide

[0222] 1H NMR (400MHz, methanol-d4) δ8.18(s,1H),7.63(dd,J=11.9,1.59Hz,1H),7.27-7.18( m,4H),7.15-7.11(m1H),5.03-493(m,1H),1.42-1.38(m,2H),1.36-1.32(m,2H).

[0223] LC-MS: tR (min) 1.90 (20–100% ACN with 0.1% TFA, 4 min) m / z [M+H] + C 15 H 14 FN3O2 measured value: 288.3

[0224] HPLC tR (min), % (20–100% ACN with 0.1% TFA, 10 min)

[0225] Example 9

[0226] Preparation of 5-fluoro-N-hydroxy-6-(4-(2-methoxyphenyl)piperazin-1-yl)nicotinamide (IV-1) [ka]

[0227] Step 1: Methyl 5-fluoro-6-(4-(2-methoxyphenyl)piperazin-1-yl)nicotinate

[0228] The title compound was synthesized according to the same experimental procedure described in Example 7, Step 1, using instead methyl 5-fluoro-6-bromonicotinate and 1-(2-methoxyphenyl)piperazine. LC-MS: m / z [M+H] + 346.3

[0229] Step 2: 5-Fluoro-N-hydroxy-6-(4-(2-methoxyphenyl)piperazin-1-yl)nicotinamide

[0230] Following the same experimental procedure as described in Example 1, methyl 5-fluoro-6-(4-(2-methoxyphenyl)piperazin-1-yl)nicotinate from Step 1 above was converted to the title compound.

[0231] Analysis of 5-fluoro-N-hydroxy-6-(4-(2-methoxyphenyl)piperazin-1-yl)nicotinamide

[0232] 1 H NMR (400MHz, methanol-d4) δ8.40(s,1H),7.76(d,J=14.7Hz,1H),7.01-6.87(m,4H),3.81(s,3H),3.67(br,d,J=4.65Hz,4H),3.12-3.12(m,4H).

[0233] LC-MS: m / z [M+H] + C 17 H 19 Required FN4O2: 346.4, Actual: 347.2

[0234] HPLC tR (min) 4.50, 98% (20–100% ACN with 0.1% TFA, 10 min)

[0235] Example 10

[0236] Preparation of (R)-5-fluoro-N-hydroxy-6-((1-phenylethyl)amino)nicotinamide (I-7A) [ka]

[0237] Step 1: (R)-5-fluoro-6-((1-phenylethyl)amino) nicotinate methyl ester

[0238] The title compound was synthesized according to the same experimental procedure described in Step 1 of Example 7, using instead methyl 5-fluoro-6-bromonicotinate and commercially available (R)-1-phenylethan-1-amine. LC-MS: m / z [M+H] +302.3

[0239] Step 2: (R)-5-Fluoro-N-hydroxy-6-((1-phenylethyl)amino)nicotinamide

[0240] Following the same experimental procedure as described in Example 1, (R)-methyl 5-fluoro-6-((1-phenylethyl)amino)nicotinate from Step 1 above was converted to the title compound.

[0241] Analysis of (R)-5-fluoro-N-hydroxy-6-((1-phenylethyl)amino)nicotinamide

[0242] 1 H NMR (400MHz, methanol-d4) δ8.19(s,1H),7.57(s,1H),7.57(dd,J=11.9,1.35Hz,1H),7.39(d,J=7.83 Hz,2H),7.30(t,J=7.70Hz,2H),7.23-7.18(m,1H),5.34(q,J=7.01Hz,1H),1.58(d,J=7.09Hz,3H).

[0243] LC-MS: tR (min) 1.86 (20–100% ACN with 0.1% TFA, 4 min) m / z [M+H] + C 14 H 13 Required FN3O2: 275.3, Actual: 276.1

[0244] HPLC tR (min) 4.06, 99% (20–100% ACN with 0.1% TFA, 10 min)

[0245] Example 11

[0246] Preparation of (S)-5-fluoro-N-hydroxy-6-((1-phenylethyl)amino)nicotinamide (I-7B) [ka]

[0247] Step 1: (S)-5-fluoro-6-((1-phenylethyl)amino)nicotinic acid methyl ester

[0248] The title compound was synthesized according to the same experimental procedure described in Step 1 of Example 7, using instead methyl 5-fluoro-6-bromonicotinate and (S)-1-phenylethan-1-amine. LC-MS: m / z [M+H] + 302.3

[0249] Step 2: (S)-5-Fluoro-N-hydroxy-6-((1-phenylethyl)amino)nicotinamide

[0250] Following the same experimental procedure as described in Example 1, (S)-methyl 5-fluoro-6-((1-phenylethyl)amino)nicotinate from Step 1 above was converted to the title compound.

[0251] Analysis of (S)-5-fluoro-N-hydroxy-6-((1-phenylethyl)amino)nicotinamide:

[0252] 1 H NMR (400 MHz, methanol-d₄) δ 8.19 (s, 1H), 7.59 (s, 1H), 7.56 (s, 1H), 7.42-7.36 (m, 2H), 7.30 (t, J = 7.70 Hz, 2H), 7.23-7.18 (m, 1H), 5.34 (q, J = 7.01 Hz, 1H), 1.58 (d, J = 7.09 Hz, 3H).

[0253] LC-MS: tR (min) 1.86 (20–100% ACN with 0.1% TFA, 4 min), m / z [M+H] + C 14 H 13 Required FN3O2: 275.3, Actual: 276.1

[0254] HPLC tR (min) 4.06, 97% (20–100% ACN with 0.1% TFA, 10 min)

[0255] Example 12

[0256] Preparation of (S)-6-((cyclopropyl(phenyl)methyl)amino-5-fluoro-N-hydroxynicotinamide (I-8B) [ka]

[0257] Step 1: (S,E)-N-(cyclopropylmethylene)-2-methylpropane-sulfinamide

[0258] To a solution of cyclopropylcarbaldehyde (5.33 mL, 71.3 mmol) in THF (150 mL) was added (S)-(-)2-methyl-2-propanesulfonamide (8.65 g, 71.3 mmol) and tetraisopropyl orthotitanate (41.8 mL, 143 mmol). The mixture was stirred at ambient temperature for 18 hours. After completion of the reaction, the mixture was poured into brine and the slurry was filtered through Celite. The filtrate was extracted with ethyl acetate, and the organic layer was dried (Na2O4) and concentrated. 12.4 g (100%) of the crude title compound was carried on to the next step without purification. LC-MS: m / z [M+H] + 174.2

[0259] Step 2: (S)-N-((S)-cyclopropyl(phenyl)methyl)-2-methylpropane-2-sulfonamide

[0260] To a solution of (S,E)-N-(cyclopropylmethylene)-2-methylpropane-sulfinamide (12.4 g, 71.6 mmol) from Step 1 above in THF (25 mL) was added phenylmagnesium bromide (1.0 N, 71.6 mL) dropwise at ambient temperature. The mixture was then stirred at 50-60 °C for 2 hours. After the reaction was complete, the reaction mixture was quenched with saturated ammonium chloride, followed by the addition of water. After filtration, the sold was washed with ethyl ester, and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by chromatography (silica gel, hexane / ethyl acetate) to give 5.0 g (28%) of the title compound. LC-MS: m / z [M+H] + 252.3

[0261] Step 3: (S)-Cyclopropyl(phenyl)methanamine hydrochloride

[0262] (S)-N-((S)-cyclopropyl(phenyl)methyl)-2-methylpropane-2-sulfonamide was converted to the title compound by treatment with 4N HCl in methanol at 0° C. to ambient temperature for 18 hours. Ethyl acetate was added to the mixture to form a white solid as the title compound (85%). LC-MS: m / z [M+H] + 148.2

[0263] Step 4: (S)-6-((cyclopropyl(phenyl)methyl)amino)-5-fluoronicotinate methyl ester

[0264] Commercially available methyl 5-bromo-3-fluoronicotinate (50 mg, 0.214 mmol) was mixed with (S)-cyclopropyl(phenyl)methanamine hydrochloride (59 mg, 0.320 mmol) and diisopropylethylamine (166 mg, 1.28 mmol) in DMSO (2 mL). The mixture was stirred and heated at 100 °C under microwave irradiation for 1 h. After cooling, the reaction was added with water and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by chromatography (silica gel, hexane / ethyl acetate, 1:0 to 1:1) to give 10 mg (15.5%) of the title compound. LC-MS: m / z [M+H] + 301.3

[0265] Step 5: (S)-6-((cyclopropyl(phenyl)methyl)amino-5-fluoro-N-hydroxynicotinamide

[0266] Following the same experimental procedure as described in Example 1, (S)-methyl 6-((cyclopropyl(phenyl)methyl)amino)-5-fluoronicotinate from Step 4 above was converted to the title compound.

[0267] Analysis of (S)-6-((cyclopropyl(phenyl)methyl)amino-5-fluoro-N-hydroxynicotinamide:

[0268] 1 H NMR (400MHz, methanol-d4) δ8.16(s,1H),7.58(d,J=1.71Hz,1H),7.49-7.41(m,2H),7.36-7.27(m,2H) ),7.24-7.18(m,1H),4.59-4.55(m,1H),1.40-1.30(m,1H),0.66-0.60(m,2H),0.40-0.30(m,2H).

[0269] LC-MS: tR (min) 3.67 (20–100% ACN with 0.1% TFA, 6 min), m / z [M+H] + C 16 H 16 Required FN3O2: 301.3, Actual: 302.1

[0270] HPLC tR (min) 4.09, 94% (20–100% ACN with 0.1% TFA, 10 min)

[0271] Example 13

[0272] Preparation of (R)-6-((cyclopropyl(pyridin-2-yl)methyl)amino)-5-fluoro-N-hydroxynicotinamide (I-9A) [ka]

[0273] The title compound was synthesized according to the same experimental procedure as described in Example 12, substituting 5-bromo-2,3-difluoropyridine and (R)-cyclopropyl(pyridin-2-yl)methanamine.

[0274] Analysis of (R)-6-((cyclopropyl(pyridin-2-yl)methyl)amino)-5-fluoro-N-hydroxynicotinamide:

[0275] 1 H NMR (400 MHz, methanol-d₄) δ 8.49 (d, J = 4.65 Hz, 1H), 8.14 (s, 1H), 7.80 (t, J = 7.83 Hz, 1H), 7.51-7.61 (m, 2H), 7.33-7.27 (m, 1H), 4.60-4.65 (m, 1H), 0.72-0.62 (m, 1H), 0.59-0.49 (m, 3H).

[0276] LC-MS: tR (min) 1.38 (20–100% ACN with 0.1% TFA, 6 min), m / z [M+H] + C 14 H 16 Required FN4O2: 302.3, Actual: 303.1

[0277] HPLC tR (min) 3.38, 98% (20–100% ACN with 0.1% TFA, 10 min)

[0278] Example 14

[0279] Preparation of (S)-6-((cyclopropyl(pyridin-2-yl)methyl)amino)-5-fluoro-N-hydroxynicotinamide (I-9B) [ka]

[0280] The title compound was synthesized according to the same experimental procedure as described in Example 12, using instead 5-bromo-2,3-difluoropyridine and (S)-cyclopropyl(pyridin-2-yl)methanamine.

[0281] Analysis of (S)-6-((cyclopropyl(pyridin-2-yl)methyl)amino)-5-fluoro-N-hydroxynicotinamide:

[0282] 1 H NMR (400 MHz, methanol-d₄) δ 8.49 (d, J = 4.65 Hz, 1H), 8.14 (s, 1H), 7.80 (t, J = 7.83 Hz, 1H), 7.51-7.61 (m, 2H), 7.33-7.27 (m, 1H), 4.60-4.65 (m, 1H), 0.72-0.62 (m, 1H), 0.59-0.49 (m, 3H).

[0283] LC-MS: tR (min) 1.41 (20–100% ACN with 0.1% TFA, 6 min), m / z [M+H] + C 14 H 16 Required FN4O3 value: 302.3, Actual value: 303.1

[0284] HPLC tR (min) 3.38, 98% (20–100% ACN with 0.1% TFA, 10 min)

[0285] Example 15

[0286] Preparation of 5-fluoro-N-hydroxy-6-(phenylsulfonamido)nicotinamide (I-10) [ka]

[0287] Step 1: 5-Fluoro-6-(phenylsulfonamido)nicotinic acid methyl ester

[0288] Commercially available methyl 6-bromo-5-fluoronicotinate (100 mg, 0.427 mmol) was mixed with benzenesulfonamide (67.2 mg, 0.427 mmol), sodium tert-butoxide (41.1 mg, 0.427 mmol), palladium acetate (2.4 mg, 0.0107 mmol), and Xantphos (12.4 mg, 0.0214 mmol) in 1,4-dioxane in an oven-dried sealed tube under a N atmosphere. The reaction mixture was stirred and heated at 120 °C in a microwave oven for 1 h. After cooling, saturated NaHCO was added to the reaction mixture and extracted with ethyl ester (X3). The combined organic layers were dried (NaSO), filtered, and concentrated. The resulting residue was purified by chromatography (silica gel, DCM / 15% MeOH in DCM, 1:0 to 0:1) to give the title compound as a white solid (45 mg, 34%). LC-MS: m / z [M+H] + 311.3

[0289] Step 2: 5-Fluoro-N-hydroxy-6-(phenylsulfonamido)nicotinamide

[0290] Following the same experimental procedure as described in Example 1, methyl 5-fluoro-6-(phenyl-sulfonamido)nicotinate from Step 1 above was converted to the title compound.

[0291] Analysis of 5-fluoro-N-hydroxy-6-(phenylsulfonamido)nicotinamide

[0292] 1 H NMR (400 MHz, methanol-d₄) δ 8.33 (s, 1H), 8.10 (d, J = 7.34 Hz, 2H), 7.83 (s, 1H), 7.80 (s, 1H), 7.66-7.52 (m, 3H).

[0293] LC-MS: tR (min) 2.81 (20–100% ACN with 0.1% TFA, 6 min), m / z [M+H] + C 12 H 10 FSN3O4 required value: 311.1, actual value: 312.0

[0294] HPLC tR (min) 4.66, 93% (20–100% ACN with 0.1% TFA, 10 min)

[0295] Example 16

[0296] Preparation of 5-fluoro-N-hydroxy-6-morpholinonicotinamide (IV-2) [ka]

[0297] The title compound was synthesized according to the same experimental procedure described in Example 7, substituting methyl 5-fluoro-6-bromonicotinate and morpholine.

[0298] Analysis of 5-fluoro-N-hydroxy-6-morpholinonicotinamide:

[0299] 1 H NMR (400MHz, DMSO-d4) δ8.35 (s, 1H), 7.68 (d, J = 14.4Hz, 1H), 3.674-3.69 (m, 4H), 3.44-3.39 (m, 4H).

[0300] LC-MS: m / z [M+H] + C 10 H 12 Required FN3O3 value: 241.2, Actual value: 242.1

[0301] HPLC tR (min) 5.56, 99% (20–100% ACN with 0.1% TFA, 10 min)

[0302] Example 17

[0303] Preparation of 5-fluoro-N-hydroxy-6-((4-phenylpropan-2-yl)amino)nicotinamide (I-11) [ka]

[0304] Step 1: 5-Bromo-3-fluoro-N-(2-phenylpropan-2-yl)pyridin-2-amine

[0305] To a solution of 5-bromo-2,3-difluoropyridine (50 mg, 0.26 mmol) in DMSO (1.0 mL) was added 2-phenylpropan-2-amine (52 mg, 0.39 mmol) and DIPEA (0.23 mL, 1.30 mmol). The mixture was stirred and heated at 120 °C for 15 h. After cooling, water was added to the reaction and extracted with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by chromatography (silica gel, hexane / ethyl acetate, 0:1 to 9:1) to give 25.8 mg (32.4%) of the title compound as a colorless oil. LC-MS: m / z [M+H] + 310.1

[0306] Step 2: Methyl 5-fluoro-6-((2-phenylpropan-2-yl)amino)nicotinate

[0307] 5-Bromo-3-fluoro-N-(2-phenylpropan-2-yl)pyridin-2-amine from Step 1 above was mixed with palladium acetate (0.8 mg, 0.0003 mmol), XantPhos (3.9 mg, 0.007 mmol), methanol, and triethylamine (0.5 mL). The mixture was sparged with CO for 1 minute, stirred, and heated at 65 °C under a CO atmosphere. The reaction was monitored by LCMS and additional palladium acetate (0.80 mg), XantPhos (3.9 mg), methanol (0.2 mL), and triethylamine (0.2 mL) were added. After the reaction was complete, the mixture was poured into water / brine and washed with ethyl acetate. The organic layer was dried (NaSO), filtered, and concentrated. The resulting residue was purified by chromatography (silica gel, hexane / ethyl acetate, 1:0 to 4:1) to yield 13.5 mg (56.1%) of the title compound as a white solid. LC-MS: m / z [M+H] + 289.1

[0308] Step 3: 5-Fluoro-N-hydroxy-6-((4-phenylpropan-2-yl)amino)nicotinamide

[0309] Following the same experimental procedure as described in Example 1, methyl 5-fluoro-6-((2-phenylpropan-2-yl)amino)nicotinate from Step 2 above was converted to the title compound.

[0310] Analysis of 5-fluoro-N-hydroxy-6-((4-phenylpropan-2-yl)amino)nicotinamide:

[0311] 1 H NMR (400 MHz, methanol-d₄) δ 8.00 (s, 1H), 7.54 (dJ = 12.2 Hz, 1H), 7.40 (d, J = 8.07 Hz, 2H), 7.25 (t, J = 7.58 Hz, 2H), 7.17–7.12 (m, 1H), 1.80 (s, 6H).

[0312] LC-MS: m / z [M+H] + C 15 H 16FN3O2, required value: 289.3, actual value: 290.1

[0313] HPLC tR (min) 5.14, 99% (20–100% ACN with 0.1% TFA, 10 min)

[0314] Example 18

[0315] Preparation of 5-fluoro-N-hydroxy-6-(4-phenylpiperidin-1-yl)nicotinamide (IV-3) [ka]

[0316] The title compound was synthesized according to the same experimental procedure as described in Example 7, using instead methyl 5-fluoro-6-bromonicotinate and 4-phenylpiperidine.

[0317] Analysis of 5-fluoro-N-hydroxy-6-(4-phenylpiperidin-1-yl)nicotinamide:

[0318] 1 H NMR(400MHz,DMSO-d4)δ8.37(s,1H),7.71(d,J=14.7Hz,1H),7.33-7.18(m,5H),4.25(br,d,J=13.0Hz,2H) ,3.02(br,t,J=11.9Hz,2H),2.85-2.76(m,1H),1.86(br,d,J=11.4Hz,2H),1.72(qd,J=12.5,3.30Hz,2H).

[0319] LC-MS: m / z [M+H] + C 17 H 18 FN3O2, required value: 315.3, actual value: 316.1

[0320] HPLC tR (min) 5.92, 99% (20–100% ACN with 0.1% TFA, 10 min)

[0321] Example 19

[0322] Preparation of 6-(3,4-dihydroisoquinolin-2(1H)-yl-5-fluoro-N-hydroxynicotinamide (IV-4) [ka]

[0323] Step 1: Methyl 6-(3,4-dihydroisoquinolin-2(1H)-yl-5-fluoronicotinate

[0324] To a solution of methyl 6-bromo-5-fluoropyridine-3-carboxylate (0.15 g, 0.64 mmol) in DMF was added 1,2,3,4-tetrahydroisoquinoline (0.17 g, 1.28 mmol) and DMAP (2.0 mg). The mixture was stirred and heated at 80 °C in a microwave oven for 3 h. After cooling, saturated ammonium chloride was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by chromatography (silica gel, hexane / ethyl acetate, 1:0 to 0:1) to give 160 mg (87.2%) of the title compound as an oil.

[0325] Step 2: 6-(3,4-dihydroisoquinolin-2(1H)-yl-5-fluoro-N-hydroxynicotinamide):

[0326] Following the same experimental procedure as described in Example 1, methyl 5-fluoro-6-bromonicotinate and 1,2,3,4-tetrahydroisoquinoline were converted to the title compound.

[0327] Analysis of 6-(3,4-dihydroisoquinolin-2(1H)-yl-5-fluoro-N-hydroxynicotinamide):

[0328] 1H NMR (400MHz, DMSO-d4) δ8.38(s,1H),7.73(d,J=14.7Hz,1H),7.24-7.16(m,4H),4.71(s,2H),3.81(t,J=5.75Hz,2H),2.93(t,J=5.75Hz,2H).

[0329] LC-MS: m / z [M+H] + C 15 H14FN3O2 required value: 287.3, actual value: 288.1

[0330] HPLC tR (min) 5.30, 97% (20–100% ACN with 0.1% TFA, 10 min)

[0331] Example 20

[0332] Preparation of (S)-6-(1-phenylpropyl)amino-5-fluoro-N-hydroxynicotinamide (I-12B) [ka]

[0333] The title compound was synthesized according to the same experimental procedure as described in Example 11, substituting methyl 5-fluoro-6-bromonicotinate and (S)-1-phenylpropyl-1-amine.

[0334] Analysis of (S)-6-(1-phenylpropyl)amino-5-fluoro-N-hydroxynicotinamide:

[0335] 1 H NMR(400MHz,DMSO-d4)δ8.19(s,1H),7.56(br,d,J=12.2Hz,1H),7.41-7.36(m,2H),7.30(t,J= 7.58Hz,2H),7.23-7.18(m,1H),5.10(t,J=7.46Hz,1H),2.00-1.86(m,2H),1.01-0.91(m,3H).

[0336] LC-MS: m / z [M+H] +C 15 H 16 Required FN3O2: 289.3, Actual: 290.2

[0337] HPLC tR (min) 5.08, 95% (20–100% ACN with 0.1% TFA, 10 min)

[0338] Example 21

[0339] Preparation of (R)-6-((cyclopropyl(phenyl)methyl)amino-5-fluoro-N-hydroxynicotinamide (I-8A) [ka]

[0340] The title compound was synthesized according to the same experimental procedure as described in Example 11, using instead methyl (R)-5-fluoro-6-((1-phenylethyl)amino)nicotinate.

[0341] Analysis of (R)-6-((cyclopropyl(phenyl)methyl)amino-5-fluoro-N-hydroxynicotinamide:

[0342] 1 H NMR(400MHz,DMSO-d4)δ8.16(s,1H),7.57(br,d,J=12.2Hz,1H),7.44(br,d,J=7.34Hz,2H),7.30(t,J=7 .46Hz,2H),7.24-7.18(m,1H),4.66-4.55(m,2H),1.41-1.25(m,2H),0.67-0.58(M,2H),0.44(br,s,2H).

[0343] LC-MS: m / z [M+H] + C 16 H 16 Required FN3O2: 301.3, Actual: 302.1

[0344] HPLC tR (min) 4.03, 96% (20–100% ACN with 0.1% TFA, 10 min)

[0345] Example 22

[0346] Preparation of 6-((methyl(1-phenylcyclopropyl)amino)methyl-5-fluoro-N-hydroxynicotinamide (I-13) [ka]

[0347] Step 1: Methyl 5-fluoro-6-((methyl(1-phenylcyclopropyl)amino)methyl)nicotinate

[0348] Methyl 5-fluoro-6-(((1-phenylcyclopropyl)amino)methyl)nicotinate (36 mg, 0.12 mmol) was dissolved in acetonitrile / water (10:1), followed by the addition of 37% formaldehyde (19.5 mg, 0.24 mmol), NaCNBH (15.1 mg, 0.24 mmol), and one drop of acetic acid. The reaction mixture was stirred at ambient temperature for 15 min. Quenched with water, the mixture was extracted with ethyl acetate. The organic layer was dried (NaSO), concentrated, and purified by chromatography (silica gel, hexane / EtOAc, 1:0 to 1:1) to give the title compound, 20 mg (53.1%). LC-MS: m / z [M+H] + 315.1

[0349] Step 2: 6-((methyl(1-phenylcyclopropyl)amino)methyl-5-fluoro-N-hydroxynicotinamide

[0350] Following the same experimental procedure as described in Example 1, methyl 5-fluoro-6-((methyl(1-phenylcyclopropyl)amino)methyl)nicotinate was converted to the title compound.

[0351] Analysis of 6-((methyl(1-phenylcyclopropyl)amino)methyl-5-fluoro-N-hydroxynicotinamide

[0352] 1H NMR(400MHz,DMSO-d4)δ8.68(s,1H),7.89(d,J=10.0Hz,1H),7.47-7.29(m,5H), 4.54(br,s,1H),3.83(s,2H),2.19(3,3H),1.12-1.06(m,2H),0.95-0.83(m,2H).

[0353] Analysis of 6-((methyl(1-phenylcyclopropyl)amino)methyl-5-fluoro-N-hydroxynicotinamide:

[0354] LC-MS: m / z [M+H] + C 17 H 18 Required FN3O2: 315.3, Actual: 316.1

[0355] HPLC tR (min) 4.12, 100% (20 to 100% ACN with 0.1% TFA, 10 min)

[0356] Example 23

[0357] Preparation of 6-(((oxetan-3-yl-methyl)(1-phenylcyclopropyl)amino)methyl)-5-fluoro-N-hydroxynicotinamide (I-14) [ka]

[0358] Following the same experimental procedure as described in the previous example, the title compound was prepared by reductive amination between methyl 5-fluoro-6-(((1-phenylcyclopropyl)amino)methyl)nicotinate and oxetane-3-carbaldehyde followed by formation of the hydroxamic acid.

[0359] Analysis of 6-(((oxetan-3-yl-methyl)(1-phenylcyclopropyl)amino)methyl)-5-fluoro-N-hydroxynicotinamide:

[0360] 1H NMR(400MHz,DMSO-d4)δ8.71(s,1H),7.89(d,J=9.90Hz,1H),7.49(d,J=6.85Hz,2H),7.41-7.28(m,3H),4.63(t,J=6 .73Hz,2H),4.54(s,1H),4.15-4.09(m,2H),3.96(s,2H),3.23-316(m,1H),2.87(d,J=8.31,2H),0.78-0.82(m,4H).

[0361] LC-MS: m / z [M+H] + C 20 H 22 Required FN3O3 value: 371.4, Actual value: 372.1

[0362] HPLC tR (min) 4.77, 100% (20 to 100% ACN with 0.1% TFA, 10 min)

[0363] Example 24

[0364] Preparation of 6-(dicyclopropylamino)-5-fluoro-N-hydroxynicotinamide (I-15) [ka]

[0365] The title compound was prepared according to the same experimental procedure as described in Example 7, substituting methyl 5-fluoro-6-bromonicotinate and 1,1-dicyclopropylmethylamine.

[0366] Analysis of 6-(dicyclopropylamino)-5-fluoro-N-hydroxynicotinamide:

[0367] 1 H NMR(400MHz,DMSO-d4)δ8.18(s,1H),7.55(d,J=11.5Hz,1H),3.39-3.35(m,1H),1.19-1.08(m,2H),0.60-0.55(m,2H),0.54-0.50(m,6H).

[0368] LC-MS: m / z [M+H] + C 13 H 16 Required FN3O2: 265.3, Actual: 266.1

[0369] HPLC tR (min) 3.37, 97% (20–100% ACN with 0.1% TFA, 10 min)

[0370] Example 25

[0371] Preparation of 6-(dimethylamino)-5-fluoro-N-hydroxynicotinamide (I-16) [ka]

[0372] Step 1: Methyl 6-(dimethylamino)-5-fluoronicotinate

[0373] The title compound was synthesized according to the same experimental procedure described in Example 7, Step 1, using instead methyl 5-fluoro-6-bromonicotinate and dimethylamine.

[0374] 1H NMR (400MHz, chloroform-d) δ ppm 8.57 (t, J = 1.59 Hz, 1H) 7.68 (dd, J = 14.55, 1.83 Hz, 1H) 3.87 (s, 3H) 3.22 (d, J = 2.69 Hz, 6H) LC-MS: m / z [M+H] + 199.3

[0375] Step 2: 6-(dimethylamino)-5-fluoro-N-hydroxynicotinamide

[0376] Following the same experimental procedure as described in Example 1, methyl 6-(dimethylamino)-5-fluoronicotinate from Step 1 above was converted to the title compound.

[0377] Analysis of 6-(dimethylamino)-5-fluoro-N-hydroxynicotinamide

[0378] 1H NMR(400MHz,DMSO-d6)δppm11.05(br s,1H)8.97(s,1H)8.35(s,1H)7.68(brd,J=15.41Hz,1H)3.09-3.14(m,6H)

[0379] LC-MS: m / z [M+H] + C8H 11 Required FN3O2: 200.2, Actual: 200.1

[0380] HPLC tR (min) 5.23, 99% (10 to 100% ACN with 0.1% TFA, 10 min)

[0381] Example 26

[0382] Preparation of 6-(1,1-dioxidethiomorpholino)-5-fluoro-N-hydroxynicotinamide (IV-5) [ka]

[0383] Step 1: Methyl 6-(1,1-dioxidethiomorpholino)-5-fluoronicotinate

[0384] The title compound was synthesized according to the same experimental procedure described in Example 7, Step 1, substituting methyl 5-fluoro-6-bromonicotinate and 1,1-dioxidethiomorpholine.

[0385] 1H NMR (400 MHz, chloroform-d) δ ppm 8.63 (s, 1H) 7.85 (dd, J = 13.82, 1.59 Hz, 1H) 4.20-4.28 (m, 4H) 3.91 (s, 3H) 3.07-3.22 (m, 4H)

[0386] LC-MS: m / z [M+H] + 289.1

[0387] Step 2: 6-(dimethylamino)-5-fluoro-N-hydroxynicotinamide

[0388] Following the same experimental procedure as described in Example 1, methyl 6-(1,1-dioxidethiomorpholino)-5-fluoronicotinate from Step 1 above was converted to the title compound.

[0389] Analysis of 6-(1,1-dioxidethiomorpholino)-5-fluoro-N-hydroxynicotinamide

[0390] 1H NMR(400MHz,DMSO-d6)δppm11.20(br s,1H)9.10(br s,1H)8.43(s,1H)7.83(d,J=14.43Hz,1H)4.04(br s,4H)3.25(brs,4H)

[0391] LC-MS: m / z [M+H] + C 10 H 12 FN3O4S Required value: 290.2, Actual value: 290.0

[0392] HPLC tR (min) 3.94, 98% (10 to 100% ACN with 0.1% TFA, 10 min)

[0393] Example 27

[0394] Preparation of 5-fluoro-N-hydroxy-6-(4-methylpiperazin-1-yl)nicotinamide (IV-6) [ka]

[0395] Step 1: Methyl 5-fluoro-6-(4-methylpiperazin-1-yl)nicotinate

[0396] The title compound was synthesized according to the same experimental procedure described in Example 7, Step 1, using instead methyl 5-fluoro-6-bromonicotinate and N-methylpiperazine.

[0397] 1H NMR (400 MHz, chloroform-d) δ ppm 8.59 (s, 1H) 7.74 (d, J = 1.22 Hz, 1H) 4.37 (s, 1H) 3.88 (s, 3H) 3.71-3.80 (m, 4H) 2.50-2.55 (m, 4H) 2.34 (s, 3H)

[0398] LC-MS: m / z [M+H] + 254.3

[0399] Step 2: 6-(dimethylamino)-5-fluoro-N-hydroxynicotinamide

[0400] Following the same experimental procedure as described in Example 1, methyl 5-fluoro-6-(4-methylpiperazin-1-yl)nicotinate from Step 1 above was converted to the title compound.

[0401] Analysis of 5-fluoro-N-hydroxy-6-(4-methylpiperazin-1-yl)nicotinamide

[0402] 1H NMR(400MHz,DMSO-d6)δppm11.07(s,1H)9.03(s,1H)8.38(s,1H)7.74(d,J=14.67Hz,1H)3.51-3.58(m,4H)2.40-2.45(m,4H)2.21(s,3H)

[0403] LC-MS: m / z [M+H] + C 11 H 15 FN4O2 required value: 255.3, actual value: 255.1

[0404] HPLC tR (min) 1.46, 99% (10 min with 0.1% TFA to 100% ACN)

[0405] Example 28

[0406] Preparation of 5-chloro-N-hydroxy-6-morpholinonicotinamide (3) [ka]

[0407] Step 1: Methyl 5-chloro-6-morpholinonicotinate

[0408] To a 10 mL microwave vial was added methyl 5,6-dichloropyridine-3-carboxylate (100 mg, 0.485 mmol) and morpholine (1 mL, 23.9 mmol). The resulting mixture was stirred at 100 °C for 2 h and then cooled to room temperature. The crude material was mixed with silica gel, the volatiles were evaporated, and then purified by ISCO using EtOAc-hexane (0-20%) to give the product as a white solid (35 mg, 28%). LC-MS: m / z [M+H] + 257.1.

[0409] Step 2: 5-chloro-N-hydroxy-6-morpholinonicotinamide

[0410] Following the same experimental procedure as described in Example 1, methyl 5-chloro-6-morpholinonicotinate (35 mg, 0.14 mmol) from Step 1 above was converted to the title compound as a tan solid, 20 mg (57%).

[0411] Analysis of 5-chloro-N-hydroxy-6-morpholinonicotinamide:

[0412] 1 H NMR (400MHz, DMSO-d6) δ11.23(br,s,1H),9.12(s,1H),8.56(m,1H),8.06(m,1H),3.73(m,4H),3.39(m,4H).

[0413] LC-MS: m / z [M+H] + C 10 H 12Required ClN3O3 value: 257.1, Measured value: 258.1

[0414] HPLC tR (min) 4.52, 100% (20 to 100% ACN with 0.1% TFA, 10 min)

[0415] Example 29

[0416] Preparation of 6-(benzhydrylamino)-5-fluoro-N-hydroxynicotinamide (I-17) [ka]

[0417] The title compound was synthesized following the same experimental procedure as described in Example 12, using instead 6-bromo-5-fluoropyridine-3-carboxylate and diphenylmethanamine.

[0418] Analysis of 6-(benzhydrylamino)-5-fluoro-N-hydroxynicotinamide:

[0419] 1 H NMR (400MHz, DMSO-d6) δ10.97(br,s,1H),8.93(s,1H),8.22(s,1H),7.91(m,1H),87.66(m,1H),3.39-7.21(m,11H),6.59(d,J=8.8Hz,1H).

[0420] LC-MS: m / z [M+H] + C19H16FN3O2 Required value: 337.1, Measured value: 338.1

[0421] HPLC tR (min) 5.49, 100% (20 to 100% ACN with 0.1% TFA, 10 min)

[0422] Example 30

[0423] Preparation of 5-fluoro-N-hydroxy-6-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)nicotinamide (4) [ka]

[0424] Step 1: Methyl 5-bromo-3-fluoropicolinate

[0425] To a solution of 5-bromo-3-fluoropyridine-2-carboxylic acid in MeOH (40 mL) was added SOCl (2 mL) slowly at room temperature. 、60℃ The mixture was stirred at rt overnight. The volatiles were evaporated to give the product as a white solid (2.24 g, 100%). 1 H NMR(400MHz,DMSO-d6)δ8.71(m,1H),8.44-8.41(m,1H),3.90(s,1H), LC-MS:m / z[M+H] + 233.9,235.9.

[0426] Step 2: (5-Bromo-3-fluoropyridin-2-yl)methanol

[0427] Methyl 5-bromo-3-fluoropyridine-2-carboxylate (1.2 g, 5.13 mmol) was dissolved in dry methanol (30 mL) and sodium borohydride (813 mg, 15.4 mmol) was added slowly in an ice bath. After complete addition, the ice bath was removed, and the mixture was warmed to room temperature and stirred overnight. LC-MS showed complete conversion. Next, the pH was adjusted to 1 with 1N HCl, and again to 10 with saturated sodium bicarbonate solution. Extraction with ethyl acetate was then performed. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product. This was purified by ISCO column using EtOAc-hexane (0-40%) to give the product as a white solid (800 mg, 76%). 1H NMR(400MHz,CDCl3)δ8.49(m,1H),7.61-7.59(m,1H),4.80-4.79(m,2H),3.51(t,J=5.2Hz,1H), LC-MS:m / z[M+H] + 205.9,207.9.

[0428] Step 3: 5-Bromo-2-(bromomethyl)-3-fluoropyridine

[0429] To a stirred solution of (5-bromo-3-fluoropyridin-2-yl)methanol (0.25 g, 1.21 mmol) and triphenylphosphine (0.51 g, 1.94 mmol), dichloromethane (10 mL) was added, and a solution of CBr (0.644 g, 1.94 mmol) in DCM (5 mL) was added dropwise at 0 °C and allowed to stir at room temperature overnight. The reaction mixture was quenched with saturated NaHCO and extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography using ethyl acetate / hexane (0–15%) as the eluent to give the product as a white solid (240 mg, 74%). 1 H NMR(400MHz,CDCl3)δ8.49(m,1H),7.64-7.61(m,1H),4.57(s,2H), LC-MS:m / z[M+H] + 269.9,271.9.

[0430] Step 4: 1-((5-bromo-3-fluoropyridin-2-yl)methyl)-2-methyl-1H-benzo[d]imidazole

[0431] To a solution of 2-methyl-1H-1,3-benzodiazole (153 mg, 1.16 mmol) in dry DMF (3 mL) was added 60% NaH (46 mg, 1.16 mmol) at 0 °C, and the mixture was then stirred at 0 °C for 20 min. A solution of 5-bromo-2-(bromomethyl)-3-fluoropyridine (240 mg, 1.0 mmol) in dry DMF (2 mL) was added dropwise. The resulting mixture was stirred at 0 °C for 20 min and then at room temperature overnight. The mixture was carefully quenched with water at 0 °C, diluted, and treated with EtOAc-water. The combined organic layers were dried over MgSO4, and the residual DMF was then removed by lyophilization. The crude was evaporated and purified by ISCO using EtOAc-hexane (0-100%) to give the product as a white solid (190 mg, 66%). LC-MS: m / z [M+H] + 319.1,321.1.

[0432] Step 5: Methyl 5-fluoro-6-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)nicotinate

[0433] The title compound was synthesized according to the same experimental procedure as described in Example 17 (Step 2), using 1-((5-bromo-3-fluoropyridin-2-yl)methyl)-2-methyl-1H-benzo[d]imidazole instead. LC-MS: m / z [M+H] + 300.1.

[0434] Step 6: 5-Fluoro-N-hydroxy-6-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)nicotinamide

[0435] The title compound was synthesized according to the same experimental procedure as described in Example 17, using instead methyl 5-fluoro-6-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)nicotinate.

[0436] Analysis of 5-fluoro-N-hydroxy-6-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)nicotinamide:

[0437] 1 H NMR (400MHz, DMSO-d6) δ11.35(br,s,1H),9.25(s,1H),8.59(s,1H),8.01(m,1H),7.51(m,1H),7.39(m,1H),7.13(m,2H),5.68(s,2H).

[0438] LC-MS: m / z [M+H] + C 15 H 13 FN4O2 required value: 300.1, actual value: 301.1

[0439] HPLC tR (min) 1.65, 98% (10 to 100% ACN with 0.1% TFA, 10 min)

[0440] Example 31

[0441] Preparation of 5-fluoro-N-hydroxy-6-((3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)nicotinamide (IV-7) [ka]

[0442] The title compound was synthesized according to the same experimental procedure as described in Example 30, using instead 2H-benzo[b][1,4]oxazin-3(4H)-one.

[0443] Analysis of 5-fluoro-N-hydroxy-6-((3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)nicotinamide:

[0444] 1 H NMR (400MHz, DMSO-d6) δ11.39(br,s,1H),9.28(s,1H),8.59(s,1H),7.98(m,1H),7.04-6.96(m,4H),5.34(s,2H),4.72(s,2H).

[0445] LC-MS: m / z [M+H] + C 15 H 12 Required FN3O4 value: 317.1, Actual value: 318.1

[0446] HPLC tR (min) 4.76, 99% (10 to 100% ACN with 0.1% TFA, 10 min)

[0447] Example 32

[0448] Preparation of 6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-fluoro-N-hydroxynicotinamide (IV-8) [ka]

[0449] The title compound was synthesized following the same experimental procedure as described in Example 30, substituting 1,2,3,4-tetrahydroisoquinoline.

[0450] Analysis of 6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-fluoro-N-hydroxynicotinamide:

[0451] 1 H NMR (400MHz, DMSO-d6) δ11.45(br,s,1H),9.41(s,1H),8.74(s,1H),7.97(m,1H),7.08-6.99(m,4H),3.86(s,2H),3.62(s,2H),2.77(m,4H).

[0452] LC-MS: m / z [M+H] + C16H16FN3O2 Required value: 301.1, Actual value: 302.1

[0453] HPLC tR (min) 4.63, 97% (10 to 100% ACN with 0.1% TFA, 10 min)

[0454] Example 33

[0455] Preparation of 5-fluoro-N-hydroxy-6-((1-(pyridin-2-yl)cyclopropyl)amino)nicotinamide (I-18) [ka]

[0456] Step 1: 1-(pyridin-2-yl)cyclopropan-1-amine

[0457] To an oven-dried 200 mL round-bottom flask containing a 1.5-inch egg-shaped stir bar under a N atmosphere was added pyridine-2-carbonitrile (2.08 g, 20 mmol), followed by THF (80 mL). To the pale yellow solution, titanium tetraisopropoxide (7.1 mL, 24 mmol, 1.2 equiv.) was added in one portion, resulting in no visible change. Ethyl magnesium bromide (3 M in ether, 16.7 mL, 50 mmol, 2.5 equiv.) was added dropwise over 10 min with vigorous stirring, immediately yielding a viscous black, opaque suspension (CAUTION: exotherm, gas evolution). After stirring at room temperature for 90 min, the black suspension 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: exotherm, gas evolution). The ice bath was removed, and the viscous black suspension was allowed to warm to room temperature overnight. The next day, the reaction was quenched by first adding 1M NaOH (100 mL, 5 equiv.) in portions, followed by ethyl acetate (50 mL), and then stirred vigorously at room temperature for 2 hours to give a biphasic mixture consisting of an upper orange organic layer and a lower black aqueous emulsion. This biphasic mixture was filtered directly through water-wetted Celite and washed once with water (50 mL) and once with ethyl acetate (50 mL). The filtrate was collected and the layers were separated. The aqueous layer was extracted twice more with ethyl acetate (50 mL). The combined organic layers were washed twice with water (50 mL) and once with brine (25 mL), then dried over MgSO, filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography (silica gel, 0–10% methanol in DCM with 1% NHOH) to give 346 mg (13%) of the title compound as a brown oil. LC-MS: m / z [M+H] + 135.1. [ka]

[0458] Step 2: 5-Bromo-3-fluoro-N-(1-(pyridin-2-yl)cyclopropyl)pyridin-2-amine

[0459] To a vial was added 1-(pyridin-2-yl)cyclopropan-1-amine (171 mg, 1.27 mmol), DMSO (3 mL), DIPEA (1.1 mL, 6.4 mmol, 5 equiv.), and 5-bromo-2,3-difluoropyridine (0.26 mL, 1.9 mmol, 1.5 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, 0-50% EtOAc / hexanes) to give 185.3 mg (47%) of the title compound as a yellow oil that solidified to a beige solid at room temperature. LC-MS: m / z [M+H] + 308.1, 310.1 (1:1 ratio). [ka]

[0460] Step 3: Methyl 5-fluoro-6-((1-(pyridin-2-yl)cyclopropyl)amino)nicotinate

[0461] To the vial was added 5-bromo-3-fluoro-N-(1-(pyridin-2-yl)cyclopropyl)pyridin-2-amine (85.0 mg, 0.28 mmol), followed by palladium diacetate (1.2 mg, 5 μmol, 0.02 equiv.) and Xantphos (6.4 mg, 11 μmol, 0.04 equiv.). Triethylamine (2 mL) and methanol (0.5 mL) were then added, resulting in a dark yellow, heterogeneous suspension. The reaction mixture was sparged with a CO balloon for 1 minute, and then heated to 70 °C overnight under a static CO atmosphere (CO balloon). The next day, LCMS analysis of the gray heterogeneous mixture revealed complete conversion of the bromide starting material. The reaction was worked up by dry-loading directly onto silica gel: the reaction was diluted with ethyl acetate (5 mL), silica gel (2 g) was added, and all volatiles were removed by rotary evaporation. The material was purified by column chromatography (silica gel, 0-50% EtOAc / hexanes) to give 51.7 mg (65%) of the title compound as a colorless oil. LC-MS: m / z [M+H] + 288.1. [ka]

[0462] Step 4: 5-Fluoro-N-hydroxy-6-((1-(pyridin-2-yl)cyclopropyl)amino)nicotinamide

[0463] To the vial was added methyl 5-fluoro-6-((1-(pyridin-2-yl)cyclopropyl)amino)nicotinate (28.3 mg, 0.098 mmol), followed by methanol (1 mL) and THF (1 mL). The colorless, homogeneous solution was cooled to 0 °C in an ice bath. 50% aqueous hydroxylamine (0.18 mL, 3.0 mmol, 30 equiv.) was then added in one portion. Finally, one pellet of KOH (55 mg, 1.0 mmol, 10 equiv.) was added. The vial was capped and the ice bath was removed. The reaction was allowed to warm to room temperature with vigorous stirring. After 1 h, the reaction was quenched by the addition of 1 M HCl (3 mL, 30 equiv.). The pH was tested via colorimetric strip and found to be pH 5-6. The reaction was poured into 50 mL of half-saturated aqueous NaHCO3 and then extracted three times with EtOAc (30 mL). The combined organic layers were washed once with half-saturated NaHCO3 (50 mL) and once with brine (30 mL), then dried over MgSO4, filtered, and concentrated by rotary evaporation to give 26.9 mg (95%) of the analytically pure title compound as a pale yellow oil.

[0464] Analysis of 5-fluoro-N-hydroxy-6-((1-(pyridin-2-yl)cyclopropyl)amino)nicotinamide:

[0465] 1 H NMR(400MHz,d6-DMSO),δppm10.98(brs,1H)8.94(br s,1H)8.43(d,J=4.16Hz,1H)8.17(s,1H)8.09(s,1H)7.67(d,J=11.98Hz,1H)7.59(t,J=7 .59Hz,1H)7.24(d,J=7.83Hz,1H)7.11(dd,J=6.48,5.26Hz,1H)1.51-1.64(m,2H)1.24(br d,J=2.69Hz,2H).

[0466] LC-MS: m / z [M+H] + C 14 H 13 FN4O2 required value: 288.1, actual value: 289.1.

[0467] HPLC tR (min) 1.41, 97.8% (with 0.1% TFA, 10 to 100% MeCN / HO, 10 min)

[0468] Example 34

[0469] Preparation of 6-((1-(2,6-difluorophenyl)cyclopropyl)amino)-5-fluoro-N-hydroxynicotinamide (I-19) [ka]

[0470] Step 1: 1-(2,6-difluorophenyl)cyclopropan-1-amine

[0471] 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. Titanium tetraisopropoxide (7.3 mL, 24 mmol, 1.2 equiv.) was added in one portion, producing no visible change. Ethyl magnesium bromide (3 M in ether, 16.7 mL, 50 mmol, 2.5 equiv.) was added dropwise with vigorous stirring over 5 minutes 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 hours 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 ethyl acetate (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 ethyl acetate (50 mL). The filtrate was collected, and the layers were separated. The aqueous layer was extracted twice more with ethyl acetate (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% ethyl acetate in hexanes) to give 1.66 g (49%) of the title compound as a pale yellow oil. LC-MS: m / z [M+H] + 170.1. [ka]

[0472] Step 2: 5-Bromo-N-(1-(2,6-difluorophenyl)cyclopropyl)-3-fluoropyridin-2-amine

[0473] 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 give 400.5 mg (65%) of the title compound as a pale yellow oil. LC-MS: Does not ionize. 1 H NMR (CDCl3): δppm8.00(s,1H)7.22(dd,J=10.15,1.83Hz,1H)7.10-7.19(m,1H)6.81(t,J=8.07Hz,2H)5.53(br s,1H)1.31(s,4H). [ka]

[0474] Step 3: Methyl 6-((1-(2,6-difluorophenyl)cyclopropyl)amino)-5-fluoronicotinate

[0475] To the vial was added 5-bromo-N-(1-(2,6-difluorophenyl)cyclopropyl)-3-fluoropyridin-2-amine (110 mg, 0.32 mmol), followed by palladium diacetate (1.4 mg, 6 μmol, 0.02 equiv.) and Xantphos (7.4 mg, 13 μmol, 0.04 equiv.). Triethylamine (2 mL) and methanol (0.5 mL) were then added, resulting in a pale yellow heterogeneous suspension. The reaction mixture was sparged with a CO balloon for 1 minute, and then heated to 70 °C overnight under a static CO atmosphere (CO balloon). The next day, LCMS analysis of the gray heterogeneous mixture revealed complete conversion of the bromide starting material. The reaction was worked up by dry-loading directly onto silica gel: the reaction was diluted with ethyl acetate (5 mL), silica gel (2 g) was added, and all volatiles were removed by rotary evaporation. The material was purified by column chromatography (silica gel, 0-40% EtOAc / hexanes) to afford 73.6 mg (72%) of the title compound as a colorless oil. LC-MS: m / z [M+H] + 323.1. [ka]

[0476] Step 4: 6-((1-(2,6-difluorophenyl)cyclopropyl)amino)-5-fluoro-N-hydroxynicotinamide

[0477] To a vial was added methyl 6-((1-(2,6-difluorophenyl)cyclopropyl)amino)-5-fluoronicotinate (30.5 mg, 0.095 mmol), followed by methanol (1 mL) and THF (1 mL). The colorless, homogeneous solution was cooled to 0 °C in an ice bath. 50% aqueous hydroxylamine (0.17 mL, 2.8 mmol, 30 equiv.) was then added in one portion. Finally, one pellet of KOH (53 mg, 0.95 mmol, 10 equiv.) was added. The vial was capped, and the ice bath was removed. The reaction was allowed to warm to room temperature with vigorous stirring. After 1 h, the reaction was quenched by the addition of 1 M HCl (3 mL, 30 equiv.). The pH was tested via colorimetric strip and found to be pH 5-6. The reaction was poured into 50 mL of half-saturated aqueous NaHCO3 and then extracted three times with EtOAc (30 mL). The combined organic layers were washed once with half-saturated NaHCO3 (50 mL) and once with brine (30 mL), then dried over MgSO4, filtered, and concentrated by rotary evaporation to give the title compound as a pale yellow oil, 37.6 mg (117%) of high analytical purity, excluding traces of residual dichloromethane.

[0478] Analysis of 6-((1-(2,6-difluorophenyl)cyclopropyl)amino)-5-fluoro-N-hydroxynicotinamide:

[0479] 1 H NMR(400MHz,d6-DMSO),δppm10.9(brs,1H)8.91(br s,1H)8.23(s,1H)7.82(s,1H)7.56(d,J=12.23Hz,1H)7.28(quintet,J=7.40Hz,1H)6.97(t,J=8.31Hz,2H)1.26-1.35(m,2H)1.14-1.23(m,2H).

[0480] LC-MS: m / z [M+H] + C 15 H 12 F3N3O2 required value: 323.1, actual value: 324.1.

[0481] HPLC tR (min) 5.03, 95.5% (with 0.1% TFA, 10 to 100% MeCN / HO, 10 min)

[0482] Example 35

[0483] Preparation of 5-fluoro-N-hydroxy-6-((1-(pyridin-3-yl)cyclopropyl)amino)nicotinamide (I-20) [ka]

[0484] Step 1: 1-(pyridin-3-yl)cyclopropan-1-amine

[0485] To an oven-dried 200 mL round-bottom flask containing a 1.5-inch egg-shaped stir bar under a N2 atmosphere was added pyridine-3-carbonitrile (2.08 g, 20 mmol), followed by tert-butyl ether (MTBE) (100 mL). The colorless, homogeneous solution was cooled to -78 °C. Ethyl magnesium bromide (3 M in ether, 16.7 mL, 50 mmol, 2.5 equiv.) was added dropwise over 5 min with vigorous stirring (CAUTION: exotherm and possible gas evolution). Titanium tetraisopropoxide (7.3 mL, 24 mmol, 1.2 equiv.) was added dropwise over 5 min. No gas evolution was observed. A bright orange solution formed. After addition of the above reagents, the dry ice bath was removed. Upon warming to room temperature, a viscous, opaque, brown suspension formed. After stirring at room temperature for 3 h, the suspension 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 ethyl acetate (50 mL), and then vigorously stirred at room temperature for 2 h to give a biphasic mixture consisting of an upper pale yellow organic layer and a lower yellow aqueous emulsion. This biphasic mixture was filtered directly through water-wetted Celite and washed once with water (50 mL) and once with ethyl acetate (50 mL). The filtrate was collected, and the layers were separated. The aqueous layer was extracted twice more with ethyl acetate (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, 0-10% methanol in DCM with 1% NH4OH) to give 822 mg (31%) of the title compound as an orange oil. LC-MS: m / z [M+H] + 135.2. [ka]

[0486] Step 2: 5-Bromo-3-fluoro-N-(1-(pyridin-3-yl)cyclopropyl)pyridin-2-amine

[0487] To a vial was added 1-(pyridin-3-yl)cyclopropan-1-amine (134 mg, 1.0 mmol), DMSO (3 mL), DIPEA (0.87 mL, 5 mmol, 5 equiv.), and 5-bromo-2,3-difluoropyridine (0.20 mL, 1.5 mmol, 1.5 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, 0-100% EtOAc / hexanes) to afford 127 mg (41%) of the title compound as a pale orange oil. LC-MS: m / z [M+H] + 308.1, 310.1 (1:1 ratio). [ka]

[0488] Step 3: Methyl 5-fluoro-6-((1-(pyridin-3-yl)cyclopropyl)amino)nicotinate

[0489] To the vial was added 5-bromo-3-fluoro-N-(1-(pyridin-3-yl)cyclopropyl)pyridin-2-amine (44.6 mg, 0.15 mmol), followed by palladium diacetate (0.6 mg, 3 μmol, 0.02 equiv.) and Xantphos (3.3 mg, 6 μmol, 0.04 equiv.). Triethylamine (2 mL) and methanol (0.5 mL) were then added, resulting in a pale yellow heterogeneous suspension. The reaction mixture was sparged with a CO balloon for 1 minute, and then heated to 70 °C overnight under a static CO atmosphere (CO balloon). The next day, LCMS analysis of the gray heterogeneous mixture revealed complete conversion of the bromide starting material. The reaction was worked up by dry-loading directly onto silica gel: the reaction was diluted with ethyl acetate (5 mL), silica gel (2 g) was added, and all volatiles were removed by rotary evaporation. The material was purified by column chromatography (silica gel, 0-100% EtOAc / hexanes) to give 35.8 mg (86%) of the title compound as a pale yellow waxy solid. LC-MS: m / z [M+H] + 288.1. [ka]

[0490] Step 4: 5-Fluoro-N-hydroxy-6-((1-(pyridin-3-yl)cyclopropyl)amino)nicotinamide

[0491] To the vial was added methyl 5-fluoro-6-((1-(pyridin-3-yl)cyclopropyl)amino)nicotinate (35.8 mg, 0.13 mmol), followed by methanol (1 mL) and THF (1 mL). The colorless, homogeneous solution was cooled to 0 °C in an ice bath. 50% aqueous hydroxylamine (0.23 mL, 3.7 mmol, 30 equiv.) was then added in one portion. Finally, one pellet of KOH (70 mg, 1.3 mmol, 10 equiv.) was added. The vial was capped and the ice bath was removed. The reaction was allowed to warm to room temperature with vigorous stirring. After 1 h, the reaction was quenched by the addition of 1 M HCl (3 mL, 30 equiv.). The pH was tested via colorimetric strip and found to be pH 5-6. The reaction was poured into 50 mL of half-saturated aqueous NaHCO3 and then extracted three times with EtOAc (30 mL). The combined organic layers were washed once with half-saturated NaHCO3 (50 mL) and once with brine (30 mL), then dried over MgSO4, filtered, and concentrated by rotary evaporation to give 25.3 mg (70%) of the title compound in high analytical purity as a white powder.

[0492] 1 H NMR (400 MHz, d6-DMSO), δ ppm 11.01 (br s, 1H), 8.99 (br s, 1H), 8.40 (br s, 1H), 8.33 (br d, J = 3.42 Hz, 1H), 8.10-8.27 (two overlapping br s, 2H), 7.65 (br d, J = 12.47 Hz, 1H), 7.54 (br d, J = 7.34 Hz, 1H), 7.23-7.30 (m, 1H), 1.36 (br s, 2H), 1.28 (br s, 2H).

[0493] LC-MS: m / z [M+H] + C 14 H 13 FN4O2 required value: 288.1, actual value: 289.1.

[0494] HPLC tR (min) 1.49: 76.7% with a protonation state shoulder artifact, 1.65: 20.4%. The sum of both peaks is 97.1%. (10-100% MeCN / HO, 10 min with 0.1% TFA)

[0495] Example 36

[0496] Preparation of 5-fluoro-N-hydroxy-6-((2-(pyridin-2-yl)propan-2-yl)amino)nicotinamide (I-21) [ka]

[0497] Step 1: 2-(pyridin-2-yl)propan-2-amine

[0498] To a vial containing pyridine-2-carbonitrile (521 mg, 5.0 mmol), toluene (6 mL) was added. The pale orange-brown homogeneous solution was cooled to 0°C in an ice bath. Methylmagnesium bromide (1.4 M in 3:1 toluene:THF, 8.9 mL, 12.5 mmol, 2.5 equiv.) was added dropwise over 5 min with vigorous stirring. The resulting brown, opaque solution was heated to 70°C overnight under a N2 atmosphere (balloon). The next day, LCMS analysis showed complete conversion. The black, heterogeneous mixture was cooled to 0°C in an ice bath and then treated by adding 1 M HCl (20 mL) (Caution: exothermic, gas evolution). The lower, brown aqueous layer was separated from the upper, clear toluene layer. The aqueous layer was basified (pH > 10) using 1 M NaOH (30 mL) and then extracted three times with EtOAc (30 mL each). 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, 485 mg (71%) as a brown oil, which was carried on without further purification. LC-MS: m / z [M+H] + 137.1. [ka]

[0499] Step 2: 5-Bromo-3-fluoro-N-(2-(pyridin-2-yl)propan-2-yl)pyridin-2-amine

[0500] To a vial was added 2-(pyridin-2-yl)propan-2-amine (144 mg, 1.06 mmol), DMSO (2 mL), DIPEA (0.92 mL, 5.3 mmol, 5 equiv.), and 5-bromo-2,3-difluoropyridine (0.21 mL, 1.6 mmol, 1.5 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 199.5 mg (61%) of the title compound as a yellow oil. LC-MS: m / z [M+H] + 310.1, 312.1 (1:1 ratio). [ka]

[0501] Step 3: Methyl 5-fluoro-6-((2-(pyridin-2-yl)propan-2-yl)amino)nicotinate

[0502] To the vial was added oily 5-bromo-3-fluoro-N-(2-(pyridin-2-yl)propan-2-yl)pyridin-2-amine (63.4 mg, 0.20 mmol), followed by palladium diacetate (1 mg, 4 μmol, 0.02 equiv.) and Xantphos (4.7 mg, 8 μmol, 0.04 equiv.). Triethylamine (2 mL) and methanol (0.5 mL) were then added, resulting in a pale yellow heterogeneous suspension. The reaction mixture was sparged with a CO balloon for 1 minute, and then heated to 70 °C overnight under a static CO atmosphere (CO balloon). The next day, LCMS analysis of the gray heterogeneous mixture revealed complete conversion of the bromide starting material. The reaction was worked up by dry-loading directly onto silica gel: the reaction was diluted with ethyl acetate (5 mL), silica gel (2 g) was added, and all volatiles were removed by rotary evaporation. The material was purified by column chromatography (silica gel, 0-30% EtOAc / hexanes) to afford 44.1 mg (75%) of the title compound as a colorless oil. LC-MS: m / z [M+H] + 290.1. [ka]

[0503] Step 4: 5-Fluoro-N-hydroxy-6-((2-(pyridin-2-yl)propan-2-yl)amino)nicotinamide

[0504] To a vial was added methyl 5-fluoro-6-((2-(pyridin-2-yl)propan-2-yl)amino)nicotinate (44.1 mg, 0.15 mmol), followed by methanol (1 mL) and THF (1 mL). The colorless, homogeneous solution was cooled to 0 °C in an ice bath. 50% aqueous hydroxylamine (0.28 mL, 4.5 mmol, 30 equiv.) was then added in one portion. Finally, one pellet of KOH (85 mg, 1.5 mmol, 10 equiv.) was added. The vial was capped and the ice bath was removed. The reaction was allowed to warm to room temperature with vigorous stirring. After 1 h, the reaction was quenched by the addition of 1 M HCl (3 mL, 20 equiv.). The pH was tested via colorimetric strip and found to be pH 5-6. The reaction was poured into 50 mL of half-saturated aqueous NaHCO3 and then extracted three times with EtOAc (30 mL). The combined organic layers were washed once with half-saturated NaHCO3 (50 mL) and once with brine (30 mL), then dried over MgSO4, filtered, and concentrated by rotary evaporation to give 37.7 mg (85%) of the title compound in high analytical purity as a yellow solid powder.

[0505] Analysis of 5-fluoro-N-hydroxy-6-((2-(pyridin-2-yl)propan-2-yl)amino)nicotinamide:

[0506] 1 NMR(400MHz,d6-DMSO),δppm10.92(br s,1H)8.91(s,1H)8.51(d,J=4.65Hz,1H)8.06(s,1H)7.71(t,J=7.83Hz,1H)7.63(br d,J=12.47Hz,1H)7.39-7.49(m,2H)7.22(dd,J=6.85,5.38Hz,1H)1.76(s,6H).

[0507] LC-MS: m / z [M+H] + C 14 H 15 FN4O2 required value: 290.1, actual value: 291.1.

[0508] HPLC tR (min) 3.67, 98.8% (with 0.1% TFA, 10 to 100% MeCN / HO, 10 min)

[0509] Example 37

[0510] Preparation of 5-fluoro-N-hydroxy-6-(methyl(1-phenylcyclopropyl)amino)nicotinamide (I-22) [ka]

[0511] Step 1: 5-Bromo-3-fluoro-N-(1-phenylcyclopropyl)pyridin-2-amine

[0512] To a vial was added 1-phenylcyclopropan-1-amine (244 mg, 1.83 mmol), DMSO (3 mL), DIPEA (1.7 mL, 10 mmol, 5 equiv.), and 5-bromo-2,3-difluoropyridine (0.40 mL, 3.0 mmol, 1.5 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 orange 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 orange oil was dry-loaded onto silica gel and purified by column chromatography (silica gel, 0-20% EtOAc / hexanes) to give the title compound as a granular oil, which was triturated from hexanes (2 mL) at room temperature to give a crystalline white solid, 208.1 mg (34%). LC-MS: m / z [M+H] + 307.2, 309.2 (1:1 ratio). [ka]

[0513] Step 2: 5-Bromo-3-fluoro-N-methyl-N-(1-phenylcyclopropyl)pyridin-2-amine

[0514] To the vial was added 5-bromo-3-fluoro-N-(1-phenylcyclopropyl)pyridin-2-amine (59.4 mg, 0.19 mmol) dissolved in THF (1 mL). The reaction was cooled to 0 °C in an ice bath. Sodium hydride (60 wt% in mineral oil, 40 mg, 1 mmol, 5 equiv.) was added in one portion, and the reaction was allowed to warm to room temperature for 10 minutes with vigorous stirring (Caution: gas evolution) open to the air, resulting in a beige suspension. Iodomethane (62 μL, 1 mmol, 5 equiv.) was then added in one portion. The reaction was continued to stir at room temperature for 2 hours, after which point TLC and LCMS analysis indicated complete and clean conversion. The reaction was worked up by pouring into water (50 mL) and then extracting three times with EtOAc (30 mL). The combined organic layers were washed with water (30 mL), then brine (30 mL), dried over MgSO, filtered, and concentrated by rotary evaporation to give the title product as a brown oil of suitable purity, which was carried on to the next step without further purification. LC-MS: m / z [M+H] + 321.2, 323.2 (1:1 ratio). [ka]

[0515] Step 3: Methyl 5-fluoro-6-(methyl(1-phenylcyclopropyl)amino)nicotinate

[0516] To the vial was added 5-bromo-3-fluoro-N-methyl-N-(1-phenylcyclopropyl)pyridin-2-amine (69.5 mg, 0.22 mmol), followed by palladium diacetate (1 mg, 4 μmol, 0.02 equiv.) and Xantphos (5.0 mg, 9 μmol, 0.04 equiv.). Triethylamine (2 mL) and methanol (0.5 mL) were then added, resulting in an orange heterogeneous suspension. The reaction mixture was sparged with a CO balloon for 1 minute, and then heated to 70 °C overnight under a static CO atmosphere (CO balloon). The next day, LCMS analysis of the gray heterogeneous mixture revealed complete conversion of the bromide starting material. The reaction was worked up by dry-loading directly onto silica gel: the reaction was diluted with ethyl acetate (5 mL), silica gel (2 g) was added, and all volatiles were removed by rotary evaporation. The material was purified by column chromatography (silica gel, 0-15% EtOAc / hexanes) to afford 32.6 mg (50%) of the title compound as a colorless oil. LC-MS: m / z [M+H] + 301.1. [ka]

[0517] Step 4: Methyl 5-fluoro-6-(methyl(1-phenylcyclopropyl)amino)nicotinate

[0518] To the vial was added methyl 5-fluoro-6-((1-(pyridin-2-yl)cyclopropyl)amino)nicotinate (32.6 mg, 0.11 mmol), followed by methanol (1 mL) and THF (1 mL). The colorless, homogeneous solution was cooled to 0 °C in an ice bath. 50% aqueous hydroxylamine (0.20 mL, 3.3 mmol, 30 equiv.) was then added in one portion. Finally, one pellet of KOH (61 mg, 1.1 mmol, 10 equiv.) was added. The vial was capped, and the ice bath was removed. The reaction was allowed to warm to room temperature with vigorous stirring. After 1 h, the reaction was quenched by the addition of 1 M HCl (3 mL, 30 equiv.). The pH was tested via colorimetric strip and found to be pH 5-6. The reaction was poured into 50 mL of half-saturated aqueous NaHCO3 and then extracted three times with EtOAc (30 mL). The combined organic layers were washed once with half-saturated NaHCO3 (50 mL) and once with brine (30 mL), then dried over MgSO4, filtered, and concentrated by rotary evaporation to give 32.2 mg (98%) of the analytically pure title compound as a pale yellow oil.

[0519] Analysis of methyl 5-fluoro-6-(methyl(1-phenylcyclopropyl)amino)nicotinate:

[0520] 1 H NMR(400MHz,d6-DMSO),δppm11.06(br s,1H)9.00(br s,1H)8.38(s,1H)7.66(br d,J=13.69Hz,1H)7.27-7.34(m,2H)7.15-7.21(m,1H)7.08(d,J=8.07Hz,2H)3.18(s,3H)1.38(br d,J=6.85Hz,4H).

[0521] LC-MS: m / z [M+H] + C 16 H 16 FN3O2 required value: 301.1, actual value: 302.1.

[0522] HPLC tR (min) 5.47, 99.0% (with 0.1% TFA, 10 to 100% MeCN / HO, 10 min) [ka]

[0523] A mixture of methyl 6-bromo-5-fluoropyridine-3-carboxylate (70 mg, 0.3 mmol), cyclopropylboronic acid (128 mg, 1.5 mmol), and potassium carbonate (62.0 mg, 0.45 mmol) in 1,4-dioxane (1.5 mL) was flushed with nitrogen for 10 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (43.8 mg, 0.06 mmol) was added, and the mixture was again flushed with nitrogen for 5 minutes and heated in a microwave at 110 °C for 4 hours. LCMS showed complete conversion. The mixture was partitioned between ethyl acetate and water. The layers were separated. The aqueous layer was extracted with ethyl acetate (2x), and the combined organic layers were filtered through a pad of Celite. The filtrate was concentrated to half its volume, washed with water (3x), brine, and concentrated to give 169 mg of a crude volatile oil. This material was purified by column chromatography (4 g SiO, 0-10% ethyl acetate in hexanes). Fractions containing the desired product were combined and collected to 55.3 mg (95%) of a colorless oil.

[0524] Methyl 6-cyclopropyl-5-fluoropyridine-3-carboxylate:

[0525] LCMS m / z[M+H] + C9H9FN2O2 Required value: 195.07, Measured value: 195.1

[0526] 1H NMR (400MHz, CDCl3) δ=8.85(s,1H),7.85(dd,J=9.90,1.59Hz,1H),3.94(s,3H),2.35-2.45(m,1H),1.19-1.26(m,2H),1.09-1.15(m,2H)ppm.

[0527] A mixture of methyl 6-cyclopropyl-5-fluoropyridine-3-carboxylate (55.3 mg, 0.283 mmol), methanol (1 mL), and THF (1 mL) was cooled to 0 °C. Hydroxylamine (0.52 mL, 50 wt% in water, 8.5 mmol) was added dropwise, potassium hydroxide (80 mg, 1.42 mmol) was added in one portion, and the reaction was then stirred while warming to room temperature. After 10 min, the reaction was complete by LCMS. The reaction mixture was concentrated under reduced pressure to remove the organic solvent. The crude mixture was then diluted with water and neutralized to pH 7 with 1 M HCl (aq). The product was extracted with EtOAc (3x), dried over NaSO, and concentrated to give 39.1 mg (70%) of a colorless solid product.

[0528] 6-Cyclopropyl-5-fluoro-N-hydroxypyridine-3-carboxamide

[0529] LCMS m / z[M+H] + C9H9FN2O2 required value: 196.06, actual value: 197.1

[0530] HPLC method 2 Rt(min) purity 3.5, 99% 1H NMR (400MHz, CD3OD) δ = 8.57 (s, 1H), 7.77 (d, J = 10.27Hz, 1H), 2.31-2.46 (m, 1H), 1.08-1.16 (m, 4H) ppm.

[0531] Example 38

[0532] Preparation of 5-fluoro-N-hydroxy-6-{[3-(pyridin-2-yl)oxetan-3-yl]oxy}pyridine-3-carboxamide (III-2) [ka]

[0533] Step 1: 3-(pyridin-2-yl)oxetan-3-ol

[0534] A solution of 2-bromopyridine (0.91 μL, 9.5 mmol) in 50 mL of THF was cooled to −78°C and stirred under nitrogen for 30 minutes. One equivalent of n-BuLi (4.5 mL of a 2.5 M solution in hexanes, 11.4 mmol) was added slowly over 5 minutes. After stirring the solution at −78°C for 2 hours, oxetan-3-one (560 μL, 9.5 mmol) was added, and the reaction solution was brought to room temperature and stirred overnight under nitrogen. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. The organic layer was evaporated to an oil on a rotary evaporator and dried onto silica. The product was purified by column chromatography using a 0-55% Hex:EtOAc gradient to afford 517 mg (35%) of the title compound as a colorless oil.

[0535] 1 H NMR(400MHz,chloroform-d)δppm8.52(br d,J=4.89Hz,1H)8.00(d,J=7.83Hz,1H)7.89(t,J=7.32Hz,1H)7.33(t,J=6.05Hz,1H)6.03(s,1H)5.11(d,J=7.09Hz,2H)4.74(d,J=6.85Hz,2H)

[0536] Step 2: 5-Bromo-3-fluoro-2-{[3-(pyridin-2-yl)oxetan-3-yl]oxy}pyridine

[0537] 3-(Pyridin-2-yl)oxetan-3-ol (200 mg, 1.32 mmol) was dissolved in THF (13 mL) under nitrogen and cooled in an ice bath. NaH (60% in mineral oil, 80 mg) was added portionwise, and the mixture was stirred for 30–45 minutes. 5-Bromo-2,3-difluoropyridine (385 mg, 1.98 mmol) was then added dropwise, and the mixture was heated to 60°C overnight. Upon completion, the reaction was cooled to room temperature and quenched with saturated ammonium chloride. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography using a 0–100% Hex:EtOAc gradient to yield 364 mg (85%) of the title compound as a colorless oil.

[0538] 1 H NMR(400MHz,chloroform-d)δppm8.71(d,J=5.09Hz,1H)7.69-7.73(m,1H)7.59-7.64(m,1H)7. 56(dd,J=9.05,1.96Hz,1H)7.19-7.31(m,2H)5.22(d,J=7.58Hz,2H)5.13(d,J=7.34Hz,2H)

[0539] Step 3: 5-fluoro-6-{[3-(pyridin-2-yl)oxetan-3-yl]oxy}pyridine-3-carboxylate methyl ester

[0540] A mixture of 5-bromo-3-fluoro-2-{[3-(pyridin-2-yl)oxetan-3-yl]oxy}pyridine (340 mg, 1.05 mmol), palladium(II) acetate (9.47 mg, 0.0418 mmol), and Xantphos (48.4 mg, 0.0837 mmol) in MeOH (1.3 mL) and TEA (10 mL) was sparged with CO for 5-10 minutes and then heated to 72 °C overnight. After the reaction was complete, the mixture was diluted with ethyl acetate and filtered through a pad of Celite. The filtrate was washed with water followed by brine. The combined organic layers were dried over MgSO, filtered, and concentrated. The product was purified by column chromatography using a Hex:EtOAc gradient 0-100% to afford 268 mg (85%) of the title compound as a white solid.

[0541] 1 H NMR (400 MHz, chloroform-d): δ ppm 8.71 (br d, J = 4.65 Hz, 1H), 8.32 (s, 1H), 7.93-8.00 (m, 1H), 7.61 (t, J = 7.83 Hz, 1H), 7.30 (d, J = 8.07 Hz, 1H), 7.18-7.24 (m, 1H), 5.23-5.28 (m, 2H), 5.17 (d, J = 7.34 Hz, 2H), 3.88 (s, 3H).

[0542] Step 4: 5-Fluoro-N-hydroxy-6-{[3-(pyridin-2-yl)oxetan-3-yl]oxy}pyridine-3-carboxamide

[0543] Methyl 5-fluoro-6-{[3-(pyridin-2-yl)oxetan-3-yl]oxy}pyridine-3-carboxylate (100 mg, 0.33 mmol) was dissolved in THF:MeOH (1:1, 3 mL) and cooled in an ice bath with stirring. Hydroxylamine (50% solution in water, 0.3 mL, 9.89 mmol) was added dropwise, followed by KOH (94.2 mg, 1.65 mmol). The ice bath was removed, and the reaction was stirred until the starting material was completely consumed. Upon completion, the reaction mixture was concentrated, diluted with water, and neutralized with 2N HCl (pH = 7). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to give 99 mg (99%) of the title compound as a white solid. 1H NMR (400MHz, methanol-d4) δppm8.60(br d,J=4.16Hz,1H)8.02(s,1H)7.90(br d,J=11.00Hz,1H)7.71-7.81(m,1H)7.45(d,J=7.83Hz,1H)7.27-7.35(m,1H)5.18-5.23(m,2H)5.13(d,J=7.34Hz,2H)

[0544] LC-MS: tR (min) 4.20 (20–100% ACN in 0.1% TFA, 6 min), m / z [M+H] + C14H12FN3O4 Required value: 305.27, Measured value: 306.0 HPLC tR (min) 4.04, 100% (20 to 100% ACN with 0.1% TFA, 10 min)

[0545] Example 39

[0546] Synthesis of 5-fluoro-N-hydroxy-6-((1-(pyrimidin-2-yl)cyclopropyl)amino)nicotinamide (I-46) [ka]

[0547] 1-(pyrimidin-2-yl)cyclopropan-1-amine

[0548] To a cooled (15°C) light suspension of pyrimidine-2-carbonitrile (5.00 g, 47.6 mmol) in dry THF (120 mL, 0.2 M) was added titanium isopropoxide (14.9 g, 42.3 mmol, 15.9 mL), followed by the dropwise addition of ethylmagnesium bromide (20.8 g, 97.5 mmol, 32.5 mL) within 15 min. Towards the end, the reaction was slightly exothermic, and the addition rate was reduced accordingly (internal temperature ca. 50°C). After complete addition, the mixture was stirred for 45 min until TLC showed complete conversion of the starting material. The mixture was quenched with water (20 mL) and stirred for 10 min, followed by the addition of 2N NaOH (75 mL) and stirring for 20 min. The fine suspension was filtered through a pad of Celite (slow filtration). The Celite pad was washed with ethyl acetate. Additional water was added to the filtrate. The layers were separated. The aqueous layer was extracted with ethyl acetate (2x). The combined organics were washed with brine, dried (Na2SO4), and concentrated to give 615 mg (10%) of 1-(pyrimidin-2-yl)cyclopropan-1-amine. 1 H NMR(400MHz,CDCl3)δ=8.62(d,J=4.65Hz,2H),7.05(t,J=4.89Hz,1H),2.05(s,2H),1.42-1.48(m,2H),1.20-1.24(m,2H)ppm

[0549] 5-Bromo-3-fluoro-N-(1-(pyrimidin-2-yl)cyclopropyl)pyridin-2-amine A mixture of 1-(pyrimidin-2-yl)cyclopropan-1-amine (202 mg, 1.49 mmol), 5-bromo-2,3-difluoropyridine (522 mg, 2.69 mmol), and DIPEA (7.47 mmol, 966 mg, 1.3 mL) in DMSO (6 mL) was stirred at 110 °C for 40 h. After completion of the reaction as indicated by TLC, the mixture was poured into water (60 mL) and extracted with ethyl acetate (3x). The combined organics were washed with water (3x), brine, dried (NaSO), and concentrated to give 551 mg of a brown oil. The crude material was purified by column chromatography (24 g SiO, 0-30% EA in hexanes). Fractions containing the desired product were combined and concentrated to give 132 mg (29%) of 5-bromo-3-fluoro-N-(1-(pyrimidin-2-yl)cyclopropyl)pyridin-2-amine as a yellow solid.

[0550] 1 H NMR(400MHz,CDCl3)δ=8.56(d,J=4.89Hz,2H),7.88(s,1H),7.28-7.37(m,1H),7.02(t,J=4.89Hz,1H),5.63(br s,1H),1.77-1.86(m,2H),1.38-1.45(m,2H)ppm.

[0551] 5-Fluoro-6-((1-(pyrimidin-2-yl)cyclopropyl)amino)nicotinic acid methyl ester

[0552] A mixture of 5-bromo-3-fluoro-N-[1-(pyrimidin-2-yl)cyclopropyl]pyridin-2-amine (112 mg, 0.362 mmol), palladium(II) acetate (3.25 mg, 0.0145 mmol), and Xantphos (16.8 mg, 0.029 mmol) in anhydrous triethylamine (3.62 mL, 0.1 M based on starting material) and anhydrous methanol (10.9 mmol, 1.07 mL, 30 equiv.) was flushed with CO (balloon) for 5 minutes with a needle in the solution. After 5 minutes, the needle was removed from the solution so that it floated above the mixture, and the mixture was stirred at 70 °C. After 16 hours, LCMS indicated complete conversion. The mixture was partitioned between water and ethyl acetate. The layers were separated, and the aqueous was extracted with ethyl acetate (2x). The combined organics were washed with water (2x), brine, dried (NaSO), and concentrated to give 113 mg of crude material, which was purified by column chromatography (4 g SiO, 0-60% EA in hexanes). Fractions containing the desired product were combined and concentrated to give 89.1 mg (85%) of methyl 5-fluoro-6-((1-(pyrimidin-2-yl)cyclopropyl)amino)nicotinate as an off-white solid. 1 H NMR(400MHz,CDCl3)δ=8.55(d,J=4.89Hz,2H),8.52(s,1H),7.68-7.76(m,1H),7.03(t ,J=4.89Hz,1H),5.99(brs,1H),3.85(s,3H),1.84-1.88(m,2H),1.42-1.51(m,2H)ppm.

[0553] To a cooled (0 °C) solution of methyl 5-fluoro-N-hydroxy-6-((1-(pyrimidin-2-yl)cyclopropyl)amino)nicotinamide (86 mg, 0.298 mmol) in methanol (2 mL) and THF (2 mL), NHOH (591 mg, 50% w / w, 8.95 mmol, 547 μL) was added dropwise, followed by KOH (124 mg, 2.21 mmol) in one portion. Five minutes after complete addition, the bath was removed and the mixture was stirred at room temperature. After 15 minutes, LCMS showed complete conversion. The reaction mixture was concentrated under reduced pressure to remove the organic solvent. The crude mixture was then diluted with water and neutralized to pH 7 by adding 1 M HCl (aq). The product was extracted with EtOAc (3x), dried over Na2SO4, and concentrated to give 52.1 mg (60%) of 5-fluoro-N-hydroxy-6-((1-(pyrimidin-2-yl)cyclopropyl)amino)nicotinamide as a pink solid.

[0554] 1 H NMR (400MHz, MeOD) δ=8.60(d,J=4.89Hz,2H),8.14(s,1H),7.58-7.69(m,1H),7.21(t,J=4.89Hz,1H),1.78-1.86(m,2H),1.40-1.47(m,2H)ppm. LC-MS: tR (min) 1.10, m / z [M+H] + C 13 H 12 Required FN5O2: 290.3, Actual: 291.1 (20-100% ACN with 0.1% TFA, 6 min)

[0555] HPLC tR (min) 1.88, 99% (20–100% ACN with 0.1% TFA, 10 min)

[0556] Example 40

[0557] Preparation of N-cyclopropyl-1-((3-fluoro-5-(hydroxycarbamoyl)pyridin-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-55)

[0558] [ka]

[0559] Step 1: 1-((5-bromo-3-fluoropyridin-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate methyl ester

[0560] To a solution of methyl 1H-pyrrolo[2,3-b]pyridine-5-carboxylate (170 mg, 0.97 mmol) in dry DMF (3 mL) was added 60% NaH (38 mg, 0.97 mmol) at 0 °C, and the mixture was then stirred at 0 °C for 20 min. A solution of 5-bromo-2-(bromomethyl)-3-fluoropyridine (200 mg, 0.74 mmol) in dry DMF (2 mL) was added dropwise. The resulting mixture was stirred at 0 °C for 20 min and then allowed to warm to room temperature overnight. The mixture was carefully quenched with water at 0 °C, diluted, and treated with EtOAc-water. The combined organic layers were dried over MgSO4, and the residual DMF was then removed by lyophilization. The crude was then subjected to ISCO purification using MeOH-DCM (0-10%) to give the product as a white solid (230 mg, 85%). LC-MS: m / z [M+H] + 364.0,366.0.

[0561] Step 2: 1-((5-bromo-3-fluoropyridin-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid

[0562] To a 20 mL vial containing methyl 1-((5-bromo-3-fluoropyridin-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (230 mg, 0.63 mmol), LiOH·HO (53 mg, 2.1 mmol) and THF-MeOH-HO (v / v / v 1:1:1, 6 mL) were added. The mixture was then stirred at 50 °C overnight. LC-MS showed complete conversion. The volatiles were evaporated. Water (ca. 10 mL) was then added, and the pH was adjusted to 6 by adding 1 N HCl (ca. 2 mL). The white solid was filtered and washed with water (ca. 20 mL) and EtOAc (ca. 10 mL). (200 mg of product was obtained as a colorless solid after drying overnight by lyophilization.) LC-MS: 350.1, 352.1.

[0563] Step 3: 1-((5-bromo-3-fluoropyridin-2-yl)methyl)-N-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

[0564] The crude acid from the previous step (110 mg, 0.31 mmol) was dissolved in DMF (4 mL), followed by the addition of cyclopropanamine (21 mg, 0.37 mmol), EDCI (72 mg, 0.37 mmol), HOBt (51 mg, 0.37 mmol), and DIPEA (102 mg, 0.78 mmol). The mixture was then stirred at room temperature for 3 h, then poured into water (15 mL), and the product was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product, which was purified by ISCO using 10% MeOH:DCM (0-60%) in DCM as the eluent to give the product as a white solid. LC-MS: 389.1, 391.1. 1 H NMR (400MHz, CDCl3) δ8.04(s,1H),7.38(m,1H),6.59(m,1H),4.99(br s,1H),2.27(m,1H),1.70(m,2H),0.96(m,2H),0.74(m,2H),0.45(m,2H).

[0565] The last two steps followed the same experimental procedure as described for 5-fluoro-N-hydroxy-6-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)nicotinamide, using 1-((5-bromo-3-fluoropyridin-2-yl)methyl)-N-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide instead.

[0566] Analysis of N-cyclopropyl-1((3-fluoro-5-(hydroxycarbamoyl)pyridin-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide:

[0567] 1 H NMR(400MHz,DMSO-d6)δ11.41(br s,1H),9.33(s,1H),8.64(s,1H),8.56(m,1H),8.46(m,1H),8.41(m,1H),8. 00(m,1H),7.67(m,1H),6.63(m,1H),5.75(s,2H),0.71(m,2H),0.58(m,2H).

[0568] LC-MS: m / z [M+H] + C18H16FN5O3 Required value: 369.3, Measured value: 370.1

[0569] HPLC tR (min) 4.73, 100% (10 to 100% ACN with 0.1% TFA, 10 min)

[0570] Example 41

[0571] Preparation of 5-fluoro-6-{[1-(3-fluoropyridin-2-yl)cyclopropyl]amino}-N-hydroxypyridine-3-carboxamide (I-45) [ka]

[0572] Step 1: 5-Bromo-3-fluoro-N-[1-(3-fluoropyridin-2-yl)cyclopropyl]pyridin-2-amine

[0573] N-Ethyldiisopropylamine (0.42 mL, 2.46) was added to a mixture of 5-bromo-2,3-difluoropyridine (191 mg, 0.986 mmol) and 1-(3-fluoropyridin-2-yl)cyclopropan-1-amine (75 mg, 0.493 mmol) in anhydrous DMSO (2.5 mL) under nitrogen. The reaction mixture was stirred at 110° C. overnight. After completion of the reaction, the mixture was cooled, diluted with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography using a Hex:EtOAc gradient from 0 to 100% to afford 71 mg (44%) of the title compound as a yellow solid.

[0574] 1 H NMR (400 MHz, chloroform-d) δ ppm 8.30 (br d, J = 4.65 Hz, 1H) 7.92 (s, 1H) 7.21-7.32 (m, 3H) 7.12 (dt, J = 8.31, 4.16 Hz, 1H) 5.66 (br s, 1H) 1.68-1.74 (m, 2H) 1.27-1.33 (m, 2H)

[0575] Step 2: methyl 5-fluoro-6-{[1-(3-fluoropyridin-2-yl)cyclopropyl]amino}pyridine-3-carboxylate

[0576] A mixture of 5-bromo-3-fluoro-N-[1-(3-fluoropyridin-2-yl)cyclopropyl]pyridin-2-amine (71 mg, 0.218 mmol), palladium(II) acetate (1.97 mg, 0.0087 mmol), and Xantphos (10.1 mg, 0.0174 mmol) in MeOH (0.5 mL) and TEA (2 mL) was sparged with CO for 5-10 minutes and then heated to 72 °C overnight. After the reaction was complete, the mixture was diluted with ethyl acetate and filtered through a pad of Celite. The filtrate was washed with water followed by brine. The combined organic layers were dried over MgSO, filtered, and concentrated. The product was purified by column chromatography using a Hex:EtOAc gradient 0-100% to afford 49.2 mg (74%) of the title compound as a white solid.

[0577] 1 H NMR (400 MHz, chloroform-d): δ ppm 8.55 (s, 1H), 8.28-8.33 (m, 1H), 7.68 (dd, J = 11.49, 0.73 Hz, 1H), 7.28 (br d, J = 2.45 Hz, 1H), 7.12 (dt, J = 8.25, 4.07 Hz, 1H), 6.06 (br s, 1H), 3.84 (s, 3H), 1.71-1.82 (m, 2H), 1.24-1.40 (m, 3H).

[0578] Step 3: 5-Fluoro-6-{[1-(3-fluoropyridin-2-yl)cyclopropyl]amino}-N-hydroxypyridine-3-carboxamide

[0579] Methyl 5-fluoro-6-{[1-(3-fluoropyridin-2-yl)cyclopropyl]amino}pyridine-3-carboxylate (48 mg, 0.157 mmol) was dissolved in THF:MeOH (1:1, 1 mL) and cooled in an ice bath with stirring. Hydroxylamine (50% solution in water, 0.15 mL, 4.72 mmol) was added dropwise, followed by KOH (45 mg, 0.786 mmol). The ice bath was removed, and the reaction was stirred until the starting material was completely consumed. Upon completion, the reaction mixture was concentrated, diluted with water, and neutralized with 2N HCl (pH = 7). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to give 48 mg (99%) of the title compound as a white solid.

[0580] 1 H NMR (400 MHz, methanol-d4) δ ppm 8.21-8.27 (m, 1H) 8.14 (s, 1H) 7.58 (br d, J = 12.96 Hz, 1H) 7.34-7.44 (m, 1H) 7.17-7.24 (m, 1H) 1.69-1.75 (m, 2H) 1.27-1.32 (m, 3H)

[0581] LC-MS: tR (min) 4.20 (20–100% ACN in 0.1% TFA, 6 min), m / z [M+H] + C14H12F2N4O2 Required: 306.27; Found: 307.0

[0582] HPLC tR (min) 3.29, 98.3% (0.1% TFA, 20–100% ACN, 10 min)

[0583] In the following examples, compound I-37 was synthesized following the same experimental procedure as described in Example 12, using the aldehyde starting material listed for Step 1 and the organometallic reagent precursor listed for Step 2. [Table 2]

[0584] Examples 43 to 61

[0585] In the following examples, compounds were synthesized following the same experimental procedure as described in Example 7 using the listed amine and methyl 5-fluoro-6-bromonicotinate starting material in Step 1. [Table 3-1] [Table 3-2] [Table 3-3]

[0586] Examples 62 to 74

[0587] In the following examples (62-74), the compounds were synthesized following the same experimental procedure as described in Example 30, using the listed amine and 5-bromo-2-(bromomethyl)-3-fluoropyridine as the starting material in Step 4. [Table 4-1] [Table 4-2]

[0588] Examples 75-80: Compound Characterization [Table 5]

[0589] Example 81

[0590] 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 is summarized in Table 2. 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 6-1] [Table 6-2] [Table 6-3]

[0591] Embodiment 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, [ka] , During the ceremony, n is 0 or 1, X is O, NR 4 , or CR 4 R 4’ and Y is a bond, CR 2 R 3 or S(O)2, R 1 is selected from the group consisting of H, amido, carbocyclyl, heterocyclyl, aryl, and heteroaryl; R 2 and R 3 is independently selected from the group consisting of H, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH)-carbocyclyl, -(CH)-heterocyclyl, -(CH)-aryl, and -(CH)-heteroaryl; or R 1 and R 2 together with the carbon atom to which they are attached form a carbocyclyl or heterocyclyl, or R 2 and R 3 together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl, R 4 and R 4’ are each independently selected from the group consisting of H, alkyl, -CO2-alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH2)-carbocyclyl, -(CH2)-heterocyclyl, -(CH2)-aryl, and -(CH2)-heteroaryl; or R 4 and R 4’ together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl, A compound, or a pharmaceutically acceptable salt thereof, wherein each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, oxo, hydroxy, alkoxy, -OCH3, -CO2CH3, -C(O)NH(OH), -CH3, morpholine, and -C(O)N-cyclopropyl. 2. The compound of embodiment 1, wherein n is 1. 3. The compound of embodiment 1, wherein n is 0. 4.X is NR 4 or CR 4 R 4’ The compound of any one of embodiments 1 to 3, wherein 5. Y is CR 2 R3 The compound of any one of embodiments 1 to 4, wherein 6.X is NR 4 and Y is S(O)2. 7.R 1 The compound of any one of embodiments 1-6, wherein is a heteroaryl selected from the group consisting of pyrimidinyl, pyridinyl, pyridazine, and pyrazine. 8.R 1 The compound of any one of embodiments 1-7, wherein is pyridinyl. 9.R 1 The compound of any one of embodiments 1-6, wherein is phenyl. 10.X is CR 4 R 4’ Y is a bond and R 1 The compound of any one of embodiments 1-5, wherein is H. 11.R 1 and R 2 together with the carbon atoms to which they are attached, C 3~12 The compound of any one of embodiments 1 to 6, which forms a carbocyclyl. 12.R 2 and R 3 are independent, H, F, C 1~6 Alkyl, C 3~6 Cycloalkyl, -(CH2)-C 3~6 The compound of any one of embodiments 1-10, wherein the compound is selected from the group consisting of cycloalkyl, 4- to 6-membered heterocyclyl, and -(CH2)-(4- to 6-membered heterocyclyl). 13.R 2 and R 3 together with the carbon atoms to which they are attached, C 3~6 The compound of any one of embodiments 1 to 10, which forms a cycloalkyl. 14.R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl. 15.R2 and R 3 taken together with the carbon atom to which they are attached form a 4-6 membered heterocyclyl. 16.R 2 is H and R 3 But C 3~6 The compound of any one of embodiments 1-10, which is cycloalkyl. 17.R 2 is H and R 3 The compound of any one of embodiments 1-10, wherein is cyclopropyl. 18.R 2 and R 3 But C 1~6 The compound of any one of embodiments 1-10, wherein is alkyl. 19.R 2 and R 3 The compound of any one of embodiments 1-10, wherein is methyl. 20.R 1 But C 3~6 is cycloalkyl or aryl, and R 2 is H and R 3 But C 3~6 The compound of any one of embodiments 1-10, which is cycloalkyl or aryl. 21.R 4 The compound of any one of embodiments 1-20, wherein is selected from the group consisting of H, alkyl, carbocyclyl, heterocyclyl, -(CH2)-carbocyclyl, and -(CH2)-heterocyclyl. 22.R 4 The compound of any one of embodiments 1-21, wherein is H. 23.R 4 The compound of any one of embodiments 1-21, wherein is -(CH2)-heterocyclyl. 24.R 4 The compound of any one of embodiments 1-21, wherein is —(CH 2 )-oxetane. 25.R 4 The compound of any one of embodiments 1-21, wherein is alkyl. 26.R 4 The compound of any one of embodiments 1-21, wherein is methyl. 27.R 4 and R 4’ and R are each H. 28.R 4 and R 4’ The compound of any one of embodiments 1-21, wherein each is alkyl. 29.R 4 and R 4’ and R are each methyl. 30.R 4 and R 4’ together with the carbon atoms to which they are attached, C 3~6 The compound of any one of embodiments 1 to 21, which forms a cycloalkyl. 31.R 4 and R 4’ together with the carbon atom to which they are attached form cyclopropyl. 32. The compound is a compound of formula (Ia), [ka] , During the ceremony, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 independently, N and CR 5 is selected from R 5 are independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —COH, —CO-alkyl, —O-alkyl, —O-haloalkyl, —O-aryl, —O-heteroaryl, —SO-alkyl, and —CN. 33.X is NR 4or CR 4 R 4’ 33. The compound of embodiment 32, wherein 34.X is NR 4 and Y is CR 2 R 3 34. The compound of embodiment 32 or 33, wherein 35.X is NR 4 and Y is S(O)2. 36.Z 1 , Z 2 , Z 3 , Z 4 and Z 5 But, CR 5 33. The compound of embodiment 32, wherein 37.Z 1 is N and Z 2 , Z 3 , Z 4 and Z 5 But, CR 5 33. The compound of embodiment 32, wherein 38.Z 2 is N and Z 1 , Z 3 , Z 4 and Z 5 But, CR 5 33. The compound of embodiment 32, wherein 39.Z 3 is N and Z 1 , Z 2 , Z 4 and Z 5 But, CR 5 33. The compound of embodiment 32, wherein 40. The compound of any one of embodiments 32-39, wherein n is 1. 41. The compound according to any one of embodiments 32 to 39, wherein n is 0. 42.R 2 and R 3 are independent, H, F, C 1~6 Alkyl, C 3~6 Cycloalkyl, -(CH2)-C 3~6The compound of any one of embodiments 32-41, wherein the aryl group is selected from the group consisting of cycloalkyl, 4- to 6-membered heterocyclyl, and —(CH 2 )—(4- to 6-membered heterocyclyl). 43.R 2 and R 3 together with the carbon atoms to which they are attached, C 3~6 The compound of any one of embodiments 32-41, which forms a cycloalkyl. 44.R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl. 45.R 2 and R 3 taken together with the carbon atom to which they are attached form a 4-6 membered heterocyclyl. 46.R 2 is H and R 3 But C 3~6 The compound of any one of embodiments 32-41, which is cycloalkyl. 47.R 2 is H and R 3 The compound of any one of embodiments 32-41, wherein is cyclopropyl. 48.R 2 and R 3 But C 1~6 The compound of any one of embodiments 32-41, wherein is alkyl. 49.R 2 and R 3 The compound of any one of embodiments 32-41, wherein is methyl. 50.R 4 The compound of any one of embodiments 32-49, wherein is selected from the group consisting of H, alkyl, carbocyclyl, heterocyclyl, -(CH2)-carbocyclyl, and -(CH2)-heterocyclyl. 51.R 4 The compound of any one of embodiments 32-50, wherein is H. 52.R 4The compound of any one of embodiments 32-50, wherein is -(CH2)-heterocyclyl. 53.R 4 The compound of any one of embodiments 32-50, wherein is —(CH 2 )-oxetane. 54.R 4 The compound of any one of embodiments 32-50, wherein is alkyl. 55.R 4 The compound of any one of embodiments 32-50, wherein is methyl. 56.R 5 The compound of any one of embodiments 32-55, wherein is independently selected from H and halogen. 57.R 5 The compound of any one of embodiments 32-55, wherein is independently selected from H and fluoro. 58. The compound is a compound of formula (Ib), [ka] , During the ceremony, R 6 , R 7 R 8 , R 9 , and R 10 are independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -COH, -CO-alkyl, -O-alkyl, -O-haloalkyl, -O-aryl, -O-heteroaryl, -SO-alkyl, and -CN. 59.X is NR 4 or CR 4 R 4’ 59. The compound of embodiment 58, wherein 60.X is NR 4 60. The compound of embodiment 58 or 59, wherein 61.Y is CR 2 R 3 The compound of any one of embodiments 58-60, wherein 62. The compound according to any one of embodiments 58-60, wherein Y is S(O)2. 63.R 6 , R 7 R 8 , R 9 , and R 10 The compound of any one of embodiments 58-62, wherein is independently selected from the group consisting of H and halogen. 64.R 6 and R 10 is a halogen, and R 7 R 8 , and R 9 The compound of any one of embodiments 58-62, wherein is H. 65.R 6 and R 10 is fluoro and R 7 R 8 , and R 9 The compound of any one of embodiments 58-62, wherein is H. 66. The compound of formula (I) is a compound of formula (Ic), [ka] , During the ceremony, R 6 , R 7 R 8 , and R 9 are independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -COH, -CO-alkyl, -O-alkyl, -O-haloalkyl, -O-aryl, -O-heteroaryl, -SO-alkyl, and -CN. 67.X is NR 4 or CR 4 R 4’ 67. The compound of embodiment 66, wherein 68.X is NR 4 68. The compound of embodiment 66 or 67, wherein 69.Y is CR 2 R 3 69. The compound of any one of embodiments 66-68, wherein 70. The compound according to any one of embodiments 66-68, wherein Y is S(O)2. 71. The compound is [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof. 72.n is 0 or 1, X is NR 4 or CR 4 R 4’ and Y is CR 2 R 3 or S(O)2, R 1 is selected from the group consisting of carbocyclyl, heterocyclyl, aryl, and heteroaryl; R 2 and R 3 are independently selected from the group consisting of H, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH)-carbocyclyl, -(CH)-heterocyclyl, -(CH)-aryl, and -(CH)-heteroaryl; or R 2 and R 3 together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl; R 4 and R 4’ are independently selected from the group consisting of H, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH)-carbocyclyl, -(CH)-heterocyclyl, -(CH)-aryl, and -(CH)-heteroaryl; or R 4 and R 4’ together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl, The compound of embodiment 1, wherein each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, alkoxy, —OCH3, —CO2CH3, and —CH3. 73. The compound according to embodiment 72, wherein n is 1. 74. The compound according to embodiment 72, wherein n is 0. 75.X is NR 4 The compound of any one of embodiments 72-74, wherein 76.Y is CR 4 R ’ The compound of any one of embodiments 72-75, wherein 77.R 1 The compound of any one of embodiments 72-76, wherein is heteroaryl selected from the group consisting of pyrimidinyl, pyridinyl, pyridazine, and pyrazine. 78.R 1 The compound of any one of embodiments 72-77, wherein is pyridinyl. 79.R 1 The compound of any one of embodiments 72-76, wherein is phenyl. 80.R 2 and R 3 are independent, H, F, C1~6 Alkyl, C 3~6 Cycloalkyl, -(CH2)-C 3~6 The compound of any one of embodiments 72-79, wherein the compound is selected from the group consisting of cycloalkyl, 4- to 6-membered heterocyclyl, and -(CH2)-(4- to 6-membered heterocyclyl). 81.R 2 and R 3 together with the carbon atoms to which they are attached, C 3~6 The compound of any one of embodiments 72-79, which forms a cycloalkyl. 82.R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl. 83.R 2 and R 3 taken together with the carbon atom to which they are attached form a 4-6 membered heterocyclyl. 84.R 2 is H and R 3 But C 3~6 The compound of any one of embodiments 72-80, which is cycloalkyl. 85.R 2 is H and R 3 The compound of any one of embodiments 72-80, wherein is cyclopropyl. 86.R 2 and R 3 But C 1~6 The compound of any one of embodiments 72-80, wherein is alkyl. 87.R 2 and R 3 The compound of any one of embodiments 72-80, wherein is methyl. 88.R 4 The compound of any one of embodiments 72-87, wherein is selected from the group consisting of H, alkyl, carbocyclyl, heterocyclyl, -(CH2)-carbocyclyl, and -(CH2)-heterocyclyl. 89.R 4The compound of any one of embodiments 72-88, wherein is H. 90.R 4 The compound of any one of embodiments 72-88, wherein is -(CH2)-heterocyclyl. 91.R 4 The compound of any one of embodiments 72-88, wherein is —(CH 2 )-oxetane. 92.R 4 The compound of any one of embodiments 72-88, wherein is alkyl. 93.R 4 The compound of any one of embodiments 72-88, wherein is methyl. 94. The compound is a compound of formula (IIa), [ka] , During the ceremony, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 independently, N and CR 5 is selected from R 5 are independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —COH, —CO-alkyl, —O-alkyl, —O-haloalkyl, —O-aryl, —O-heteroaryl, —SO-alkyl, and —CN. 95.Z 1 , Z 2 , Z 3 , Z 4 and Z 5 But, CR 5 95. The compound of embodiment 94, wherein 96.Z 1 is N and Z 2 , Z 3 , Z 4 and Z 5 But, CR 5 95. The compound of embodiment 94, wherein 97.Z 2 is N and Z 1 , Z 3 , Z 4 and Z 5 But, CR 5 95. The compound of embodiment 94, wherein 98.Z 3 is N and Z 1 , Z 2 , Z 4 and Z 5 But, CR 5 95. The compound of embodiment 94, wherein 99. The compound of any one of embodiments 94-98, wherein n is 1. 100. The compound of any one of embodiments 94-98, wherein n is 0. 101.R 2 and R 3 are independent, H, F, C 1~6 Alkyl, C 3~6 Cycloalkyl, -(CH2)-C 3~6 The compound according to any one of embodiments 94-100, wherein the compound is selected from the group consisting of cycloalkyl, 4- to 6-membered heterocyclyl, and -(CH2)-(4- to 6-membered heterocyclyl). 102.R 2 and R 3 together with the carbon atoms to which they are attached, C 3~6 The compound of any one of embodiments 94-100, which forms a cycloalkyl. 103.R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl. 104.R 2 and R 3 taken together with the carbon atom to which they are attached form a 4-6 membered heterocyclyl. 105.R 2 is H and R 3 But C 3~6The compound of any one of embodiments 94-100, which is cycloalkyl. 106.R 2 is H and R 3 The compound of any one of embodiments 94-100, wherein is cyclopropyl. 107.R 2 and R 3 But C 1~6 The compound of any one of embodiments 94-100, wherein is alkyl. 108.R 2 and R 3 The compound of any one of embodiments 94-100, wherein is methyl. 109.R 4 The compound of any one of embodiments 94-108, wherein is selected from the group consisting of H, alkyl, carbocyclyl, heterocyclyl, -(CH2)-carbocyclyl, and -(CH2)-heterocyclyl. 110.R 4 The compound of any one of embodiments 94-109, wherein is H. 111.R 4 The compound of any one of embodiments 94-109, wherein is -(CH2)-heterocyclyl. 112.R 4 The compound of any one of embodiments 94-109, wherein is —(CH 2 )-oxetane. 113.R 4 The compound of any one of embodiments 94-109, wherein is alkyl. 114.R 4 The compound of any one of embodiments 94-109, wherein is methyl. 115.R 5 The compound of any one of embodiments 94-114, wherein is independently selected from H and halogen. 116.R 5 The compound of any one of embodiments 94-114, wherein is independently selected from H and fluoro. 117. The compound is a compound of formula (IIb), [ka] , During the ceremony, R 6 , R 7 R 8 , R 9 , and R 10 are independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -COH, -CO-alkyl, -O-alkyl, -O-haloalkyl, -O-aryl, -O-heteroaryl, -SO-alkyl, and -CN. 118.R 6 , R 7 R 8 , R 9 , and R 10 is independently selected from the group consisting of H and halogen. 119.R 6 and R 10 is a halogen, and R 7 R 8 , R 9 , and R 10 is H. 120.R 6 and R 10 is fluoro and R 7 R 8 , and R 9 is H. 121. The compound is a compound of formula (IIc), [ka] , During the ceremony, R 6 , R 7 R 8 , and R 9are independently selected from the group consisting of H, halogen, alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -COH, -CO-alkyl, -O-alkyl, -O-haloalkyl, -O-aryl, -O-heteroaryl, -SO-alkyl, and -CN. 122. The compound is [ka] [ka] or a pharmaceutically acceptable salt thereof. 123. The compound is a compound of formula (III), or a pharmaceutically acceptable salt thereof: [ka] , During the ceremony, n is 0 or 1, Y is a bond or CR 2 R 3 and R 1 is selected from the group consisting of H, carbocyclyl, heterocyclyl, aryl, and heteroaryl; R 2 and R 3 are independently selected from the group consisting of H, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH)-carbocyclyl, -(CH)-heterocyclyl, -(CH)-aryl, and -(CH)-heteroaryl; or R 1 and R 2 when present, together with the carbon atom to which they are attached form a carbocyclyl or heterocyclyl, or R 2 and R 3together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl, The compound of embodiment 1, wherein each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, alkoxy, -OCH3, -CO2CH3, and -CH3, or a pharmaceutically acceptable salt thereof. 124. The compound according to embodiment 123, wherein Y is a bond. 125.Y is CR 2 CR 3 The compound of embodiment 123, wherein 126. The compound according to any one of embodiments 123-125, wherein n is 1. 127. The compound according to any one of embodiments 123-125, wherein n is 0. 128.R 1 The compound of any one of embodiments 123-127, wherein is selected from the group consisting of carbocyclyl, heterocyclyl, aryl, and heteroaryl. 129.R 1 The compound of any one of embodiments 123-128, wherein is heteroaryl selected from the group consisting of pyrimidinyl, pyridinyl, pyridazine, and pyrazine. 130.R 1 The compound according to any one of embodiments 123-128, wherein is pyridinyl. 131.R 1 The compound according to any one of embodiments 123-128, wherein is phenyl. 132. Y is a bond and R 1 The compound of any one of embodiments 123-127, wherein is H. 133.R 1 and R 2 together with the carbon atoms to which they are attached, C 3~12 The compound according to any one of embodiments 123-124 or 126-127, which forms a carbocyclyl. 134.R2 and R 3 are independent, H, F, C 1~6 Alkyl, C 3~6 Cycloalkyl, -(CH2)-C 3~6 The compound according to any one of embodiments 123-132, wherein the compound is selected from the group consisting of cycloalkyl, 4- to 6-membered heterocyclyl, and -(CH2)-(4- to 6-membered heterocyclyl). 135.R 2 and R 3 together with the carbon atoms to which they are attached, C 3~6 The compound of any one of embodiments 123-132, which forms a cycloalkyl. 136.R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl. 137.R 2 and R 3 together with the carbon atoms to which they are attached form a 4-6 membered heterocyclyl. 138.R 2 is H and R 3 But C 3~6 The compound of any one of embodiments 123-132, which is cycloalkyl. 139.R 2 is H and R 3 The compound according to any one of embodiments 123-132, wherein is cyclopropyl. 140.R 2 and R 3 But C 1~6 The compound of any one of embodiments 123-132, wherein is alkyl. 141.R 2 and R 3 The compound of any one of embodiments 123-132, wherein is methyl. 142. The compound is [ka] or a pharmaceutically acceptable salt thereof. 143. A compound of formula (IV) or a pharmaceutically acceptable salt thereof, [ka] , During the ceremony, n is 0 or 1, p is 0, 1, 2, 3, or 4; each q is independently 0, 1, or 2; X is O, S(O)2, NR 12 , or CHR 12 and R 11 are each independently H, F, alkyl, or oxo; Two adjacent R 11 together with the carbon atoms to which they are attached form an aryl, heteroaryl, or heterocyclyl ring; or Two non-adjacent R 11 together with the atoms to which they are attached form a carbocyclyl or heterocyclyl ring; R 12 is selected from the group consisting of alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH)-carbocyclyl, -(CH)-heterocyclyl, -(CH)-aryl, and -(CH)-heteroaryl; or R 11 and R 12 together with the carbon atom and / or nitrogen atom to which they are attached form an aryl ring, heteroaryl ring, or heterocyclyl ring; A compound, or a pharmaceutically acceptable salt thereof, wherein each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, alkoxy, -OCH3, -CO2CH3, and -CH3. 144. The compound according to embodiment 143, wherein n is 1. 145. The compound according to embodiment 143, wherein n is 0. 146. The compound according to any one of embodiments 143-145, wherein q is 1. 147. The compound according to any one of embodiments 143-145, wherein q is 0. 148. The compound according to any one of embodiments 143-146, wherein X is O. 149. The compound according to any one of embodiments 143-146, wherein X is S(O)2. 150.X is NR 12 The compound of any one of embodiments 143-146, wherein 151.X is CHR 12 The compound of any of embodiments 143-146, wherein 152.R 12 The compound of embodiment 150 or 151, wherein is H, Me, or Ph. 153. The compound according to any one of embodiments 143-152, wherein p is 4. 154. The compound according to any one of embodiments 143-152, wherein p is 3. 155. The compound according to any one of embodiments 143-152, wherein p is 2. 156. The compound according to any one of embodiments 143-152, wherein p is 1. 157. The compound according to any one of embodiments 143-152, wherein p is 0. 158.R 11 The compound according to any one of embodiments 143-156, wherein is oxo. 159. Two adjacent Rs 11 and together with the carbon atoms to which they are attached form an aryl ring. 160. The compound according to embodiment 159, wherein the aryl ring is a phenyl ring. 161. Two adjacent R 11together with the carbon atoms to which they are attached form a heteroaryl or heterocyclyl ring. 162. The compound according to embodiment 161, wherein the heteroaryl ring is a pyridinyl ring. 163. A heterocyclyl ring is [ka] 162. The compound of embodiment 161, wherein 164.X is CHR 12 When R 11 and R 12 and R 1 and R 2 together with the carbon atoms to which they are attached form an aryl ring. 165. The compound according to embodiment 164, wherein the aryl ring is a phenyl ring. 166.X is NR 12 When R 11 and R 12 taken together with the carbon and nitrogen atoms to which they are attached form a heteroaryl or heterocyclyl ring. 167 Compounds according to embodiment 166, wherein the heteroaryl ring is a pyridinyl ring. 168.When p is 4, two adjacent R 11 together with the carbon atoms to which they are attached form an aryl ring, and two adjacent R 11 together with the carbon atoms to which they are attached form a heterocyclyl ring. 169. The compound according to embodiment 168, wherein the aryl ring is a phenyl ring. 170. A heterocyclyl ring is [ka] 169. The compound of embodiment 168 or 169, wherein 171. A compound of formula (IV): [ka] or a pharmaceutically acceptable salt thereof. 172. A composition comprising a compound according to any one of embodiments 1-171 and a pharmaceutically acceptable excipient. 173. A method for improving sarcomere quality or preventing sarcomere damage in cardiomyocytes, comprising contacting cardiomyocytes with an effective amount of a compound according to any one of embodiments 1-171 or a composition according to embodiment 172, wherein said method induces an improvement in sarcomere quality. 174. The method of embodiment 173, wherein the improvement in sarcomere quality is measured using an artificial intelligence algorithm. 175. The method of embodiment 174, wherein the algorithm is trained to construct a neuron net model that separates classes of cells based on cardiomyocytes with sarcomere damage versus cardiomyocytes with limited sarcomere damage. 176. A method for increasing tubulin acetylation in cardiomyocytes using an effective amount of a compound according to any one of embodiments 1 to 171, or a composition according to embodiment 172, wherein the method increases the level of tubulin acetylation in cardiomyocytes. 177. The method of any one of embodiments 173 to 176, wherein the cardiomyocytes are in vivo cardiomyocytes. 178. A method for treating cardiac disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of embodiments 1-171 or the composition of embodiment 172. 179. The method of embodiment 178, wherein the cardiac disease is dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), left ventricular non-compaction (LVNC), arrhythmogenic right ventricular cardiomyopathy (ARVC), or arrhythmogenic right ventricular dysplasia (ARVD). 180. The method of embodiment 178, wherein the cardiac disease is myocardial infarction. 181. The method of any one of embodiments 178 to 180, wherein the method causes at least one of the following effects in cardiomyocytes: increased tubulin acetylation, increased contractility, reduced sarcomere damage, and increased autophagy. For example, the present invention provides the following items: (Item 1) A compound of formula (I), or a pharmaceutically acceptable salt thereof, [ka] 、 During the ceremony, n is 0 or 1, X is O, NR 4 , or CR 4 R 4’ and Y is a bond, CR 2 R 3 or S(O) 2 and R 1 is selected from the group consisting of H, amido, carbocyclyl, heterocyclyl, aryl, and heteroaryl; R 2 and R 3 are independently H, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH 2 )-carbocyclyl, -(CH 2 )-heterocyclyl, -(CH 2 )-aryl, and -(CH 2 )-heteroaryl; or R 1 and R 2 together with the carbon atom to which they are attached form a carbocyclyl or heterocyclyl, or R2 and R 3 together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl, R 4 and R 4’ are each independently H, alkyl, or -CO 2 -Alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH 2 )-carbocyclyl, -(CH 2 )-heterocyclyl, -(CH 2 )-aryl, and -(CH 2 )-heteroaryl; or R 4 and R 4’ together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl, Each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently represents halogen, haloalkyl, oxo, hydroxy, alkoxy, -OCH 3 , -CO 2 CH 3 , -C(O)NH(OH), -CH 3 , morpholine, and -C(O)N-cyclopropyl, or a pharmaceutically acceptable salt thereof. (Item 2) Item 1, wherein n is 1. (Item 3) Item 2. The compound according to item 1, wherein n is 0. (Item 4) X is NR 4 or CR 4 R 4’ 4. The compound according to any one of items 1 to 3, wherein (Item 5) Y is CR 2 R 3 5. The compound according to any one of items 1 to 4, wherein (Item 6) R 1 is a heteroaryl selected from the group consisting of pyrimidinyl, pyridinyl, pyridazine, and pyrazine. (Item 7) R 1 is phenyl. (Item 8) R 2 and R 3 are independent, H, F, C 1~6 Alkyl, C 3~6 Cycloalkyl, -(CH 2 )-C 3~6 Cycloalkyl, 4- to 6-membered heterocyclyl, and -(CH 2 8. The compound according to any one of items 1 to 7, wherein the compound is selected from the group consisting of )-(4- to 6-membered heterocyclyl). (Item 9) R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl. (Item 10) R 4 is H, alkyl, carbocyclyl, heterocyclyl, -(CH 2 )-carbocyclyl, and -(CH 2 10. The compound according to any one of items 1 to 9, wherein the compound is selected from the group consisting of )-heterocyclyl. (Item 11) R 4 and R 4’ and R are each H. (Item 12) The compound is

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Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, 【Chemical 1】 、 During the ceremony, n is 0 or 1; X is NR ４ , or CR ４ R ４’ and Y is a bond, CR ２ R ３ or S(O) ２ and R １ is selected from the group consisting of H, amide, heterocyclyl, and heteroaryl; R ２ and R ３ are independently H, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH ２ )-carbocyclyl, -(CH ２ )-heterocyclyl, -(CH ２ )-aryl, and —(CH ２ )-heteroaryl, with the proviso that R ２ and R ３ is not H, or R １ and R ２ together with the carbon atom to which they are attached form a carbocyclyl or heterocyclyl, or R ２ and R ３ together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl, R ４ is H, alkyl, carbocyclyl, heterocyclyl, -(CH ２ )-carbocyclyl, and —(CH ２ )-heterocyclyl, and R ４’ is H, alkyl, -CO ２ -Alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH ２ )-carbocyclyl, -(CH ２ )-heterocyclyl, -(CH ２ )-aryl, and —(CH ２ )-heteroaryl; or R ４ and R ４’ together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl, Each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from halogen, haloalkyl, oxo, hydroxy, alkoxy, —OCH ３ , -CO ２ CH ３ , -C(O)NH(OH), -CH ３ , morpholine, and —C(O)N-cyclopropyl, or a pharmaceutically acceptable salt thereof.

2. 2. The compound of claim 1, wherein n is 1.

3. The compound of claim 1 , wherein n is 0.

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

5. Y is CR ２ R ３ The compound according to any one of claims 1 to 4,

6. R １ The compound of any one of claims 1 to 5, wherein is heteroaryl, and said heteroaryl is selected from the group consisting of pyrimidinyl, pyridinyl, pyridazine, and pyrazine.

7. The compound of claim 6 , wherein the heteroaryl is pyridinyl.

8. R ２ and R ３ are independent, H, F, C １～６ Alkyl, C ３～６ Cycloalkyl, -(CH ２ )-C ３～６ Cycloalkyl, 4- to 6-membered heterocyclyl, and —(CH ２ 8. The compound of claim 1, wherein the aryl group is selected from the group consisting of aryl, ...

9. R ２ and R ３ The compound of any one of claims 1 to 7, wherein together with the carbon atom to which they are attached form a cyclopropyl.

10. R ４ is H, alkyl, carbocyclyl, heterocyclyl, -(CH ２ )-carbocyclyl, and —(CH ２ 10. The compound of claim 1, wherein the heterocyclyl is selected from the group consisting of:

11. R ４ and R ４’ The compound of any one of claims 1 to 10, wherein each is H.

12. structure: 【Chemistry 104】 【Chemistry 105】 【Chemistry 106】 2. The compound of claim 1, having the formula: or a pharmaceutically acceptable salt thereof.

13. structure: 【Chemistry 2-1】 【Chemistry 2-2】 【Chemistry 2-3】 【Chemistry 2-4】 【Chemistry 2-5】 【Chemistry 2-6】 or a pharmaceutically acceptable salt thereof.

14. The compound has the structure: 【Chemistry 107】 【Chemistry 108】 【Chemistry 109】 14. The compound of claim 13, having the formula: or a pharmaceutically acceptable salt thereof.

15. Each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from halogen, oxo, hydroxy, alkoxy, —OCH ３ , -CO ２ CH ３ , and -CH ３ 10. The compound of claim 1, optionally substituted with one or more substituents selected from the group consisting of:

16. A compound of formula (I), or a pharmaceutically acceptable salt thereof, 【Chemical 1】 During the ceremony, n is 0, X is O, Y is CR ２ R ３ and R １ is selected from the group consisting of carbocyclyl, heterocyclyl, aryl, and heteroaryl; R ２ and R ３ are independently H, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -(CH ２ )-carbocyclyl, -(CH ２ )-heterocyclyl, -(CH ２ )-aryl, and —(CH ２ )-heteroaryl; or R ２ and R ３ together with the carbon atoms to which they are attached form a carbocyclyl or heterocyclyl, and Each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from halogen, oxo, hydroxy, alkoxy, —OCH ３ , -CO ２ CH ３ , and -CH ３ or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents selected from the group consisting of:

17. The compound is 【Chemistry 6】 or a pharmaceutically acceptable salt thereof.

18. A composition comprising a compound according to any one of claims 1 to 17 and a pharmaceutically acceptable excipient.

19. 20. The composition of claim 18 for use in improving sarcomere quality or preventing sarcomere damage in cardiac myocytes of a subject.

20. The composition of claim 18 for use in increasing tubulin acetylation in a subject's cardiomyocytes.

21. 20. The composition of claim 18 for use in treating cardiac disease in a subject in need thereof.

22. 20. Use of a compound according to any one of claims 1 to 17 in the manufacture of a medicament for treating a cardiac disorder in a subject.

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