SMYD modulators and uses thereof

Abstract

The present disclosure provides compounds or salts of Formula (A), (I) or (II), useful for epigenetic regulation via the modulation of SMYD. In another aspect, the present disclosure provides methods of modulating a SMYD protein via the administration of a compound or salt of Formula (A), (I) or (II), to a subject in need thereof.

Description

SMYD MODULATORS AND USES THEREOFCROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefits of U.S. Provisional Patent Application No. 63 / 612,845, filed December 20, 2023, which is incorporated by reference herein in its entirety.BACKGROUND OF THE INVENTION

[0002] Epigenetic regulation of gene expression is an important biological determinant of protein production and cellular differentiation and plays a significant pathogenic role in a number of human diseases. Epigenetic regulation involves heritable modification of genetic material without changing its nucleotide sequence. Typically, epigenetic regulation is mediated by selective and reversible modification (e.g., methylation) of DNA and proteins (e.g., histones) that control the conformational transition between transcriptionally active and inactive states of chromatin. These covalent modifications can be controlled by enzymes such as methyltransferases (e.g., SMYD proteins such as SMYD3 and SMYD2), many of which are associated with genetic alterations that can cause human disease, such as proliferative disorders. SMYD3 is a histone lysine methyltransferase that plays an important role in transcriptional activation as a member of an RNA polymerase complex. Thus, there is a need for the development of small molecules that are capable of inhibiting the activity of SMYD proteins such as SMYD3 and SMYD2.SUMMARY OF THE INVENTION

[0003] In one aspect, provided herein is a compound having the structure of Formula (I),or a pharmaceutically acceptable salt thereof, wherein:R1is a 4- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)S(O)2R11, -C(O)OR11, -OC(O)R11, -S(O)R11, -S(O)2R11, -NO2, -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, - C(O)OR11, -OC(O)R11, -S(O)R11, -S(O)2R11, -NO2, =O, =S, =N(R11), and CN;Ring A is selected from 6- to 12-membered heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -C(O)OR12, -OC(O)R12, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -C(O)OR12, -OC(O)R12, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN;R2is selected from -[C(R15)2]n-(3- to 12-membered heterocycle) and -[C(R15)2]n-( C3-12carbocycle), wherein the 3- to 12-membered heterocycle of -[C(R15)2]n-(3- to 12- membered heterocycle) and the C3-12carbocycle of -[C(R15)2]n-(C3-12carbocycle) are each optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl;R11, R12, R13, and R15, are each independently selected at each occurrence from: hydrogen;C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selectedfrom: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and n is selected from 0, 1, and 2.

[0004] In another aspect, provided herein is a compound having the structure of Formula (II),or a pharmaceutically acceptable salt thereof, wherein:R21is selected from C1-3alkyl and C3-6carbocycle, the C1-3alkyl is substituted with one or more substituents independently selected from:-O( C1-6alkyl), -O(C1-6haloalkyl), -SR31, -N(R31)2, -C(O)R31, - C(O)N(R31)2, -N(R31)C(O)R31, -N(R31)S(O)2R31, -C(O)OR31, -OC(O)R31, - S(O)R31, -S(O)2R31, -NO2, =O, and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -C(O)N(R31)2, -N(R31)C(O)R31, - C(O)OR31, -OC(O)R31, -S(O)R31, -S(O)2R31, -NO2, =O, =S, =N(R31), -CN; and C1- 6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -C(O)N(R31)2, - N(R31)C(O)R31. -C(O)OR31, -OC(O)R31, -S(O)R31, -S(O)2R31, -NO2, =O, =S, =N(R31), and -CN; and the C3-6carbocycle is substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)N(R32)2, - N(R32)C(O)R32-C(O)OR32, -OC(O)R32, -S(O)R32, -S(O)2R32, -NO2, =O, =S, =N(R32), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, - C(O)N(R32)2, -N(R32)C(O)R32-C(O)OR32, -OC(O)R32, -S(O)R32, -S(O)2R32, -NO2, =O, =S, =N(R32), and -CN;Ring A is selected from 6- to 12-membered heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)N(R32)2, -N(R32)C(O)R32, -N(R32)S(O)2R32, -C(O)OR32, -OC(O)R32, -S(O)R32, -S(O)2R32, -NO2, =O, =S, =N(R32), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)N(R32)2, -N(R32)C(O)R32, -N(R32)S(O)2R32, -C(O)OR32, -OC(O)R32, -S(O)R32, -S(O)2R32, -NO2, =O, =S, =N(R32), and -CN;R22is selected from -[C(R25)2]n-(3- to 12-membered heterocycle) and -[C(R25)2]n-(C3-12carbocycle), wherein the 3- to 12-membered heterocycle of -[C(R25)2]n-(3- to 12- membered heterocycle) and the C3-12carbocycle of -[C(R25)2]n-(C3-12carbocycle) are each optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)S(O)2R33, -C(O)OR33, -OC(O)R33, -S(O)R33, -S(O)2R33, -NO2, =O, =S, =N(R33), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)S(O)2R33, -C(O)OR33, -OC(O)R33, -S(O)R33, -S(O)2R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)S(O)2R33, -C(O)OR33, - OC(O)R33, -S(O)R33, -S(O)2R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl;R25, R31, R32, and R33are each independently selected at each occurrence from: hydrogen;C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selectedfrom: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and n is selected from 0, 1, and 2.

[0005] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I) or (II), and a pharmaceutically acceptable excipient.

[0006] In another aspect, the present disclosure provides a method of treating cancer comprising administering to a subject in need thereof a compound or salt of Formula (I) or (II), or a pharmaceutical composition as disclosed herein.

[0007] In another aspect, the present disclosure provides a method of modulating a SYMD protein, comprising administering to a subject in need thereof a compound or salt of Formula (I) or (II), or a pharmaceutical composition as disclosed herein. In some embodiments, the SYMD protein is selected from SMYD2 and SMYD3.

[0008] In another aspect, the present disclosure provides a method of inhibiting a SYMD protein, comprising administering to a subject in need thereof a compound or salt of Formula (I) or (II), or a pharmaceutical composition as disclosed herein. In some embodiments, the SYMD protein is selected from SMYD2 and SMYD3.INCORPORATION BY REFERENCE

[0009] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0010] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0011] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0012] “Alkyl” refers to a straight or branched hydrocarbon chain monovalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to twelve carbon atoms (i.e., C1-C12alkyl). The alkyl is attached to the remainder of the molecule through a single bond. In certain embodiments, an alkyl comprises one to twelve carbon atoms (i.e., C1-C12alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., C1-C8alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-C5alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C1-C4alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-C3alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1-C2alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-C8alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C2- C5alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-C5alkyl). For example, the alkyl group may be attached to the rest of the molecule by a single bind, such as, methyl, ethyl, 1 -propyl (n-propyl), 1 -methylethyl (iso-propyl), 1 -butyl (n-butyl), 1 -methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1 -dimethylethyl (tert-butyl), 1-pentyl (n-pentyl), and the like.

[0013] The term “Cx-y” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “C1-6alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. The term -Cx-yalkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example, -C1-6alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0014] The terms “Cx-yalkenyl” and “Cx-yalkynyl” refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term -Cx-yalkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, - C2-6alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term -Cx-yalkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in thealkynylene chain. For example, -C2-6alkynylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0015] The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle include 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Bicyclic carbocycles may be fused, bridged or spiro- ring systems. In some embodiments, the bicyclic carbocycle is selected from a fused bicyclic carbocycle, bridged bicyclic carbocycle, and spirocyclic carbocycle. In some embodiments, the carbocycle is an aryl. In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Carbocycle may be optionally substituted by one or more substituents such as those substituents described herein.

[0016] The term “carbocyclene” as used herein refers to a divalent saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. The carbocyclene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. A carbocyclene may be optionally substituted by one or more substituents such as those substituents described herein. Carbocyclene includes divalent 3- to 10-membered monocyclic rings and divalent polycyclic rings (e.g., 6- to 12-membered bicyclic rings). Each ring of a polycyclic carbocyclene may be selected from saturated, unsaturated, and aromatic rings. Polycyclic carbocyclenes may be fused, bridged or spiro-ring systems. Polycyclic carbocyclenes may be fused, bridged or spiro-ring systems. The single bond connecting the carbocyclene to the rest of the molecule and the single bond connecting the carbocyclene to the radical group may be located on the same ring or different rings of a polycyclic carbocyclene. In some embodiments, the carbocycle is an arylene, for example, a phenylene. A “phenylene” as used herein refers to a divalent benzene group. The phenylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. A phenylene may be optionally substituted by one or more substituents such as those substituents described herein.

[0017] “Cycloalkyl” refers to a stable fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, and preferably having from three to twelve carbon atoms (i.e., C3-12cycloalkyl). In certain embodiments, a cycloalkyl comprises three to ten carbon atoms (i.e., C3-10cycloalkyl). In other embodiments, a cycloalkyl comprises five to seven carbon atoms (i.e., C5-7cycloalkyl). The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbomenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Cycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0018] “Cycloalkenyl” refers to a stable unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond (i.e., C3-12cycloalkenyl). In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms (i.e., C3-10cycloalkenyl). In other embodiments, a cycloalkenyl comprises five to seven carbon atoms (i.e., C5-7cycloalkenyl). The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkenyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0019] A “Cx-y carbocycle” is meant to include groups that contain from x to y carbons in a ring. For example, the term “C3-6carbocycle” can be a saturated, unsaturated or aromatic ring system that contains from 3 to 6 carbon atoms — any of which is optionally substituted as provided herein.

[0020] The term “heterocycle” as used herein refers to a saturated, unsaturated, non-aromatic or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings and 6- to 12- membered bicyclic rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycle comprises at least oneheteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl. Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl. Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein. Bicyclic heterocycles may be fused, bridged or spiro-ring systems. In some embodiments, the bicyclic heterocycle is selected from a fused bicyclic heterocycle, bridged bicyclic heterocycle, and spirocyclic heterocycle In an exemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein.

[0021] The term “heterocyclene” as used herein refers to a divalent saturated, unsaturated, non-aromatic or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. The heterocyclene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The single bond attaching the heterocyclene group to the rest of the molecule and the single bond attaching the heterocyclene group to the radical group may be each independently connected through any atom of the heterocyclene as valency permits, including a carbon atom in the heterocyclene ring or a heteroatom in the heterocyclene ring. A heterocyclene may be optionally substituted by one or more substituents such as those substituents described herein. Heterocyclenes include 3- to 10- membered monocyclic rings and polycyclic rings (e.g., 6- to 12-membered bicyclic rings). Each ring of a polycyclic heterocyclene may be selected from saturated, unsaturated, and aromatic rings. Polycyclic heterocyclenes may be fused, bridged or spiro-ring systems. The single bond connecting the heterocyclene to the rest of the molecule and the single bond connecting the heterocyclene to the radical group may be located on the same ring or different rings of a polycyclic heterocyclene and may be attached to the rest of the molecule or the radical group through any atom of the heterocyclene, valence permitting, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocyclene comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, theheterocyclene comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocyclene comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocyclene comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocyclene is a heteroarylene. In some embodiments, the heterocyclene is a heterocycloalkylene.

[0022] “Heterocycloalkyl” refers to a stable 3 to 12 membered non-aromatic ring radical that comprises two to twelve carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, Si, P, B, and S atoms. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. The heterocycloalkyl may be selected from monocyclic or bicyclic, and fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocyclo alkyl. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2oxopiperidinyl, 2- oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. Heterocyclo alkyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0023] The term “heteroaryl” refers to a radical derived from a 3- to 12-membered aromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heteroaryl comprises at least oneheteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hiickel theory. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Heteroaryl includes aromatic single ring structures, preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Heteroaryl may be optionally substituted by one or more substituents such as those substituents described herein. Heteroaryl also includes polycyclic ring systems having two or more rings in which two or more atoms are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other rings can be aromatic or non-aromatic carbocyclic, or heterocyclic. Heteroaryl may be optionally substituted by one or more substituents such as those substituents described herein.

[0024] An “X-membered heterocycle” refers to the number of endocylic atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.

[0025] “Alkoxy” refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0026] “Halo” or “halogen” refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.

[0027] As used herein, the term “haloalkyl” or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes (“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2- haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane,1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, and I). When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected for example, 1 -chloro, 2-fluoroethane.

[0028] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound,a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[0029] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N-NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N (Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo(=N-OH), hydrazine(=N-NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N (Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); wherein each Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine(=N-NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N (Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and wherein each Rbis independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate.

[0030] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0031] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0032] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0033] The terms “subject,” “individual,” and “patient” may be used interchangeably and refer to humans, the as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like). In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.

[0034] As used herein, the phrase “a subject in need thereof’ refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.

[0035] The terms “administer”, “administered”, “administers” and “administering” are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certain embodiments, oral routes of administering a composition can be used. The terms ““administer”, “administered”, “administers” and “administering” a compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need.

[0036] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. In certain embodiments, treatment or treating involves administering a compound or composition disclosed herein to a subject. A therapeutic benefit may include the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.

[0037] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0038] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.Compounds

[0039] In some aspects, the present disclosure provides a compound of Formula (A):or a pharmaceutically acceptable salt thereof wherein,Ring B is a 5-membered heterocycle,R1is selected from C1-3alkyl, C3-6carbocycle, and 4- to 6-membered heterocycle, the 4- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)S(O)2R11, -C(O)OR11, -OC(O)R11, -S(O)R11, -S(O)2R11, -NO2, -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -N(R11)C(O)R11. -C(O)OR11, -OC(O)R11, -S(O)R11, -S(O)2R11, -NO2, =O, =S, =N(R11), and -CN; the C1-3alkyl is substituted with one or more substituents independently selected from: -O(C1-6alkyl), -O(C1-6haloalkyl), -SR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)S(O)2R11, -C(O)OR11, -OC(O)R11, - S(O)R11, -S(O)2R11, -NO2, =O, and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, - C(O)OR11, -OC(O)R11, -S(O)R11, -S(O)2R11, -NO2, =O, =S, =N(R11), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, - C(O)OR11, -OC(O)R11, -S(O)R11, -S(O)2R11, -NO2, =O, =S, =N(R11), and -CN; and the C3-6carbocycle is substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -S(O)R11, -S(O)2R11, -NO2, =O, =S, =N(R11), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, OR11, -SR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -N(R11)C(O)R11. -C(O)OR11, -OC(O)R11, -S(O)R11, -S(O)2R11, -NO2, =O, =S, =N(R11), -CN;Ring A is selected from 6- to 12-membered heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -C(O)OR12, -OC(O)R12, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -C(O)OR12, -OC(O)R12, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN;R2is selected from -[C(R15)2]n-(3- to 12-membered heterocycle) and -[C(R15)2]n-(C3-12carbocycle), wherein the 3- to 12-membered heterocycle of -[C(R15)2]n-(3- to 12- membered heterocycle) and the C3-12carbocycle of -[C(R15)2]n-(C3-12carbocycle) are each optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl;R11, R12, R13, and R15are each independently selected at each occurrence from: hydrogen;C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and n is selected from 0, 1, and 2.

[0040] In some embodiments of a compound or salt of Formula (A), Ring B is a 5-membered heterocycle with at least one heteroatom selected from oxygen, nitrogen, and sulfur. In some embodiments, Ring B is a 5-membered heteroaryl. In some embodiments, Ring B is a 5- membered heteroaryl with at least one heteroatom selected from oxygen, nitrogen, and sulfur. In some embodiments, Ring B is a 5-membered heteroaryl with at least one oxygen atom, nitrogen atom, sulfur atom, or a combination thereof. In some embodiments, Ring B is selected from pyrrole, isoxazole, oxazole, oxadiazole, thiodiazole, thiophene, isothiazole, thiazole, furan, imidazole, pyrazole, triazole, and tetrazole, any of which is optionally substituted with R1. In some embodiments, Ring B is selected from

[0041] In another aspect, Formula (A) is represented by the structure of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is a 4- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)S(O)2R11, -C(O)OR11, -OC(O)R11, -S(O)R11, -S(O)2R11, -NO2, -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11. -C(O)OR11, -OC(O)R11, -S(O)R11, -S(O)2R11, -NO2, =O, =S, =N(R11), and -CN;Ring A is selected from 6- to 12-membered heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -C(O)OR12, -OC(O)R12, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -C(O)OR12, -OC(O)R12, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN;R2is selected from -[C(R15)2]n-(3- to 12-membered heterocycle) and -[C(R15)2]n-(C3-12carbocycle), wherein the 3- to 12-membered heterocycle of -[C(R15)2]n-(3- to 12- membered heterocycle) and the C3-12carbocycle of -[C(R15)2]n-(C3-12carbocycle) are each optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl;R11, R12, R13, and R15, are each independently selected at each occurrence from: hydrogen;C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and n is selected from 0, 1, and 2.

[0042] In some embodiments, for a compound or salt of Formula (A) or (I), R1is 4- to 6- membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, - N(R11)2, -C(O)R11, =O, =S, and -CN. In some embodiments, R1is 4- to 5-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, - OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, =O, =S, and -CN. In some embodiments, R1is 4-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, =O, =S, and -CN

[0043] In some embodiments, for a compound or salt of Formula (A) or (I), R1is a 4- to 6- membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -CN; and C1-6alkyl optionally substituted with halogen. In some embodiments, R1is a 4- to 5-membered heterocycle optionally substituted with one ormore substituents independently selected from: halogen, -OR11, -N(R11)2, -CN; and C1-6alkyl optionally substituted with halogen. In some embodiments, R1is a 4-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, - OR11, -N(R11)2, -CN; and C1-6alkyl optionally substituted with halogen.

[0044] In some embodiments, for a compound or salt of Formula (A) or (I), the 4- to 6- membered heterocycle of R1is selected from saturated 4- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, - N(R11)2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R1is a saturated 4- to 5- membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, and -CN. In some embodiments, R1is saturated 4- membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R1is a saturated 4-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, and -CN.

[0045] In some embodiments, for a compound or salt of Formula (A) or (I), R1is tetrahydrofuranyl or oxetanyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R1is tetrahydrofuranyl or oxetanyl optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -CN, methyl, and ethyl. In some embodiments, R1is oxetanyl optionally substituted with -F. In some embodiments, R1is unsubstituted oxetanyl. In some embodiments, R1is unsubstituted tetrahydrofuranyl. In some embodiments, R1is selected from oxetanyl and tetrahydrofuranyl. In some embodiments, R1is selected from. In some embodiments, R1is,

[0046] In some embodiments, for a compound or salt of Formula (A) or (I), Ring A is selected from 6- to 12-membered heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, and -CN. In some embodiments, Ring A is selected from 6- to 12-membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR11,-N(R11)2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, Ring A is selected from 6- to 10-membered heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, and -CN. In some embodiments, Ring A is selected from 6- to 9-membered heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, and -CN. In some embodiments, Ring A is selected from saturated 6- to 9-membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -CN, C1-6alkyl, and C1-6haloalkyl.

[0047] In some embodiments, for a compound or salt of Formula (A) or (I), Ring A is selected from saturated 6- to 12-membered fused bicyclic heterocyclene and saturated 6- to 12-membered bridged heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, and -CN. In some embodiments, Ring A is selected from saturated 6- to 12-membered fused bicyclic heterocyclene and saturated 6- to 12-membered bridged heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -CN, C1-6alkyl, and C1-6haloalkyl.

[0048] In some embodiments, for a compound or salt of Formula (A) or (I), Ring A is selected from saturated 6- to 9-membered fused bicyclic heterocyclene and saturated 6- to 9-membered bridged heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, and -CN. In some embodiments, Ring A is selected from saturated 6- to 9-membered fused bicyclic heterocyclene and saturated 6- to 9-membered bridged heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -CN, C1-6alkyl, and C1-6haloalkyl.

[0049] In some embodiments, for a compound or salt of Formula (A) or (I), wherein Ring A is selected from saturated 6- to 9-membered fused bicyclic heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, and -CN. In some embodiments, wherein Ring A isselected from saturated 6- to 9-membered fused bicyclic heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -CN, C1-6alkyl, and C1-6haloalkyl.

[0050] In some embodiments, for a compound or salt of Formula (A) or (I), Ring A is selected from saturated 7- to 8-membered fused bicyclic heterocyclene each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, and -CN. In some embodiments, Ring A is selected from 2-azabicyclo[4.1.0]heptanylene, hexahydro-1H-cyclopenta[c]pyrrolylene and 3- azabicyclo[4.1.0]heptanylene, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, and -CN. In some embodiments, Ring A is selected from 2- azabicyclo[4.1.0]heptanylene, hexahydro-1H-cyclopenta[c]pyrrolylene and 3- azabicyclo[4.1.0]heptanylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, Ring A is selected from 2-azabicyclo[4.1.0]heptanylene and 3- azabicyclo[4.1.0]heptanylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, Ring A is 2-azabicyclo[4.1.0]heptanylene. In some embodiments, Ring A is hexahydro-1H-cyclopenta[c]pyrrolylene. In some embodiments, Ring A is 3 -azabicyclo [4.1.0]heptanylene.

[0051] In some embodiments, for a compound or salt of Formula (A) or (I), Ring A is selected

[0052] In some embodiments, for a compound or salt of Formula (A) or (I), Ring A is selected from saturated 6- to 9-membered bridged heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, and -CN. In some embodiments, Ring A is selected from saturated 6- to 9-memberedbridged heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -CN, C1-6alkyl, and C1-6haloalkyl.

[0053] In some embodiments, for a compound or salt of Formula (A) or (I), Ring A is selected from saturated 8- to 9-membered bridged heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, and -CN. In some embodiments, Ring A is selected from 3-oxa-9- azabicyclo[3.3.1]nonanylene and 8-azabicyclo[3.2.1]octanylene, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, and -CN. In some embodiments, Ring A is selected from 3-oxa-9-azabicyclo[3.3.1]nonanylene and 8-azabicyclo[3.2.1]octanylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, Ring A is 3-oxa-9- azabicyclo[3.3.1]nonanylene. In some embodiments, Ring A is 8-azabicyclo[3.2.1]octanylene.

[0054] In some embodiments, for a compound or salt of Formula (A) or (I), Ring A is selected

[0055] In some embodiments, for a compound or salt of Formula (A) or (I), n is 0.

[0056] In some embodiments, for a compound or salt of Formula (A) or (I), R2is a 4- to 12- membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is a 4- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0057] In some embodiments, for a compound or salt of Formula (A) or (I), R2is selected from 4- to 12-membered monocyclic heterocycle and 4- to 12-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is selected from 4- to 10- membered monocyclic heterocycle and 6- to 10-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0058] In some embodiments, for a compound or salt of Formula (A) or (I), R2is a 4- to 12- membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is a 4- to 10-membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted withone or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is a 4- to 8- membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0059] In some embodiments, for a compound or salt of Formula (A) or (I), R2is a 6-membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is 4-piperidinyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is 4-piperidinyl optionally substituted with one or more substituents independently selected from: C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -CN, C1-3alkyl, and C1- 3 haloalkyl. In some embodiments, R2is 4-piperidinyl optionally substituted with one or more substituents independently selected from:. In some

[0060] In some embodiments, for a compound or salt of Formula (A) or (I), R2is a 4- to 12- membered bicyclic fused heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is a 4- to 10-membered bicyclic fused heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is a 4- to 8- membered bicyclic fused heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0061] In some embodiments, for a compound or salt of Formula (A) or (I), R2is a 4- to 12- membered bicyclic fused saturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionallysubstituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is a 4- to 10-membered bicyclic fused saturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is a 4- to 8-membered bicyclic fused saturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0062] In some embodiments, for a compound or salt of Formula (A) or (I), R2is an 8-membered bicyclic fused saturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is octahydro-5-cyclopenta[c]pyrrolyl, optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is octahydro-5-cyclopenta[c]pyrrolyl, optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -CN; and C1-6alkyl optionallysubstituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is an unsubstituted octahydro-5-cyclopenta[c]pyrrolyl. In some embodiments,

[0063] In some embodiments, for a compound or salt of Formula (A) or (I), the 3- to 12- membered heterocycle of R2is represented by, whereinis optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, - S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, - C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, -S(O)2R13, - NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,a 3- to 12-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,a 3- to 9-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2,=O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0064] In some embodiments, for a compound or salt of Formula (A) or (I), the 3- to 12- membered heterocycle ofselected from 3- to 12-membered monocyclic heterocycle and 4- to 12-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, the 3- to 12-membered heterocycle ofis selected from 3- to 8-membered monocyclic heterocycle and 6- to 12-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0065] In some embodiments, for a compound or salt of Formula (A) or (I),is 3- to 12- membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13,-NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodimentsis 4-to 10-membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13,-NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is 4- to 8-membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0066] In some embodiments, for a compound or salt of Formula (A) or (I),is a 6- membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13,-NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is a6-membered saturated monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In someembodiments,is selected from 1-piperazinyl and 1-piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is selected from 1-piperazinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is selected from 1-piperazinyl, each of which is optionally substituted with one or more substituents independently selected from: C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S,=N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,piperazinyl, each of which is optionally substituted with one or more substituents independently selected from: C1-6alkyl optionally substituted with one or more substituents independently selected from: C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is selected from 1-piperazinyl, each of which is optionally substitutedwith one or more substituents independently selected from: C1-6alkyl optionally substituted with one or more substituents independently selected from: C3-6carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is selected from 1-piperazinyl, each of which is optionally substituted with one or more substituents independently selected from: C1-6alkyl optionally substituted with one or more substituents independently selected from: C3-6carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13,-SR13, -N(R13)2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is selected from 1-piperazinyl, each of which is optionally substituted with one or more substituents independently selected from: C1-6alkyl optionally substituted with one or more substituents independently selected from: C3-6carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen and -OH. In some embodiments,is selected from 1 -piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is selected from 1 -piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN. In some embodiments,is selected from 1- piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: -N(R13)2.

[0068] In some embodiments, for a compound or salt of Formula (A) or (I),is selected from a 4- to 12-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, - NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, the 4- to 12-membered bicyclic heterocycle ofselected from 6- to 12- membered fused heterocycle, 6- to 12-membered spirocyclic heterocycle, and 6- to 12-membered bridged heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted withone or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0069] In some embodiments, for a compound or salt of Formula (A) or (I),4- to 12- membered fused heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S,=N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,6- to 12- membered fused heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S,=N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,6- to 10- membered fused heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0070] In some embodiments, for a compound or salt of Formula (A) or (I),12-membered fused saturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independentlyselected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13,-NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,a6- to 9-membered fused saturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments ,is a 6-membered fused saturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,a 8-membered fused saturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0071] In some embodiments, for a compound or salt of Formula (A) or (I),selected from octahydrocyclopenta[c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, and 3- azabicyclo[3.1.0]hexanyl, each of which is optionally substituted with one or more substituentsindependently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13,-NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,selected from octahydrocyclopenta[c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, and 3- azabicyclo[3.1.0]hexanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN. In some embodiments,selected from octahydrocyclopenta[c]pyrrolyl and octahydropyrrolo[3,4-c]pyrrolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O,=S, =N(R13), and -CN. In some embodiments,3-azabicyclo[3.1.0]hexanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN. In some embodiments,selected from octahydrocyclopenta[c]pyrrolyl, octahy drop yrrolo [3,4- c]pyrrolyl, and 3-azabicyclo[3.1.0]hexanyl, each of which is optionally substituted with one or more substituents independently selected from: -N(R13)2.

[0072] In some embodiments, for a compound or salt of Formula (A) or (I),selected from octahydrocyclopenta[c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, and 3- azabicyclo[3.1.0]hexanyl, each of which is optionally substituted with one or more -N(R13)2; and each R13is selected from: hydrogen; and C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN. In some embodiments,selected from octahydrocyclopenta[c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, and 3- azabicyclo[3.1.0]hexanyl, each of which is optionally substituted with one or more -N(R13)2; and each R13is selected from hydrogen; and C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, C3-10carbocycle and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10- membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, and -CN. In some embodiments,selected from octahydrocyclopenta[c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, and 3-azabicyclo[3.1.0]hexanyl, each of which is optionally substituted with one or more -N(R13)2; and each R13is selected from hydrogen and C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, C3-6carbocycle and 3- to 6-membered heterocycle, wherein eachC3-6carbocycle and 3- to 6-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl,-O-C1-6haloalkyl, -NH2, and -CN. In some embodiments,is selected from octahydrocyclopenta[c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, and 3-

[0073] In some embodiments, for a compound or salt of Formula (A) or (I),12-membered spirocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13,-NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,6- to 10-membered spirocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13,-NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0074] In some embodiments, for a compound or salt of Formula (A) or (I),a 6- to12-membered saturated spirocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In someembodiments,a 6- to 9-membered saturated spirocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0075] In some embodiments, for a compound or salt of Formula (A) or (I),membered saturated spirocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13,-NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,selected from 2-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octanyl and 6- azaspiro[3.4]octanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13,-NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,selected from 2-azaspiro[3.3]heptyl and 2,6-diazaspiro[3.3]heptyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN. In some embodiments,selected from2-azaspiro[3.3]heptyl and 2,6-diazaspiro[3.3]heptyl, each of which is optionally substituted withone or more substituents independently selected from: halogen, -OH, -NH2, and -CN. In some embodiments,selected from 2,6-diazaspiro[3.4]octanyl and 6-azaspiro[3.4]octanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN. In some embodiments,selected from 2,6-diazaspiro[3.4]octanyl and 6-azaspiro[3.4]octanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -CN, and C1-6alkyl. In some embodiments,diazaspiro[3.4]octanyl and 6-azaspiro[3.4]octanyl, each of which is optionally substituted with one or more substituents independently selected from -NH2, -CN, and C1-6alkyl.

[0076] In some embodiments, for a compound or salt of Formula (A) or (I),selected

[0077] In some embodiments, for a compound or salt of Formula (A) or (I),a 6- to12-membered bridged heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or moresubstituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O,=S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,membered bridged heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0078] In some embodiments, for a compound or salt of Formula (A) or (I),12-membered saturated bridged heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13,-NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,6- to 9-membered saturated bridged heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,a 7- to 8-membered saturated bridged heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one ormore substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0079] In some embodiments, for a compound or salt of Formula (A) or (I),selected from 8 -azabicyclo [3.2.1]octanyl and 3-azabicyclo[3.1.1]heptanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is selected from 8-azabicyclo[3.2.1]octanyl and 3- azabicyclo [3. l.l]heptanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2wherein each R13is independently selected at each occurrence from hydrogen and C1-6alkyl optionally substituted with one more substituents independently selected from C3-6carbocycle and 4- to 6-membered heterocycle, wherein each C3-6carbocycle and 4- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN. In some embodiments,selected from 8-azabicyclo[3.2.1]octanyl and 3-azabicyclo[3.1.1]heptanyl, each of which is optionally substituted with one or more substituents independently selected from: -NH2,

[0080] In some embodiments, for a compound or salt of Formula (A) or (I), R2is selected from

[0081] In some embodiments, for a compound or salt of Formula (A) or (I), R2is a C3-12carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S,=N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, the C3-12carbocycle of R2is represented by optionally substituted with one or moresubstituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0082] In some embodiments, for a compound or salt of Formula (A) or (I)bicyclic fused saturated carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted withone or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13,-NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,C5-10 bicyclic fused saturated carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13,-NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,C5-8 bicyclic fused saturated carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0083] In some embodiments, for a compound or salt of Formula (A) or (I),is selected from a Cf> bicyclic fused saturated carbocycle or a C8bicyclic fused saturated carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S,=N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is selected from 3- bicyclo[3.1.0]hexyl and octahydro-2-pentalenyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is selected from 3-bicyclo[3.1.0]hexyl and octahydro-2-pentalenyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN. In some embodiments,selected from 3-bicyclo[3.1.0]hexyl and octahydro-2-pentalenyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN. In some embodiments,is selected from 3-bicyclo[3.1.0]hexyl optionally substituted with one or more substituents independently selected from: halogen, -OH, -SH, -NH2, and -CN. In some embodiments,is selected from octahydro-2-pentalenyl, optionally substituted with one or more substituents independently selected from: halogen, -OH, -SH, -NH2, and -CN.

[0084] In some embodiments, for a compound or salt of Formula (A) or (I), R2is selected from, some embodiments,some embodiments, for a compound or salt ofFormula (A) or (I),is C3-12monocyclic saturated carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is C4-10monocyclic saturated carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, - NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is C5-9monocyclic saturated carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, - NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0085] In some embodiments, for a compound or salt of Formula (A) or (I), R2is a cyclohexyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is a cyclohexyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each ofwhich is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is a cyclohexyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -CN. In some embodiments, R2is a cyclohexyl optionally

[0086] In some embodiments, for a compound or salt of Formula (A) or (I), n is 1.

[0087] In some embodiments, for a compound or salt of Formula (A) or (I), R2is -[C(R15)2]-(4- to 12-membered heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, - S(O)2R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is -[C(R15)2]-(4- to 12-membered heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13),and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0088] In some embodiments, for a compound or salt of Formula (A) or (I), the 4- to 12- membered heterocycle of -[C(R15)2]-(4- to 12-membered heterocycle) is selected from a 4- to 12- membered monocyclic heterocycle and 4- to 12-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, the 4- to 12-membered heterocycle of -[C(R15)2]-(4- to 12-membered heterocycle) is selected from a 4- to 10-membered monocyclic heterocycle and 4- to 10-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0089] In some embodiments, for a compound or salt of Formula (A) or (I), R2is -[C(R15)2]-(4- to 12-membered monocyclic heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is - [C(R15)2]-(4- to 10-membered monocyclic heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13),and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is -[C(R15)2]-(4- to 10-membered saturated monocyclic heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is -[C(R15)2]-(4- to 8-membered monocyclic heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is -[C(R15)2]-(5- to 7-membered monocyclic heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0090] In some embodiments, for a compound or salt of Formula (A) or (I), R2is -[C(R15)2]-(6- membered monocyclic heterocycle), the 6-membered monocyclic heterocycle is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is -[C(R15)2]-(6-membered saturated monocyclic heterocycle), 6-membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0091] In some embodiments, for a compound or salt of Formula (A) or (I), -[C(R15)2]-(6- membered monocyclic heterocycle) of R2is -[C(H)2]-(6-membered monocyclic heterocycle), the 6-membered monocyclic heterocycle is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, -[C(H)2]-(6- membered monocyclic heterocycle) of R2is -[C(H)2]-piperdinyl, the piperidinyl is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. . In some embodiments, -[C(H)2]-(6-membered monocyclic heterocycle) of R2is -methyl-piperdinyl, the piperidinyl is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0092] In some embodiments, for a compound or salt of Formula (A) or (I), R2is methyl- piperidinyl optionally substituted with one or more substituents independently selected from:halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is methyl-piperidinyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-3alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, and -CN; and C3-6carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is methyl-piperidinyl optionally substituted with one or more substituents independently selected from: C1-3alkyl optionally substituted with C3-6carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR13, -CN, C1-3alkyl, and C1-3 haloalkyl. In some embodiments, R2is methyl-piperidinyl optionally substituted

[0093] In some embodiments, for a compound or salt of Formula (A) or (I), R2is -[C(R15)2]-(4- to 12-membered bicyclic fused heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independentlyselected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is - [C(R15)2]-(4- to 10-membered bicyclic fused heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0094] In some embodiments, for a compound or salt of Formula (A) or (I), R2is selected from - [C(R15)2]-(4- to 8-membered bicyclic fused saturated heterocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, - NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is selected from -[C(R15)2]-(8-membered bicyclic fused saturated heterocycle) optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0095] In some embodiments, for a compound or salt of Formula (A) or (I), R2is selected from - [C(R15)2]-(6-membered bicyclic fused saturated heterocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionallysubstituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is selected from 6-methyl-3-azabicyclo[3.1.0]hexyl and 5- methyloctahydrocyclopenta[c]pyrrolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is selected from 6-methyl-3-azabicyclo[3.1.0]hexyl and 5- methyloctahydrocyclopenta[c]pyrrolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R26- methyl-3-azabicyclo[3.1.0]hexyl or 5-methyloctahydrocyclopenta[c]pyrrolyl each of which is independently optionally substituted with, OH . In some embodiments, R2is unsubstituted 6- methyl-3-azabicyclo[3.1.0]hexyl. In some embodiments, R2is unsubstituted 5- methyloctahydrocyclopenta[c]pyrrolyl. In some embodiments, R2is selected from,

[0096] In some embodiments, for a compound or salt of Formula (A) or (I), R2is -[C(R15)2]-(C3-12 carbocycle), represented by, optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0097] In some embodiments, for a compound or salt of Formula (A) or (I), the C3-12carbocycleis selected from C3-12monocyclic carbocycle and C4-12 bicyclic carbocycle, optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, the C3-12carbocycle ofis selected from C4-10 monocyclic carbocycle and C4-10bicyclic carbocycle, optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O,=S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0098] In some embodiments, for a compound or salt of Formula (A) or (I), R2is -[C(R15)2]-( C4- 12 bicyclic fused carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is -[C(R15)2]-( C4-10bicyclic fused carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is -[C(R15)2]-( C4-10bicyclic fused saturated carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0099] In some embodiments, for a compound or salt of Formula (A) or (I), R2is -[C(R15)2]-( C6bicyclic fused carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituentsindependently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is selected from 3- methylbicyclo[3.1.0]hexyl and 6-methylbicyclo[3.1.0]hexyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is selected from 3-methylbicyclo[3.1.0]hexyl and 6- methylbicyclo[3.1.0]hexyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN. In some embodiments, R2is selected from 3-methylbicyclo[3.1.0]hexyl and 6- methylbicyclo[3.1.0]hexyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, and -CN. In some embodiments, R2is selected from 3-methylbicyclo[3.1.0]hexyl and 6-methylbicyclo[3.1.0]hexyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -SH, -NH2, and -CN. In some embodiments,

[0100] In some embodiments, for a compound or salt of Formula (A) or (I), R2is -[C(R15)2]-( C4-12monocyclic carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is -[C(R15)2]-( C4-10monocyclic carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is -[C(R15)2]-( C4-8monocyclic carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is -[C(R15)2]-( C5-7monocyclic carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

[0101] In some embodiments, for a compound or salt of Formula (A) or (I), R2is -[C(R15)2]-( C6monocyclic carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is methylcyclohexyl, optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2is methylcyclohexyl, optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13,-NO2, =O, =S, =N(R13), -CN; wherein each R13is independently selected at each occurrence from hydrogen and C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN. In some embodiments, R2is methylcyclohexyl, optionally substituted with one or more substituents independently selected from: -N(R13)2; wherein each R13is independently selected at each occurrence from hydrogen and C1-6alkyl optionally substituted with one more substituents independently selected from C3-10carbocycle, wherein each C3-10carbocycle is optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl,C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN. In some embodiments, R2is methylcyclohexyl, optionally substituted with one or more substituents independently

[0102] In some embodiments, for a compound or salt of Formula (A) or (I), the compound is

[0103] In another aspect, the present disclosure provides compounds represented by the structure of Formula (II):or a pharmaceutically acceptable salt thereof, wherein:R21is selected from C1-3alkyl and C3-6carbocycle, the C1-3alkyl is substituted with one or more substituents independently selected from:-O(C1-6alkyl), -O(C1-6haloalkyl), -SR31, -N(R31)2, -C(O)R31, - C(O)N(R31)2, -N(R31)C(O)R31, -N(R31)S(O)2R31, -C(O)OR31, -OC(O)R31, - S(O)R31, -S(O)2R31, -NO2, =O, and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -C(O)N(R31)2, -N(R31)C(O)R31, - C(O)OR31, -OC(O)R31, -S(O)R31, -S(O)2R31, -NO2, =O, =S, =N(R31), -CN; and C1- 6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -C(O)N(R31)2, - N(R31)C(O)R31. -C(O)OR31, -OC(O)R31, -S(O)R31, -S(O)2R31, -NO2, =O, =S, =N(R31), and -CN; andthe C3-6carbocycle is substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)N(R32)2, - N(R32)C(O)R32-C(O)OR32, -OC(O)R32, -S(O)R32, -S(O)2R32, -NO2, =O, =S, =N(R32), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, - C(O)N(R32)2, -N(R32)C(O)R32-C(O)OR32, -OC(O)R32, -S(O)R32, -S(O)2R32, -NO2, =O, =S, =N(R32), and -CN;Ring A is selected from 6- to 12-membered heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)N(R32)2, -N(R32)C(O)R32, -N(R32)S(O)2R32, -C(O)OR32, -OC(O)R32, -S(O)R32, -S(O)2R32, -NO2, =O, =S, =N(R32), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)N(R32)2, -N(R32)C(O)R32, -N(R32)S(O)2R32, -C(O)OR32, -OC(O)R32, -S(O)R32, -S(O)2R32, -NO2, =O, =S, =N(R32), and -CN;R22is selected from -[C(R25)2]n-(3- to 12-membered heterocycle) and -[C(R25)2]n-(C3-12carbocycle), wherein the 3- to 12-membered heterocycle of -[C(R25)2]n-(3- to 12- membered heterocycle) and the C3-12carbocycle of -[C(R25)2]n-(C3-12carbocycle) are each optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)S(O)2R33, -C(O)OR33, -OC(O)R33, -S(O)R33, -S(O)2R33, -NO2, =O, =S, =N(R33), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)S(O)2R33, -C(O)OR33, -OC(O)R33, -S(O)R33, -S(O)2R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)S(O)2R33, -C(O)OR33, -OC(O)R33, -S(O)R33, -S(O)2R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl;R25R31R32and R33 are each independently selected at each occurrence from: hydrogen;C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and n is selected from 0, 1, and 2.

[0104] In some embodiments, for a compound or salt of Formula (A) or (II), R21is C1-3alkyl substituted with one or more substituents independently selected from: -O(C1-6alkyl), -O(C1-6haloalkyl), -SR31, -N(R31)2, -C(O)R31, -C(O)N(R31)2, -N(R31)C(O)R31, -N(R31)S(O)2R31, -C(O)OR31, -OC(O)R31, -S(O)R31, -S(O)2R31, -NO2, =O, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, - C(O)N(R31)2, -N(R31)C(O)R31. -C(O)OR31, -OC(O)R31, -S(O)R31, -S(O)2R31, -NO2, =O, =S, =N(R31), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -C(O)N(R31)2, - N(R31)C(O)R31. -C(O)OR31, -OC(O)R31, -S(O)R31, -S(O)2R31, -NO2, =O, =S, =N(R31), and -CN. In some embodiments, R21is C1-3alkyl substituted with one or more substituents independently selected from: -O(C1-6alkyl), -O(C1-6haloalkyl), -SR31, -N(R31)2, -C(O)R31, -NO2, =O, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, - C(O)R31, -NO2, =O, =S, =N(R31), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -NO2, =O, =S, =N(R31), and -CN. In some embodiments, R21is C1-3alkyl substituted with one or more substituents independently selected from: -O(C1-6alkyl), -O(C1-6haloalkyl), -SR31, -N(R31)2, - C(O)R31, -NO2, =O, and -CN. In some embodiments, R21is selected from methyl and ethyl,substituted with one or more substituents independently selected from: -O(C1-6alkyl), -O(C1-6haloalkyl), -SR31, -N(R31)2, -C(O)R31, -NO2, =O, and -CN. In some embodiments, R21is selected from methyl and ethyl, substituted with one or more substituents independently selected from =O and -CN. In some embodiments,

[0105] In some embodiments, for a compound or salt of Formula (A) or (II), R21is C1-3alkyl substituted with one or more substituents independently selected from: C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -NO2, =O, =S, =N(R31), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -NO2, =O, =S, =N(R31), and -CN. In some embodiments, R21is C1-3alkyl substituted with one or more substituents independently selected from: C3-6carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, - C(O)N(R31)2, -N(R31)C(O)R31. -C(O)OR31, -OC(O)R31, -S(O)R31, -S(O)2R31, -NO2, =O, =S, =N(R31), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -C(O)N(R31)2, - N(R31)C(O)R31. -C(O)OR31, -OC(O)R31, -S(O)R31, -S(O)2R31, -NO2, =O, =S, =N(R31), and -CN. In some embodiments, R21is C1-3alkyl substituted with one or more substituents independently selected from: C3-6carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -NO2, =O, =S, =N(R31), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -NO2, =O, =S, =N(R31), and -CN.

[0106] In some embodiments, for a compound or salt of Formula (A) or (II), R21is ethyl, substituted with one or more substituents independently selected from: C3-6carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -NO2, =O, =S, =N(R31), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -NO2, =O, =S, =N(R31), and -CN. In some embodiments, R21is ethyl, substituted with one or more substituents independently selected from: C3-6carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -NO2, =O, =S, =N(R31), -CN. In some embodiments,R21is ethyl, substituted with C3-6carbocycle. In some embodiments, R21is ethyl substituted with cyclopropyl. In some embodiments, R21is

[0107] In some embodiments, for a compound or salt of Formula (A) or (II), R21is C3-6carbocycle, wherein the C3-6carbocycle is substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)N(R32)2, - N(R32)C(O)R32-C(O)OR32, -OC(O)R32, -S(O)R32, -S(O)2R32, -NO2, =O, =S, =N(R32), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)N(R32)2, -N(R32)C(O)R32-C(O)OR32, - OC(O)R32, -S(O)R32, -S(O)2R32, -NO2, =O, =S, =N(R32), and -CN. In some embodiments, R21isC3-6carbocycle, wherein the C3-6carbocycle is substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -NO2, =O, =S, =N(R32), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -SR32, -N(R32)2, -NO2, =O, =S, =N(R32), and -CN.

[0108] In some embodiments, for a compound or salt of Formula (A) or (II), the C3-6carbocycle of R21is selected from monocyclic C3-6carbocycle and bicyclic C4-6carbocycle, each of which is substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, - N(R32)2, -NO2, =O, =S, =N(R32), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -SR32, -N(R32)2, -NO2, =O, =S, =N(R32), and -CN.

[0109] In some embodiments, for a compound or salt of Formula (A) or (II), R21is monocyclicC3-6carbocycle, substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -NO2, =O, =S, =N(R32), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -SR32, -N(R32)2, -NO2, =O, =S, =N(R32), and -CN. In some embodiments, R21is monocyclic C3-6carbocycle, substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -NO2, =O, =S, =N(R32), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -SR32, -N(R32)2, -NO2, =O, =S, =N(R32), and -CN. In some embodiments, R21is monocyclic C3-4 carbocycle, substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -NO2, =O, =S, =N(R32), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -SR32, -N(R32)2, -NO2, =O, =S, =N(R32), and -CN.

[0110] In some embodiments, for a compound or salt of Formula (A) or (II), R21is cyclopropyl substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, - N(R32)2, -NO2, =O, =S, =N(R32), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -SR32, -N(R32)2, -NO2, =O, =S, =N(R32), and -CN. In some embodiments, R21is cyclopropyl substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -CN, and C1-6alkyl. In some embodiments, R21is cyclopropyl substituted with one or more substituents independently selected from: -OH, fluoro and methyl. In some embodiments, R21is selected from,

[0111] In some embodiments, for a compound or salt of Formula (A) or (II), R21is bicyclic C4-6carbocycle, substituted with one or more substituents independently selected from: halogen, - OR32, -SR32, -N(R32)2, -NO2, =O, =S, =N(R32), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -SR32, -N(R32)2, -NO2, =O, =S, =N(R32), and -CN.

[0112] In some embodiments, for a compound or salt of Formula (A) or (II), R21is a fused bicyclic C4-6carbocycle substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -NO2, =O, =S, =N(R32), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -SR32, - N(R32)2, -NO2, =O, =S, =N(R32), and -CN. In some embodiments, R21is a fused bicyclic C4-6carbocycle substituted with one or more substituents independently selected from: halogen, - OR32, -SR32, -N(R32)2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -SR32, -N(R32)2, and -CN.

[0113] In some embodiments, for a compound or salt of Formula (A) or (II), Ring A is selected from 6- to 12-membered heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, and -CN. In some embodiments, Ring A is selected from 6- to 32-membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, Ring A is selected from 6- to 10-membered heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, =O, and -CN; and C1-6alkyl optionally substituted withone or more substituents independently selected from halogen, -OR32, -N(R32)2, and -CN. In some embodiments, Ring A is selected from 6- to 9-membered heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, and -CN. In some embodiments, Ring A is selected from saturated 6- to 9-membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C1-6alkyl, and C1-6haloalkyl.

[0114] In some embodiments, for a compound or salt of Formula (A) or (II), Ring A is selected from saturated 6- to 12-membered fused bicyclic heterocyclene and saturated 6- to 12-membered bridged heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, and -CN. In some embodiments, Ring A is selected from saturated 6- to 32-membered fused bicyclic heterocyclene and saturated 6- to 32-membered bridged heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C1-6alkyl, and C1-6haloalkyl.

[0115] In some embodiments, for a compound or salt of Formula (A) or (II), Ring A is selected from saturated 6- to 9-membered fused bicyclic heterocyclene and saturated 6- to 9-membered bridged heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, and -CN. In some embodiments, Ring A is selected from saturated 6- to 9-membered fused bicyclic heterocyclene and saturated 6- to 9-membered bridged heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C1-6alkyl, and C1-6haloalkyl.

[0116] In some embodiments, for a compound or salt of Formula (A) or (II), wherein Ring A is selected from saturated 6- to 9-membered fused bicyclic heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, and -CN. In some embodiments, wherein Ring A is selected from saturated 6- to 9-membered fused bicyclic heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C1-6alkyl, and C1-6haloalkyl.

[0117] In some embodiments, for a compound or salt of Formula (A) or (II), Ring A is selected from saturated 7- to 8-membered fused bicyclic heterocyclene each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, and -CN. In some embodiments, Ring A is selected from 2-azabicyclo[4.1.0]heptanylene, hexahydro-1H-cyclopenta[c]pyrrolylene and 3- azabicyclo[4.1.0]heptanylene, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, and -CN. In some embodiments, Ring A is selected from 2- azabicyclo[4.1.0]heptanylene, hexahydro-1H-cyclopenta[c]pyrrolylene and 3- azabicyclo[4.1.0]heptanylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, Ring A is selected from 2-azabicyclo[4.1.0]heptanylene and 3- azabicyclo[4.1.0]heptanylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, Ring A is 2-azabicyclo[4.1.0]heptanylene. In some embodiments, Ring A is hexahydro-1H-cyclopenta[c]pyrrolylene. In some embodiments, Ring A is 3 -azabicyclo [4.1.0]heptanylene.

[0118] In some embodiments, for a compound or salt of Formula (I) or (A), Ring A is selected

[0119] In some embodiments, for a compound or salt of Formula (A) or (II), Ring A is selected from saturated 6- to 9-membered bridged heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, and -CN. In some embodiments, Ring A is selected from saturated 6- to 9-membered bridged heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C1-6alkyl, and C1-6haloalkyl.

[0120] In some embodiments, for a compound or salt of Formula (A) or (II), Ring A is selected from saturated 8- to 9-membered bridged heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, and -CN. In some embodiments, Ring A is selected from 3-oxa-9- azabicyclo[3.3.1]nonanylene and 8-azabicyclo[3.2.1]octanylene, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, and -CN. In some embodiments, Ring A is selected from 3-oxa-9-azabicyclo[3.3.1]nonanylene and 8-azabicyclo[3.2.1]octanylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, Ring A is 3-oxa-9- azabicyclo[3.3.1]nonanylene. In some embodiments, Ring A is 8-azabicyclo[3.2.1]octanylene.

[0121] In some embodiments, for a compound or salt of Formula (A) or (II), Ring A is selected,

[0122] In some embodiments, for a compound or salt of Formula (A) or (II), n is 0.

[0123] In some embodiments, for a compound or salt of Formula (A) or (II), R22is a 4- to 12- membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is a 4- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituentsindependently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0124] In some embodiments, for a compound or salt of Formula (A) or (II), R22is selected from 4- to 12-membered monocyclic heterocycle and 4- to 12-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is selected from 4- to 10- membered monocyclic heterocycle and 6- to 10-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0125] In some embodiments, for a compound or salt of Formula (A) or (II), R22is a 4- to 12- membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is a 4- to 10-membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33,-NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is a 4- to 8-membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0126] In some embodiments, for a compound or salt of Formula (A) or (II), R22is a 6- membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is 4- piperidinyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is 4-piperidinyl optionally substituted with one or more substituents independently selected from: C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -CN, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R22is 4-piperidinyl optionally substituted with one or more substituents independently selected from:

[0127] In some embodiments, for a compound or salt of Formula (A) or (II), R22is a 4- to 12- membered bicyclic fused heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is a 4- to10-membered bicyclic fused heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is a 4- to 8-membered bicyclic fused heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0128] In some embodiments, for a compound or salt of Formula (A) or (II), R22is a 4- to 12- membered bicyclic fused saturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituentsindependently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is a 4- to 10-membered bicyclic fused saturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is a 4- to 8-membered bicyclic fused saturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0129] In some embodiments, for a compound or salt of Formula (A) or (II), R22is an 8- membered bicyclic fused saturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is octahydro-5-cyclopenta[c]pyrrolyl, optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In someembodiments, R22is octahydro-5-cyclopenta[c]pyrrolyl, optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is an unsubstituted octahydro-5-cyclopenta[c]pyrrolyl. In some embodiments,

[0130] In some embodiments, for a compound or salt of Formula (A) or (II), the 3- to 12- membered heterocycle of R22is represented by, whereinis optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)S(O)2R33, -C(O)OR33, -OC(O)R33, - S(O)R33, -S(O)2R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, - C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)S(O)2R33, -C(O)OR33, -OC(O)R33, -S(O)R33, -S(O)2R33, - NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)S(O)2R33, -C(O)OR33, -OC(O)R33, -S(O)R33, -S(O)2R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,a 3- to 12-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,a 3- to 9-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0131] In some embodiments, for a compound or salt of Formula (A) or (II), the 3- to 12- membered heterocycle ofselected from 3- to 12-membered monocyclic heterocycle and 4- to 12-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, the 3- to 12-membered heterocycle ofis selected from 3- to 8-membered monocyclic heterocycle and 6- to 12-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0132] In some embodiments, for a compound or salt of Formula (A) or (II),is 3- to12-membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33,-NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodimentsis 4- to 10-membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33,-NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is 4- to 8-membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0133] In some embodiments, for a compound or salt of Formula (A) or (II),is a 6- membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33,-NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is a6-membered saturated monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionallysubstituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is selected from 1-piperazinyl and 1-piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is selected from 1-piperazinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is selected from 1-piperazinyl, each of which is optionally substituted with one or more substituents independently selected from: C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S,=N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,piperazinyl, each of which is optionally substituted with one or more substituents independently selected from: C1-6alkyl optionally substituted with one or more substituents independently selected from: C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In someembodiments,is selected from 1-piperazinyl, each of which is optionally substituted with one or more substituents independently selected from: C1-6alkyl optionally substituted with one or more substituents independently selected from: C3-6carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is selected from 1-piperazinyl, each of which is optionally substituted with one or more substituents independently selected from: C1-6alkyl optionally substituted with one or more substituents independently selected from: C3-6carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33,-SR33, -N(R33)2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is selected from 1-piperazinyl, each of which is optionally substituted with one or more substituents independently selected from: C1-6alkyl optionally substituted with one or more substituents independently selected from: C3-6carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen and -OH. In some embodiments,is selected from 1-piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is selected from 1-piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN. In some embodiments,piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: -N(R33)2.

[0135] In some embodiments, for a compound or salt of Formula (A) or (II),is selected from a 4- to 12-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, - NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, the 4- to 12-membered bicyclic heterocycle ofselected from 6- to 12- membered fused heterocycle, 6- to 12-membered spirocyclic heterocycle, and 6- to 12-membered bridged heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted withone or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0136] In some embodiments, for a compound or salt of Formula (A) or (II),4- to 12- membered fused heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S,=N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,6- to 12- membered fused heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S,=N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,6- to 10- membered fused heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0137] In some embodiments, for a compound or salt of Formula (A) or (II),12-membered fused saturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independentlyselected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33,-NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,a6- to 9-membered fused saturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments ,is a 6-membered fused saturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,a 8-membered fused saturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0138] In some embodiments, for a compound or salt of Formula (A) or (II),selected from octahydrocyclopenta[c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, and 3- azabicyclo[3.1.0]hexanyl, each of which is optionally substituted with one or more substituentsindependently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33,-NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,selected from octahydrocyclopenta[c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, and 3- azabicyclo[3.1.0]hexanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN. In some embodiments,selected from octahydrocyclopenta[c]pyrrolyl and octahydropyrrolo[3,4-c]pyrrolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O,=S, =N(R33), and -CN. In some embodiments,3-azabicyclo[3.1.0]hexanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN. In some embodiments,selected from octahydrocyclopenta[c]pyrrolyl, octahy drop yrrolo [3,4- c]pyrrolyl, and 3-azabicyclo[3.1.0]hexanyl, each of which is optionally substituted with one or more substituents independently selected from: -NH2.

[0139] In some embodiments, for a compound or salt of Formula (A) or (II),selected

[0140] In some embodiments, for a compound or salt of Formula (A) or (II),12-membered spirocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independentlyselected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33,-NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,6- to 10-membered spirocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33,-NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0141] In some embodiments, for a compound or salt of Formula (A) or (II),12-membered saturated spirocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,a 6- to 9-membered saturated spirocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0142] In some embodiments, for a compound or salt of Formula (A) or (II),membered saturated spirocyclic heterocycle optionally substituted with one or more substituentsindependently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33,-NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,selected from 2-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octanyl and 6- azaspiro[3.4]octanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33,-NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,selected from 2-azaspiro[3.3]heptyl and 2,6-diazaspiro[3.3]heptyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN. In some embodiments,selected from2-azaspiro[3.3]heptyl and 2,6-diazaspiro[3.3]heptyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -NH2, and -CN. In some embodiments,selected from 2,6-diazaspiro[3.4]octanyl and 6-azaspiro[3.4]octanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN. In some embodiments,selected from 2,6-diazaspiro[3.4]octanyl and 6-azaspiro[3.4]octanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -CN, and C1-6alkyl. In some embodiments,diazaspiro[3.4]octanyl and 6-azaspiro[3.4]octanyl, each of which is optionally substituted with one or more substituents independently selected from -NH2, -CN, and C1-6alkyl.

[0143] In some embodiments, for a compound or salt of Formula (A) or (II),selected

[0144] In some embodiments, for a compound or salt of Formula (A) or (II), R22is a C3-12carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, the C3-12carbocycle of R2is represented by, whereinoptionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0145] In some embodiments, for a compound or salt of Formula (A) or (II),is C4-12 bicyclic fused saturated carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33,-NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is C5-10 bicyclic fused saturated carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33,-NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is C5-8 bicyclic fused saturated carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0146] In some embodiments, for a compound or salt of Formula (A) or (II),is selected from a Cf> bicyclic fused saturated carbocycle or a C8bicyclic fused saturated carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S,=N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is selected from 3- bicyclo[3.1.0]hexyl and octahydro-2-pentalenyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, - NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is selected from 3-bicyclo[3.1.0]hexyl and octahydro-2-pentalenyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN. In some embodiments,selected from 3-bicyclo[3.1.0]hexyl and octahydro-2-pentalenyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN. In some embodiments,is selected from 3-bicyclo[3.1.0]hexyl optionally substituted with one or more substituents independently selected from: halogen, -OH, -SH, -NH2, and -CN. In some embodiments,is selected from octahydro-2-pentalenyl, optionally substituted with one or more substituents independently selected from: halogen, -OH, -SH, -NH2, and -CN.

[0147] In some embodiments, for a compound or salt of Formula (A) or (II), R22is selected from

[0148] In some embodiments, for a compound or salt of Formula (A) or (II),monocyclic saturated carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33,-NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is C4-10monocyclic saturated carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33,-NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments,is C5-9monocyclic saturated carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0149] In some embodiments, for a compound or salt of Formula (A) or (II), R22is a cyclohexyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is a cyclohexyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is a cyclohexyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -CN. In some embodiments, R22is a cyclohexyl optionally substituted with one or more substituents independently selected from:,

[0150] In some embodiments, for a compound or salt of Formula (A) or (II), n is 1.

[0151] In some embodiments, for a compound or salt of Formula (A) or (II), R22is -[C(R25)2]-(4- to 12-membered heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)S(O)2R33, -C(O)OR33, -OC(O)R33, -S(O)R33, -S(O)2R33, -NO2, =O, =S, =N(R33), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)S(O)2R33, -C(O)OR33, -OC(O)R33, -S(O)R33, -S(O)2R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, - C(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)S(O)2R33, -C(O)OR33, -OC(O)R33, -S(O)R33, -S(O)2R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is -[C(R25)2]-(4- to 12-membered heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0152] In some embodiments, for a compound or salt of Formula (A) or (II), the 4- to 12- membered heterocycle of -[C(R25)2]-(4- to 12-membered heterocycle) is selected from a 4- to 12- membered monocyclic heterocycle and 4- to 12-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, the 4- to 12-membered heterocycle of -[C(R25)2]-(4- to 12-membered heterocycle) is selected from a 4- to 10-membered monocyclic heterocycle and 4- to 10-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0153] In some embodiments, for a compound or salt of Formula (A) or (II), R22is -[C(R25)2]-(4- to 12-membered monocyclic heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33,-NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is - [C(R25)2]-(4- to 10-membered monocyclic heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is -[C(R25)2]-(4- to 10-membered saturated monocyclic heterocycle), optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is -[C(R25)2]-(4- to 8-membered monocyclic heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is -[C(R25)2]-(5- to 7- membered monocyclic heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0154] In some embodiments, for a compound or salt of Formula (A) or (II), R22is -[C(R25)2]-(6- membered monocyclic heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S,=N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is - [C(R25)2]-(6-membered saturated monocyclic heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is 4-methylpiperidinyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is 4- methylpiperidinyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-3alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, and -CN; and C3-6carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is 4-methylpiperidinyl optionally substituted with one or more substituents independently selected from: C1-3alkyl optionally substituted with C3-6carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR33, -CN, C1-3alkyl, and C1-3 haloalkyl. In some embodiments, R22is 4-methylpiperidinyl optionally substituted with one or more substituents independently selected from: methyl,someembodiments, R22is selected from

[0155] In some embodiments, for a compound or salt of Formula (A) or (II), R22is -[C(R25)2]-(4- to 12-membered bicyclic fused heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is - [C(R25)2]-(4- to 10-membered bicyclic fused heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0156] In some embodiments, for a compound or salt of Formula (A) or (II), R22is selected from -[C(R25)2]-(4- to 8-membered bicyclic fused saturated heterocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is selected from -[C(R25)2]-(8-membered bicyclic fused saturated heterocycle) optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0157] In some embodiments, for a compound or salt of Formula (A) or (II), R22is selected from -[C(R25)2]-(6-membered bicyclic fused saturated heterocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is selected from 6-methyl-3-azabicyclo[3.1.0]hexyl and 5- methyloctahydrocyclopenta[c]pyrrolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is selected from 6-methyl-3-azabicyclo[3.1.0]hexyl and 5- methyloctahydrocyclopenta[c]pyrrolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is unsubstituted 6-methyl-3-azabicyclo[3.1.0]hexyl. In some embodiments, R22is unsubstituted 5-methyloctahydrocyclopenta[c]pyrrolyl. In some embodiments, R22is selected from

[0158] In some embodiments, for a compound or salt of Formula (A) or (II), R22is -[C(R25)2]-(C3-12carbocycle), represented byoptionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0159] In some embodiments, for a compound or salt of Formula (A) or (II), the C3-12carbocycleis selected from C3-12monocyclic carbocycle and C4-12 bicyclic carbocycle, optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, the C3-12carbocycle of ^ZZ^ isselected from C4- 10 monocyclic carbocycle and C4-10bicyclic carbocycle, optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionallysubstituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0160] In some embodiments, for a compound or salt of Formula (A) or (II), R22is -[C(R25)2]-( C4-12 bicyclic fused carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is - [C(R25)2]-( C4- 10 bicyclic fused carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is - [C(R25)2]-( C4- 10 bicyclic fused saturated carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0161] In some embodiments, for a compound or salt of Formula (A) or (II), R22is -[C(R25)2]-( Ce bicyclic fused carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is selected from 3- methylbicyclo[3.1.0]hexyl and 6-methylbicyclo[3.1.0]hexyl, each of which is optionallysubstituted with one or more substituents independently selected from: halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is selected from 3-methylbicyclo[3.1.0]hexyl and 6- methylbicyclo[3.1.0]hexyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN. In some embodiments, R22is selected from 3-methylbicyclo[3.1.0]hexyl and 6- methylbicyclo[3.1.0]hexyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, and -CN. In some embodiments, R22is selected from 3-methylbicyclo[3.1.0]hexyl and 6-methylbicyclo[3.1.0]hexyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -SH, -NH2, and -CN. In some embodiments,

[0162] In some embodiments, for a compound or salt of Formula (A) or (II), R22is -[C(R25)2]-( C4-12 monocyclic carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is -[C(R25)2]-( C4-10monocyclic carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is -[C(R25)2]-( C4-8monocyclic carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is -[C(R25)2]-( C5-7monocyclic carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

[0163] In some embodiments, for a compound or salt of Formula (A) or (II), R22is -[C(R25)2]-( Ce monocyclic carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is methylcyclohexyl, optionally substituted with one or more substituents independently selected from: halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, - N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22is methylcyclohexyl, optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; wherein each R33is independently selected at each occurrence from hydrogen and C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycleand 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN. In some embodiments, R22is methylcyclohexyl, optionally substituted with one or more substituents independently selected from: -N(R33)2; wherein each R33is independently selected at each occurrence from hydrogen and C1-6alkyl optionally substituted with one more substituents independently selected from C3-10carbocycle, wherein each C3-10carbocycle is optionally substituted with one or more substituents independently selected from: halogen, -OH,C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN. In some embodiments, R22is methylcyclohexyl, optionally substituted with one or more substituents independently selected from: -NH2,. In some embodiments, R22is selected from

[0164] In some embodiments, for a compound or salt of Formula (A) or (II), the compound is

[0165] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0166] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds or salts of Formula (A), (I), or (II), are intended to include all Z-, E- and tautomeric forms as well.

[0167] “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(+)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0168] The compounds or salts for Formula (A), (I), or (II), herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and / or trituration.

[0169] In certain embodiments, compounds or salts for Formula (A), (I), or (II), may comprise two or more enantiomers or diatereomers of a compound wherein a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers. Methods of producing substantially pure enantiomers are well known to those of skill in the art. For example, a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3): 283-302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for service basis.

[0170] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds or salts for Formula (A), (I), or (II), exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers may exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some nonlimiting examples of tautomeric equilibrium include:

[0171] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0172] In certain embodiments, the compounds disclosed herein have some or all of theatoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0173] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000;6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0174] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0175] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0176] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, thecompounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,11C,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35CI,37CI,79Br,81Br, and125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0177] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds of Formula (A), (I), or (II). The compounds of the present disclosure may possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.

[0178] The methods and compositions of Formula (A), (I), or (II), include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0179] Compounds of Formula (A), (I), or (II), also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0180] In certain embodiments, compounds or salts of Formula (A), (I), or (II), may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates(e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0181] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.

[0182] In certain embodiments, the prodrug may be converted, e.g., enzymatically or chemically, to the parent compound under the conditions within a cell. In certain embodiments, the parent compound comprises an acidic moiety, e.g., resulting from the hydrolysis of the prodrug, which may be charged under the conditions within the cell. In particular embodiments, the prodrug is converted to the parent compound once it has passed through the cell membrane into a cell. In certain embodiments, the parent compound has diminished cell membrane permeability properties relative to the prodrug, such as decreased lipophilicity and increased hydrophilicity.

[0183] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above-defined compounds. The compounds may be synthesized using conventional techniques.Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0184] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieserand Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).Pharmaceutical Formulations

[0185] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (A), (I), or (II), and at least one pharmaceutically acceptable excipient.

[0186] Pharmaceutical compositions can be formulated using one or more physiologically- acceptable carriers comprising excipients and auxiliaries. Formulation can be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a compound, salt or conjugate can be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate. The pharmaceutical compositions can also include the compounds, salts or conjugates in a free-base form or pharmaceutically-acceptable salt form.

[0187] Methods for formulation of the conjugates can include formulating any of the compounds, salts or conjugates with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives.

[0188] Pharmaceutical compositions may also be prepared from a compound or salt of any one of Formula (A), (I), or (II) and one or more pharmaceutically acceptable excipients suitable for transdermal, inhalative, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical composition are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001;Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999).Methods of Treatment

[0189] The compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.

[0190] The compositions containing the compound(s) described herein can be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.

[0191] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0192] In some aspects, the present disclosure provides a method of treating cancer, comprising administering to a subject in need thereof a compound or salt of Formulas (A), (I), or (II), or a pharmaceutical composition of Formula (A), (I), or (II). In some embodiments, the administering comprises a compound or salt of Formula (A), or a pharmaceutical composition thereof. In some embodiments, the administering comprises a compound or salt of Formula (I), or a pharmaceutical composition thereof. In some embodiments, the administering comprises a compound or salt of Formula (II), or a pharmaceutical composition thereof. In some embodiments, the cancer is selected from breast cancer, bladder cancer, cervical cancer, colon cancer, kidney cancer, liver cancer, lung cancer, head and neck cancer, skin cancer, pancreatic cancer, ovarian cancer, esophageal cancer, prostate cancer, and leukemia. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the caner is cervical cancer. In some embodiments, the cancer is colon cancer. Insome embodiments, the cancer is kidney cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments the cancer is esophageal cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is leukemia.

[0193] In some aspects, the present disclosure provides a method of modulating a SMYD protein, comprising administering to a patient in need thereof a compound or salt of Formulas (A), (I), or (II), or a pharmaceutical composition of Formulas (A), (I), or (II). In some embodiments, the administering comprises a compound or salt of Formula (A), or a pharmaceutical composition thereof. In some embodiments, the administering comprises a compound or salt of Formula (I), or a pharmaceutical composition thereof. In some embodiments, the administering comprises a compound or salt of Formula (II), or a pharmaceutical composition thereof. In some embodiments, the SMYD protein is selected from SMYD2 and SMYD3. In some embodiments, the SMYD protein is SMYD2. In some embodiments, the SMYD protein is SMYD3.

[0194] In some aspects, the present disclosure provides a method of inhibiting a SMYD protein comprising administering to a patient in need thereof a compound or salt of Formulas (A), (I), or (II), or a pharmaceutical composition of Formulas (A), (I), or (II). In some embodiments, the administering comprises a compound or salt of Formula (A), or a pharmaceutical composition thereof. In some embodiments, the administering comprises a compound or salt of Formula (I), or a pharmaceutical composition thereof. In some embodiments, the administering comprises a compound or salt of Formula (II), or a pharmaceutical composition thereof. In some embodiments, the SMYD protein is selected from SMYD2 and SMYD3. In some embodiments, the SMYD protein is SMYD2. In some embodiments, the SMYD protein is SMYD3.

[0195] Examples

[0196] The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention in any way.

[0197] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similarmethods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.

[0198] Examples 1 to 91 and Examples 93 to 251 show general and exemplary procedures for the preparation of the claimed SMYD modulators. One of ordinary skill in the art will appreciate that variations on the following synthetic procedures may be necessary to obtain compounds disclosure herein, including changes in protecting group chemistry, reaction conditions, and / or order of synthetic steps. Such variations are within the ability of the ordinarily skilled artisan.

[0199] For the sake of conciseness, certain abbreviations are used herein. Some of the abbreviations and their corresponding names are as follows. It is noted that, for those abbreviations not specified, the person of ordinary skill in the art will understand the meaning by referring to the context and the general knowledge in the chemistry field.

[0200] Intermediates

[0201] Example 1: Synthesis of (1R,3r,5S)-8-(((1-methylpiperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-amine (Int 1)Step 1 Step 2Step 3

[0202] Step 1: Benzyl 4-((((1R,3r, 5S)-3-((ferf-butoxycarbonyl)amino)-8-azabicyclo[3.2.1]octan- 8-yl)sulfonyl)methyl)piperidine-1-carboxylate. To a solution of benzyl 4- ((chlorosulfonyl)methyl)piperidine-1-carboxylate (7.32 g, 22.1 mmol, 1.0 eq) in anhydrous DCM (10 mL) was added tert-butyl ((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)carbamate (5.0 g, 22.1 mmol, 1 eq) and DIEA (8.56 g, 66.4 mmol, 3 eq) in anhydrous DCM (50 mL) at 0 °C slowly under nitrogen. The resulting mixture was stirred at 0 °C for 1 h. The mixture was diluted with DCM (150 mL) and sequentially washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by silica gel column chromatography (0-100 % EA in PE) to give the title compound (8 g, 69 % yield) as a white solid. LCMS: ESI-MS m / z: 422.2 [M+H-100]+.

[0203] Step 2: tert-Butyl ((1R,3r,5S)-8-(((1-methylpiperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1] octan-3-yl)carbamate. To a solution of e benzyl 4-((((1R,3 r,5S)-3-((tert- butoxycarbo nyl)amino)-8-azabicyclo[3.2.1] octan-8-yl)sulfonyl)methyl)piperidine-1-carboxylate (8 g, 15.4 mmol, 1 eq) in MeOH (80 ml) was added Pd-C (3.28 g, 30.8 mmol, 10 %, 2 eq). Themixture was stirred under H2(ballon)at room temperature for 3 h. HCHO (a.q., 8 mL) was added to the mixture. The resulting mixture was stirred at room temperature for overnight. The catalyst was filtered off and the filtrate was concentrated in vacuum. The residue was purified by silica gel column chromatography (0-20 % MeOH in DCM) to give the title compound (4.9 g, 79% yield) as a white solid. LCMS: ESI-MS m / z: 402.1 [M+H]+.

[0204] Step 3: (1R,3r,5S)-8-(((1-methylpiperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-amine. A solution of tert-butyl ((1R,3r,5S)-8-(((1-methylpiperidin-4- yl)methyl)sulfonyl)-8-azabicyclo [3.2.1] octan-3-yl)carbamate (4.9 g, 12.2 mmol 1 eq) in HCl- dioxane (4 M, 30 mL) was stirred at room temperature for overnight. The mixture was concentrated in vacuum to give the title compound (4 g, HCl salt) as a white solid. LCMS: ESI- MS m / z: 302.2 [M+H]+.

[0205] Example 2: Synthesis of tert-Butyl 6-(chlorosulfonyl)-2,6-diazaspiro[3.4]octane-2- carboxylate (Int 2)

[0206] Step 1 : tert-Butyl 6-(chlorosulfonyl)-2,6-diazaspiro[3.4]octane-2-carboxylate. To a solution of tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (2 g, 9.4 mmol, 1 eq) and pyridine (1.12 g, 14.1 mmol, 1.5 eq) in DCM (20 mL) was added a solution of SO2CI2(1.52 g, 11.2 mmol, 1.2 eq) in DCM (20 mL) dropwise at 0 °C. The reaction was stirred at R.T. overnight. The mixture was washed with HCl (1 M ), H2O and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give tert-butyl 6-(chlorosulfon yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (2.2 g, 75.3 % yield) as a yellow solid. LCMS: ESI- MS m / z: 255.1 [M+H-t-Bu]+.

[0207] Example 3: Synthesis of benzyl ((1R,3r,5S)-8-(chlorosulfonyl)-8-azabicyclo[3.2.1]octan- 3-yl)carbamate (Int 3)Step 3

[0208] Step 1 : tert-Butyl (1R,3r,5S)-3-(((benzyloxy)carbonyl)amino)-8-azabicyclo[3.2.1]octane- 8-carboxylate. To a solution of tert-butyl (1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8- carboxylate (5 g, 22.1 mmol, 1.0 eq) and DIEA (8.6 g, 66.4 mmol, 3 eq) in anhydrous DCM (50 mL) was added CbzCl (4.2 g, 24.3 mmol, 1.1 eq) at 0 °C slowly under nitrogen. The resulting mixture was stirred at 0 °C for 2 h. The mixture was diluted with DCM (150 mL) and sequentially washed with HCl (1 M), Water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by silica gel column chromatography (0-50 % EA in PE) to give the title compound (6 g, 75 % yield) as a white solid. LCMS: ESI-MS m / z: 261.2 [M+H-100]+.

[0209] Step 2: Benzyl ((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)carbamate. A solution of tert- butyl (1R,3r,5S)-3-(((benzyloxy)carbonyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (6 g, 16.6 mmol, 1 eq) in HCl-dioxane (4 M, 50 mL) was stirred at room temperature for 1 h. The mixture was concentrated in vacuum to give the title compound (5 g, crude ) as a white solid. LCMS: ESI-MS m / z. 261.1 [M+H]+.

[0210] Step 3: Benzyl ((1R,3r,5S)-8-(chlorosulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate. The solution of benzyl ((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)carbamate (1.0 g, 3.84 mmol, 1 eq) and Py (0.46 g, 5.76 mmol, 1.5 eq) in anhydrous DCM (10 mL) was added to a solution of sulfuryl chloride (0.62 g, 4.6 mmol, 1.2 eq) in anhydrous DCM (5 mL) slowly at 0 °C under nitrogen. The reaction was stirred at room temperature overnight. The mixture was diluted with DCM (50 mL) and sequentially washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The resulting residue was purified by silica gel column chromatography (0-50 % ethyl acetate in Petroleum ether) to give the title compound (0.6 g, 43 % yield) as a white solid. LCMS: ESI-MS m / z. 381.1 [M+Na]+.

[0211] Example 4: Synthesis of tert-Butyl ((3aR,5s,6aS)-2-(chlorosulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)carbamate (Int 4)

[0212] Step 1 : tert-Butyl ((3aR,5s,6aS)-2-(chlorosulfonyl)octahydrocyclopenta[c]pyrrol-5-yl) carbamate. To a solution of sulfuryl dichloride (358 mg, 2.65 mmol, 1.2 eq) in DCM (7 mL) was added a solution of tert-butyl ((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)carbamate (500 mg, 2.21 mmol, 1.0 eq) and pyridine (262 mg, 3.31 mmol, 1.5 eq) in DCM (3 mL) under an atmosphere of argon at 0 °C. The resulting mixture was stirred at room temperature for 5 h. The reaction was quenched with water (1 mL) and washed with HCl (1 M). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum to afford tert-butyl ((3aR,5s, 6aS)-2-(chlorosulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)carbamate (550 mg, crude) as a white solid. Used without further purification. LCMS: ESI-MS m / z. 347.1 [M+Na]+.

[0213] Example 5: Synthesis of N-((1R,3r,5S)-8-Azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3- yl)isoxazole-3-carboxamide (Int 5)

[0214] Step 1: 3-Ethynyloxetane. To a solution of oxetane-3-carbaldehyde (20 g, 232.3 mmol, 1 equiv) in methanol (200 mL) was added Ohira-Bestmann reagent (66.94 g, 34.85 mmol, 1.5 equiv) and potassium carbonate (64.21 g, 464.6 mmol, 2 equiv) at 0°C. The reaction mixture was stirred at 0°C for 3 h. The reaction was quenched with water and extracted with ethyl ether (200 mL x2). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to 200 mL. The solution was used directly in next step withoutfurther purification.1H NMR (400 MHz, CDCI3) δ 4.74 (ddd, J = 8.5, 5.6, 1.2 Hz, 2H), 4.65 (ddd, J = 7.1, 5.7, 1.2 Hz, 2H), 3.81 - 3.75 (m, 1H), 1.99 (d, J = 1.2 Hz, 1H).

[0215] Step 2: Ethyl 5-(oxetan-3-yl)isoxazole-3-carboxylate. To a solution of 3-ethynyloxetane in diethyl ether (200 mL) was added ethyl 2-chloro-2-(hydroxyimino)acetate (42 g, TH .6 mmol, 1 equiv) at 0°C. Then triethylamine (52 g, 555.3 mmol, 2 equiv) was added slowly to the reaction at 0°C over Ih. The mixture was stirred at 25°C for 18 h. The reaction was quenched with water (200 mL) and extracted with ethyl acetate (200 mLx 2). The combined organic layers were washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0-20% EtOAc in PE) to give ethyl 5-(oxetan-3-yl)isoxazole-3-carboxylate (12.2 g, two step yield 24%) as a light-yellow solid. LCMS: ESI-MS m / z: 197.9 [M+H]+.

[0216] Step 3: 5-(Oxetan-3-yl)isoxazole-3-carboxylic acid. To a solution of ethyl 5-(oxetan-3- yl)isoxazole-3-carboxylate (12.2 g, 61.9 mmol, 1 equiv) in tetrahydrofuran / water (v / v = 2 / 1, 24 mL) was added lithium hydroxide monohydrate (3.9 g, 92.8 mmol, 1.5 equiv). The reaction mixture was stirred at 25°C for 3 h. The reaction was diluted with water, then the pH was set to ~2 using 2 M aq. HCl solution. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 5-(oxetan-3- yl)isoxazole-3-carboxylic acid (9.8 g) as a light-yellow solid, which was used for the next step without further purification. LCMS: ESI-MS m / z: 169.9 [M+H]+.

[0217] Step 4 : tert-Butyl (1R,3r,5S)-3-(5-(Oxetan-3-yl)isoxazole-3-carboxamido)-8- azabicyclo[3.2.1]octane-8-carboxylate. To a solution of 5-(oxetan-3-yl)isoxazole-3-carboxylic acid (7.56 g, 44.7 mmol, 1 equiv) in DMAc (50 mL) was added N-Boc-endo-3-aminotropane (12.19 g, 53.6 mmol, 1.2 equiv) and NMI (12.85 g, 156.4 mmol, 3.5 equiv). Then TCFH (18.81 g, 67.1 mmol, 1.5 equiv) was added to the mixture. The mixture was stirred at 25°C for 2 h. The reaction was quenched with water (200 mL) and extracted with ethyl acetate (200 mLx2). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0-25% EtOAc in DCM) to give tert-butyl (1R,3r,5S)-3-(5-(oxetan-3-yl)isoxazole-3- carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate (13.9 g, yield 78%) as a light-yellow solid. LCMS: ESI-MS m / z: 399.9 [M+Na]+.

[0218] Step 5: N-((1R,3r,5S)-8-Azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3-yl)isoxazole-3- carboxamide. To a stirred solution of tert-butyl (1R,3r,5S)-3-(5-(oxetan-3-yl)isoxazole-3- carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate (13.9 g, 36.7 mmol, 1 equiv) in DCM (90mL) was added TFA (30 mL), and the resulting mixture was stirred at 25°C for 3 h. Then solvent was removed under reduced pressure. The resulting residue was dissolved with water, then the pH was set to ~12 using 2 M aq. NaOH solution. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give N-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3-yl)isoxazole-3-carboxamide (9.2 g) as a light-yellow solid, which was used for the next step without further purification. LCMS: ESI-MS m / z: 277.9 [M+H]+.

[0219] Example 6: Synthesis of 5-Cyclopropyl-N-((3aR,5s,6aS)-octahydrocyclopenta(c)pyrrol-5- yl)isoxazole-3-carboxamide (Int 6)

[0220] Step 1: tert-Butyl (3aR,5s,6aS)-5-(5-cyclopropylisoxazole-3- carboxamido)hexahydrocyclo penta(c)pyrrole-2(1H)-carboxylate. To a solution of 5- cyclopropylisoxazole-3-carboxylic acid (2.6 g, 17 mmol, 1 equiv), tert-butyl (3aR,5s,6aS)-5- aminohexahydrocyclopenta(c)pyrrole-2(1H)- carboxylate (4.25 g, 18.7 mmol, 1.1 equiv) and NMI (4.88 g, 59.5 mmol, 3.5 equiv) in DMAc (30 mL) was added TCFH (7.15 g, 25.5 mol, 1.5 equiv) stirred under nitrogen at 25°C. The reaction mixture was stirred at 25°C for 2h. The reaction mixture was quenched with water (150 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0-33% EtOAc in hexane) to give tert-butyl (3aR,5s,6aS)-5-(5- cyclopropylisoxazole-3-carboxamido)hexahydrocyclopenta(c)pyrrole-2(1H)-carboxylate (5 g, 72.9% yield) as a white solid. LCMS: ESI-MS m / z: 384.2 [M+Na]+.

[0221] Step 2: 5-Cyclopropyl-N-((3aR,5s,6aS)-octahydrocyclopenta(c)pyrrol-5-yl)isoxazole- 3-carboxamide. To a solution of tert-butyl (3aR,5s,6aS)-5-(5-cyclopropylisoxazole-3- carboxamido)hexahydrocyclopenta(c)pyrrole-2(1H)-carboxylate (2 g, 5.5 mmol, 1 equiv) in EtOAc (20 mL) stirred at 25°C was added 1,4-dioxane / HCl (4M, 10 mL, 40 mmol, 7.3 equiv). The reaction mixture was stirred at 25°C for 2h. LCMS showed the rection was completed, the mixture was evaporated. The residue was diluted with DCM (30 mL) and adjusted PH to 9 by saturated NaHCO3solution. After separated, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purifiedby silica gel column chromatography (0-10% MeOH in DCM) to give 5-cyclopropyl-N- ((3aR,5s,6aS)-octahydrocyclopenta(c)pyrrol-5-yl)isoxazole-3-carboxamide (1.2 g, 67.3% yield) as a white solid. LCMS: ESI-MS m / z: 262.1 [M+H]+.

[0222] Example 7: Synthesis of N-((1R,3r,5S)-8-(((1-Methylpiperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3-yl)isoxazole-3-carboxamide (Compound 1)

[0223] Step 1: N-((1R,3r,5S)-8-(((1-Methylpiperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3-yl)isoxazole-3-carboxamide. To a solution of 5- (oxetan-3-yl)isoxazole-3-carboxylic acid (20 mg, 0.12 mmol, 1.0 equiv) in DMSO (3 mL) was added (1R,3r,5S)-8-(((1-methylpiperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- amine (47 mg, 0.15 mmol, 1.3 equiv) and NMI (34 mg, 0.41 mmol, 3.5 equiv). Then TCFH (50 mg, 0.18 mmol, 1.5 equiv) was added. The mixture was stirred at 25°C for 3 h. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0-25% EtOAc in PE) to give N- ((1R,3r,5S)-8-(((1-methylpiperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- (oxetan-3-yl)isoxazole-3-carboxamide (2.55 mg, yield 4.65%) as a light-yellow solid.1H NMR (400 MHz, CD3OD) δ 6.63 (s, 1H), 4.94 (dd, J = 8.5, 6.1 Hz, 2H), 4.72 (t, J = 6.4 Hz, 2H), 4.46 (td, J = 8.5, 4.3 Hz, 1H), 4.17 (s, 2H), 4.08 (t, J = 6.6 Hz, 1H), 3.43 (d, J = 12.2 Hz, 2H), 3.05 (d, J = 1.3 Hz, 2H), 3.02 - 2.82 (m, 2H), 2.77 (s, 3H), 2.25 - 2.04 (m, 5H), 2.05 - 1.96 (m, 4H), 1.92 (d, J = 14.9 Hz, 2H), 1.52 (d, J = 11.1 Hz, 2H). LCMS: ESI-MS m / z: 452.9 [M+H]+.

[0224] Example 8: Synthesis of N-((1R,3r,5S)-8-((2,6-Diazaspiro[3.4]octan-6-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3-yl)isoxazole-3-carboxamide (Compound 2)

[0225] Step 1 : tert-butyl 6-(((1R,3r,5S)-3-(5-(Oxetan-3-yl)isoxazole-3-carboxamido)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)-2,6-diazaspiro[3.4]octane-2-carboxylate. To a solution of N-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3-yl)isoxazole-3-carboxamide (250 mg, 0.9 mmol, 1 equiv) in DCM (4 mL) was added triethylamine (274 mg, 2.7 mmol, 3 equiv) at 0°C. Then a solution of tert-butyl 6-(chlorosulfonyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (394 mg, 1.26 mmol, 1.4 equiv) in DCM (1 mL) was added to the reaction at 0°C. The mixture was stirred at 25°C for 18 h. The reaction was diluted with DCM, then washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0-20% EtOAc in DCM) to give tert-butyl 6-(((1R,3r,5S)-3-(5-(oxetan-3-yl)isoxazole-3-carboxamido)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (390 mg, yield 72%) as a light-yellow solid. LCMS: ESI-MS m / z: 573.8 [M+Na]+.

[0226] Step 2: N-((1R,3r,5S)-8-((2,6-Diazaspiro[3.4]octan-6-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3-yl)isoxazole-3-carboxamide. To a stirred solution of tert-butyl 6-(((1R,3r,5S)-3-(5-(oxetan-3-yl)isoxazole-3-carboxamido)-8-azabicyclo[3.2.1]octan- 8-yl)sulfonyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (380 mg, 0.69 mmol, 1 equiv) in DCM (6 mL) was added TFA (2 mL), and the resulting mixture was stirred at 25°C for 3 h. Then solvent was removed under reduced pressure. The mixture was dissolved with ethyl acetate and the pH was set to ~12 using 1 M aq. NaOH solution. The mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0-15% MeOH in DCM) to give N-((1R,3r,5S)-8-((2,6-diazaspiro[3.4]octan-6-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3-yl)isoxazole-3-carboxamide (280 mg, yield 87%) as a light-yellow solid.1H NMR (400 MHz, CD3OD) δ 6.73 (s, 1H), 5.04 (dd, J = 8.5, 6.1 Hz, 2H),4.82 (t, 7= 6.4 Hz, 2H), 4.60 - 4.51 (m, 1H), 4.16 (dd, J = 6.0, 1.0 Hz, 3H), 4.09 (q, J = 11.0 Hz, 4H), 3.55 (s, 2H), 3.38 (t, J = 7.1 Hz, 2H), 2.33 - 2.26 (m, 4H), 2.18 - 2.10 (m, 2H), 2.07 (t, J = 8.3 Hz, 2H), 1.99 (d, J = 14.9 Hz, 2H). LCMS: ESI-MS m / z: 451.9 [M+H]+.

[0227] Example 9: Synthesis of N-((1R,3r,5S)-8-((2-Methyl-2,6-diazaspiro[3.4]octan-6- yl)sulfonyl)-8-azabicyclo[3.2.1] octan-3-yl)-5-(oxetan-3-yl)isoxazole-3-carboxamide (Compound 3)

[0228] Step 1: N-((1R,3r,5S)-8-((2-Methyl-2,6-diazaspiro[3.4]octan-6-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3-yl)isoxazole-3-carboxamide. To a solution of N- ((1R,3r,5S)-8-((2,6-diazaspiro[3.4]octan-6-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-(oxetan- 3-yl)isoxazole-3-carboxamide (80 mg, 0.18 mmol, 1 equiv) in MeOH (3 mL) was added formaldehyde aqueous solution (29 mg, 0.36 mmol, 37% in water, 2 equiv). Then NaBH3CN (23 mg, 0.36 mmol, 2 equiv) was added. The mixture was stirred at 25°C for 1 h. Then solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-10% MeOH in DCM) to give N-((1R,3r,5S)-8-((2-methyl-2,6- diazaspiro[3.4]octan-6-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3-yl)isoxazole-3- carboxamide (40 mg, 44% yield) as a light-yellow solid.1H NMR (400 MHz, CD3OD) δ 6.73 (s, 1H), 5.04 (dd, J = 8.5, 6.1 Hz, 2H), 4.82 (t, J = 6.4 Hz, 2H), 4.60 - 4.51 (m, 1H), 4.20 - 4.14 (m, 3H), 4.09 (q, J = 10.5 Hz, 4H), 3.54 (s, 2H), 3.37 (t, 7 = 7.1 Hz, 2H), 2.90 (s, 3H), 2.32 (dd, J = 6.2, 4.7 Hz, 1H), 2.28 (t, 7 = 7.1 Hz, 3H), 2.18 - 2.11 (m, 2H), 2.07 (dd, 7 = 11.0, 5.6 Hz, 2H), 1.99 (d, 7= 15.1 Hz, 2H). LCMS: ESI-MS m / z: 465.8 [M+H]+.

[0229] Example 10: Synthesis of 5-((1S,2S)-2-Methylcyclopropyl)-N-((1R,3r,5S)-8-(((1- methylpiperidin-4-yl)methyl) sulfonyl)-8-azabicyclo(3.2.1)octan-3-yl)isoxazole-3-carboxamide & 5-((1R,2S)-2-Methylcyclopropyl)-N-((1R,3r,5S)-8-(((1-methylpiperidin-4- yl)methyl)sulfonyl)-8-azabicyclo(3.2.1)octan-3-yl)isoxazole-3-carboxamide (Compound 4 & Compound 5).* indicates a stereocenter with unknown absolute stereochemistry

[0230] Step 1: 5-((1S,2S)-2-Methylcyclopropyl)-N-((1R,3r,5S)-8-(((1-methylpiperidin-4- yl)methyl) sulfonyl)-8-azabicyclo(3.2.1)octan-3-yl)isoxazole-3-carboxamide & 5-((1R,2S)-2- Methylcyclopropyl)-N-((1R,3r,5S)-8-(((1-methylpiperidin-4-yl)methyl)sulfonyl)-8- azabicyclo(3.2.1)octan-3-yl)isoxazole-3-carboxamide. To a solution of 5-(2- Methylcyclopropyl)isoxazole-3-carboxylic acid (70 mg, 0.42 mmol, 1.0 equiv), (1R,3r,5S)-3-(12- Azaneyl)-8-(((1-methylpiperidin-4-yl)methyl)sulfonyl)-8-azabicyclo(3.2.1)octane (126 mg, 0.42 mmol, 1.0 equiv) and NMI (104 mg, 1.26 mmol, 3 equiv) in DMSO (4 mL) stirred under nitrogen at 25°C was added a solution of TCFH (176 mg, 0.63 mmol, 1.5 equiv) in DMSO (1 mL). The reaction mixture was stirred at 25°C for 2h. Then the mixture was purified by prep- HPLC (Method , 0-10% MeCN in H2O + 0.1% FA) to afford 5-((2S)-2-Methylcyclopropyl)-N- ((1R,3r,5S)-8-(((1-methylpiperidin-4-yl)methyl)sulfonyl)-8-azabicyclo(3.2.1)octan-3- yl)isoxazole-3-carboxamide (Compound 4, 20.41 mg, 12.2% yield) as a white solid.1H NMR (400 MHz, CD3OD) δ 6.34 (s, 1H), 4.27 (s, 2H), 4.17 (t, J = 6.3 Hz, 1H), 3.55 (d, J = 11.8 Hz, 2H), 3.15 (d, J = 4.5 Hz, 2H), 3.07 (t, J = 12.5 Hz, 2H), 2.88 (s, 3H), 2.32 - 2.19 (m, 5H), 2.08 (d, J = 9.8 Hz, 4H), 2.01 (d, J = 14.7 Hz, 2H), 1.93 - 1.84 (m, 1H), 1.63 (d, J = 12.5 Hz, 2H), 1.36 (dd, J = 11.8, 7.1 Hz, 1H), 1.22 (d, J =5.9 Hz, 3H), 1.20 - 1.15 (m, 1H), 0.95 (dt, J = 8.7, 5.6 Hz, 1H). LCMS: ESI-MS m / z: 451.2 [M+H]+.

[0231] 5-((2S)-2-Methylcyclopropyl)-N-((1R,3r,5S)-8-(((1-methylpiperidin-4- yl)methyl)sulfonyl)-8-azabicyclo(3.2.1)octan-3-yl)isoxazole-3-carboxamide (Compound 5, 3.71 mg, 2.2% yield) as a white solid.1HNMR (400 MHz, CD3OD) δ 6.39 (s, 1H), 4.23 (s, 2H), 4.14 (t, J = 5.9 Hz, 1H), 3.48 (s, 2H), 3.08 (d, J = 35.0 Hz, 4H), 2.84 (s, 3H), 2.21 (tt, J = 23.0, 7.1 Hz, 6H), 2.07 (s, 4H), 1.98 (d, J = 14.6 Hz, 2H), 1.60 (s, 2H), 1.44 - 1.34 (m, 1H), 1.28 - 1.24 (m, 1H), 0.96 (d, J = 6.2 Hz, 3H), 0.80 (dd, J = 11.2, 5.6 Hz, 1H). LCMS: ESI-MS m / z: 451.2 [M+H]+.

[0232] Example 11: Synthesis of 5-(1-Hydroxycyclopropyl)-N-((1R,3r,5S)-8-(((1- methylpiperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide (Compound 6)

[0233] Step 1: 5-(1-Hydroxycyclopropyl)isoxazole-3-carboxylic acid. To a solution of ethyl 5- (1-hydroxycyclopropyl)isoxazole-3-carboxylate (90 mg, 0.46 mmol, 1 equiv) in THF / water (v / v = 2 / 1, 3 mL) was added Lithium hydroxide (29 mg, 0.69 mmol, 1.5 equiv) at 0°C. The reaction mixture was stirred at 0°C for 1 h. The reaction mixture was stirred at 0°C for 1 h. The reaction was diluted with water, then the pH was set to ~2 using 2 M aq. HCl solution. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 5-(1-hydroxycyclopropyl)isoxazole-3-carboxy lie acid (40 mg) as a light-yellow solid, which was used for the next step without further purification. LCMS: ESI-MS m / z: 169.9 [M+H]+.

[0234] Step 2: 5-(1-Hydroxycyclopropyl)-N-((1R,3r,5S)-8-(((1-methylpiperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide. To a solution of 5- (1-hydroxycyclopropyl)isoxazole-3-carboxylic acid (40 mg, 0.24 mmol, 1.0 equiv) in DMSO (3 mL) was added (1R,3r,5S)-8-(((1-methylpiperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-amine (94 mg, 0.30 mmol, 1.3 equiv) and NMI (68 mg, 0.82 mmol, 3.5 equiv). Then TCFH (100 mg, 0.36 mmol, 1.5 equiv) was added. The mixture was stirred at 25°C for 3 h. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by RP-HPLC (0-25% MeCN in H2O + 0.1% FA) to give 5-(1-hydroxycyclopropyl)-N-((1R,3r,5S)-8-(((1-methylpiperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide (3.30 mg, yield 3%) as a white solid.1H NMR (400 MHz, CD3OD) δ 8.50 (s, 1H), 6.58 (s, 1H), 4.26 (s, 2H), 4.17 (t, J = 6.6 Hz, 1H), 3.39 (d, J = 12.2 Hz, 2H), 3.14 (d, J = 6.0 Hz, 2H), 2.92 (t, J = 11.8 Hz, 2H), 2.76 (s, 3H), 2.32 - 2.24 (m, 2H), 2.18 (d, J = 13.3 Hz, 3H), 2.13 - 2.05 (m, 4H), 2.01 (d, J = 14.9 Hz, 2H), 1.64 (dd, J = 25.5, 13.3 Hz, 2H), 1.26 (d, J = 3.2 Hz, 4H). LCMS: ESI-MS m / z: 453.3 [M+H]+.

[0235] Example 12: Synthesis of N-((1R,3R,5S)-8-((((1R,5S,6r)-3-Azabicyclo[3.1.0]hexan-6- yl)methyl)sulfonyl)-8-azabicyclo [3.2.1]octan-3-yl)-5-(oxetan-3-yl)isoxazole-3-carboxamide (Compound 7)Step 2

[0236] Step 1: Benzyl (1R,5S,6r)-6-((((1R,3R,5S)-3-(5-(oxetan-3-yl)isoxazole-3-carboxamido)- 8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. To a solution of N-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3-yl)isoxazole-3- carboxamide (170 mg, 0.61 mmol, 1 equiv) in DCM (4 mL) was added triethylamine (187 mg, 1.83 mmol, 3 equiv) at 0°C. Then a solution of benzyl (1R,5S,6r)-6-((chlorosulfonyl)methyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (283 mg, 0.86 mmol, 1.4 equiv) in DCM (1 mL) was added to the reaction at 0°C. The mixture was stirred at 25°C for 18 h. The reaction was diluted with DCM, then washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0-20% EtOAc in DCM) to give benzyl (1R,5S,6r)-6-((((1R,3R,5S)-3-(5- (oxetan-3-yl)isoxazole-3-carboxamido)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (170 mg, yield 44%) as a yellow solid. LCMS: ESI-MS m / z: 570.8 [M+H]+.

[0237] Step 2: N-((1R,3R,5S)-8-((((1R,5S,6r)-3-Azabicyclo[3.1.0]hexan-6-yl)methyl)sulfonyl)- 8-azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3-yl)isoxazole-3-carboxamide. A solution of benzyl (1R,5S,6r)-6-((((1R,3R,5S)-3-(5-(oxetan-3-yl)isoxazole-3-carboxamido)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (170 mg, 0.3 mmol, 1 equiv) in TFA (5 mL) was stirred at 25°C for 18 h. Then solvent was removed under reduced pressure. The mixture was dissolved with ethyl acetate and the pH was set to ~12 using 1 M aq. NaOH solution. The mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0-15% MeOH in DCM) togive N-((1R,3R,5S)-8-((((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3-yl)isoxazole-3-carboxamide (50 mg, yield 38%) as a white solid.1HNMR (400 MHz, CD3OD) δ 8.50 (s, 1H), 6.73 (s, 1H), 5.04 (dd, J = 8.5, 6.1 Hz, 2H), 4.82 (t, J = 6.3 Hz, 2H), 4.61 - 4.51 (m, 1H), 4.26 (s, 2H), 4.19 (t, J = 6.6 Hz, 1H), 3.47 - 3.38 (m, 4H), 3.15 (d, J = 7.0 Hz, 2H), 2.35 - 2.26 (m, 2H), 2.10 (s, 4H), 2.02 (d, J = 14.9 Hz,2H), 1.94 (s, 2H), 1.22 (tt, J = 6.9, 3.4 Hz, 1H). LCMS: ESI-MS m / z: 436.9 [M+H]+.

[0238] Example 13: Synthesis of Compound trans-5-((1R,2S)-2-Fluorocyclopropyl)- / V- ((1R,3r,5S)-8-(((1-methylpiperidin-4-yl)methyl) sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide (Compound 8)

[0239] Step 1 : trans- 1-(2-Fluorocyclopropyl)ethan-1-one. To a solution of trans-2- fluorocyclopropane-1-carboxylic acid (2 g, 19.2 mmol, 1 equiv) in Et2O (20 mL) stirred at -78 °C was added LiMe (24 mL, 1.6 M in Et2O, 38.4 mmol, 2.0 equiv). The mixture was stirred at -78 °C for 2 h. The reaction was quenched with 30 mL of saturated NH4CI solution and extracted with Et2O (20 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give trans- 1-(2-Fluorocyclopropyl)ethan-1-one which was dissolved in ethyl ether (5 mL). NMR (400 MHz, CDCI3) δ 4.76 - 4.57 (m, 1H), 2.49 - 2.31 (m, 1H), 2.27 (d, J = 1.5 Hz, 3H), 1.50 - 1.31 (m, 2H).

[0240] Step 2 : trans-Methyl 4-(2-fluorocyclopropyl)-2,4-dioxobutanoate. To a stirred solution of trans- 1-(2-Fluorocyclopropyl)ethan-1-one (in 5 mL Et2O) and diethyl oxalate (2.86 g, 19.6 mmol, 1 equiv) in 10 mL MeOH was added MeONa (6 mL, 5 M in MeOH, 1.5 equiv) and the resulting mixture was stirred at 25°C for 2 h. Then the solvent was removed under reduced pressure. The residue was dissolved with ethyl acetate and the pH was set to ~3 using 1 M HCl solution. The mixture was extracted with ethyl acetate (20 mL). The combined organic phase waswashed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give trans-methyl 4-(2-fluorocyclopropyl)-2,4-dioxobutanoate (500 mg) as a yellow oil, which was used for the next step without further purification.1H NMR (400 MHz, CDCI3) δ 6.56 (s, 1H), 5.01 - 4.92 (m, 0.5 H), 4.83 - 4.80 (m, 0.5 H), 2.51 - 2.37 (m, 1H), 2.35 (s, 3H), 1.63 - 1.46 (m, 2H).

[0241] Step 3 : trans-Methyl 5-(2-fluorocyclopropyl)isoxazole-3-carboxylate. To a solution of trans-methyl 4-(2-fluorocyclopropyl)-2,4-dioxobutanoate (400 mg, 2.13 mmol, 1.0 equiv) in MeOH (5 mL) was added hydroxylamine hydrochloride (295 mg, 4.25 mmol, 2 equiv). The mixture was stirred at 60°C for 2h. Then the solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (0-50% EtOAc in PE) to give trans-methyl 5-(2-fluorocyclopropyl)isoxazole-3-carboxylate (400 mg, 91% yield) as a yellow oil. LCMS: ESI-MS m / z: 185.9 [M+H]+.

[0242] Step 4 : trans-5-(2-fluorocyclopropyl)isoxazole-3-carboxylic acid. To a solution of trans- methyl 5-(2-fluorocyclopropyl)isoxazole-3-carboxylate (400 mg, 2.16 mmol, 1.0 equiv) in 10 mL THF / H2O (v / v = 4 / 1) was added LiOH (155 mg, 6.48 mmol, 3 equiv). The reaction mixture was stirred at 0°C for Ih. The mixture was dissolved with ethyl acetate (20 mL) and the pH was set to ~4 using 1 M HCl solution. The mixture was extracted with ethyl acetate (20 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give trans-5-(2-fluorocyclopropyl)isoxazole-3-carboxylic acid (400 mg, crude) which was used for the next step without further purification. LCMS: ESI-MS m / z: 172.0 [M+H]+.

[0243] Step 5 : trans-5-(2-Fluorocyclopropyl)-N-((1R,3r,5S)-8-(((1-methylpiperidin-4- yl)methyl) sulfonyl) -8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide. To a solution of trans-5-(2-fluorocyclopropyl)isoxazole-3-carboxylic acid (34 mg, 0.20 mmol, 1.5 equiv), TCFH (56 mg, 0.20 mmol, 1.5 equiv) and NMI (38 mg, 0.46 mmol, 3.5 equiv) in DMSO (3 mL) was added (1R,3r,5S)-8-(((1-methylpiperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- amine (40 mg, 0.13 mmol, 1.0 equiv). The mixture was stirred at 25°C for 2 h. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by RP-HPLC (0-30% MeCN in H2O + 0.1% FA) to give trans- 5-(2-fluorocyclopropyl)-N-((1R,3r,5S)-8-(((1-methylpiperidin-4-yl)methyl)sulfonyl)-8- azabicyclo [3.2.1]octan-3-yl)isoxazole-3-carboxamide (1.96 mg, 3% yield) as a white solid.1H NMR (400 MHz, CDCI3) δ 7.08 (d, J = 7.2 Hz, 1H), 6.39 (s, 1H), 4.98 - 4.67 (m, 1H), 4.31 -4.26 (m, 3H), 3.50 (d, J = 11.2 Hz, 2H), 2.97 (d, J = 5.9 Hz, 2H), 2.82 - 2.79 (m, 5H), 2.60 -2.51 (m, 1H), 2.32 - 2.17 (m, 7H), 2.04 - 1.83 (m, 6H), 1.76 - 1.65 (m, 1H), 1.37 - 1.29 (m, 1H).LCMS: ESI-MS m / z: 455.3 [M+H]+.

[0244] Example 14: Synthesis of N-((1R,3R,5S)-8-(((3aR,5S,6aS)-5-Aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3-yl)isoxazole-3-carboxamide (Compound 9)

[0245] Step 1: tert-butyl ((3aR,5S,6aS)-2-(((1R,3R,5S)-3-(5-(Oxetan-3-yl)isoxazole-3- carboxamido)-8-azabicyclo [3.2.1] octan-8 -yl) sulfonyl)octahydrocy clopenta[c]pyrrol-5- yl)carbamate. To a solution of N-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3- yl)isoxazole-3-carboxamide (200 mg, 0.72 mmol, 1 equiv) in DCM (5 mL) was added triethylamine (219 mg, 2.16 mmol, 3 equiv) at 0°C. Then a solution of tert-butyl ((3aR,5s,6aS)-2- (chloro sulfonyl) octahydrocyclopenta[c]pyrrol-5-yl)carbamate (306 mg, 0.94 mmol, 1.3 equiv) in DCM (3 mL) was added to the reaction at 0°C. The mixture was stirred at 25°C for 18 h. The reaction was diluted with DCM, then washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0-20% EtOAc in DCM) to give tert-butyl ((3aR,5S,6aS)- 2-(((1R,3R,5S)-3-(5-(Oxetan-3-yl)isoxazole-3-carboxamido)-8-azabicyclo[3.2.1]octan-8- yl)sulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)carbamate (370 mg, yield 81%) as a light-yellow solid. LCMS: ESI-MS m / z: 587.8 [M+Na]+.

[0246] Step 2: N-((1R,3R,5S)-8-(((3aR,5S,6aS)-5-Aminohexahydrocyclopenta[c]pyrrol-2(1H)- yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3-yl)isoxazole-3-carboxamide. To a stirred solution of tert-butyl ((3aR,5S,6aS)-2-(((1R,3R,5S)-3-(5-(Oxetan-3-yl)isoxazole-3- carboxamido)-8-azabicyclo [3.2.1] octan-8 -yl) sulfonyl)octahydrocy clopenta[c]pyrrol-5- yl)carbamate (350 mg, 0.62 mmol, 1 equiv) in DCM (9 mL) was added TFA (3 mL), and theresulting mixture was stirred at 25°C for 3 h. Then solvent was removed under reduced pressure. The mixture was dissolved with ethyl acetate and the pH was set to ~12 using 1 M aq. NaOH solution. The mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0-15% MeOH in DCM) to give N-((1R,3R,5S)-8- (((3aR,5S,6aS)-5-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3-yl)isoxazole-3-carboxamide (220 mg, yield 75%) as a white solid.1HNMR (400 MHz, CD3OD) δ 6.73 (s, 1H), 5.04 (dd, J = 8.5, 6.1 Hz, 2H), 4.82 (t, J = 6.4 Hz, 2H), 4.60 - 4.50 (m, 1H), 4.20 - 4.13 (m, 3H), 3.75 (p, 7 = 7.1 Hz, 1H), 3.28 (s, 2H), 3.10 (d, J = 10.0 Hz, 2H), 2.96 (d, J = 2.6 Hz, 2H), 2.34 - 2.26 (m, 2H), 2.13 (dd, 7 = 10.7, 5.8Hz, 2H), 2.07 (dd, 7 = 10.3, 6.2 Hz, 2H), 2.00 (d, 7 = 7.4 Hz, 2H), 1.95 (dd, 7 = 14.3, 6.6 Hz, 4H). LCMS: ESI-MS m / z: 466.2 [M+H]+.

[0247] Example 15: Synthesis of 5-(Cyclopropylmethyl)-N-((1R,3r,5S)-8-((piperidin-4- ylmethyl)sulfonyl)-8-azabicyclo[3.2.1] octan-3-yl)isoxazole-3-carboxamide (Compound 10)

[0248] Step 1: (3-Cyclopropylprop-1-yn-1-yl)trimethylsilane. To a solution of ethynyl(trimethyl)silane (6 g, 61.1 mmol, 1 equiv) in THF (60 mL) was added n-BuLi (2.5 M, 31.8 mL, 1.3 equiv) dropwise at -78°C under N2. The mixture was stirred at 0°C for 10 min. Then HMPA (16.42 g, 91.65 mmol, 1.5 equiv) was added dropwise at -78°C. The mixture was stirred at -78°C for 20 min under nitrogen atmosphere. Then (bromomethyl)cyclopropane (8.25 g, 61.1 mmol, 1 equiv) was added dropwise at -78°C. Then the mixture was stirred 25°C for 10 h. The reaction was quenched with water and extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0-5% EtOAc in PE) to give (3-cyclopropylprop-1-yn-1-yl)trimethylsilane (4.8 g, yield 46%) as a colorless oil.1H NMR (400 MHz, CDCI3) δ 2.29 (d, J = 5.7 Hz, 2H), 0.91 - 0.84 (m, 1H), 0.48 - 0.40 (m, 2H), 0.23 (q, J = 4.8 Hz, 2H), 0.14 (s, 9H).

[0249] Step 2: Prop-2-yn-1-ylcyclopropane. To a solution of ethyl (3-cyclopropylprop-1-yn-1- yl)trimethylsilane (4.8 g, 31.5 mmol, 1 equiv) in tetrahydrofuran (30 mL) was added TBAF (23.6 mL, 47.3 mmol, 2 M in THF, 1.5 equiv). The reaction mixture was stirred at 25°C for 3 h. The reaction was quenched with water and extracted with ethyl ether. The combined organic layers were washed with saturated citric acid aqueous solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The product prop-2-yn-1-ylcyclopropane was dissolved in ethyl ether (20 mL), which was used for the next step without further purification.

[0250] Step 3: Ethyl 5-(cyclopropylmethyl)isoxazole-3-carboxylate. To a solution of prop-2-yn- 1-ylcyclopropane in diethyl ether (20 mL) was added ethyl 2-chloro-2-(hydroxyimino)acetate (3.5 g, 23.1 mmol, 1 equiv) at 0°C. Then triethylamine (4.67 g, 46.2 mmol, 2 equiv) was added slowly to the reaction at 0°C. The mixture was stirred at 25°C for 18 h. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0-20% EtOAc in PE) to give ethyl ethyl 5-(cyclopropylmethyl)isoxazole-3-carboxylate (470 mg, two step yield 9.52%) as a colorless oil. LCMS: ESI-MS m / z: 195.9 [M+H]+.

[0251] Step 4: 5-(Cyclopropylmethyl)isoxazole-3-carboxylic acid. To a solution of ethyl ethyl 5- (cyclopropylmethyl)isoxazole-3-carboxylate (470 mg, 2.41 mmol, 1 equiv) in THF / water (v / v = 2 / 1, 9 mL) was added Lithium hydroxide (173 mg, 7.22 mmol, 3 equiv). The reaction mixture was stirred at 25°C for 3 h. The reaction was diluted with water, then the pH was set to ~2 using 2 M aq. HCl solution. The mixture was extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 5- (cyclopropylmethyl)isoxazole-3-carboxylic acid (360 mg) as a light-yellow solid, which was used for the next step without further purification. LCMS: ESI-MS m / z: 168.0 [M+H]+.

[0252] Step 5: Benzyl 4-((((1R,3r,5S)-3-(5-(cyclopropylmethyl)isoxazole-3-carboxamido)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)piperidine-1-carboxylate. To a solution of 5- (cyclopropylmethyl)isoxazole-3-carboxylic acid (60 mg, 0.36 mmol, 1 equiv) in DMAc (3 mL) was added benzyl 4-((((1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl) piperidine-1-carboxylate (166 mg, 0.39 mmol, 1.1 equiv) and NMI (103 mg, 1.26 mmol, 3.5 equiv). Then TCFH (151 mg, 0.54 mmol, 1.5 equiv) was added to the mixture. The mixture was stirred at 25°C for 2 h. The reaction was quenched with water and extracted with ethyl acetate (30 mLx2). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0-25% EtOAc in DCM) to give benzyl 4-((((1R,3r,5S)-3-(5- (cyclopropylmethyl)isoxazole-3-carboxamido)-8-azabicyclo[3.2.1]octan-8- yl)sulfonyl)methyl)piperidine-1-carboxylate (180 mg, yield 79%) as a light-yellow solid. LCMS: ESI-MS m / z: 571.3 [M+H]+.

[0253] Step 6: 5-(Cyclopropylmethyl)-N-((1R,3r,5S)-8-((piperidin-4-ylmethyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide. To a stirred solution of benzyl 4- ((((1R,3r,5S)-3-(5-(cyclopropylmethyl)isoxazole-3-carboxamido)-8-azabicyclo[3.2.1]octan-8- yl)sulfonyl)methyl)piperidine-1-carboxylate (180 mg, 0.32 mmol, 1 equiv) in DCM (3 mL) was added TFA (3 mL), and the resulting mixture was stirred at 25°C for 18 h. Then solvent was removed under reduced pressure. The mixture was dissolved with ethyl acetate and the pH was set to ~12 using 1 M aq. NaOH solution. The mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0-10% MeOH in DCM) to give 5-(cyclopropylmethyl)-N-((1R,3r,5S)-8-((piperidin-4-ylmethyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide (116 mg, yield 82%) as a white solid.1H NMR (400 MHz, CD3OD) δ 6.54 (s, 1H), 4.26 (s, 2H), 4.17 (t, J = 6.6 Hz, 1H), 3.43 - 3.37 (m, 2H), 3.14 (d, J = 6.3 Hz, 2H), 3.06 (td, J = 12.8, 2.8 Hz, 2H), 2.73 (d, J = 7.1 Hz, 2H), 2.33 - 2.24 (m, 3H), 2.20 (d, J = 14.5 Hz, 2H), 2.14 - 2.06 (m, 4H), 2.02 (d, J = 14.8 Hz, 2H), 1.59 (td, J = 14.8, 3.9 Hz, 2H), 1.09 (ddd, J = 12.4, 7.5, 4.8 Hz, 1H), 0.60 (q, 7 = 5.6 Hz, 2H), 0.27 (q, J = 4.9 Hz, 2H). LCMS: ESI-MS m / z: 436.9 [M+H]+.

[0254] Example 16: Synthesis of N-((1R,3R,5S)-8-((((1R,5S,6r)-3-((5-Fluoropyridin-2- yl)methyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- (oxetan-3-yl)isoxazole-3-carboxamide (Compound 11)

[0255] N-((1R,3R,5S)-8-((((1R,5S,6r)-3-((5-Fluoropyridin-2-yl)methyl)-3- azabicyclo[3.1.0]hexan-6-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3- yl)isoxazole-3-carboxamide. A solution of N-((1R,3R,5S)-8-((((1R,5S,6r)-3- Azabicyclo[3.1.0]hexan-6-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3- yl)isoxazole-3-carboxamide (Compound 7) (100 mg, 0.23 mmol, 1.0 equiv), 5-fluoropyridine-2- carbaldehyde (57 mg, 0.46 mmol, 2 equiv) and DIPEA (118 mg, 0.92 mmol, 4 equiv) in DMAc (2 mF) was stirred at rt for 2 h. The mixture was cooled to 0°C. Sodium cyanoborohydride (43 mg, 0.69 mmol, 3 equiv) was added to the mixture, the mixture was stirred at the room temperature for another 16 h. The reaction was quenched with saturated sodium bicarbonate solution (20 mL), then extracted with EtOAc (20 mLx2). The combined organic phase was washed brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (2-10% MeOH in DCM) to give N-((1R,3R,5S)-8-((((1R,5S,6r)-3-((5-Fluoropyridin-2-yl)methyl)-3- azabicyclo[3.1.0]hexan-6-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3- yl)isoxazole-3-carboxamide (6 mg, 6% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.26 (d, J = 2.6 Hz, 1H), 7.52 (td, J = 8.6, 2.8 Hz, 1H), 7.40 (dd, J = 8.6, 4.6 Hz, 1H), 6.63 (s, 1H), 4.94 (dd, J = 8.5, 6.1 Hz,2H), 4.72 (t, J = 6.4 Hz, 2H), 4.51 - 4.42 (m, 1H), 4.20 - 4.05 (m, 3H), 3.65 (s, 2H), 2.93 (t, J = 8.9 Hz, 4H), 2.42 (d, J = 8.2 Hz, 2H), 2.24 - 2.15 (m, 2H), 1.98(brs, 3H), 1.92-1.89(m, 1H), 1.53-1.51 m, 1H), 1.46 (brs, 2H), 1.19 - 1.12 (m, 1H). LCMS: ESI-MS m / z: 546.1 [M+H]+.

[0256] Example 17: Synthesis of N-((1R,3R,5S)-8-(((3aR,5S,6aS)-5-((2- Hydroxyethyl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3-yl)isoxazole-3-carboxamide (Compound 12)

[0257] Step 1: N-((1R,3R,5S)-8-(((3aR,5S,6aS)-5-((2-Hydroxyethyl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3-yl)isoxazole-3-carboxamide. A solution of N- ((1R,3R,5S)-8-(((3aR,5S,6aS)-5-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3-yl)isoxazole-3-carboxamide (50 mg, 0.11 mmol, 1.0 equiv), 2-bromoethanol (40 mg, 0.33 mmol, 3 equiv) and K2CO3(76 mg, 0.55 mmol, 5 equiv) in ACN (5 mL) was stirred at 40°C for 16 h. The reaction was diluted with DCM (20 mL), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (5-10% MeOH (2% NH3.H2O contained) in DCM) to give N-((1R,3R,5S)-8- (((3aR,5S,6aS)-5-((2-hydroxyethyl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-(oxetan-3-yl)isoxazole-3-carboxamide (14 mg, 25% yield) as a white solid.1H NMR (400 MHz, CD3OD) δ 6.74 (s, 1H), 5.06 (dd, J = 8.5, 6.1 Hz, 2H), 4.84 (t, J = 6.4 Hz, 2H), 4.62 - 4.53 (m, 1H), 4.22 - 4.14 (m, 3H), 3.68 (t, J = 5.6 Hz, 2H), 3.41 - 3.35 (m, 2H), 3.04 (dd, J = 9.8, 2.8 Hz, 2H), 2.92 - 2.86 (m, 2H), 2.77 (t, J = 5.6 Hz, 2H), 2.35 - 2.27 (m, 2H), 2.18 - 1.98 (m, 7H), 1.90 - 1.83 (m, 2H), 1.78 - 1.69 (m, 2H). LCMS: ESI-MS m / z: 510.0 [M+H]+.

[0258] Example 18: Synthesis of 5-(Oxetan-3-yl)-N-((1R,3R,5S)-8-(((3aR,5S,6aS)-5-((4,4,4- trifluorobutyl)amino)Hexahydro cyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide (Compound 13)

[0259] Step 1: 5-(Oxetan-3-yl)-N-((1R,3R,5S)-8-(((3aR,5S,6aS)-5-((4,4,4- trifluorobutyl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)-8-azabicyclo[3.2.1]octan- 3-yl)isoxazole-3-carboxamide. A solution of N-((1R,3R,5S)-8-(((3aR,5S,6aS)-5- aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- (oxetan-3-yl)isoxazole-3-carboxamide (75 mg, 0.16 mmol, 1.0 equiv), 4,4,4-trifluorobutanal (20 mg, 0.16 mmol, 1 equiv) and DIPEA (104 mg, 0.81 mmol, 5 equiv) in DMAc (2 mL) was stirred at rt for 2 h. The mixture was cooled to 0°C. STAB (102 mg, 0.48 mmol, 3 equiv) was added tothe mixture. The mixture was stirred at the same temperature for another 4 h. The reaction was quenched with saturated sodium bicarbonate solution (10 mL), then extracted with EtOAc (10 mL). The organic phase was washed brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica ...

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A compound represented by the structure of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is a 4- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)S(O)2R11, -C(O)OR11, -OC(O)R11, -S(O)R11, -S(O)2R11, -NO2, -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11. -C(O)OR11, -OC(O)R11, -S(O)R11, -S(O)2R11, -NO2, =O, =S, =N(R11), and -CN;Ring A is selected from 6- to 12-membered heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -C(O)OR12, -OC(O)R12, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -C(O)OR12, -OC(O)R12, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN;R2is selected from -[C(R15)2]n-(3- to 12-membered heterocycle) and -[C(R15)2]n-(C3-12carbocycle), wherein the 3- to 12-membered heterocycle of -[C(R15)2]n-(3- to 12- membered heterocycle) and the C3-12carbocycle of -[C(R15)2]n-(C3-12carbocycle) are each optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl;R11, R12, R13, and R15, are each independently selected at each occurrence from: hydrogen;C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, - NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl - O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and n is selected from 0, 1, and 2.

2. The compound or pharmaceutically acceptable salt of claim 1, wherein R1is 4- to 6- membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, =O, =S, and -CN.

3. The compound or pharmaceutically acceptable salt of claim 2, wherein R1is 4- to 6- membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -CN; andC1-6alkyl optionally substituted with halogen.

4. The compound or pharmaceutically acceptable salt according to any one of claims 1-3, wherein the 4- to 6-membered heterocycle of R1is selected from saturated 4- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -CN, C1-6alkyl optionally substituted with halogen.

5. The compound or pharmaceutically acceptable salt of claim 4, wherein R1is saturated 4- to 5- membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -CN, C1-6alkyl, and C1-6haloalkyl.

6. The compound or pharmaceutically acceptable salt of claim 5, wherein R1is tetrahydrofuranyl or oxetanyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -CN, C1-6alkyl optionally substituted with halogen.

7. The compound or pharmaceutically acceptable salt of claim 6, wherein R1is,8. The compound or pharmaceutically acceptable salt according to any one of claims 1-7, wherein Ring A is selected from 6- to 12-membered heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, =O, and -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, and -CN.

9. The compound or pharmaceutically acceptable salt according to any one of claims 1-8, wherein Ring A is selected from 6- to 12-membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -CN, C1-6alkyl, and C1-6haloalkyl.

10. The compound or pharmaceutically acceptable salt according to any one of claims 1-9, wherein Ring A is selected from saturated 6- to 9-membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR11, - N(R11)2, -CN, C1-6alkyl, and C1-6haloalkyl.

11. The compound or pharmaceutically acceptable salt of claim 10, wherein Ring A is selected from saturated 6- to 9-membered fused bicyclic heterocyclene and saturated 6- to 9- membered bridged heterocyclene, each of which is optionally substituted with one or moresubstituents independently selected from halogen, -OR11, -N(R11)2, -CN, C1-6alkyl, and C1-6haloalkyl.

12. The compound or pharmaceutically acceptable salt of claim 11, wherein Ring A is selected from saturated 6- to 9-membered fused bicyclic heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -CN, C1-6alkyl, and C1-6haloalkyl.

13. The compound or pharmaceutically acceptable of claim 12, wherein Ring A is selected from 2-azabicyclo[4.1.0]heptanylene, hexahydro-1H-cyclopenta[c]pyrrolylene and 3- azabicyclo[4.1.0]heptanylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -CN, C1-6alkyl, and C1-6haloalkyl.

14. The compound or pharmaceutically acceptable salt of claim 13, wherein Ring A is selected15. The compound or pharmaceutically acceptable salt of claim 11, wherein Ring A is selected from saturated 6- to 9-membered bridged heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -CN, C1-6alkyl, andC1-6haloalkyl.

16. The compound or pharmaceutically acceptable salt according to claim 15, wherein Ring A is selected from 3-oxa-9-azabicyclo[3.3.1]nonanylene and 8-azabicyclo[3.2.1]octanylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -CN, C1-6alkyl, and C1-6haloalkyl.

17. The compound or pharmaceutically acceptable salt according to claim 16, wherein Ring A is selected from18. The compound or pharmaceutically acceptable salt of any one of claims 1-17 , wherein n is 0.

19. The compound or pharmaceutically acceptable salt of claim 18 , wherein R2is a 4- to 12- membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

20. The compound or pharmaceutically acceptable salt of claim 19, wherein R2is selected from 4- to 10-membered monocyclic heterocycle and 6- to 10- membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

21. The compound or pharmaceutically acceptable salt of claim 20, wherein R2is a 4- to 10- membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

22. The compound or pharmaceutically acceptable salt of claim 21, wherein R2is 4-piperidinyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

23. The compound or pharmaceutically acceptable salt of claim 22, wherein R2is selected from24. The compound or pharmaceutically acceptable salt of claim 20, wherein R2is a 4- to 10- membered bicyclic fused heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

25. The compound or pharmaceutically acceptable salt of claim 24, wherein R2is a 4- to 10- membered bicyclic fused saturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

26. The compound or pharmaceutically acceptable salt of claim 25, wherein R2is an optionally substituted octahydro-5-cyclopenta[c]pyrrolyl.

27. The compound or pharmaceutically acceptable salt of claim 26, wherein28. The compound or pharmaceutically acceptable salt of claim 19, wherein the 4- to 12- membered heterocycle of R2is represented by is optionallysubstituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2R13, -C(O)OR13, - 0C(O)R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

29. The compound or pharmaceutically acceptable salt of claim 28, wherein the 3- to 12- membered heterocycle ofselected from 3- to 8-membered monocyclic heterocycle and 6- to 12-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

30. The compound or pharmaceutically acceptable salt of claim 29 , whereinmembered monocyclic heterocycle optionally substituted with one or more substituents independently selected from:halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

31. The compound or pharmaceutically acceptable salt of claim 30 , whereinis selected from 1-piperazinyl and 1-piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

32. The compound or pharmaceutically acceptable salt of claim 31, whereinselected33. The compound or pharmaceutically acceptable salt of claim 29 , wherein the 6- to 12- membered bicyclic heterocycle ofis selected from 6- to 12-membered fused heterocycle, 6- to 12-membered spirocyclic heterocycle, and 6- to 12-membered bridged heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

34. The compound or pharmaceutically acceptable salt of claim 33, wherein6- to 12- membered fused heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, - -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.membered fused saturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

36. The compound or pharmaceutically acceptable salt of claim 35 , whereinselected from octahydrocyclopenta[c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, and 3-azabicyclo[3.1.0]hexanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.12-membered spirocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

39. The compound or pharmaceutically acceptable salt of claim 38, whereinmembered saturated spirocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

40. The compound or pharmaceutically acceptable salt of claim 39, whereinis selected from 2-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octanyl and 6- azaspiro[3.4]octanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

41. The compound or pharmaceutically acceptable salt of claim 40, whereinselected42. The compound or pharmaceutically acceptable salt of claim 33, whereinis a 6- to12-membered bridged heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.membered saturated bridged heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

44. The compound or pharmaceutically acceptable salt of claim 43, whereinselected from 8 -azabicyclo [3.2.1]octanyl and 3-azabicyclo[3.1.1]heptanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

45. The compound or pharmaceutically acceptable salt of claim 44, whereinis selected46. The compound or pharmaceutically acceptable salt of claim 18, wherein R2is a C3-12carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

47. The compound or pharmaceutically acceptable salt of claim 45, wherein the C3-12carbocycle of R2is representedmore substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

48. The compound or pharmaceutically acceptable salt of claim 47, whereinis C5-10 bicyclic fused saturated carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

49. The compound or pharmaceutically acceptable salt of claim 48, whereinis selected from 3-bicyclo[3.1.0]hexyl and octahydro-2-pentalenyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

50. The compound or pharmaceutically acceptable salt of claim 49, wherein R2is selected from51. The compound or pharmaceutically acceptable salt of claim 47, whereinis C5-9monocyclic saturated carbocycle optionally substituted with one or more substituents independently selected from:halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

52. The compound or pharmaceutically acceptable salt of claim 47, wherein R2is a cyclohexyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

53. The compound or pharmaceutically acceptable salt of claim 48, wherein R2is selected from54. The compound or pharmaceutically acceptable salt of any one of claims 1-17, wherein n is 1.

55. The compound or pharmaceutically acceptable salt of claim 54, wherein R2is -[C(R15)2]-(4- to 12-membered heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2R13, -C(O)OR13, -OC(O)R13, -S(O)R13, - S(O)2R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

56. The compound or pharmaceutically acceptable salt of claim 55, wherein the 4- to 12- membered heterocycle of -[C(R15)2]-(4- to 12-membered heterocycle) is selected from a 4- to 10-membered monocyclic heterocycle and 4- to 10-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

57. The compound or pharmaceutically acceptable salt of claim 56, wherein R2is -[C(R15)2]-(4- to 10-membered monocyclic heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

58. The compound or pharmaceutically acceptable salt of claim 57, wherein R2is 4- methylpiperidinyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

59. The compound or pharmaceutically acceptable salt of claim 58, wherein R2is selected from60. The compound or pharmaceutically acceptable salt of claim 56, wherein R2is -[C(R15)2]-(4- to 10-membered bicyclic fused heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

61. The compound or pharmaceutically acceptable salt of claim 60, wherein R2is selected from - [C(R15)2]-(4- to 8-membered bicyclic fused saturated heterocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

62. The compound or pharmaceutically acceptable salt of claim 61, wherein R2is selected from 6- methyl-3-azabicyclo[3.1.0]hexyl and 5-methyloctahydrocyclopenta[c]pyrrolyl, each of which is optionally substituted halogen, -OR13, -SR13, -N(R13)2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, and -CN; and3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -CN, C1-6alkyl, and C1-6haloalkyl.

63. The compound or pharmaceutically acceptable salt of claim 62, wherein R2is selected from64. The compound or pharmaceutically acceptable salt of claim 55, wherein R2is -[C(R15)2]-(C3-12 carbocycle), represented by, optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl65. The compound or pharmaceutically acceptable salt of claim 64, wherein the C3-12carbocycle ofis selected from C4-10monocyclic carbocycle and C4-10bicyclic carbocycle, optionally substituted with one or more substituents independently selected from:halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

66. The compound or pharmaceutically acceptable salt of claim 65, wherein R2is -[C(R15)2]-( C4- 10 bicyclic fused carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

67. The compound or pharmaceutically acceptable salt of claim 66, wherein R2is selected from 3-methylbicyclo[3.1.0]hexyl and 6-methylbicyclo[3.1.0]hexyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

68. The compound or pharmaceutically acceptable salt of claim 67, wherein69. The compound or pharmaceutically acceptable salt of claim 66, wherein R2is -[C(R15)2]-( C4- 10 monocyclic carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

70. The compound or pharmaceutically acceptable salt of claim 69, wherein R2is methylcyclohexyl, optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -NO2, =O, =S, =N(R13), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -NO2, =O, =S, =N(R13), -CN, C1-6alkyl, and C1-6haloalkyl.

71. The compound or pharmaceutically acceptable salt of claim 70, wherein R2is selected from72. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound is73. A compound represented by structure of Formula (II):or a pharmaceutically acceptable salt thereof, wherein:R21is selected from C1-3alkyl and C3-6carbocycle, the C1-3alkyl is substituted with one or more substituents independently selected from:-O(C1-6alkyl), -O(C1-6haloalkyl), -SR31, -N(R31)2, -C(O)R31, -C(O)N(R31)2, -N(R31)C(O)R31, -N(R31)S(O)2R31, -C(O)OR31, -OC(O)R31, -S(O)R31, -S(O)2R31, -NO2, =O, and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -C(O)N(R31)2, -N(R31)C(O)R31. -C(O)OR31, -OC(O)R31, -S(O)R31, -S(O)2R31, -NO2, =O, =S, =N(R31), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, - OR31, -SR31, -N(R31)2, -C(O)R31, -C(O)N(R31)2, -N(R31)C(O)R31. -C(O)OR31, - OC(O)R31, -S(O)R31, -S(O)2R31, -NO2, =O, =S, =N(R31), and -CN; and the C3-6carbocycle is substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)N(R32)2, -N(R32)C(O)R32-C(O)OR32, - OC(O)R32, -S(O)R32, -S(O)2R32, -NO2, =O, =S, =N(R32), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)N(R32)2, - N(R32)C(O)R32-C(O)OR32, -OC(O)R32, -S(O)R32, -S(O)2R32, -NO2, =O, =S, =N(R32), and -CN;Ring A is selected from 6- to 12-membered heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)N(R32)2, -N(R32)C(O)R32, -N(R32)S(O)2R32, -C(O)OR32, -OC(O)R32, -S(O)R32, -S(O)2R32, -NO2, =O, =S, =N(R32), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)N(R32)2, -N(R32)C(O)R32, -N(R32)S(O)2R32, -C(O)OR32, -OC(O)R32, -S(O)R32, -S(O)2R32, -NO2, =O, =S, =N(R32), and -CN;R22is selected from -[C(R25)2]n-(3- to 12-membered heterocycle) and -[C(R25)2]n-(C3-i2 carbocycle), wherein the 3- to 12-membered heterocycle of -[C(R25)2]n-(3- to 12- membered heterocycle) and the C3-12carbocycle of -[C(R25)2]n-(C3-i2 carbocycle) are each optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)S(O)2R33, -C(O)OR33, -OC(O)R33, -S(O)R33, -S(O)2R33, -NO2, =O, =S, =N(R33), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)S(O)2R33, -C(O)OR33, -OC(O)R33, -S(O)R33, -S(O)2R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, - N(R33)S(O)2R33, -C(O)OR33, -OC(O)R33, -S(O)R33, -S(O)2R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl;R25, R31, R32, and R33are each independently selected at each occurrence from: hydrogen;C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, - NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl - O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and n is selected from 0, 1, and 2.

74. The compound or pharmaceutically acceptable salt of claim 73, wherein R21is C1-3alkyl substituted with one or more substituents independently selected from:-O(C1-6alkyl), -O(C1-6haloalkyl), -SR31, -N(R31)2, -C(O)R31, -C(O)N(R31)2, - N(R31)C(O)R31, -N(R31)S(O)2R31, -C(O)OR31, -OC(O)R31, -S(O)R31, -S(O)2R31, -NO2, =O, and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR31, - SR31, -N(R31)2, -C(O)R31, -C(O)N(R31)2, -N(R31)C(O)R31. -C(O)OR31, -OC(O)R31, - S(O)R31, -S(O)2R31, -NO2, =O, =S, =N(R31), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, - N(R31)2, -C(O)R31, -C(O)N(R31)2, -N(R31)C(O)R31. -C(O)OR31, -OC(O)R31, -S(O)R31, - S(O)2R31, -NO2, =O, =S, =N(R31), and -CN.

75. The compound or pharmaceutically acceptable salt of any one of claims 73 or 74, wherein R21is C1-3alkyl substituted with one or more substituents independently selected from: -O(C1-6alkyl), -O(C1-6haloalkyl), -SR31, -N(R31)2, -C(O)R31, -NO2, =O, and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR31, - SR31, -N(R31)2, -C(O)R31, -NO2, =O, =S, =N(R31), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR31, - SR31, -N(R31)2, -C(O)R31, -NO2, =O, =S, =N(R31), and -CN.

76. The compound or pharmaceutically acceptable salt of any one of claims 73-75, wherein R21is C1-3alkyl substituted with one or more substituents independently selected from: - O(C1-6alkyl), -O(C1-6haloalkyl), -SR31, -N(R31)2, -C(O)R31, -NO2, =O, and -CN.

77. The compound or pharmaceutically acceptable salt of claim 76, wherein R21is selected from methyl and ethyl, substituted with one or more substituents independently selected from:-O(C1-6alkyl), -O(C1-6haloalkyl), -SR31, -N(R31)2, -C(O)R31, -NO2, =O, and -CN.

078. The compound or pharmaceutically acceptable salt of claim 77, wherein R 21 is A7’ / or79. The compound or pharmaceutically acceptable salt of any one of claims 73-75, wherein R21is C1-3alkyl substituted with one or more substituents independently selected from:C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, - N(R31)2, -C(O)R31, -NO2, =O, =S, =N(R31), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, - N(R31)2, -C(O)R31, -NO2, =O, =S, =N(R31), and -CN.

80. The compound or pharmaceutically acceptable salt of claim 79, wherein R21is C1-3alkyl substituted with one or more substituents independently selected from: C3-6carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -NO2, =O, =S, =N(R31), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -NO2, =O, =S, =N(R31), and -CN.

81. The compound or pharmaceutically acceptable salt of claim 80, wherein R21is ethyl, substituted with one or more substituents independently selected from: C3-6carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -NO2, =O, =S, =N(R31), -CN;and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -NO2, =O, =S, =N(R31), and -CN.

82. The compound or pharmaceutically acceptable salt of claim 81, wherein R21is83. The compound or pharmaceutically acceptable salt of claim 73, wherein R21is C3-6carbocycle, wherein the C3-6carbocycle is substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)N(R32)2, -N(R32)C(O)R32-C(O)OR32, - OC(O)R32, -S(O)R32, -S(O)2R32, -NO2, =O, =S, =N(R32), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)N(R32)2, -N(R32)C(O)R32-C(O)OR32, - OC(O)R32, -S(O)R32, -S(O)2R32, -NO2, =O, =S, =N(R32), and -CN.

84. The compound or pharmaceutically acceptable salt of claim 83, wherein R21is C3-6carbocycle, wherein the C3-6carbocycle is substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -NO2, =O, =S, =N(R32), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -SR32, -N(R32)2, -NO2, =O, =S, =N(R32), and -CN.

85. The compound or pharmaceutically acceptable salt of claim 84, wherein the C3-6carbocycle of R21is selected from monocyclic C3-6carbocycle and bicyclic C4-6carbocycle, each of which is substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -NO2, =O, =S, =N(R32), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -SR32, -N(R32)2, -NO2, =O, =S, =N(R32), and -CN.

86. The compound or pharmaceutically acceptable salt of claim 85, wherein R21is monocyclic C3-6carbocycle, substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -NO2, =O, =S, =N(R32), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -SR32, -N(R32)2, -NO2, =O, =S, =N(R32), and -CN.

87. The compound or pharmaceutically acceptable salt of claim 86, wherein R21is cyclopropyl substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -NO2, =O, =S, =N(R32), -CN; and C1-6alkyl optionallysubstituted with one or more substituents independently selected from halogen, -OR32, - SR32, -N(R32)2, -NO2, =O, =S, =N(R32), and -CN.

88. The compound or pharmaceutically acceptable salt of claim 87, wherein R21is selected89. The compound or pharmaceutically acceptable salt of claim 85, wherein R21is bicyclic C4-6carbocycle, substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -NO2, =O, =S, =N(R32), -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, - SR32, -N(R32)2, -NO2, =O, =S, =N(R32), and -CN.

90. The compound or pharmaceutically acceptable salt of claim 89, wherein R21is a substituted fused bicyclic C4-6carbocycle.

91. The compound or pharmaceutically acceptable salt according to any one of claims 73-90, wherein Ring A is selected from 6- to 12-membered heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, and -CN.

92. The compound or pharmaceutically acceptable salt according to any one of claims 73-91, wherein Ring A is selected from 6- to 12-membered heterocyclene optionally substituted with one or more substituents independently selected from: halogen, and -OR32; and C1-6alkyl optionally substituted with halogen.

93. The compound or pharmaceutically acceptable salt according to claim 92, wherein Ring A is selected from saturated 6- to 9-membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, and -OR32; and C1-6alkyl optionally substituted with halogen.

94. The compound or pharmaceutically acceptable salt of claim 93, wherein Ring A is selected from saturated 6- to 9-membered fused bicyclic heterocyclene and saturated 6- to 9-membered bridged heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, and -OR32; and C1-6alkyl optionally substituted with halogen .

95. The compound or pharmaceutically acceptable salt of claim 94, wherein Ring A is selected from saturated 6- to 9-membered fused bicyclic heterocyclene optionallysubstituted with one or more substituents independently selected from halogen, and - OR32; and C1-6alkyl optionally substituted with halogen.

96. The compound or pharmaceutically acceptable salt of claim 95, wherein Ring A is selected from 2-azabicyclo[4.1.0]heptanylene, hexahydro-1H-cyclopenta[c]pyrrolylene and 3-azabicyclo[4.1.0]heptanylene, each of which is optionally substituted with one or more substituents independently selected from halogen, and -OR32; and C1-6alkyl optionally substituted with halogen.

97. The compound or pharmaceutically acceptable salt of claim 96, wherein Ring A is selected from98. The compound or pharmaceutically acceptable salt of claim 94, wherein Ring A is selected from and optionally substituted saturated 6- to 9-membered bridged heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C1-6alkyl, and C1-6haloalkyl.

99. The compound or pharmaceutically acceptable salt according to claim 98, wherein Ring A is selected from 3-oxa-9-azabicyclo[3.3.1]nonanylene and 8- azabicyclo[3.2.1]octanylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C1-6alkyl, andC1-6haloalkyl.

100. The compound or pharmaceutically acceptable salt according to claim 99, wherein RingA is selected from101. The compound or pharmaceutically acceptable salt of any one of claims 73-100, wherein n is 0.

102. The compound or pharmaceutically acceptable salt of claim 101, wherein R22is selected from4- to 12-membered heterocycle, optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

103. The compound or pharmaceutically acceptable salt of claim 102, wherein R22is selected from a 4- to 10-membered monocyclic heterocycle and 6- to 10-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

104. The compound or pharmaceutically acceptable salt of claim 103, wherein R22is a 4- to 10-membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

105. The compound or pharmaceutically acceptable salt of claim 104, wherein R22is 4- piperidinyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

106. The compound or pharmaceutically acceptable salt of claim 105, wherein R22is selected107. The compound or pharmaceutically acceptable salt of claim 103, wherein R22is a 4- to 10-membered bicyclic fused heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

108. The compound or pharmaceutically acceptable salt of claim 107, wherein R22is a 4- to 10-membered bicyclic fused saturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

109. The compound or pharmaceutically acceptable salt of claim 108, wherein R22is an optionally substituted octahydro-5-cyclopenta[c]pyrrolyl.

110. The compound or pharmaceutically acceptable salt of claim 109, wherein R22is111. The compound or pharmaceutically acceptable salt of claim 102, wherein the 4- to 12-membered heterocycle of R22is represented by 'A_y , wherein 'A_y is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)S(O)2R33, -C(O)OR33, -OC(O)R33, -S(O)R33, -S(O)2R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)S(O)2R33, -C(O)OR33, -OC(O)R33, -S(O)R33, -S(O)2R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)S(O)2R33, -C(O)OR33, - OC(O)R33, -S(O)R33, -S(O)2R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

112. The compound or pharmaceutically acceptable salt of claim 111, wherein the 4- to 12-membered heterocycle of A_> isselected from 4- to 8-membered monocyclic heterocycle and 6- to 12-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

113. The compound or pharmaceutically acceptable salt of claim 112, wherein s 4-to 8-membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

114. The compound or pharmaceutically acceptable salt of claim 113 , whereinselected from 1-piperazinyl and 1-piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

115. The compound or pharmaceutically acceptable salt of claim 114, wherein116. The compound or pharmaceutically acceptable salt of claim 112, wherein the 6- to 12- membered bicyclic heterocycle ofselected from 6- to 12-membered fused heterocycle, 6- to 12-membered spirocyclic heterocycle, and 6- to 12-membered bridged heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

117. The compound or pharmaceutically acceptable salt of claim 116, wherein6- to12-membered fused heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, - -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

118. The compound or pharmaceutically acceptable salt of claim 117, whereina 6- to 9-membered fused saturated heterocycle, optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

119. The compound or pharmaceutically acceptable salt of claim 118, whereinselected from octahydrocyclopenta[c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, and 3- azabicyclo[3.1.0]hexanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

120. The compound or pharmaceutically acceptable salt of claim 119, whereinThe compound or pharmaceutically acceptable salt of claim 112, wherein12-membered spirocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

122. The compound or pharmaceutically acceptable salt of claim 121, wherein is a 6-to 9-membered saturated spirocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

123. The compound or pharmaceutically acceptable salt of claim 122, whereinselected from 2-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octanyl and 6-azaspiro[3.4]octanyl, optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

124. The compound or pharmaceutically acceptable salt of claim 123, wherein125. The compound or pharmaceutically acceptable salt of claim 101, wherein R22is a C3-12carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

126. The compound or pharmaceutically acceptable salt of claim 125, wherein the C3-12carbocycle of R22is represented by, whereinoptionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

127. The compound or pharmaceutically acceptable salt of claim 126, whereinis C5-10bicyclic fused saturated carbocycle, optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

128. The compound or pharmaceutically acceptable salt of claim 127, whereinis selected from 3-bicyclo[3.1.0]hexyl and octahydro-2-pentalenyl, optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

129. The compound or pharmaceutically acceptable salt of claim 128, wherein R2is selected from130. The compound or pharmaceutically acceptable salt of claim 126, whereinis C5-9 monocyclic saturated carbocycle, optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

131. The compound or pharmaceutically acceptable salt of claim 130, wherein R22is a cyclohexyl, optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

132. The compound or pharmaceutically acceptable salt of claim 131, wherein R22is selected133. The compound or pharmaceutically acceptable salt of any one of claims 73-100, wherein n is 1.

134. The compound or pharmaceutically acceptable salt of claim 133, wherein R22is - [C(R25)2]-(4- to 12-membered heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)S(O)2R33, -C(O)OR33, -OC(O)R33, -S(O)R33, -S(O)2R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)S(O)2R33, -C(O)OR33, -OC(O)R33, -S(O)R33, -S(O)2R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)S(O)2R33, -C(O)OR33, - OC(O)R33, -S(O)R33, -S(O)2R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

135. The compound or pharmaceutically acceptable salt of claim 134, wherein the 4- to 12- membered heterocycle of -[C(R25)2]-(4- to 12-membered heterocycle) is selected from an 4- to 10-membered monocyclic heterocycle and 4- to 10-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

136. The compound or pharmaceutically acceptable salt of claim 135, wherein R22is - [C(R25)2]-(4- to 10-membered monocyclic heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

137. The compound or pharmaceutically acceptable salt of claim 136, wherein R22is 4- methylpiperidinyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

138. The compound or pharmaceutically acceptable salt of claim 137, wherein R22is selected139. The compound or pharmaceutically acceptable salt of claim 135, wherein R22is - [C(R25)2]-(4- to 10-membered bicyclic fused heterocycle), optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

140. The compound or pharmaceutically acceptable salt of claim 139, wherein R2is selected from -[C(R25)2]-(4- to 8-membered bicyclic fused saturated heterocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

141. The compound or pharmaceutically acceptable salt of claim 140, wherein R2is selected from optionally substituted 6-methyl-3-azabicyclo[3.1.0]hexyl and optionally substituted 5-methyloctahydrocyclopenta[c]pyrrolyl.

142. The compound or pharmaceutically acceptable salt of claim 142, wherein R2is selected143. The compound or pharmaceutically acceptable salt of claim 133, wherein R22is -[C(R25)2]-(C3-I2carbocycle), represented byoptionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

144. The compound or pharmaceutically acceptable salt of claim 143, wherein the C3-12carbocycle ofis selected from C4-10monocyclic carbocycle and C4-10bicyclic carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

145. The compound or pharmaceutically acceptable salt of claim 144, wherein R22is - [C(R25)2]-( C4- 10 bicyclic fused carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

146. The compound or pharmaceutically acceptable salt of claim 145, wherein R22is selected from 3-methylbicyclo[3.1.0]hexyl and 6-methylbicyclo[3.1.0]hexyl, optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

147. The compound or pharmaceutically acceptable salt of claim 146, wherein R22is148. The compound or pharmaceutically acceptable salt of claim 135, wherein R22is - [C(R25)2]-( C4- 10 monocyclic carbocycle) optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

149. The compound or pharmaceutically acceptable salt of claim 148, wherein R22is methylcyclohexyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), and -CN; andC3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, - SR33, -N(R33)2, -C(O)R33, -NO2, =O, =S, =N(R33), -CN, C1-6alkyl, and C1-6haloalkyl.

50. The compound or pharmaceutically acceptable salt of claim 149, wherein R22is selected151. The compound or pharmaceutically acceptable salt of claim 73, wherein the compound is152. A pharmaceutical composition comprising a compound or salt of any one of claims 1 to 151 and a pharmaceutically acceptable excipient.

153. A method of treating cancer comprising administering to a patient in need thereof a compound or salt of any of any one of claims 1 to 151 or a pharmaceutical composition of claim 152.

154. The method of claim 153, wherein the cancer is selected from breast cancer, bladder cancer, cervical cancer, colon cancer, kidney cancer, liver cancer, lung cancer, head and neck cancer, skin cancer, pancreatic cancer, ovarian cancer, esophageal cancer, prostate cancer, and leukemia.

155. A method of modulating a SMYD protein, comprising administering to a patient in need thereof a compound or salt of any of any one of claims 1 to 151 or a pharmaceutical composition of claim 152.

156. The method of claim 155, wherein the SMYD protein is selected from SMYD2 and SMYD3.

157. A method of inhibiting a SMYD protein, comprising administering to a patient in need thereof a compound or salt of any of any one of claims 1 to 151 or a pharmaceutical composition of claim 152.

158. The method of claim 157, wherein the SMYD protein is selected from SMYD2 and SMYD3.

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