Cysteine covalent modifiers of AKT1 and uses thereof

Abstract

Provided herein are covalent modifiers of AKT1 of Formula (I), (II), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), and (IV-D), and pharmaceutical compositions thereof. In some embodiments, the present disclosure provides methods of modulating AKT1 using a compound or salt of Formula (I), (II), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), and (IV-D), and pharmaceutical compositions thereof.

Description

WSGR Docket No.61402-716.601 CYSTEINE COVALENT MODIFIERS OF AKT1 AND USES THEREOF CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 632,217 filed April 10, 2024, and U.S. Provisional Application No.63 / 716,968 filed November 6, 2024, each of which is hereby incorporated herein by reference in their entireties. BACKGROUND OF THE INVENTION

[0002] The AKT or Protein Kinase B (PKB) family of serine / threonine protein kinases is comprised of 3 highly homologous members, AKT1, AKT2 and AKT3. The family of AKT proteins are involved in signal transduction pathways that regulate cellular processes including apoptosis, proliferation, differentiation, and metabolism. The AKT1 pathway is the most frequently dysregulated signaling pathways in human cancers. Enhanced activation of all the isoforms can be implicated in tumor development and progression, and has been demonstrated in breast, ovarian, pancreatic, and prostate cancers among others (Song et al., 2019). In cancer cells, AKT1 is involved in proliferation and growth, promoting tumor initiation, and suppressing apoptosis, whereas AKT2 regulates cytoskeleton dynamics, favoring local tissue invasion and metastasis. The role of AKT3 hyperactivation in cancer is hypothesized to be involved with possible stimulation of cell proliferation (Hinz et al., Cell Commun Signal 2019, 17(1), 154; Pascual et al., Ann. Oncol.2019, 30(7), 1051-1060). Expression of these AKT family members is altered in many human malignant carcinomas including gastric, breast, prostate, ovarian, and pancreatic. AKT family members are rarely mutated however, the most common mutation is AKT1 E17K which has been reported in 6-8% of breast cancers, 2-6% of colorectal cancers, and in 6% of meningiomas, in humans (Yu et al., PLoS One 2015, 10 (10), No. e0140479). Thus, there is a need to develop new treatments for the modulation of AKT1 and mutants thereof. SUMMARY OF THE INVENTION

[0003] In one aspect, the present disclosure provides compounds represented by the Formula (I):or a pharmaceutically acceptable salt thereof wherein: - 1 -WSGR Docket No.61402-716.601 X is selected from O, C(R5A)2, S, and N(R5B); Y1is selected from N and C(R1D); Y2is selected from N and C(R1D); wherein one of Y1or Y2is N and the other of Y1or Y2is C(R1D); R1A, R1B, R1C, and R1Dare each independently selected at each occurrence from (i), (ii), and (iii): (i) hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -(ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -(iii) 3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, - N(OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -S(O)R11, -S(O)2R11, -S(O)2N(R11)2, -NO2, =O, =S, =N(R11), and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one 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, -N(R11)C(O)OR11, - OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -S(O)R11, -S(O)2R11, - N(R11)S(O)2R11, -S(O)2N(R11)2, -NO2, =O, =S, =N(R11), and -CN; R2is selected from halogen, -OR12, -SR12, -N(R12)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, - SR12, -N(R12)2, -NO2, and -CN; L is represented by -L1-L2-L3-L4-, wherein L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -O-, -N(R13)-, -S-, -S(O)-, -S(O)2-, -S(O)(NR13)-, -N(R13)C(O)-, -N(R13)C(O)O-, -N(R13)S(O)2-, -N(R13)S(O)2N(R13)-, -S(O)(NR13)N(R13)-, -N(R13)N(R13)-, - N(R13)C(O)N(R13)-, and -N(R13)C(O)N(R13)N(R13)-; (b) C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, each of which is optionally substituted with one or more substituents independently selected halogen, -OR13, - 2 -WSGR Docket No.61402-716.601 -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, - OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, -S(O)R13, - S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =N(R13), -NO2, and -CN; and (c) C3-10 carbocyclene and 3- to 10-membered heterocyclene, 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, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, - N(R13)C(O)N(R13)2, -S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =N(R13), -NO2, and -CN; and C1-6 alkyl 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, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, - OC(O)N(R13)2, -N(R13)C(O)N(R13)2, -S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, - S(O)2N(R13)2, =O, =S, =N(R13), -NO2, and -CN; wherein L2, L3, and L4are each optionally absent; wherein no more than two of L1, L2, L3, and L4are selected from (a) and the two selected are not adjacent; R3is a cysteine susceptible electrophile; each R4is independently selected at each occurrence from halogen, -OR14, -SR14, -N(R14)2, - NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -NO2, and -CN; each R5Ais independently selected at each occurrence from hydrogen, halogen, -OR15, -SR15, - N(R15)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -NO2, and - CN; R5Bis selected from hydrogen and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR16, -SR16, -N(R16)2, -NO2, and -CN; R11, R12, R13, R14, R15, and R16are each independently selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle 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, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and - 3 -WSGR Docket No.61402-716.601 C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; m is selected from 1 and 2; n is selected from 0, 1, 2, and 3; and o is selected from 0, 1, 2, 3, 4, 5, and 6.

[0004] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), and a pharmaceutically acceptable excipient.

[0005] In another aspect, the present disclosure provides a method of modulating activity of wild-type AKT1 comprising, administering to a subject in need thereof a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D) or a pharmaceutical composition comprising a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III- F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), and a pharmaceutically acceptable excipient.

[0006] In another aspect, the present disclosure provides a method of modulating activity of mutant AKT1 comprising, administering to a subject in need thereof a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D) or a pharmaceutical composition comprising a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III- F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), and a pharmaceutically acceptable excipient.

[0007] In another aspect, the present disclosure provides a method of selectively modulating activity of wild-type AKT1 over wild-type AKT2 comprising administering to a subject in need thereof a compound or salt of Formula ((I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), or a pharmaceutical composition comprising a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), and a pharmaceutically acceptable excipient.

[0008] In another aspect, the present disclosure provides a method of selectively modulating activity of a mutant AKT1 over wild-type AKT2 comprising administering to a subject in need thereof a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III- E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), or a pharmaceutical - 4 -WSGR Docket No.61402-716.601 composition comprising a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), and a pharmaceutically acceptable excipient. In some embodiments, the mutant AKT1 is AKT1 E17K.

[0009] In another aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), or a pharmaceutical composition comprising a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III- F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), and a pharmaceutically acceptable excipient. In some embodiments, the cancer is selected from breast cancer, colorectal cancer, and meningioma. In some embodiments, the administration modulates activity of a mutant AKT1. In some embodiments, the mutant AKT1 is AKT1 E17K. In some embodiments, the administration modulates activity of wild-type AKT1. INCORPORATION BY REFERENCE

[0010] 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. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0012] FIGS.1A-1B illustrate X-ray co-crystal structure of AKT1-WT DrLink / Compound 1 (FIG.1A) and AKT1-E17K DrLink / Compound 1 (FIG.1B) in the allosteric binding site formed at the combined interface of the PH domain and Kinase domain. DETAILED DESCRIPTION OF THE INVENTION

[0013] The AKT or Protein Kinase B (PKB) family of serine / threonine protein kinases regulate a myriad of key cellular functions, including apoptosis, proliferation, differentiation, and metabolism. The AKT family is comprised of 3 highly homologous members, AKT1, AKT2 and - 5 -WSGR Docket No.61402-716.601 AKT3, and each member possesses a unique tissue distribution and may perform a unique set of biological functions. Aberrant expression and / or activation of all AKT isoforms has been implicated in tumor development, including breast, ovarian, pancreatic, and prostate cancers among others.

[0014] Inhibitors of AKT proteins have been developed for the treatment of cancer, including the two major classes of small-molecule AKT inhibitors being investigated in the clinic: allosteric and ATP-competitive inhibitors. First, allosteric inhibitors (such as miransertib (ARQ 092) and MK-2206) interfere with PH-domain mediated membrane recruitment (the first step in AKT activation) and inhibit AKT kinase activation and AKT phosphorylation. Second, ATP- competitive inhibitors of AKT (such as ipatasertib and capivasertib) bind to the active kinase, in which the PH-domain has shifted from the kinase domain and exposed the ATP-binding pocket site, thus inhibiting ATP binding.

[0015] Provided herein are compounds for modulating (e.g., inhibiting) AKT1 function, as well as methods and compositions for using compounds of the present disclosure in the treatment of cancer. In some embodiments, the compounds selectively inhibit (e.g., 2x, 5x, 10x, 50x, 100x, etc.) an AKT1 protein over an AKT2 and / or AKT3 protein.

[0016] Definitions

[0017] 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.

[0018] As used in the specification and claims, the singular form “a,” “an,” and “the” includes plural references unless the context clearly dictates otherwise.

[0019] “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., C1-12 alkyl). The alkyl is attached to the remainder of the molecule through a single bond. An alkyl chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkyl comprises one to twelve carbon atoms (i.e., C1-12 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., C1-8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C1-4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-3alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1-2 alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-8 alkyl). In other - 6 -WSGR Docket No.61402-716.601 embodiments, an alkyl comprises two to five carbon atoms (i.e., C2-5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-5alkyl). For example, the alkyl group may be attached to the rest of the molecule by a single bond, 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.

[0020] “Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C2-12 alkenyl). An alkenyl chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-8 alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-6 alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (i.e., C2-4 alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.

[0021] “Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon--carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-12 alkynyl). An alkylnyl chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., C2-8 alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C2-6 alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-4 alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0022] “Alkylene” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, (methyl)ethylene, butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. An alkylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkylene comprises one to ten carbon atoms (i.e., C1-10 alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., C1-8alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-3 alkylene). In other embodiments, an alkylene comprises one to two carbon - 7 -WSGR Docket No.61402-716.601 atoms (i.e., C1-2 alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., C1alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., C5-8alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C2-5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C3-5 alkylene).

[0023] “Alkenylene” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. An alkenylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkenylene comprises two to ten carbon atoms (i.e., C2-10 alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (i.e., C2-8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2-5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (i.e., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C5-8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C3-5 alkenylene).

[0024] “Alkynylene” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. An alkynylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkynylene comprises two to ten carbon atoms (i.e., C2-10 alkynylene). In certain embodiments, an alkynylene comprises two to eight carbon atoms (i.e., C2-8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (i.e., C2-5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C2-4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (i.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C5-8alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C3-5 alkynylene).

[0025] 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, - 8 -WSGR Docket No.61402-716.601 the term “C1-6 alkyl” refers to 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 an alkylene chain with from x to y carbons in the alkylene chain. For example, -C1-6 alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which may be optionally substituted.

[0026] The terms “Cx-y alkenyl” and “Cx-y alkynyl” 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-y alkenylene- refers to a alkenylene chain with from x to y carbons in the alkenylene chain. For example, -C2-6 alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which may be optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term -Cx-y alkynylene- refers to a alkynylene chain with from x to y carbons in the alkynylene chain. For example, -C2-6 alkynylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which may be optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0027] The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle includes 3- to 10-membered monocyclic rings and polycyclic rings (e.g., 6- to 12-membered bicyclic rings). Each ring of a polycyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Polycyclic carbocycles may be fused, bridged or spiro-ring systems. 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 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.

[0028] 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 - 9 -WSGR Docket No.61402-716.601 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.

[0029] “Cycloalkyl” refers to a stable fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused, bridged, or spiro- ring systems, and preferably having from three to twelve carbon atoms (i.e., C3-12 cycloalkyl). In certain embodiments, a cycloalkyl comprises three to ten carbon atoms (i.e., C3-10 cycloalkyl). In other embodiments, a cycloalkyl comprises five to seven carbon atoms (i.e., C5-7 cycloalkyl). 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), norbornenyl, 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.

[0030] “Aryl” refers to a radical derived from an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) p–electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Aryl may be optionally substituted by one or more substituents such as those substituents described herein.

[0031] A “Cx-y carbocycle” is meant to include groups that contain from x to y carbons in a ring. For example, the term “C3-6 carbocycle” can be a saturated, unsaturated or aromatic ring system that contains from 3 to 6 carbon atoms―any one of which may be optionally substituted as provided herein.

[0032] 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, - 10 -WSGR Docket No.61402-716.601 B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings and polycyclic rings (e.g., 6- to 12-membered bicyclic rings). Polycyclic heterocycles may be fused, bridged or spiro-ring systems. Each ring of a polycyclic 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 one heteroatom 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 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.

[0033] 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 - 11 -WSGR Docket No.61402-716.601 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, the heterocyclene 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.

[0034] “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, bridged, or spiro-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 heterocycloalkyl. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]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. Heterocycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0035] The term “heteroaryl” refers to a radical derived from a 5- to 12-membered aromatic ring radical whose ring structure comprise at least one heteroatom, preferably between one to four heteroatoms. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heteroaryl - 12 -WSGR Docket No.61402-716.601 comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom 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 wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) p–electron system in accordance with the Hückel 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.

[0036] An “X-membered heterocycle” refers to the number of endocyclic 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.

[0037] “Alkoxy” refers to a radical bonded through an oxygen atom of the formula: –O-alkyl, where alkyl is an alkyl chain as defined above.

[0038] “Halo” or “halogen” refers to halogen substituents such as bromo, chloro, fluoro, and iodo substituents.

[0039] 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, - 13 -WSGR Docket No.61402-716.601 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 radical, each halogen may be independently selected for example, 1-chloro,2-fluoroethane.

[0040] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2 of a compound. Unless specified otherwise (e.g., by using the terms “substituted” or “optionally substituted,” or by the inclusion of an “-R” group), chemical groups described herein are unsubstituted. 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, i.e., 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, and 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.

[0041] 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 0, 1, or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb-S(O)tN(Ra)2 (where t is 1 or 2), and -P(O)(Ra)2; and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl any one 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 0, 1, or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb-S(O)tN(Ra)2 (where t is 1 or 2), and -P(O)(Ra)2; wherein each Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or - 14 -WSGR Docket No.61402-716.601 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 0, 1, or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb-S(O)tN(Ra)2 (where t is 1 or 2) , and -P(O)(Ra)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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] The terms “subject,” “individual,” and “patient” may be used interchangeably and refer to humans 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.

[0046] 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. - 15 -WSGR Docket No.61402-716.601

[0047] 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 or salt of the invention or a prodrug of a compound or salt of the invention to the individual in need.

[0048] 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.

[0049] 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.

[0050] 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. - 16 -WSGR Docket No.61402-716.601

[0051] Compounds

[0052] In one aspect, the present disclosure provides a compound represented by the structure of Formula (I):or a pharmaceutically acceptable salt thereof wherein: X is selected from O, C(R5A)2, S, and N(R5B); Y1is selected from N and C(R1D); Y2is selected from N and C(R1D); wherein one of Y1or Y2is N and the other of Y1or Y2is C(R1D); R1A, R1B, R1C, and R1Dare each independently selected at each occurrence from (i), (ii), and (iii): (i) hyd(ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -S(O)2N(R11)2, -NO2, =O, =S, =N(R11), and -CN; and (iii) 3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, - N(OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -S(O)R11, -S(O)2R11, -S(O)2N(R11)2, -NO2, =O, =S, =N(R11), and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one 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)S(O)2R11, -S(O)2N(R11)2, -NO2, =O, =S, =N(R11), and -CN; R2is selected from halogen, -OR12, -SR12, -N(R12)2, -NO2, and -CN; and C1-6 alkyl optionally - 17 -WSGR Docket No.61402-716.601 substituted with one or more substituents independently selected from: halogen, -OR12, - SR12, -N(R12)2, -NO2, and -CN; L is represented by -L1-L2-L3-L4-, wherein L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -O-, -N(R13)-, -S-, -S(O)-, -S(O)2-, -S(O)(NR13)-, -N(R13)C(O)-, -N(R13)C(O)O-, -N(R13)S(O)2-, -N(R13)S(O)2N(R13)-, -S(O)(NR13)N(R13)-, -N(R13)N(R13)-, - N(R13)C(O)N(R13)-, and -N(R13)C(O)N(R13)N(R13)-; (b) C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, each of which is optionally substituted with one or more substituents independently selected halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, - OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, -S(O)R13, - S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =N(R13), -NO2, and -CN; and (c) C3-10 carbocyclene and 3- to 10-membered heterocyclene, 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, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, - N(R13)C(O)N(R13)2, -S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =N(R13), -NO2, and -CN; and C1-6 alkyl 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, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, - OC(O)N(R13)2, -N(R13)C(O)N(R13)2, -S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, - S(O)2N(R13)2, =O, =S, =N(R13), -NO2, and -CN; wherein L2, L3, and L4are each optionally absent; wherein no more than two of L1, L2, L3, and L4are selected from (a) and the two selected are not adjacent; R3is a cysteine susceptible electrophile; each R4is independently selected at each occurrence from halogen, -OR14, -SR14, -N(R14)2, - NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -NO2, and -CN; each R5Ais independently selected at each occurrence from hydrogen, halogen, -OR15, -SR15, - N(R15)2, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -NO2, and - CN; R5Bis selected from hydrogen and C1-6 alkyl optionally substituted with one or more substituents - 18 -WSGR Docket No.61402-716.601 independently selected from: halogen, -OR16, -SR16, -N(R16)2, -NO2, and -CN; R11, R12, R13, R14, R15, and R16are each independently selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; m is selected from 1 and 2; n is selected from 0, 1, 2, and 3; and o is selected from 0, 1, 2, 3, 4, 5, and 6.

[0053] In some embodiments, for the compound or salt of Formula (I), Y1is C(R1D) and Y2is N.

[0054] In some embodiments, the compound or salt of Formula (I) is represented by the structure of Formula

[0055] In some embodiments, the compound or salt of Formula (I) is represented by the structure of Formulawherein each of R1A, R1b, R1C, R1D, R2, R3, R4, X, L, m, n, and o, are defined as in Formula (I).

[0056] In some embodiments, for the compound or salt of Formula (I) or (II), m is 1.

[0057] In some embodiments, for the compound or salt of Formula (I) or (II), m is 2.

[0058] In some embodiments, the compound or salt of Formula (I) or (II) is represented by the structure of Formula (II-A):wherein each of R1A, R1B, R1C, R2, R3, R4, X, L, n, - 19 -WSGR Docket No.61402-716.601 and o are defined as in Formula (I).

[0059] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), the cysteine susceptible electrophile of R3is selected from: -C(O)R16, -S(O)2R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), -N(R17)S(O)2R16, - S(O)2N(R16)(R17), and -CN; and C1-6 alkyl substituted with one or more substituents independently selected from - C(O)R16, -S(O)2R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), -N(R17)S(O)2R16, - S(O)2N(R16)(R17), and -CN; R16is independently selected at each occurrence from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR18, -SR18, -N(R18)2, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, - N(R18)C(O)R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -N(R18)C(O)N(R18)2, - N(R18)C(O)OR18, -OC(O)N(R18)2, -S(O)R18, -S(O)2R18, -NO2, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; R17is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle; and R18selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl,-O-C1-6 alkyl, -O- C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN.

[0060] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R3is selected from -C(O)R16, -S(O)2R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), -N(R17)S(O)2R16, - S(O)2N(R16)(R17), and -CN. In some embodiments, R3is selected from -C(O)R16, - N(R17)C(O)(R16), and -C(O)N(R16)(R17). In some embodiments, R3is -C(O)R16. In some embodiments, R3is -N(R17)C(O)(R16). In some embodiments, R3is -C(O)N(R16)(R17). - 20 -WSGR Docket No.61402-716.601

[0061] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R3is C1-6 alkyl substituted with one or more substituents independently selected from -C(O)R16, - S(O)2R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), -N(R17)S(O)2R16, -S(O)2N(R16)(R17), and -CN. In some embodiments, R3is C1-6 alkyl substituted with one or more substituents independently selected from -C(O)R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), and -CN. In some embodiments, R3is C1-6 alkyl substituted with a substituent independently selected from -C(O)R16, - N(R17)C(O)(R16), -C(O)N(R16)(R17), and -CN. In some embodiments, R3is C1-6 alkyl substituted with -C(O)R16. In some embodiments, R3is C1-6 alkyl substituted with -N(R17)C(O)(R16). In some embodiments, R3is C1-6 alkyl substituted with -C(O)N(R16)(R17). In some embodiments, R3is selected from , , and .

[0062] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R3is selected from -C(O)R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), -NO2, and -CN; and C1-6 alkyl substituted with one or more substituents independently selected from -C(O)R16, - N(R17)C(O)(R16), -C(O)N(R16)(R17), -NO2 and -CN. In some embodiments, R3is selected from - C(O)R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17); and C1-6 alkyl substituted with one or more substituents independently selected from -C(O)R16, -N(R17)C(O)(R16), and -C(O)N(R16)(R17). In some embodiments, R3is selected from -C(O)R16, -N(R17)C(O)(R16), and -C(O)N(R16)(R17), and C1-6 alkyl substituted with -C(O)R16. In some embodiments, R3is selected from -C(O)R16, - N(R17)C(O)(R16), and -C(O)N(R16)(R17). In some embodiments, R3is -C(O)R16. In some embodiments, R3is selected from, , a .

[0063] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R16is independently selected at each occurrence from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR18, -N(R18)2, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, - N(R18)C(O)R18, -N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, -OC(O)N(R18)2, -NO2, and - CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN.

[0064] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R16is independently selected at each occurrence from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: - 21 -WSGR Docket No.61402-716.601 halogen, -OR18, -N(R18)2, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, - N(R18)C(O)R18, -NO2and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, and -O-C1-6 haloalkyl.

[0065] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R16is independently selected at each occurrence from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR18, -N(R18)2, -C(O)N(R18)2; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0066] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R16is independently selected at each occurrence from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR18, -N(R18)2, and -C(O)N(R18)2.

[0067] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R16is independently selected at each occurrence from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen. In some embodiments, R16is independently selected at each occurrence from C2 alkenyl and C3 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen. In some embodiments, R16is independently selected at each occurrence from C2alkenyl and C3alkynyl, each of which is optionally substituted with one or more substituents independently selected from fluoro. In some embodiments, R16is independently selected at each occurrence from C2 alkenyl optionally substituted with one or more substituents independently selected from fluoro.

[0068] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R3is. , .

[0069] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), n is elected from 0, 1, and 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 0 or 1.

[0070] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), each of - 22 -WSGR Docket No.61402-716.601 R1A, R1B, R1C, and R1Dis selected from hydrogen, halogen, -OR11, -N(R11)2, -C(O)N(R11)2, - N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, - N(R11)C(O)N(R11)2, -NO2, and -CN. In some embodiments, each of R1A, R1B, R1C, and R1Dis selected from hydrogen, halogen, -OR11, -N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, - OC(O)R11, -NO2, and -CN. In some embodiments, each of R1A, R1B, R1C, and R1Dis selected from hydrogen, halogen, -OR11, -N(R11)2, -NO2, and -CN.

[0071] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), each of R1A, R1B, R1C, and R1Dis selected from C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR11, -SR11, -N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, =O, =S, =N(R11), and -CN. In some embodiments, each of R1A, R1B, R1C, and R1Dis C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, - OR11, -SR11, -N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, =O, =S, =N(R11), and -CN. In some embodiments, each of R1A, R1B, R1C, and R1Dis C2-6 alkenyl optionally substituted with one or more substituents independently selected from halogen, - OR11, -SR11, -N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, =O, =S, =N(R11), and -CN. In some embodiments, each of R1A, R1B, R1C, and R1Dis C2-6 alkynyl optionally substituted with one or more substituents independently selected from halogen, - OR11, -SR11, -N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, =O, =S, =N(R11), and -CN.

[0072] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), each of R1A, R1B, R1C, and R1Dis selected from 3- to 10-membered heterocycle and C3-10carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, OC(O)R11, -N, and - CN. In some embodiments, each of R1A, R1B, R1C, and R1Dis selected from 3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, - N(R11)C(O)R11, -C(O)OR11, -NO2, =O, =N(R11), and -CN. In some embodiments, each of R1A, R1B, R1C, and R1Dis selected from 3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, and -CN.

[0073] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), each of R1A, R1B, R1C, and R1Dis 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, - - 23 -WSGR Docket No.61402-716.601N(R11)C(O)N(R11)2, -NO2, =O, =N(R11), and -CN. In some embodiments, each of R1A, R1B, R1C, and R1Dis 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, - N(R11)C(O)R11, -C(O)OR11, -NO2, =O, =N(R11), and -CN. In some embodiments, each of R1A, R1B, R1C, and R1Dis 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, and -CN.

[0074] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), each of R1A, R1B, R1C, and R1Dis C3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, - N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, - N(R11)C(O)N(R11)2, -NO2, =O, =N(R11), and -CN. In some embodiments, each of R1A, R1B, R1C, and R1Dis C3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, - NO2, =O, =N(R11), and -CN. In some embodiments, each of R1A, R1B, R1C, and R1Dis C3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, and -CN.

[0075] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), each of R1A, R1B, R1C, and R1Dis selected from 3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, - N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, - N(R11)C(O)N(R11)2, -NO2, =O, =N(R11), and -CN. In some embodiments, each of R1A, R1B, R1C, and R1Dis selected from 3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, - N(R11)C(O)R11, -C(O)OR11, -NO2, =O, =N(R11), and -CN. In some embodiments, each of R1A, R1B, R1C, and R1Dis selected from 3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, and -CN.

[0076] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), each of R1A, R1B, R1C, and R1Dis 3- to 10-membered heterocycle optionally substituted with C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, - OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, - N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -NO2, =O, =N(R11), and -CN. In some - 24 -WSGR Docket No.61402-716.601 embodiments, each of R1A, R1B, R1C, and R1Dis 3- to 10-membered heterocycle optionally substituted with C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, - NO2, =O, =N(R11), and -CN. In some embodiments, each of R1A, R1B, R1C, and R1Dis 3- to 10- membered heterocycle optionally substituted with C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, and -CN.

[0077] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), each of R1A, R1B, R1C, and R1Dis C3-10 carbocycle optionally substituted with C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, - OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -NO2, =O, =N(R11), and -CN. In some embodiments, each of R1A, R1B, R1C, and R1Dis C3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, - N(R11)C(O)R11, -C(O)OR11, -NO2, =O, =N(R11), and -CN. In some embodiments, each of R1A, R1B, R1C, and R1Dis C3-10 carbocycle optionally substituted with C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, and - CN.

[0078] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Ais selected from (i), (ii), and (iii): (i) hydrogen, halogen, -OR11, -N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, - OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -NO2, and -CN; (ii) C1-6alkyl, C2-6alkenyl, and C2-6alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -(iii) 3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -NO2, =O, =N(R11), and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen,C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, - N(R11)C(O)N(R11)2, -NO2, =O, =N(R11), and -CN. - 25 -WSGR Docket No.61402-716.601

[0079] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Ais selected from at each occurrence from (i), (ii), and (iii): (i) hydrogen, 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, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -(iii) 3- to 10-membered heterocycle and C3-10 carbocycle, 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-NO2, =O, and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one 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, -NO2, =O, and -CN.

[0080] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Ais C3- 10 carbocycle optionally substituted with one or more substituents independently selected from: halogen,-OC(O)R11, =O, -NO2, and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, - N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0081] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Ais C3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen,-OC(O)R11, =O, -NO2, and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, - N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0082] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Ais selected from cyclopropyl and phenyl, each of which is optionally substituted with one or more substituents independently selected from: - 26 -WSGR Docket No.61402-716.601 halogen,-OC(O)R11, -NO2, and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, - N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0083] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Ais selected from hydrogen, 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, -NO2, and -CN. In some embodiments, R1Ais selected from hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, and -CN. In some embodiments, R1Ais selected from hydrogen, halogen, -OR11, -N(R11)2, -C(O)R11, and -CN. In some embodiments, R1Ais selected from hydrogen, halogen, -OR11, -N(R11)2, and -CN. In some embodiments, R1Ais selected from hydrogen, halogen, -OR11, and -CN.

[0084] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Ais selected from cyclopropyl and phenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -N(R11)2, -NO2, -CN, and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, and -CN. In some embodiments, R1Ais selected from cyclopropyl and phenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, C1-3 alkyl and C1-3 haloalkyl. In some embodiments, R1Ais selected from cyclopropyl and phenyl, each of which is optionally substituted with one or more substituents independently selected from fluoro, -CN, methyl, and difluoromethyl. In some embodiments, R1Ais phenyl, optionally substituted with one or more substituents independently selected from fluoro, -CN, methyl, and difluoromethyl. In some embodiments, R1Ais selected fromcyclopropyl. In some embodiments, R1A is selected from

[0085] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Ais 3- - 27 -WSGR Docket No.61402-716.601 to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen,-OC(O)R11, =O, -NO2, and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, - N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0086] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Ais 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen,-OC(O)R11, =O, -NO2, and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, - N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0087] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Ais 4- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen,-OC(O)R11, =O, -NO2, and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, - N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0088] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Ais 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen,-OC(O)R11, =O, -NO2, and -CN; C1-6alkyl, C2-6alkenyl, and C2-6alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, - N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN. - 28 -WSGR Docket No.61402-716.601

[0089] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Ais selected from thiophenyl and pyridinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, OC1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0090] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Ais selected from thiophenyl and pyridinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, -CN, and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, - OR11, -N(R11)2, -NO2, and -CN. In some embodiments, R1Ais selected from thiophenyl and pyridinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, -CN, C1-6 alkyl and C1-6 haloalkyl. In some embodiments, R1Ais selected from thiophenyl and pyridinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -N(R11)2, C1-6 alkyl and C1-6 haloalkyl. In some embodiments, R1Ais selected from thiophenyl and pyridinyl, each of which is optionally substituted with one or more substituents independently selected from -N(R11)2. In some embodiments, R1Ais selected from thiophenyl and pyridinyl, each of which is optionally substituted with one or more substituents independently selected from -NH2. In some embodiments, R1Ais selected from.

[0091] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Ais 5- membered heterocycle optionally substituted with one or more substituents independently selected from: halogen,-OC(O)R11, =O, -NO2, and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, - N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0092] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Ais - 29 -WSGR Docket No.61402-716.601 selected from thiophenyl, optionally substituted with one or more substituents independently selected from: halogen,-OC(O)R11, =O, -NO2, and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, - N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0093] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Ais selected from thiophenyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, -CN, and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, and -CN. In some embodiments, R1Ais selected from thiophenyl optionally substituted with one or more substituents independently selected from halogen and C1-6 alkyl. In some embodiments, R1Ais selected from.

[0094] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Aisselected from.

[0095] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Ais.

[0096] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Bis selected from (i), (ii), and (iii): (i) hydrogen, 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, -N(R11)C(O)OR11, -OC(O)N(R11)2, - N(R11)C(O)N(R11)2, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted - 30 -WSGR Docket No.61402-716.601 with one or more substituents independently selected from halogen, -OR11, -SR11, - N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, =O, =S, =N(R11), and -CN; and (iii) 3- to 10-membered heterocycle and C3-10 carbocycle, 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, -NO2, =O, =S, =N(R11), and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one 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, -NO2, =O, =S, =N(R11), and -CN.

[0097] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Bis selected from at each occurrence from (i), (ii), and (iii): (i) hydrogen, 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, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, - N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, =O, =S, =N(R11), and -CN; and (iii) 3- to 10-membered heterocycle and C3-10 carbocycle, 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-NO2, =O, and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen,OC(O)R11, -NO2, =O, and -CN.

[0098] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Bis selected from hydrogen, 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, -NO2, and -CN. In some embodiments, R1Bis selected from hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, and -CN. In some embodiments, R1Bis selected from hydrogen, halogen, -OR11, -N(R11)2, -C(O)R11, and -CN. In some embodiments, R1Bis selected from hydrogen, halogen, -OR11, -N(R11)2, and -CN. In some embodiments, R1Bis selected from hydrogen, halogen, -OR11, and -CN.

[0099] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Bis - 31 -WSGR Docket No.61402-716.601 selected from hydrogen, halogen, and -OR11; wherein R11is independently selected at each occurrence from hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, and C1-6 haloalkyl; and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -NH2, =O, and -CN. In some embodiments, R1Bis selected from hydrogen, halogen, and -OR11; wherein R11is independently selected at each occurrence from hydrogen; C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, and C1-6 haloalkyl; and 3- to 10-membered heterocycle. In some embodiments, R1Bis selected from hydrogen, halogen, and -OR11; wherein R11is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 alkyl-O-C1-6 alkyl, C1-6 haloalkyl, and 3- to 6-membered heterocycle. In some embodiments, R1Bis selected from hydrogen, halogen, and -OR11; wherein R11is independently selected at each occurrence from methyl, ethyl -CHF2, ethylmethoxy, and oxetanyl.

[0100] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Bis selected from hydrogen,, , fluoro,, , .

[0101] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Bis selected from hydrogen, halogen, and -OR11; wherein R11is independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, and C1-6 haloalkyl.In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Bis selected from hydrogen and -OR11; wherein R11is independently selected at each occurrence from C1-6 alkyl optionally substituted with one more substituents independently selected from methoxy. In some embodiments, R1Bis -OR11; wherein R11is independently selected at each occurrence from C1-3 alkyl optionally substituted with one more substituents independently selected from methoxy. In some embodiments, R1Bis -OR11; wherein R11is methyl. In some embodiments, R1Bis selected from hydrogen.

[0102] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Bis selected from 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen,-OC(O)R11, =O, -NO2, and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, - - 32 -WSGR Docket No.61402-716.601 N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0103] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Bis 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen,-OC(O)R11, =O, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, - C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0104] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Bis morpholinyl or pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen,OC(O)R11, =O, -NO2, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, - C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0105] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Bis morpholinyl or pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, - N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, -CN, C1-6alkyl, and C1-6alkyl. In some embodiments, R1Bis morpholinyl or pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, =O, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Bis morpholinyl or pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR11, -N(R11)2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Bis morpholinyl or pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl. In some embodiments, R1Bis morpholinyl or pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen and C1-6 alkyl. In some embodiments, R1Bis morpholinyl. In some embodiments, R1Bis pyrazolyl.

[0106] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Bis - 33 -WSGR Docket No.61402-716.601.

[0107] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Bis a 6- membered heterocycle optionally substituted with one or more substituents independently selected from: halogen,-OC(O)R11, =O, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, - C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0108] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Bis a 6- membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, =O, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, =O, -NO2, and -CN.

[0109] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Bisselected from hydrogen, methoxy, , fluoro,, , ,

[0110] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Cis selected from at each occurrence from (i), (ii), and (iii): (i) hydrogen, 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, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -(iii) 3- to 10-membered heterocycle and C3-10 carbocycle, 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-NO2, =O, and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, - - 34 -WSGR Docket No.61402-716.601 OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, - OC(O)R11, -NO2, =O, and -CN.

[0111] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Cis selected from at each occurrence from (i) and (ii): (i) hydrogen, 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, -NO2, and -CN; and (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, - N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, =O, =S, =N(R11), and -CN.

[0112] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Cis selected from hydrogen, halogen, -OR11, -N(R11)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Cis selected from hydrogen, halogen, -OR11, -N(R11)2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Cis selected from hydrogen, halogen, -OR11, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Cis selected from hydrogen, halogen, - OR11, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Cis selected from hydrogen, halogen, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Cis selected from hydrogen and -OR11. In some embodiments, R1Cis selected from hydrogen and methoxy. In some embodiments, R1Cis methoxy.

[0113] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Cis selected from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Cis selected from hydrogen, halogen, and C1-6alkyl. In some embodiments, R1Cis selected from hydrogen, halogen, and C1-3 alkyl. In some embodiments, R1Cis selected from hydrogen and halogen. In some embodiments, R1Cis hydrogen.

[0114] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Dis selected from at each occurrence from (i), (ii), and (iii): (i) hydrogen, 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, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -(iii) 3- to 10-membered heterocycle and C3-10 carbocycle, 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, - - 35 -WSGR Docket No.61402-716.601 N(R11)C(O)R11, -C(O)OR11, -OC(O)R11-NO2, =O, and -CN; C1-6alkyl, C2-6alkenyl, and C2-6alkynyl, any one 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, -NO2, =O, and -CN.

[0115] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Dis selected from at each occurrence from (i) and (ii): (i) hydrogen, 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, -NO2, and -CN; and (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -

[0116] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R1Dis selected from hydrogen, halogen, -OR11, -N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -NO2, and - CN. In some embodiments, R1Dis selected from hydrogen, halogen, -OR11, -N(R11)2, - C(O)N(R11)2, -N(R11)C(O)R11, -NO2, and -CN. In some embodiments, R1Dis selected from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Dis selected from hydrogen, halogen, and C1-6 alkyl. In some embodiments, R1Dis selected from hydrogen, halogen, and C1-3 alkyl. In some embodiments, R1Dis hydrogen.

[0117] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -O-, -N(R13)-, -N(R13)C(O)-, -N(R13)C(O)O-, -N(R13)N(R13)-, - N(R13)C(O)N(R13)-, and -N(R13)C(O)N(R13)N(R13)-; (b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, each of which is optionally substituted with one or more substituents independently selected halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, - N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, =O, =N(R13), -NO2, and -CN; and (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, - OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, =O, =N(R13), -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)N(R13)2, - 36 -WSGR Docket No.61402-716.601 -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, - N(R13)C(O)N(R13)2, =O, =N(R13), -NO2, and -CN; wherein L2, L3, and L4are each optionally absent; and wherein no more than two of L1, L2, L3, and L4are selected from (a) and the two selected are not adjacent.

[0118] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -O-, -N(R13)-, -N(R13)C(O)-, -C(O)OR13, and -OC(O)R13-; (b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, each of which is optionally substituted with one or more substituents independently selected halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, =O, -NO2, and -CN; and (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, - OC(O)R13; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)N(R13)2, - N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, =O, -NO2, and -CN.

[0119] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -O-, -N(R13)-, -N(R13)C(O)-, -C(O)OR13, and -OC(O)R13-; (b) C1-6alkylene, C2-6alkenylene, C2-6alkynylene, each of which is optionally substituted with one or more substituents independently selected halogen, -OR13, -N(R13)2, =O, -NO2, and -CN; and (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, -NO2, and -CN.

[0120] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -O-, -N(R13)-, and -N(R13)C(O)-; (b) C1-6 alkylene optionally substituted with one or more substituents independently selected halogen, -OR13, -N(R13)2, =O, -NO2, and -CN; and (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is - 37 -WSGR Docket No.61402-716.601 optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -NO2, -CN, C1-6alkyl, and C1-6haloalkyl.

[0121] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -N(R13)-, and -N(R13)C(O)-; (b) C1-6 alkylene and C1-6 haloalkylene; and (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0122] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -N(R13)-; (b) C1-6 alkylene and C1-6 haloalkylene; and (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0123] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L3and L4are absent. In some embodiments, L4is absent. In some embodiments, L3is absent.

[0124] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L1, L2, L3, and L4are each independently selected from is optionally substituted 3- to 10-membered heterocycle, wherein the optional substituents are as defined in Formula (I). In some embodiments, L1, L2, L3, and L4are each independently selected from an optionally substituted 3- to 10-membered saturated heterocycle. In some embodiments, L1, L2, L3, and L4are each independently selected from an optionally substituted 3- to 10-membered unsaturated heterocycle. In some embodiments, L1, L2, L3, and L4are each independently selected from an optionally substituted 3- to 10-membered aromatic heterocycle. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of L1, L2, L3, and L4each independently comprise at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of L1, L2, L3, and L4each independently comprise at least one heteroatom selected from oxygen and nitrogen, or any combination thereof. In some embodiments, the optionally substituted 3- to 10- membered heterocycle of L1, L2, L3, and L4each independently comprise at least one heteroatom selected from oxygen and sulfur, or any combination thereof. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of L1, L2, L3, and L4each independently comprise at least one heteroatom selected from nitrogen and sulfur, or any combination thereof. - 38 -WSGR Docket No.61402-716.601 In some embodiments, the optionally substituted 3- to 10-membered heterocycle of L1, L2, L3, and L4each independently comprise at least one oxygen heteroatom. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of L1, L2, L3, and L4each independently comprise at least one nitrogen heteroatom. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of L1, L2, L3, and L4each independently comprise at least one sulfur heteroatom.

[0125] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L1, L2, L3, and L4each independently selected from an optionally substituted 3- to 10-membered heterocycle, the optionally substituted 3- to 10-membered heterocycle is selected from optionally substituted 3- to 4-membered heterocycle, optionally substituted 3- to 5-membered heterocycle, optionally substituted 3- to 6-membered heterocycle, optionally substituted 3- to 7- membered heterocycle, optionally substituted 3- to 8-membered heterocycle, optionally substituted 3- to 9-membered heterocycle, and optionally substituted 3- to 10-membered heterocycle, wherein the optional substituents are as defined in Formula (I). In some embodiments, L1, L2, L3, and L4each independently selected from optionally substituted 3- membered heterocycle, optionally substituted 4-membered heterocycle, optionally substituted 5- membered heterocycle, optionally substituted 6-membered heterocycle, optionally substituted 7- membered heterocycle, optionally substituted 8-membered heterocycle, optionally substituted 9- membered heterocycle, and optionally substituted 10-membered heterocycle, wherein the optional substituents are as defined in Formula (I).

[0126] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L1, L2, L3, and L4each independently selected from an optionally substituted C3-10carbocycle, wherein the optional substituents are as defined in Formula (I). In some embodiments, L1, L2, L3, and L4each independently selected from an optionally substituted C3-10 saturated carbocycle. In some embodiments, L1, L2, L3, and L4each independently selected from an optionally substituted C3-10 unsaturated carbocycle. In some embodiments, L1, L2, L3, and L4each independently selected from an optionally substituted C5-10 aromatic carbocycle. In some embodiments, L1, L2, L3, and L4each independently selected from an optionally substituted C3-10 carbocycle, the optionally substituted C3-10 carbocycle is selected from optionally substituted C3-4 carbocycle, optionally substituted C3-5 carbocycle, optionally substituted C3-6 carbocycle, optionally substituted C3-7 carbocycle, optionally substituted C3-8 carbocycle, optionally substituted C3-9 carbocycle, and optionally substituted C3-10carbocycle, wherein the optional substituents are as defined in Formula (I). In some embodiments, L1, L2, L3, and L4each independently selected from optionally substituted C3 carbocycle, optionally substituted C4 carbocycle, optionally substituted C5 carbocycle, optionally substituted C6 carbocycle, optionally substituted C7 carbocycle, - 39 -WSGR Docket No.61402-716.601 optionally substituted C8 carbocycle, optionally substituted C9 carbocycle, and optionally substituted C10carbocycle, wherein the optional substituents are as defined in Formula (I).

[0127] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L1is selected from (a) and (b): (a) -O-, -N(R13)-, -S-, -S(O)-, -S(O)2-, -S(O)(NR13)-, -N(R13)C(O)-, -N(R13)C(O)O-, -N(R13)S(O)2-, -N(R13)S(O)2N(R13)-, -S(O)(NR13)N(R13)-, -N(R13)N(R13)-, - N(R13)C(O)N(R13)-, and -N(R13)C(O)N(R13)N(R13)-; and (b) C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, each of which is optionally substituted with one or more substituents independently selected halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, - OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, -S(O)R13, - S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =N(R13), -NO2, and -CN.

[0128] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L1is selected from (a) and (b): (a) -O-, -N(R13)-, -N(R13)C(O)-, -N(R13)C(O)O-, -N(R13)N(R13)-, - N(R13)C(O)N(R13)-, and -N(R13)C(O)N(R13)N(R13)-; and (b) C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, each of which is optionally substituted with one or more substituents independently selected halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, - OC(O)R13, =O, -NO2, and -CN.

[0129] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L1is selected from -O-, -N(R13)-, -N(R13)C(O)-, -N(R13)C(O)O-, -N(R13)N(R13)-, - N(R13)C(O)N(R13)-, and -N(R13)C(O)N(R13)N(R13)-. In some embodiments, L1is selected from - O-, -N(R13)-, -N(R13)C(O)-, and -N(R13)C(O)O-. In some embodiments, L1is selected from -O-, -N(R13)-, and -N(R13)C(O)-. In some embodiments, L1is selected from -N(R13)- and - N(R13)C(O)-. In some embodiments, L1is selected from -N(R13)-. In some embodiments, L1is - N(R13)-; and R13is selected at each occurrence from hydrogen C1-6 alkyl, C1-6 cyanoalkyl and C1-6 haloalkyl. In some embodiments, L1is -N(R13)-; and R13is selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L1is -N(R13)-; and R13is selected at each occurrence from hydrogen C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, L1is -N(R13)-; and R13is selected at each occurrence from hydrogen and C1-3 alkyl. In some embodiments, L1is -N(H)-. In some embodiments, L1is -N(R13)-; and R13is selected at each occurrence from hydrogen and -CH2CN. In some embodiments, L1is selected fromand -N(H)-. - 40 -WSGR Docket No.61402-716.601

[0130] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L1is C1-6 alkylene, C2-6alkenylene, and C2-6alkynylene, each of which is optionally substituted with one or more substituents independently selected halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, - C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, - N(R13)C(O)N(R13)2, -S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =N(R13), - NO2, and -CN. In some embodiments, L1is C1-6 alkylene optionally substituted with one or more substituents independently selected halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, - N(R13)C(O)N(R13)2, -S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =N(R13), - NO2, and -CN. In some embodiments, L1is C1-6 alkylene optionally substituted with one or more substituents independently selected halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -C(O)OR13, =O, =S, =N(R13), -NO2, and -CN.

[0131] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L1is selected from C1-6 alkylene optionally substituted with one or more substituents independently selected halogen, -OR13, -N(R13)2, =O, -NO2, and -CN. In some embodiments, L1is selected from C1-3 alkylene optionally substituted with one or more substituents independently selected halogen, -OR13, -N(R13)2, =O, -NO2, and -CN. In some embodiments, L1is selected from C1-3 alkylene optionally substituted with one or more substituents independently selected halogen, - OR13, -N(R13)2, and -CN. In some embodiments, L1is selected from C1-3 alkylene and C1-3 haloalkylene. In some embodiments, L1is selected from C1-3 alkylene. In some embodiments, L1is methylene.

[0132] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L2is selected from C1-6 alkylene optionally substituted with one or more substituents independently selected halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, -S(O)R13, -S(O)2R13, - N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =N(R13), -NO2, and -CN. In some embodiments, L2is selected from C1-6 alkylene optionally substituted with one or more substituents independently selected halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, -OC(O)R13, =O, =S, =N(R13), -NO2, and -CN. In some embodiments, L2is selected from C1-6 alkylene optionally substituted with one or more substituents independently selected halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, =O, -NO2, and -CN.

[0133] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L2is selected from C1-6 alkylene optionally substituted with one or more substituents independently selected halogen, -OR13, -N(R13)2, =O, -NO2, and -CN. In some embodiments, L2is selected from C1-3 alkylene optionally substituted with one or more substituents independently selected - 41 -WSGR Docket No.61402-716.601 halogen, -OR13, -N(R13)2, =O, -NO2, and -CN. In some embodiments, L2is selected from C1-3 alkylene and C1-3haloalkylene. In some embodiments, L2is selected from C1-3alkylene. In some embodiments, L2is methylene.

[0134] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L2is selected from C3-10 carbocyclene and 3- to 10-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, - N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, =O, =N(R13), -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

[0135] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L2is C3-10 carbocyclene optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, - N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, =O, =N(R13), -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L2is C3-8 carbocyclene optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, - C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, - N(R13)C(O)N(R13)2, =O, =N(R13), -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L2is C3-6 carbocyclene optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L2is C3-4 carbocyclene optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, - C(O)N(R13)2, -NO2, -CN, C1-6alkyl, and C1-6haloalkyl.

[0136] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L2is 3- to 10-membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, - OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, =O, =N(R13), -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L2is 3- to 8-membered heterocyclene, optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, - N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, =O, =N(R13), -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L2is 3- to 6-membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L2is 4- to 6-membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -NO2, -CN, C1-6 - 42 -WSGR Docket No.61402-716.601 alkyl, and C1-6 haloalkyl.

[0137] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L2is selected from piperidinylene, piperazinylene, pyrrolidinylene, and azetidinylene, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L2is selected from piperidinylene, piperazinylene, pyrrolidinylene, and azetidinylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -NO2, -CN, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, L2is selected from piperidinylene, piperazinylene, pyrrolidinylene, and azetidinylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, L2is selected from piperidinylene, piperazinylene, pyrrolidinylene, and azetidinylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, and C1-3 alkyl. In some embodiments, L2is selected from piperidinylene, piperazinylene, pyrrolidinylene, and azetidinylene, each of which is optionally substituted with one or more substituents independently selected from halogen and

[0138] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L2is selected from piperidinylene, piperazinylene, pyrrolidinylene, and azetidinylene. In some embodiments, L2is azetidinylene. In some embodiments, L2is pyrrolidinylene. In some embodiments, L2is piperidinylene or piperazinylene. In some embodiments, L2is piperidinylene. In some embodiments, L2is piperazinylene.

[0139] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L2is

[0140] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L3is 3- to 10-membered heterocyclene optionally substituted with one or more substituents independently - 43 -WSGR Docket No.61402-716.601 selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C1-6 alkyl 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, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, - OC(O)N(R13)2, -N(R13)C(O)N(R13)2, -S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, - S(O)2N(R13)2, =O, =S, =N(R13), -NO2, and -CN.

[0141] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L3is 3- to 10-membered heterocyclene 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, - C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, -S(O)R13, - S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =N(R13), -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L3is 3- to 6-membered heterocyclene 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, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, - OC(O)N(R13)2, -N(R13)C(O)N(R13)2, -S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =N(R13), -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L3is 3- to 6- membered heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, - OC(O)R13, =O, =S, =N(R13), -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

[0142] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L3is 3- to 6-membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L3is 6-membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, - C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L3is 6- membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L3is 6-membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0143] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L3is piperidinylene, optionally substituted with one or more substituents independently selected from - 44 -WSGR Docket No.61402-716.601 halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L3is piperidinylene, optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L3is selected from piperidinylene optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -CN, C1-3 alkyl, and C1- 3 haloalkyl. In some embodiments, L3is selected from piperidinylene optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, L3is selected from piperidinylene optionally substituted with one or more substituents independently selected from halogen. In some embodiments, L3is selected from piperidinylene optionally substituted with one or more substituents independently selected from fluoro.

[0144] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L3is,

[0145] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L is

[0146] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), L is, . - 45 -WSGR Docket No.61402-716.601

[0147] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), X is O.

[0148] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), X is C(R5A)2.

[0149] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), each R5Ais independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, each R5Ais independently selected at each occurrence from hydrogen, halogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, each R5Ais independently selected at each occurrence from hydrogen, halogen, and C1-3 alkyl. In some embodiments, each R5Ais hydrogen.

[0150] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), o is selected from 0 and 1. In some embodiments, o is 0. In some embodiments, o is 1.

[0151] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R4is independently selected at each occurrence from halogen, -OR14, -N(R14)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -NO2, and -CN.

[0152] In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R4is independently selected at each occurrence from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R4is independently selected at each occurrence from halogen and C1-6 alkyl. In some embodiments, R4is independently selected at each occurrence from halogen and C1-3 alkyl. In some embodiments, R4is independently selected at each occurrence from halogen. In some embodiments, R4is independently selected at each occurrence from C1-3 alkyl.

[0153] In some embodiments, for the compound or salt of Formula (I), Y1is N and Y2is C(R1D).

[0154] In some embodiments, the compound or salt of Formula (I) is represented by the structure of Formula (III):or a pharmaceutically acceptable salt thereof wherein: X is selected from O, C(R5A)2, S, and N(R5B); R1A, R1B, R1C, and R1Dare each independently selected at each occurrence from (i), (ii), and (iii): (i) hydrogen, 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, -N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, - S(O)R11, -S(O)2R11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, - - 46 -WSGR Docket No.61402-716.601-OC(O)N(R11)2, -N(R11)C(O)N(R11)2,-S(O)R11, -S(O)2R11, -N(R11)S(O)2R11, - S(O)2N(R11)2, -NO2, =O, =S, =N(R11), and -CN; and (iii) 3- to 10-membered heterocycle and C3-10 carbocycle, 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, -C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one 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, -N(R11)C(O)OR11, - OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -S(O)R11, -S(O)2R11, - N(R11)S(O)2R11, -S(O)2N(R11)2, -NO2, =O, =S, =N(R11), and -CN; R2is selected from halogen, -OR12, -SR12, -N(R12)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, - SR12, -N(R12)2, -NO2, and -CN; L is represented by -L1-L2-L3-L4-, wherein L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -O-, -N(R13)-, -S-, -S(O)-, -S(O)2-, -S(O)(NR13)-, -N(R13)C(O)-, -N(R13)C(O)O-, -N(R13)S(O)2-, -N(R13)S(O)2N(R13)-, -S(O)(NR13)N(R13)-, -N(R13)N(R13)-, - N(R13)C(O)N(R13)-, and -N(R13)C(O)N(R13)N(R13)-; (b) C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, each of which is optionally substituted with one or more substituents independently selected halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, - OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, -S(O)R13, - S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =N(R13), -NO2, and -CN; and (c) C3-10 carbocyclene and 3- to 10-membered heterocyclene, 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, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, - N(R13)C(O)N(R13)2, -S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =N(R13), -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents - 47 -WSGR Docket No.61402-716.601 independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, - C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, - OC(O)N(R13)2, -N(R13)C(O)N(R13)2, -S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, - S(O)2N(R13)2, =O, =S, =N(R13), -NO2, and -CN; wherein L2, L3, and L4are each optionally absent; wherein no more than two of L1, L2, L3, and L4are selected from (a) and the two selected are not adjacent; R3is a cysteine susceptible electrophile; each R4is independently selected at each occurrence from halogen, -OR14, -SR14, -N(R14)2, - NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -NO2, and -CN; each R5Ais independently selected at each occurrence from hydrogen, halogen, -OR15, -SR15, - N(R15)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -NO2, and - CN; R5Bis selected from hydrogen and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -NO2, and -CN; R11, R12, R13, R14, and R15are each independently selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle 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, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; m is selected from 1 and 2; n is selected from 0, 1, 2, and 3; and o is selected from 0, 1, 2, 3, 4, 5, and 6.

[0155] In some embodiments, for the compound or salt of Formula (I), (II), or (III), the cysteine susceptible electrophile is selected from a haloacetamide, a haloalkyl ketone, a halo amidine, a halo benzylphosphonate, an acyloxyalkyl ketone, a sulfonyl oxirane, an epoxide, a diazoalkyl ketone, a halotriazine, an acrylamide, a cyano acrylamide, a vinyl sulfone, a vinyl sulfonamide, - 48 -WSGR Docket No.61402-716.601 an acrylate, a fumarate, a carbonyl acrylate, a maleimide, a ketoamide, a nitrile, an alkene, an alkyne, a keto heterocycle, an ynamide, a squaric acid group, a squaric ester group, and a squaramide ester group.

[0156] In some embodiments, for the compound or salt of Formula (I), (II), or (III), the cysteine susceptible electrophile is selected from a haloacetamide, a haloalkyl ketone, a halo amidine, a halo benzylphosphonate, an acyloxyalkyl ketone, a sulfonyl oxirane, an epoxide, a diazoalkyl ketone, a halotriazine, an acrylamide, a cyano acrylamide, a vinyl sulfone, a vinyl sulfonamide, an acrylate, a fumarate, a carbonyl acrylate, a maleimide, a ketoamide, a nitrile, an alkene, an alkyne, a keto heterocycle, and an ynamide.

[0157] In some embodiments, for the compound or salt of Formula (I), (II), or (III), the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide, an alkene, an alkyne, an epoxide group, a squaric acid group, a squaric ester group, and a squaramide ester group.

[0158] In some embodiments, for the compound or salt of Formula (I), (II), or (III), the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, a vinylsulfone group, a vinylsulfonamide group, an alkene, an alkyne, a squaric acid group, a squaric ester group, and a squaramide ester group.

[0159] In some embodiments, for the compound or salt of Formula (I), (II), or (III), the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, an alkene, an alkyne, a squaric acid group, a squaric ester group, and a squaramide ester group. In some embodiments, the cysteine susceptible electrophile is selected from a squaric acid group, a squaric ester group, and a squaramide ester group. In some embodiments, the cysteine susceptible electrophile is a squaric ester group. In some embodiments, the cysteine susceptible electrophile i.

[0160] In some embodiments, for the compound or salt of Formula (I), (II), or (III), the cysteine susceptible electrophile is selected from a haloacetamide, a haloalkyl ketone, a halo amidine, a halo benzylphosphonate, an acyloxyalkyl ketone, a sulfonyl oxirane, an epoxide, a diazoalkyl ketone, a halotriazine, an acrylamide, a cyano acrylamide, a vinyl sulfone, a vinyl sulfonamide, an acrylate, a fumarate, a carbonyl acrylate, a maleimide, a ketoamide, a nitrile, an alkene, an alkyne, a keto heterocycle, and an ynamide, any one 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, -N(R11)C(O)OR11, -OC(O)N(R11)2, - - 49 -WSGR Docket No.61402-716.601 N(R11)C(O)N(R11)2, -S(O)R11, -S(O)2R11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -NO2, and -CN, wherein each instance R11is as defined in Formula (I), (II), or (III),.

[0161] In some embodiments, for the compound or salt of Formula (I), (II), or (III), the cysteine susceptible electrophile is selected from a haloacetamide, a haloalkyl ketone, a halo amidine, an epoxide, an acrylamide, a cyano acrylamide, a vinyl sulfone, a vinyl sulfonamide, an acrylate, a fumarate, a carbonyl acrylate, a maleimide, a ketoamide, a nitrile, an alkene, an alkyne, a keto heterocycle, and an ynamide. In some embodiments, the cysteine susceptible electrophile is selected from a haloacetamide, a haloalkyl ketone, a halo amidine, an epoxide, an acrylamide, a vinyl sulfone, a vinyl sulfonamide, an acrylate, a maleimide, a nitrile, an alkene, an alkyne, and an ynamide. In some embodiments, the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide, an alkene, an alkyne, and an epoxide group. In some embodiments, the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, a vinylsulfone group, a vinylsulfonamide group, an alkene, and an alkyne. In some embodiments, the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, an alkene, and an alkyne.

[0162] In some embodiments, for the compound or salt of Formula (I), (II), or (III), the cysteine susceptible electrophile is selected from an alpha-beta unsaturated carbonyl, an alpha-beta unsaturated sulfone, an alpha-beta unsaturated amide, and an alpha-beta unsaturated sulfonamide. In some embodiments, the cysteine susceptible electrophile is selected from an alpha-beta unsaturated carbonyl and an alpha-beta unsaturated amide. In some embodiments, the cysteine susceptible electrophile is an alpha-beta unsaturated carbonyl.

[0163] In some embodiments, for the compound or salt of Formula (I), (II), or (III), the cysteine susceptible electrophile of R3is selected from: -C(O)R16, -S(O)2R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), -N(R17)S(O)2R16, - S(O)2N(R16)(R17), and -CN; and C1-6 alkyl substituted with one or more substituents independently selected from - C(O)R16, -S(O)2R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), -N(R17)S(O)2R16, - S(O)2N(R16)(R17), and -CN; R16is independently selected at each occurrence from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR18, -SR18, -N(R18)2, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, - N(R18)C(O)R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -N(R18)C(O)N(R18)2, - N(R18)C(O)OR18, -OC(O)N(R18)2, -S(O)R18, -S(O)2R18, -NO2, and -CN; and - 50 -WSGR Docket No.61402-716.601 C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; R17is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle; and R18selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl,-O-C1-6 alkyl, -O- C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN.

[0164] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R3is selected from -C(O)R16, -S(O)2R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), -N(R17)S(O)2R16, - S(O)2N(R16)(R17), and -CN; R16is selected from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -N(R18)C(O)R18, - N(R18)S(O)2R18, -S(O)2N(R18)2, -N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, -OC(O)N(R18)2, - S(O)R18, -S(O)2R18, -NO2, and -CN; and R17is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle. In some embodiments, R3is selected from -C(O)R16, -S(O)2R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), -N(R17)S(O)2R16, - S(O)2N(R16)(R17), and -CN; R16is C2-6 optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, - C(O)OR18, -OC(O)R18, -N(R18)C(O)R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, -OC(O)N(R18)2, -S(O)R18, -S(O)2R18, -NO2, and -CN; and R17is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle. In some embodiments, R3is selected from -C(O)R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), and - CN; R16is C2-6alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -NO2, and -CN; and R17is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl.

[0165] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R3is - - 51 -WSGR Docket No.61402-716.601 C(O)R16; and R16is selected from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, - N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -N(R18)C(O)R18, -N(R18)S(O)2R18, - S(O)2N(R18)2, -N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, -OC(O)N(R18)2, -S(O)R18, -S(O)2R18, - NO2, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, R3is - C(O)R16; R16is C2-6 alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -N(R18)C(O)R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, - OC(O)N(R18)2, -S(O)R18, -S(O)2R18, -NO2, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, R3is -C(O)R16; and R16is C2-6 alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -N(R18)2, -C(O)R18, - C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -NO2, -CN, C3-10 carbocycle and 3- to 10-memberedheterocycle. In some embodiments, R3 is selected from , , and . Insome embodiments, R3is -C(O)R16; and R16is C2-6 alkynyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -N(R18)2, -C(O)R18, - C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -NO2, -CN, C3-10 carbocycle and 3- to 10-memberedheterocycle. In some embodiments, R3 is selected from, ,

[0166] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R3is - N(R17)C(O)(R16); R16is selected from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, - N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -N(R18)C(O)R18, -N(R18)S(O)2R18, - S(O)2N(R18)2, -N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, -OC(O)N(R18)2, -S(O)R18, -S(O)2R18, - NO2, and -CN; R17is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R3is -N(R17)C(O)(R16); R16is C2-6 alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, - C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -N(R18)C(O)R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, - N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, -OC(O)N(R18)2, -S(O)R18, -S(O)2R18, -NO2, and -CN; and R17is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R3is - N(R17)C(O)(R16); R16is C2-6 alkenyl optionally substituted with one or more substituents - 52 -WSGR Docket No.61402-716.601 independently selected from halogen, -OR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, - OC(O)R18, -NO2, and -CN; and R17is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.

[0167] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R3is - C(O)N(R16)(R17); R16is selected from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, - N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -N(R18)C(O)R18, -N(R18)S(O)2R18, - S(O)2N(R18)2, -N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, -OC(O)N(R18)2, -S(O)R18, -S(O)2R18, - NO2, and -CN; R17is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R3is -C(O)N(R16)(R17); R16is C2-6 alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, - C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -N(R18)C(O)R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, - N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, -OC(O)N(R18)2, -S(O)R18, -S(O)2R18, -NO2, and -CN; and R17is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R3is - C(O)N(R16)(R17); R16is C2-6 alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, - OC(O)R18, -NO2, and -CN; and R17is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl.

[0168] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R3is C1-6 alkyl substituted with one or more substituents independently selected from -C(O)R16, - S(O)2R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), -N(R17)S(O)2R16, -S(O)2N(R16)(R17), and -CN; R16is selected from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -N(R18)C(O)R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, - N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, -OC(O)N(R18)2, -S(O)R18, -S(O)2R18, -NO2, and -CN; and R17is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6- membered heterocycle. In some embodiments, R3is C1-6 alkyl substituted with one or more substituents independently selected from -C(O)R16, -S(O)2R16, -N(R17)C(O)(R16), - C(O)N(R16)(R17), -N(R17)S(O)2R16, -S(O)2N(R16)(R17), and -CN; R16is C2-6 alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, - N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -N(R18)C(O)R18, -N(R18)S(O)2R18, - S(O)2N(R18)2, -N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, -OC(O)N(R18)2, -S(O)R18, -S(O)2R18, - NO2, and -CN; and R17is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle. In some embodiments, R3is C1-6alkyl substituted with one or more substituents independently selected from -C(O)R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), and -CN; R16is C2-6 alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -NO2, - 53 -WSGR Docket No.61402-716.601 and -CN; and R17is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl.

[0169] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R3is C1-6alkyl substituted with -C(O)R16; and R16is selected from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, - N(R18)C(O)R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, - OC(O)N(R18)2, -S(O)R18, -S(O)2R18, -NO2, and -CN. In some embodiments, R3is C1-6 alkyl substituted with -C(O)R16; R16is selected from C2-6 alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, - C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -N(R18)C(O)R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, - N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, -OC(O)N(R18)2, -S(O)R18, -S(O)2R18, -NO2, and -CN. In some embodiments, R3is C1-6 alkyl substituted with -C(O)R16; and R16is C2-6 alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -NO2, and -CN.

[0170] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R3is C1-6 alkyl substituted with -N(R17)C(O)(R16); R16is selected from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, - N(R18)C(O)R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, - OC(O)N(R18)2, -S(O)R18, -S(O)2R18, -NO2, and -CN; R17is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R3is -N(R17)C(O)(R16); R16is C2-6 alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, - N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -N(R18)C(O)R18, -N(R18)S(O)2R18, - S(O)2N(R18)2, -N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, -OC(O)N(R18)2, -S(O)R18, -S(O)2R18, - NO2, and -CN; and R17is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R3is C1-6 alkyl substituted with -N(R17)C(O)(R16); R16is C2-6 alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -NO2, and -CN; and R17is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl.

[0171] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R3is C1-6 alkyl substituted with -C(O)N(R16)(R17); R16is selected from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, - N(R18)C(O)R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, - OC(O)N(R18)2, -S(O)R18, -S(O)2R18, -NO2, and -CN; R17is selected from hydrogen, C1-6 alkyl, - 54 -WSGR Docket No.61402-716.601 and C1-6 haloalkyl. In some embodiments, R3is C1-6 alkyl substituted with -C(O)N(R16)(R17); R16is from C2-6alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, - N(R18)C(O)R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, - OC(O)N(R18)2, -S(O)R18, -S(O)2R18, -NO2, and -CN; and R17is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R3is C1-6 alkyl substituted with - C(O)N(R16)(R17); R16is C2-6 alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, - OC(O)R18, -NO2, and -CN; and R17is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl.

[0172] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R3is selected from -C(O)R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), and -CN; and C1-6 alkyl substituted with one or more substituents independently selected from -C(O)R16, - N(R17)C(O)(R16), -C(O)N(R16)(R17), and -CN. In some embodiments, R3is selected from - C(O)R16, -N(R17)C(O)(R16), and -C(O)N(R16)(R17); and C1-6 alkyl substituted with one or more substituents independently selected from -C(O)R16, -N(R17)C(O)(R16), and -C(O)N(R16)(R17). In some embodiments, R3is selected from -C(O)R16, -N(R17)C(O)(R16), and -C(O)N(R16)(R17); and C1-6 alkyl substituted with one or more substituents selected from -C(O)R16and- N(R17)C(O)(R16). In some embodiments, R3is selected from -C(O)R16and -N(R17)C(O)(R16); and C1-3 alkyl substituted with one or more substituents selected from -C(O)R16and - N(R17)C(O)(R16). In some embodiments, R3is selected from -C(O)R16and C1-3 alkyl substituted with -N(R17)C(O)(R16); wherein R17is selected from hydrogen, C1-3 alkyl, and C1-3 haloalkyl.

[0173] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R3is selected from -C(O)R16, -S(O)2R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), -N(R17)S(O)2R16, - S(O)2N(R16)(R17), and -CN. In some embodiments, R3is selected from -C(O)R16, - N(R17)C(O)(R16), -C(O)N(R16)(R17), and -CN. In some embodiments, R3is -C(O)R16. In some embodiments, R3is -N(R17)C(O)(R16). In some embodiments, R3is -C(O)N(R16)(R17). In some embodiments, R3is -CN.

[0174] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R3is selected from -C(O)R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), and -CN; and C1-6 alkyl substituted with one or more substituents independently selected from -C(O)R16, - N(R17)C(O)(R16), and -C(O)N(R16)(R17). In some embodiments, R3is selected from -C(O)R16, - N(R17)C(O)(R16), -C(O)N(R16)(R17), -CN, and C1-6alkyl substituted with -C(O)R16. In some embodiments, R3is selected from -C(O)R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), and -CN. In some embodiments, R3is selected from -C(O)R16and -CN. In some embodiments, R3is -CN.

[0175] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R3is C1-6 - 55 -WSGR Docket No.61402-716.601 alkyl substituted with one or more substituents independently selected from -C(O)R16, - S(O)2R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), -N(R17)S(O)2R16, -S(O)2N(R16)(R17), and -CN. In some embodiments, R3is C1-6 alkyl substituted with one or more substituents independently selected from -C(O)R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), and -CN. In some embodiments, R3is C1-6 alkyl substituted with -C(O)R16. In some embodiments, R3is C1-6 alkyl substituted with -N(R17)C(O)(R16). In some embodiments, R3is C1-6 alkyl substituted with -C(O)N(R16)(R17). In some embodiments, R3is C1-6 alkyl substituted with -CN.

[0176] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R16is independently selected at each occurrence from C2-6 alkenyl and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, - OR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -N(R18)C(O)R18, - N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, -OC(O)N(R18)2, -NO2, and -CN. In some embodiments, R16is independently selected at each occurrence from C2-4 alkenyl and C2-4 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -N(R18)C(O)R18, - NO2 and -CN. In some embodiments, R16is independently selected at each occurrence from C2-4 alkenyl and C2-4 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR18, and -N(R18)2. In some embodiments, R16is C2-4 alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, and -N(R18)2.

[0177] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R16is C2-6 alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, - N(R18)C(O)R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, - OC(O)N(R18)2, -S(O)R18, -S(O)2R18, -NO2, and -CN. In some embodiments, R16is C2-6 alkenyl optionally substituted with one or more substituents independently selected from halogen, - OR18, -N(R18)2, -C(O)R18, -NO2, and -CN. In some embodiments, R16is C2-4 alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -N(R18)2, -C(O)R18, -NO2, and -CN. In some embodiments, R16is unsubstituted C2-4 alkenyl.

[0178] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R16is C2-6 alkynyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, - N(R18)C(O)R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, - OC(O)N(R18)2, -S(O)R18, -S(O)2R18, -NO2, and -CN. In some embodiments, R16is C2-6 alkynyl optionally substituted with one or more substituents independently selected from halogen, - - 56 -WSGR Docket No.61402-716.601 OR18, -N(R18)2, -C(O)R18, -NO2, and -CN. In some embodiments, R16is C2-4 alkynyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -N(R18)2, -C(O)R18, -NO2, and -CN. In some embodiments, R16is unsubstituted C2-4 alkenyl.

[0179] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R17is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R17is independently selected at each occurrence from hydrogen and C1-6 alkyl. In some embodiments, R17is independently selected at each occurrence from hydrogen and C1-6 haloalkyl. In some embodiments, R17is independently selected at each occurrence from hydrogen. In some embodiments, R17is independently selected at each occurrence from C1-6 alkyl. In some embodiments, R17is independently selected at each occurrence from C1-6 haloalkyl.

[0180] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R18is selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN. In some embodiments, R18is selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -NH2, -NO2, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, -O-C1-6alkyl, - NH2, -NO2, and -CN.

[0181] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R18is selected at each occurrence from hydrogen, C3-10 carbocycle, and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN. In some embodiments, R18is selected at each occurrence from hydrogen, C3-10 carbocycle, and 3- to 10- membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -NH2, -NO2, and -CN.

[0182] In some embodiments, for the compound or salt of Formula (I) or Formula (III), R3is- 57 -WSGR Docket No.61402-716.601

[0183] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R3is

[0184] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R3is

[0186] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R3is selected from: -C(O)R16, -S(O)2R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), -N(R17)S(O)2R16, - S(O)2N(R16)(R17), and -CN; C1-6 alkyl substituted with one or more substituents independently selected from - C(O)R16, -S(O)2R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), -N(R17)S(O)2R16, - S(O)2N(R16)(R17), and -CN.

[0187] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R3is selected from -C(O)R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), -NO2, and -CN; and C1-6 alkyl substituted with one or more substituents independently selected from -C(O)R16, - - 58 -WSGR Docket No.61402-716.601 N(R17)C(O)(R16), -C(O)N(R16)(R17), -NO2 and -CN. In some embodiments, R3is selected from - C(O)R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17); and C1-6alkyl substituted with one or more substituents independently selected from -C(O)R16, -N(R17)C(O)(R16), and -C(O)N(R16)(R17).

[0188] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R3is selected from -C(O)R16, -N(R17)C(O)(R16), and -C(O)N(R16)(R17), and C1-6 alkyl substituted with -C(O)R16. In some embodiments, R3is selected from -C(O)R16, -N(R17)C(O)(R16), and - C(O)N(R16)(R17). In some embodiments, R3is -C(O)R16.

[0189] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R16is independently selected at each occurrence from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR18, -SR18, -N(R18)2, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, - N(R18)C(O)R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -N(R18)C(O)N(R18)2, - N(R18)C(O)OR18, -OC(O)N(R18)2, -S(O)R18, -S(O)2R18, -NO2, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN.

[0190] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R16is independently selected at each occurrence from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR18, -N(R18)2, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -N(R18)C(O)R18, - N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, -OC(O)N(R18)2, -NO2, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN.

[0191] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R16is independently selected at each occurrence from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR18, -N(R18)2, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -N(R18)C(O)R18, -NO2 and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6alkyl, and -O-C1-6haloalkyl.

[0192] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R16is independently selected at each occurrence from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, - - 59 -WSGR Docket No.61402-716.601 OR18, -N(R18)2, -C(O)N(R18)2; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R16is independently selected at each occurrence from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, C3-6 carbocycle, and 3- to 6- membered heterocycle. In some embodiments, R16is independently selected at each occurrence from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen and C3-6 carbocycle. In some embodiments, R16is independently selected at each occurrence from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from fluoro, cyclopropyl, and phenyl.

[0193] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R17is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle. In some embodiments, R17is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl. In some embodiments, R17is independently selected at each occurrence from hydrogen, C1-3 alkyl, C1-3 haloalkyl. In some embodiments, R17is hydrogen.

[0194] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R18is independently selected at each occurrence from: hydrogen; C1-6 alkyl 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 C3-10 carbocycle and 3- to 10- membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl,-O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN.

[0195] In some embodiments, for the compound or salt of Formula (I), (II), or (III), R18independently is selected at each occurrence from hydrogen; and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O- C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, R18independently is selected at each occurrence from hydrogen; and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O- - 60 -WSGR Docket No.61402-716.601 C1-6 alkyl, -O-C1-6 haloalkyl. In some embodiments, R18independently is selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R18is hydrogen.

[0196] In some embodiments, for the compound or salt of Formula (I) or (III), m is selected from 1 and 2. In some embodiments, m is 1. In some embodiments, m is 2.

[0197] In some embodiments, for the compound or salt of Formula (I) or (III), R2is selected from halogen, -OR12, -SR12, -N(R12)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -NO2, and -CN. In some embodiments, R2is selected from halogen, -OR12, -SR12, -N(R12)2, -NO2, and - CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, and -N(R12)2. In some embodiments, R2is selected from halogen, -OR12, - SR12, -N(R12)2, -NO2, and -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R2is selected from halogen, -OR12, -N(R12)2, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R2is selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0198] In some embodiments, for the compound or salt of Formula (I) or (III), n is selected from 0, 1, 2, and 3. In some embodiments, n is selected from 1, 2, and 3. In some embodiments, n is selected from 0, 1, and 2. In some embodiments, n is selected from 1 and 2. In some embodiments, n is selected from 0 and 1. In some embodiments, n is 0.

[0199] In some embodiments, for the compound or salt of Formula (I) or (III), n is selected from 1, 2, and 3; and R2is selected from halogen, -OR12, -SR12, -N(R12)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, n is selected from 1 and 2; and R2is selected from halogen, -OR12, -SR12, -N(R12)2, -NO2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, n is selected from 1 and 2; and R2is selected from halogen, -OR12, -N(R12)2, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, n is selected from 1 and 2; and R2is selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0200] In some embodiments, for the compound or salt of Formula (I) or (III), R12is independently selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with - 61 -WSGR Docket No.61402-716.601 one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, and -CN.

[0201] In some embodiments, for the compound or salt of Formula (I) or (III), R12is independently selected at each occurrence from hydrogen; and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN. In some embodiments, R12is independently selected at each occurrence from hydrogen; and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, and -NH2. In some embodiments, R12is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R12is hydrogen.

[0202] In some embodiments, a compound of Formula (I) or Formula (III) is represented by the structure of Formula (III-A):or a pharmaceutically acceptable salt thereof, wherein R1A, R1B, R1C, R1D, R2, R3, R4, X, L, n, and o, are each defined as in Formula (I).

[0203] In some embodiments, for the compound or salt of Formula (I), (II), (III), or (III-A), R1A, R1B, R1C, or R1Dare each independently selected from optionally substituted 3- to 10-membered heterocycle, wherein the optional substituents are as defined in Formula (I). In some embodiments, R1A, R1B, R1C, or R1Dare each independently selected from is an optionally substituted 3- to 10-membered saturated heterocycle. In some embodiments, R1A, R1B, R1C, or R1Dare each independently selected from optionally substituted 3- to 10-membered unsaturated heterocycle. In some embodiments, R1A, R1B, R1C, or R1Dare each independently selected from optionally substituted 3- to 10-membered aromatic heterocycle. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of R1A, R1B, R1C, or R1Dcomprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of R1A, R1B, R1C, or R1Dcomprises at least one heteroatom selected from oxygen and nitrogen, or any combination thereof. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of R1A, R1B, R1C, or R1Dcomprises at least one heteroatom selected from oxygen and sulfur, or any combination thereof. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of R1A, R1B, R1C, or R1Dcomprises at least one heteroatom selected from nitrogen and sulfur, or any combination thereof. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of R1A, R1B, R1C, or R1Dcomprises at least one oxygen heteroatom. In - 62 -WSGR Docket No.61402-716.601 some embodiments, the optionally substituted 3- to 10-membered heterocycle of R1A, R1B, R1C, or R1Dcomprises at least one nitrogen heteroatom. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of R1A, R1B, R1C, or R1Dcomprises at least one sulfur heteroatom.

[0204] In some embodiments, for the compound or salt of Formula (I), (II), (III), or (III-A), R1A, R1B, R1C, or R1Dare each independently selected from optionally substituted 3- to 10-membered heterocycle, the optionally substituted 3- to 10-membered heterocycle is selected from optionally substituted 3- to 4-membered heterocycle, optionally substituted 3- to 5-membered heterocycle, optionally substituted 3- to 6-membered heterocycle, optionally substituted 3- to 7- membered heterocycle, optionally substituted 3- to 8-membered heterocycle, optionally substituted 3- to 9-membered heterocycle, and optionally substituted 3- to 10-membered heterocycle, wherein the optional substituents are as defined in Formula (I). In some embodiments, R1A, R1B, R1C, or R1Dare each independently selected from optionally substituted 3-membered heterocycle, optionally substituted 4-membered heterocycle, optionally substituted 5-membered heterocycle, optionally substituted 6-membered heterocycle, optionally substituted 7-membered heterocycle, optionally substituted 8-membered heterocycle, optionally substituted 9-membered heterocycle, and optionally substituted 10-membered heterocycle, wherein the optional substituents are as defined in Formula (I).

[0205] In some embodiments, for the compound or salt of Formula (I), (II), (III), or (III-A), R1A, R1B, R1C, or R1Dare each independently selected from optionally substituted C3-10 carbocycle, wherein the optional substituents are as defined in Formula (I). In some embodiments, R1A, R1B, R1C, or R1Dare each independently selected from an optionally substituted C3-10saturated carbocycle. In some embodiments, R1A, R1B, R1C, or R1Dare each independently selected from optionally substituted C3-10 unsaturated carbocycle. In some embodiments, R1A, R1B, R1C, or R1Dare each independently selected from optionally substituted C5-10 aromatic carbocycle. In some embodiments, R1A, R1B, R1C, or R1Dare each independently selected from optionally substituted C3-10 carbocycle, the optionally substituted C3-10 carbocycle is selected from optionally substituted C3-4 carbocycle, optionally substituted C3-5 carbocycle, optionally substituted C3-6 carbocycle, optionally substituted C3-7 carbocycle, optionally substituted C3-8 carbocycle, optionally substituted C3-9 carbocycle, and optionally substituted C3-10 carbocycle, wherein the optional substituents are as defined in Formula (I). In some embodiments, R1A, R1B, R1C, or R1Dare each independently selected from optionally substituted C3carbocycle, optionally substituted C4 carbocycle, optionally substituted C5 carbocycle, optionally substituted C6 carbocycle, optionally substituted C7 carbocycle, optionally substituted C8 carbocycle, optionally substituted C9 carbocycle, and optionally substituted C10 carbocycle, wherein the optional substituents are - 63 -WSGR Docket No.61402-716.601 as defined in Formula (I).

[0206] In some embodiments, for the compound or salt of Formula (I), (II), (III), or (III-A), R1Cis selected from (i), (ii), and (iii): (i) hydrogen, 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, -N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, - S(O)R11, -S(O)2R11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, 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, -N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2,-S(O)R11, -S(O)2R11, -N(R11)S(O)2R11, - S(O)2N(R11)2, -NO2, =O, =S, =N(R11), and -CN; and (iii)3- to 10-membered heterocycle and C3-10 carbocycle, 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, -C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one 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)S(O)2R11, -S(O)2N(R11)2, -NO2, =O, =S, =N(R11), and -CN.

[0207] In some embodiments, for the compound or salt of Formula (I), (II), (III), or (III-A), R1Cis selected from (i), (ii), and (iii): (i) hydrogen, halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, - C(O)OR11, -OC(O)R11, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, and -CN; and (iii)3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -NO2, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -NO2, and -CN. - 64 -WSGR Docket No.61402-716.601

[0208] In some embodiments, for the compound or salt of Formula (I), (II), (III), or (III-A), R1Cis selected from hydrogen, halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, - C(O)OR11, -OC(O)R11, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, and -CN. In some embodiments, R1Cis selected from hydrogen, halogen, -OR11, -N(R11)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Cis selected from hydrogen, halogen, -OR11, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Cis selected from hydrogen, halogen, and - OR11. In some embodiments, R1Cis selected from hydrogen, halogen, and methoxy. In some embodiments, R1Cis selected from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Cis selected from hydrogen and halogen. In some embodiments, R1Cis hydrogen.

[0209] In some embodiments, a compound of Formula (I) is represented by the structure of Formula (III-B):or a pharmaceutically acceptable salt thereof.

[0210] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), or (III-B), R1Dis selected from (i), (ii), and (iii): (i) hydrogen, 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, -N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, - S(O)R11, -S(O)2R11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, 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, -(iii) 3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -NO2, =O, =S, =N(R11), and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally - 65 -WSGR Docket No.61402-716.601 substituted with on e or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -

[0211] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), or (III-B), R1Dis selected from (i), (ii), and (iii): (i) hydrogen, halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, - C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, - NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, - C(O)R11,, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, - N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -NO2, =O, =N(R11), and - CN; and (iii) 3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen,NO2, =O, =N(R11), and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen,C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, - N(R11)C(O)N(R11)2, -NO2, =O, =N(R11), and -CN.

[0212] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), or (III-B), R1Dis selected from hydrogen, halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, - N(R11)C(O)R11, -NO2, and -CN. In some embodiments, R1Dis selected from hydrogen, halogen, and OR11. In some embodiments, R1Dis selected from hydrogen, halogen, and OR11; wherein R11is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Dis selected from hydrogen, halogen, and OR11; wherein R11is independently selected at each occurrence from hydrogen, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R1Dis selected from hydrogen and -OCH3. In some embodiments, R1Dis hydrogen.

[0213] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), or (III-B), - 66 -WSGR Docket No.61402-716.601 R1Dis selected from C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2,some embodiments, R1Dis selected from C1-6 alkyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, and -CN. In some embodiments, R1Dis selected from C1-6 alkyl and C1-6 haloalkyl.

[0214] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), or (III-B), R1Dis selected from C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, - CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or more substituents independently selected from: halogen,=O, -NO2, and -CN. In some embodiments, R1Dis selected from C3-6 carbocycle and 3- to 6- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, - N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN. In some embodiments, R1Dis selected from C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, -CN, and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, and -CN. In some embodiments, R1Dis selected from C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Dis selected from C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0215] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), or (III-B), R1Dis selected from cyclopropyl and pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, - 67 -WSGR Docket No.61402-716.601 -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN. In some embodiments, R1Dis selected from cyclopropyl and pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, -CN, and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, and -CN. In some embodiments, R1Dis selected from cyclopropyl and pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Dis selected from cyclopropyl and pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Dis selected from cyclopropyl and pyrazolyl. In someembodiments, R1D is selected from:, , . In some embodiments, R1D isselected from: and . In some embodiments, R1D is. In some embodiments, R1D is. , .

[0216] In some embodiments, a compound of Formula (I) represented by the structure of Formula (III-C):or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -O-, -N(R13)-, -S-, -S(O)-, -S(O)2-, -S(O)(NR13)-, -N(R13)C(O)-, -N(R13)C(O)O-, -N(R13)S(O)2-, -N(R13)S(O)2N(R13)-, -S(O)(NR13)N(R13)-, -N(R13)N(R13)-, - N(R13)C(O)N(R13)-, and -N(R13)C(O)N(R13)N(R13)-; (b) C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, each of which is optionally substituted with one or more substituents independently selected halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, - OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, -S(O)R13, - S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =N(R13), -NO2, and -CN; and - 68 -WSGR Docket No.61402-716.601 (c) C3-10 carbocyclene and 3- to 10-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from:, =S, =N(R13), -NO2, and -CN; and C1-6 alkyl 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, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, - OC(O)N(R13)2, -N(R13)C(O)N(R13)2, -S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, - S(O)2N(R13)2, =O, =S, =N(R13), -NO2, and -CN; wherein L2, L3, and L4are each optionally absent; and wherein no more than two of L1, L2, L3, and L4are selected from (a) and the two selected are not adjacent.

[0218] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -O-, -N(R13)-, -N(R13)C(O)-, -N(R13)C(O)O-, -N(R13)N(R13)-, - N(R13)C(O)N(R13)-, and -N(R13)C(O)N(R13)N(R13)-; (b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, each of which is optionally substituted with one or more substituents independently selected halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, - N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, =O, =N(R13), -NO2, and -CN; and (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, - OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, =O, =N(R13), -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, - N(R13)C(O)N(R13)2, =O, =N(R13), -NO2, and -CN; wherein L2, L3, and L4are each optionally absent; and wherein no more than two of L1, L2, L3, and L4are selected from (a) and the two selected are not adjacent.

[0219] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or - 69 -WSGR Docket No.61402-716.601 (III-C), L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -O-, -N(R13)-, -N(R13)C(O)-, -C(O)OR13, and -OC(O)R13; (b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, each of which is optionally substituted with one or more substituents independently selected halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, =O, -NO2, and -CN; and (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, - OC(O)R13; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)N(R13)2, - N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, =O, -NO2, and -CN.

[0220] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -O-, -N(R13)-, -N(R13)C(O)-, -C(O)OR13, and -OC(O)R13; (b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, each of which is optionally substituted with one or more substituents independently selected halogen, -OR13, -N(R13)2, =O, -NO2, and -CN; and (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2, =O, -NO2, and -CN.

[0221] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -O-, -N(R13)-, and -N(R13)C(O)-, (b) C1-6 alkylene optionally substituted with one or more substituents independently selected halogen, -OR13, -N(R13)2, =O, -NO2, and -CN; and (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

[0222] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -N(R13)-, and -N(R13)C(O)-; (b) C1-6 alkylene and C1-6 haloalkylene; and - 70 -WSGR Docket No.61402-716.601 (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0223] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -N(R13)-; (b) C1-6 alkylene and C1-6 haloalkylene; and (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0224] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), L3and L4are absent. In some embodiments, L4is absent. In some embodiments, L3is absent.

[0225] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), L3is selected from C3-10 carbocyclene and 3- to 10-membered heterocyclene, 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, -C(O)OR13, - OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, -S(O)R13, -S(O)2R13, - N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =N(R13), -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L3is selected from C3-6 carbocyclene and 3- to 6-membered heterocyclene, 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, -C(O)OR13, - OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, -S(O)R13, -S(O)2R13, - N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =N(R13), -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L3is selected from C3-6 carbocyclene and 3- to 6-membered heterocyclene, 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, =O, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L3is selected from C3-6 carbocyclene and 3- to 6- membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L3is selected from C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, C1-6 alkyl, and C1-6 haloalkyl.

[0226] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), L3is selected from C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of - 71 -WSGR Docket No.61402-716.601 which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, L3is selected from 3- to 6- membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L3is selected from pyrimidinylene optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L3is pyrimidinylene.

[0227] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or

[0228] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), L1and L2are each independently selected from (a), (b), and (c): (a) -O-, -N(R13)-, and -N(R13)C(O)-, (b) C1-6 alkylene optionally substituted with one or more substituents independently selected halogen, -OR13, -N(R13)2, =O, -NO2, and -CN; and (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -NO2, -CN, C1-6alkyl, and C1-6haloalkyl.

[0229] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), L1and L2, are each independently selected from (a), (b), and (c): (a) -N(R13)-, and -N(R13)C(O)-; (b) C1-6 alkylene and C1-6 haloalkylene; and (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0230] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), L1and L2are each independently selected from (a), (b), and (c): (a) -N(R13)-; (b) C1-6 alkylene and C1-6 haloalkylene; and (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0231] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), L1is selected from (a) and L2is selected from (b) and (c): (a) -O-, -N(R13)-, and -N(R13)C(O)-, - 72 -WSGR Docket No.61402-716.601 (b) C1-6 alkylene optionally substituted with one or more substituents independently selected halogen, -OR13, -N(R13)2, =O, -NO2, and -CN; and (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

[0232] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), L1is selected from (a) and L2is selected from (b) and (c): (a) -N(R13)-, and -N(R13)C(O)-; (b) C1-6 alkylene and C1-6 haloalkylene; and (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0233] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), L1is selected from (a) and L2is selected from (b) and (c): (a) -N(R13)-; (b) C1-6 alkylene and C1-6 haloalkylene; and (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0234] In some embodiments, for the compound or salt of Formula (I), (II), (III), (III-A), (III-B), or (III-C), L1, L2, L3, and L4are each independently selected from is optionally substituted 3- to 10-membered heterocycle, wherein the optional substituents are as defined in Formula (I). In some embodiments, L1, L2, L3, and L4are each independently selected from an optionally substituted 3- to 10-membered saturated heterocycle. In some embodiments, L1, L2, L3, and L4are each independently selected from an optionally substituted 3- to 10-membered unsaturated heterocycle. In some embodiments, L1, L2, L3, and L4are each independently selected from an optionally substituted 3- to 10-membered aromatic heterocycle. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of L1, L2, L3, and L4each independently comprise at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of L1, L2, L3, and L4each independently comprise at least one heteroatom selected from oxygen and nitrogen, or any combination thereof. In some embodiments, the optionally substituted 3- to 10- membered heterocycle of L1, L2, L3, and L4each independently comprise at least one heteroatom selected from oxygen and sulfur, or any combination thereof. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of L1, L2, L3, and L4each independently - 73 -WSGR Docket No.61402-716.601 comprise at least one heteroatom selected from nitrogen and sulfur, or any combination thereof. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of L1, L2, L3, and L4each independently comprise at least one oxygen heteroatom. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of L1, L2, L3, and L4each independently comprise at least one nitrogen heteroatom. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of L1, L2, L3, and L4each independently comprise at least one sulfur heteroatom.

[0235] In some embodiments, for the compound or salt of Formula (I), (II), (III), (III-A), (III-B), or (III-C), L1, L2, L3, and L4each independently selected from an optionally substituted 3- to 10- membered heterocycle, the optionally substituted 3- to 10-membered heterocycle is selected from optionally substituted 3- to 4-membered heterocycle, optionally substituted 3- to 5- membered heterocycle, optionally substituted 3- to 6-membered heterocycle, optionally substituted 3- to 7-membered heterocycle, optionally substituted 3- to 8-membered heterocycle, optionally substituted 3- to 9-membered heterocycle, and optionally substituted 3- to 10- membered heterocycle, wherein the optional substituents are as defined in Formula (I). In some embodiments, L1, L2, L3, and L4each independently selected from optionally substituted 3- membered heterocycle, optionally substituted 4-membered heterocycle, optionally substituted 5- membered heterocycle, optionally substituted 6-membered heterocycle, optionally substituted 7- membered heterocycle, optionally substituted 8-membered heterocycle, optionally substituted 9- membered heterocycle, and optionally substituted 10-membered heterocycle, wherein the optional substituents are as defined in Formula (I).

[0236] In some embodiments, for the compound or salt of Formula (I), (II), (III), (III-A), (III-B), or (III-C), L1, L2, L3, and L4each independently selected from an optionally substituted C3-10 carbocycle, wherein the optional substituents are as defined in Formula (I). In some embodiments, L1, L2, L3, and L4each independently selected from an optionally substituted C3-10 saturated carbocycle. In some embodiments, L1, L2, L3, and L4each independently selected from an optionally substituted C3-10 unsaturated carbocycle. In some embodiments, L1, L2, L3, and L4each independently selected from an optionally substituted C5-10 aromatic carbocycle. In some embodiments, L1, L2, L3, and L4each independently selected from an optionally substituted C3-10 carbocycle, the optionally substituted C3-10 carbocycle is selected from optionally substituted C3- 4 carbocycle, optionally substituted C3-5 carbocycle, optionally substituted C3-6 carbocycle, optionally substituted C3-7carbocycle, optionally substituted C3-8carbocycle, optionally substituted C3-9 carbocycle, and optionally substituted C3-10 carbocycle, wherein the optional substituents are as defined in Formula (I). In some embodiments, L1, L2, L3, and L4each independently selected from optionally substituted C3 carbocycle, optionally substituted C4 - 74 -WSGR Docket No.61402-716.601 carbocycle, optionally substituted C5 carbocycle, optionally substituted C6 carbocycle, optionally substituted C7carbocycle, optionally substituted C8carbocycle, optionally substituted C9 carbocycle, and optionally substituted C10 carbocycle, wherein the optional substituents are as defined in Formula (I).

[0237] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), L2is selected from C3-10 carbocyclene and 3- to 10-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, - N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, =O, =N(R13), -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L2is 3- to 10-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L2is 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, - C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L2is 5- to 6- membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L2is selected from piperidinylene and pyrrolidinylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L2is selected from piperidinylene and pyrrolidinylene, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -NO2, -CN, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, L2is selected from piperidinylene and pyrrolidinylene, each of which is optionally substituted with one or more substituents independently selected from halogen and C1-3 alkyl. In some embodiments, L2is selected from piperidinylene and pyrrolidinylene, each of which is optionally substituted with one or more substituents independently selected from fluoro and methyl. In some embodiments, L2is piperidinylene optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L2is piperidinylene optionally substituted with one or more substituents independently selected from halogen, -OR13, -NO2, -CN, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, L2is piperidinylene optionally substituted with one or more substituents independently selected from fluoro and methyl. In some embodiments, L2is selected - 75 -WSGR Docket No.61402-716.601

[0238] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), L2is azetidinylene, piperidinylene, and pyrrolidinylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -NO2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, L2is selected from azetidinylene, piperidinylene, and pyrrolidinylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L2is selected from azetidinylene, piperidinylene, and pyrrolidinylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -NO2, - CN, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, L2is selected from azetidinylene, piperidinylene, and pyrrolidinylene, each of which is optionally substituted with one or more substituents independently selected from halogen and C1-3 alkyl. In some embodiments, L2is selected from azetidinylene, piperidinylene, and pyrrolidinylene, each of which is optionally substituted with one or more substituents independently selected from fluoro and methyl. In some embodiments, L2is azetidinylene. In some embodiments, L2is piperidinylene. In some embodiments, L2is pyrrolidinylene.

[0239] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), L2is piperidinylene optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, - OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, =O, =N(R13), -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L2is piperidinylene optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, - C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L2is piperidinylene optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. Insome embodiments, L2 is selected fromsomeembodiments,. some embodiments, L2is selected from , and - 76 -WSGR Docket No.61402-716.601.

[0240] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), L1is selected from -O-, -N(R13)-, and -N(R13)C(O)-. In some embodiments, L1is selected from -N(R13)- and -N(R13)C(O)-. In some embodiments, L1is -N(R13)-. In some embodiments, L1is -N(R13)-;and R13is selected at each occurrence from hydrogen C1-6alkyl, and C1-6 haloalkyl. In some embodiments, for the compound or salt of Formula L1is -N(H)-.

[0241] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), L1is selected from C1-6 alkylene optionally substituted with one or more substituents independently selected halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, =O, -NO2, and -CN. In some embodiments, L1is selected from C1-3 alkylene optionally substituted with one or more substituents independently selected halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, =O, -NO2, and -CN. In some embodiments, L1is selected from C1-3 alkylene optionally substituted with one or more substituents independently selected halogen, -OR13, -SR13, -N(R13)2, =O, -NO2, and -CN. In some embodiments, L1is selected from C1-6 alkylene. In some embodiments, L1is selected from C1-3 alkylene. In some embodiments, L1is methylene.

[0242] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or,, some embodiments, L is - 77 -WSGR Docket No.61402-716.601. , . some embodiments,.

[0243] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), R13is independently selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN.

[0244] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), R13is independently selected at each occurrence from hydrogen; and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN. In some embodiments, R13is independently selected at each occurrence from hydrogen; and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, and -NH2. In some embodiments, R13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R13is hydrogen.

[0245] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), X is selected from O, C(R5A)2, and N(R5B). In some embodiments, X is selected from O and C(R5A)2.

[0246] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), X is selected from O and C(R5A)2; wherein R5Ais selected from hydrogen, halogen, - OR15, -SR15, -N(R15)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -NO2, and -CN. In some embodiments, X is selected from O and C(R5A)2; wherein R5Ais selected from hydrogen, halogen, -OR15, -N(R15)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR15, -N(R15)2, -NO2, and -CN. In some - 78 -WSGR Docket No.61402-716.601 embodiments, X is selected from O and C(R5A)2; wherein R5Ais selected from hydrogen, halogen, -OR15; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen and -OR15. In some embodiments, X is selected from O and C(R5A)2; wherein R5Ais selected from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, X is selected from O and C(R5A)2; wherein R5Ais selected from hydrogen, and halogen.

[0247] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), X is O. In some embodiments, X is C(R5A)2. In some embodiments, X is selected from O and C(H)2. In some embodiments, X is C(H)2.

[0248] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), each R5Ais independently selected at each occurrence from hydrogen, halogen, and - OR15; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen and -OR15. In some embodiments, each R5Ais independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, each R5Ais independently selected at each occurrence from hydrogen and halogen. In some embodiments, each R5Ais hydrogen.

[0249] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), R15is independently selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle 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, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN.

[0250] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), R15is independently selected at each occurrence from hydrogen; and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, and -CN. In some embodiments, R15is independently selected at each occurrence from hydrogen; and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, and -NH2. In some embodiments, R15is independently selected at each occurrence from hydrogen, C1-6 alkyl, - 79 -WSGR Docket No.61402-716.601 and C1-6 haloalkyl. In some embodiments, R15is hydrogen.

[0251] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), X is N(R5B).

[0252] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), R5Bis selected from hydrogen and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR16, -N(R16)2, -NO2, and -CN. In some embodiments, R5Bis selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R5Bis hydrogen.

[0253] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), or (III-C), R16is independently selected at each occurrence from hydrogen; and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN. In some embodiments, R16is independently selected at each occurrence from hydrogen; and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, and -NH2. In some embodiments, R16is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R16is hydrogen.

[0254] In some embodiments, a compound of Formula (I), (III), (III-A), (III-B), or (III-C), is represented by the structure of Formula (III-D):or a pharmaceutically acceptable salt thereof; 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, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

[0255] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), or (III-D), o is selected from 0, 1, 2, 3, 4, 5, and 6. In some embodiments, o is selected from 0, 1, 2, 3, 4, and 5. In some embodiments, o is selected from 0, 1, 2, 3, and 4. In some embodiments, o is selected from 0, 1, 2, and 3. In some embodiments, o is selected from 0, 1, and 2. In some embodiments, o is selected from 0 and 1. In some embodiments, o is 0. In some embodiments, o is selected from 1, 2, 3, and 4. In some embodiments, o is selected from 1, 2, and 3. In some embodiments, o is selected from 1 and 2. In some embodiments, o is 2. In some embodiments, o is 1. - 80 -WSGR Docket No.61402-716.601

[0256] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), or (III-D), each R4is independently selected at each occurrence from halogen, -OR14, - SR14, -N(R14)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -NO2, and -CN. In some embodiments, R4is independently selected at each occurrence from halogen, -OR14, - N(R14)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -NO2, and -CN. In some embodiments, R4is independently selected at each occurrence from halogen and -OR14; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen and - OR14. In some embodiments, R4is independently selected at each occurrence from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R4is independently selected at each occurrence from halogen and methyl. In some embodiments, R4is halogen. In some embodiments, R4is fluoro.

[0257] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C) or (III-D), R14is independently selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN.

[0258] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), or (III-D), R14is independently selected at each occurrence from hydrogen; and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O- C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN. In some embodiments, R14is independently selected at each occurrence from hydrogen; and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, and -NH2. In some embodiments, R14is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R14is hydrogen.

[0259] In some embodiments, a compound of Formula (I), (III), (III-A), (III-B), (III-C), or (III- D), is represented by the structure of Formula (III-E): - 81 -WSGR Docket No.61402-716.601or a pharmaceutically acceptable salt thereof; 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, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments,optionally substituted with one or more substituents independently selected from halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments,is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments,optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments,optionally substituted with one or more substituents independently selected from halogen and C1-6 alkyl. In some embodiments,optionally substituted with one or more substituents independently selected from fluoro and methyl.

[0260] In some embodiments, for the compound or salt of Formula (I), (III-A), (III), (III-B), (III-C), (III-D), or (III-E), R1Bis selected from (i), (ii), and (iii): (i) hyd(ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, 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, -N(R11)C(O)OR11, - 82 -WSGR Docket No.61402-716.601 -OC(O)N(R11)2, -N(R11)C(O)N(R11)2,-S(O)R11, -S(O)2R11, -N(R11)S(O)2R11, - S(O)2N(R11)2, -NO2, =O, =S, =N(R11), and -CN; and (iii)3- to 10-membered heterocycle and C3-10 carbocycle, 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, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -S(O)R11, -S(O)2R11, -S(O)2N(R11)2, -NO2, =O, =S, =N(R11), and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one 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)S(O)2R11, -S(O)2N(R11)2, -NO2, =O, =S, =N(R11), and -CN.

[0261] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Bis selected from (i), (ii), and (iii): (i) hydrogen, halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, - C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, - NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -NO2, =O, =N(R11), and -CN; and (iii)3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen,C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from:

[0262] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Bis selected from (i), (ii), and (iii): - 83 -WSGR Docket No.61402-716.601 (i) hydrogen, halogen, -OR11, -N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, - OC(O)R11, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, - C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, =O, and -CN; and (iii)3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, C(O)OR1

[0263] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Bis selected from (i), (ii), and (iii): (i) hydrogen, halogen, -OR11, -N(R11)2, and -C(O)N(R11)2; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, =O, and - CN; and (iii) 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, =O, -CN, C1-6 alkyl, and C1-6haloalkyl.

[0264] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E),, R1Bis selected from hydrogen, halogen, -OR11, -N(R11)2, and - C(O)N(R11)2; wherein R11is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from C1-6 alkyl. In some embodiments, R1Bis selected from hydrogen, halogen, -OR11, -N(R11)2, and -C(O)N(R11)2; wherein R11is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle and 3- to 6-membered heterocycle, wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from C1-3alkyl. In some embodiments, R1Bis selected from hydrogen, halogen, -OR11, and -C(O)N(R11)2; wherein R11is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle and 3- to 6-membered heterocycle, wherein the C3-10 carbocycle and 3- to 6- - 84 -WSGR Docket No.61402-716.601 membered heterocycle are each optionally substituted with one or more substituents independently selected from C1-3alkyl. In some embodiments, R1Bis selected from hydrogen, halogen, -OR11, and -C(O)N(R11)2; wherein R11is independently selected at each occurrence from hydrogen, difluoromethyl, cyclopropyl, pyrazolyl, and methyl-pyrazolyl. In some embodiments, R1Bis -OR11, wherein R11is independently selected at each occurrence from hydrogen, difluoromethyl, cyclopropyl, pyrazolyl, and methyl-pyrazolyl. In some embodiments, R1Bis -OR11, wherein R11is independently selected at each occurrence from hydrogen, difluoromethyl, trifluoromethyl, cyclopropyl, pyrazolyl, and methyl-pyrazolyl. In someembodiments, hydrogen, fluoro, chloro, -OCH3,, , ,, and. In some embodiments, R1Bis selected from hydrogen, fluoro, chloro, -OCH3,

[0265] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), , R1Bis selected from hydrogen, halogen, -OR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, - N(R11)C(O)N(R11)2, -NO2, and -CN. In some embodiments, R1Bis selected from hydrogen, halogen,NO2, and -CN. In some embodiments, R1Bis selected from hydrogen, halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -NO2, and -CN. In some embodiments, R1Bis selected from hydrogen, halogen, OR11, and -C(O)N(R11)2. In some embodiments, R1Bis selected from hydrogen, halogen, OR11, and -C(O)N(R11)2; wherein R11is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Bis selected from hydrogen, halogen, OR11, and -C(O)N(R11)2; wherein R11is independently selected at each occurrence from hydrogen and methyl. In some embodiments, R1Bis selected from hydrogen, fluoro, chloro, -OCH3, and .

[0266] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Bis selected from C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen,N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -NO2, =O, =N(R11), and -CN. In some embodiments, R1Bis selected from C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is - 85 -WSGR Docket No.61402-716.601 optionally substituted with one or more substituents independently selected from halogen, - OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, =O, and -CN. In some embodiments, R1Bis C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, - N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, =O, and -CN. In some embodiments, R1Bis C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen - OR11, -N(R11)2, -NO2, and -CN. In some embodiments, R1Bis selected from C1-6 alkyl and C1-6 haloalkyl. In some embodiments, R1Bis selected from C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R1Bis selected from -CHF2, and -CH3.

[0267] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Bis selected from C1-6 alkyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR11, -N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, =O, and -CN. In some embodiments, R1Bis selected from C1-6 alkyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen and -OR11, wherein R11is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Bis selected from C1-3 alkyl and C2-3 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen and -OR11, wherein R11is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Bis selected from methyl and ethynyl, each of which is optionally substituted with one or more substituents independently selected from halogen and - OR11, wherein R11is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6 haloalkyl. In some embodiments, R1Bis selected from methyl and ethynyl, each of which is optionally substituted with one or more substituents independently selected from fluoro and methoxy. In some embodiments, R1Bis methyl, optionally substituted with one or more substituents independently selected from fluoro. In some embodiments, R1Bis methyl optionally substituted with methoxy. In some embodiments, R1Bis ethynyl. In some embodiments, R1Bis selected from

[0268] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Bis selected from 3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, - OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -NO2, =O, =N(R11), -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each - 86 -WSGR Docket No.61402-716.601 optionally substituted with one or more substituents independently selected from: halogen, - OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, - N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -NO2, =O, =N(R11), and -CN.

[0269] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Bis selected from 3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, - OC(O)R11, =O, -NO2, -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, - OC(O)R11, =O, -NO2, and -CN.

[0270] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Bis 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0271] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Bis 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, -CN, C1-6alkyl, C2-6alkenyl, and C2-6 alkynyl, the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0272] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Bis selected from pyrazolyl, triazolyl, and pyridinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, - CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0273] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Bis selected from pyrazolyl, triazolyl, and pyridinyl, each of which - 87 -WSGR Docket No.61402-716.601 is optionally substituted with one or more substituents independently selected from halogen, - OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN; and C1-6 alkyl optionally substitute with halogen, -OR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0274] In some embodiments, for the compound or salt of Formula (I), (III), (III-B), (III-A), (III-C), (III-D), or (III-E), R1Bis selected from pyrazolyl, triazolyl, and pyridinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, - CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN. In some embodiments, R1Bis selected from pyrazolyl, triazolyl, and pyridinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, -CN, and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, and -CN. In some embodiments, R1Bis selected from pyrazolyl, triazolyl, and pyridinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Bis selected from pyrazolyl, triazolyl, and pyridinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R1Bis selected from pyrazolyl, triazolyl, and pyridinyl, each of which is optionally substituted with one or more substituents independently selected from halogen and C1-3alkyl. In some embodiments, R1Bis selected from pyrazolyl, triazolyl, and pyridinyl, each of which is optionally substituted with C1- 3 alkyl. In some embodiments, R1Bis selected from pyrazolyl, triazolyl, and pyridinyl, each of- 88 -WSGR Docket No.61402-716.601 some embodiments, R1Bis selected from. In some embodiments, R1Bis selected fromsome embodiments, R1Bis selected from

[0275] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B),

[0276] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Ais selected from (i), (ii), and (iii): (i) hydrogen, 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, -N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, - S(O)R11, -S(O)2R11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, 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, -N(R11)C(O)OR11, - 89 -WSGR Docket No.61402-716.601 -OC(O)N(R11)2, -N(R11)C(O)N(R11)2,-S(O)R11, -S(O)2R11, -N(R11)S(O)2R11, - S(O)2N(R11)2, -NO2, =O, =S, =N(R11), and -CN; and (iii) 3- to 10-membered heterocycle and C3-10 carbocycle, 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, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -S(O)R11, -S(O)2R11, -S(O)2N(R11)2, -NO2, =O, =S, =N(R11), and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one 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)S(O)2R11, -S(O)2N(R11)2, -NO2, =O, =S, =N(R11), and -CN.

[0277] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Ais selected from (i), (ii), and (iii): (i) hydrogen, halogen, -OR11, -C(O)R11, -N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, - C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, - NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -NO2, =O, =N(R11), and -CN; and (iii)3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -,C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from:

[0278] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Ais C3-10 carbocycle optionally substituted with one or more - 90 -WSGR Docket No.61402-716.601 substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, - N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, -CN, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl, the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0279] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Ais C3-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, - N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0280] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Ais phenyl, optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, - N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, are each optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, - N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0281] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Ais phenyl, optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, -CN, and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, and -CN. In some embodiments, R1Ais phenyl, optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Ais phenyl, optionally substituted with one or more substituents independently selected from halogen and C1-6 alkyl. In some embodiments, R1Ais phenyl, optionally substituted with one or more substituents independently selected from halogen and C1-3 alkyl. In some embodiments, R1Ais phenyl, optionally substituted with one or more substituents independently selected from fluoro, chloro and methyl. In some embodiments, R1Ais phenyl, optionally substituted with one or more halogen. In some embodiments R1Ais phenyl, optionally, substituted with one or more fluoro. In some embodiments, R1Ais selected from: - 91 -WSGR Docket No.61402-716.601

[0282] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Ais 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen,OC(O)R11, =O, -NO2, and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0283] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Ais 4- to 9-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, OC1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0284] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Ais 4- to 6-membered heterocycle optionally substituted with one - 92 -WSGR Docket No.61402-716.601 or more substituents independently selected from: halogen,OC(O)R11, =O, -NO2, and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0285] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Ais 4- to 6-membered unsaturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, OC1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0286] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Ais selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, and thiazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, OC1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0287] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Ais selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, and thiazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, -CN, and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, and -CN. In some embodiments, R1Ais selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, and thiazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen and C1-6 alkyl. In some embodiments, R1Ais selected from from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, and thiazolyl, each - 93 -WSGR Docket No.61402-716.601 of which is optionally substituted with one or more substituents independently selected fromfluoro and methyl. In some embodiments, R1A is selected fromsome embodiments, R1A is selected froms,

[0288] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Ais 6- to 9-membered fused bicyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, OC1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

[0289] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Ais 6- to 9-membered fused bicyclic heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, -CN, C1-6 alkyl, - 94 -WSGR Docket No.61402-716.601 and C1-6 haloalkyl. In some embodiments, R1Ais 6- to 9-membered fused heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, =O, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Ais a 9-membered fused bicyclic heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, =O, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

[0290] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R1Ais 6- to 9-membered fused bicyclic heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, =O, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Ais 6- to 9- membered fused bicyclic heterocycle optionally substituted with one or more substituents independently selected from halogen, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Ais 9-membered fused bicyclic heterocycle optionally substituted with one or more substituents independently selected from halogen, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Ais pyrazolopyridinyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, =O, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Ais pyrazolopyridinyl optionally substituted with one or more substituents independently selected from halogen, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Ais pyrazolopyridinyl optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1Ais pyrazolopyridinyl.

[0291] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B),

[0293] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), - 95 -WSGR Docket No.61402-716.601

[0294] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B),

[0295] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R11is independently selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, and -CN.

[0296] In some embodiments, for the compound or salt of Formula (I), (III), (III-A), (III-B), - 96 -WSGR Docket No.61402-716.601 (III-C), (III-D), or (III-E), R11is independently selected at each occurrence from hydrogen; and C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN. In some embodiments, R11is independently selected at each occurrence from hydrogen; and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O- C1-6 haloalkyl, and -NH2. In some embodiments, R11is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R11is independently selected at each occurrence from hydrogen and methyl. In some embodiments, R11is hydrogen.

[0297] In some embodiments, a compound of Formula (I) or (III) is represented by the structure of Formula (III-F):or a pharmaceutically acceptable salt thereof, wherein R1A, R1B, R1C, R1D, R3, R4, X, L, and o, are each defined as in Formula (I).

[0298] In some embodiments, a compound of Formula (I) or (III) is represented by the structure of Formula (III-G):or a pharmaceutically acceptable salt thereof, wherein R1A, R1B, R3, R4, X, L, and o, are each defined as in Formula (I).

[0299] In some embodiments, a compound of Formula (I) or (III) is represented by the structure of Formula (III-H):or a pharmaceutically acceptable salt thereof, wherein R1A, R1B, R3, R4, X, L, and o, are each defined as in Formula (I).

[0300] In some embodiments, a compound of Formula (I) or (III) is represented by the structure of Formula (IV): - 97 -WSGR Docket No.61402-716.601or a pharmaceutically acceptable salt thereof; 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, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl; and wherein R1A, R1B, R3, R4, X, and o, are each defined as in Formula (I).

[0301] In some embodiments, a compound of Formula (I) or (III) is represented by the structure of Formula (IV-A):or a pharmaceutically acceptable salt thereof; 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, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl; and wherein R1A, R1B, R3, R4, X, and o, are each defined as in Formula (I).

[0302] In some embodiments, a compound of Formula (I) or (III) is represented by the structure of Formula (IV-B):or a pharmaceutically acceptable salt thereof; 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, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl; and wherein R1A, R1B, R3, R4, and o, are each defined as in Formula (I).

[0303] In some embodiments, a compound of Formula (I) or (III) is represented by the structure - 98 -WSGR Docket No.61402-716.601 of Formula (IV-C):or a pharmaceutically acceptable salt thereof; 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, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl; and wherein R1A, R1B, and R3are each defined as in Formula (I).

[0304] In some embodiments, the compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D) is a compound of Table 1. * Denotes a stereocenter with an undetermined absolute stereochemistry of a single isomer.

[0305] Table 1. Chemical structures of selected compounds.- 99 -WSGR Docket No.61402-716.601- 100 -WSGR Docket No.61402-716.601- 101 -WSGR Docket No.61402-716.601- 102 -WSGR Docket No.61402-716.601- 103 -WSGR Docket No.61402-716.601- 104 -WSGR Docket No.61402-716.601- 105 -WSGR Docket No.61402-716.601- 106 -WSGR Docket No.61402-716.601- 107 -WSGR Docket No.61402-716.601- 108 -WSGR Docket No.61402-716.601- 109 -WSGR Docket No.61402-716.601- 110 -WSGR Docket No.61402-716.601- 111 -WSGR Docket No.61402-716.601- 112 -WSGR Docket No.61402-716.601- 113 -WSGR Docket No.61402-716.601- 114 -WSGR Docket No.61402-716.601- 115 -WSGR Docket No.61402-716.601- 116 -WSGR Docket No.61402-716.601- 117 -WSGR Docket No.61402-716.601- 118 -WSGR Docket No.61402-716.601- 119 -WSGR Docket No.61402-716.601- 120 -WSGR Docket No.61402-716.601- 121 -WSGR Docket No.61402-716.601- 122 -WSGR Docket No.61402-716.601

[0306] 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 - 123 -WSGR Docket No.61402-716.601 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.

[0307] 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 (I), (II), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV- B), (IV-C), and (IV-D) are intended to include all Z-, E- and tautomeric forms as well.

[0308] “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 stereocenter can be specified by either R or S (chiral atom). In some embodiments, the stereocenter may be a carbon atom, a nitrogen atom, a phosphorus atom, or a sulfur atom. In some embodiments, the stereocenter is a carbon atom specified by either R or S. In some embodiments, the stereocenter is a nitrogen atom specified by either R or S. In some embodiments, the stereocenter is a sulfur atom specified by either R or S. In some embodiments, the stereocenter is a phosphorus atom 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 - 124 -WSGR Docket No.61402-716.601 determined.

[0309] In some aspects, atoms other than carbon may have an absolute stereochemistry assigned. (For example, atoms such as nitrogen, phosphorus or sulfur may have absolute stereochemistry assigned). In some embodiments, the stereocenter is a sulfur atom. For example, methyl phenyl sulfoxide can exist as an R-enantiomer or S-enantiomer, such as (R)-methyl phenyl sulfoxide: ; or (S)-methyl phenyl sulfoxide: . In these cases, the set of lone pair electrons on the sulfur atom are considered a substituent and given the lowest Cahn- Ingold-Prelog priority.

[0310] The compounds or salts for Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), 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.

[0311] In certain embodiments, compounds or salts for Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV- D)may comprise two or more enantiomers or diastereomers 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 - 125 -WSGR Docket No.61402-716.601 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.

[0312] 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 (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D) 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 non–limiting examples of tautomeric equilibrium include:

[0313] 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 may be 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 - 126 -WSGR Docket No.61402-716.601 stability and or efficacy, thus increasing the duration of action of drugs.

[0314] In certain embodiments, the compounds disclosed herein have some or all of the1H atoms 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.

[0315] 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.

[0316] 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.

[0317] 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.

[0318] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds 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,35Cl,37Cl,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.

[0319] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D). 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. - 127 -WSGR Docket No.61402-716.601

[0320] The methods and compositions of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D) 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.

[0321] Compounds of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III- F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), 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.

[0322] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of compounds represented by Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III- D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D). The compounds of the present invention that 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.

[0323] In certain embodiments, compounds or salts of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), 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. - 128 -WSGR Docket No.61402-716.601

[0324] Pharmaceutical Formulations

[0325] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), and a pharmaceutically acceptable excipient.

[0326] 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.

[0327] A compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III- E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), may be formulated in any suitable pharmaceutical formulation. A pharmaceutical formulation of the present disclosure typically contains an active ingredient (e.g., compound or salt of any one of Formula (I), (II), (II- A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, antioxidents, solubilizers, and adjuvants.

[0328] Pharmaceutical compositions may also be prepared from a compound or salt of any one of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), 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 - 129 -WSGR Docket No.61402-716.601 Pharmaceutical Press, London, 1999).

[0329] Methods of Treatment

[0330] 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.

[0331] 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.

[0332] 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.

[0333] In some aspects, the present disclosure provides a method for treatment, comprising administering to a subject in need thereof a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D). In some embodiments, the method for treatment, comprises administering to a subject in need thereof an effective amount of a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D).

[0334] In some aspects, the present disclosure provides a method for treatment, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), and a pharmaceutically acceptable excipient. In some embodiments, the method for treatment, comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), - 130 -WSGR Docket No.61402-716.601 (IV), (IV-A), (IV-B), (IV-C), or (IV-D), and a pharmaceutically acceptable excipient.

[0335] In some aspects, the present disclosure provides a method of modulating wild-type AKT1. In some embodiments, the method of modulating wild-type AKT1 comprises, administering to a subject in need thereof a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), or a pharmaceutically acceptable composition thereof. In some embodiments, the administering to the subject in need thereof comprises a compound or salt as provided in Table 1. In some embodiments, the administering to the subject in need thereof comprises a pharmaceutical composition comprising the compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), and a pharmaceutically acceptable excipient. In some embodiments, the administering to the subject in need thereof comprises a pharmaceutical composition comprising a compound or salt as provided in Table 1, and a pharmaceutically acceptable excipient.

[0336] In some aspects, the present disclosure provides a method of inhibiting wild-type AKT1. In some embodiments, the method of inhibiting wild-type AKT1 comprises, administering to a subject in need thereof a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III- C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), or a pharmaceutically acceptable composition thereof. In some embodiments, the administering to the subject in need thereof comprises a compound or salt as provided in Table 1. In some embodiments, the administering to the subject in need thereof comprises a pharmaceutical composition comprising the compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), and a pharmaceutically acceptable excipient. In some embodiments, the administering to the subject in need thereof comprises a pharmaceutical composition comprising a compound or salt as provided in Table 1, and a pharmaceutically acceptable excipient.

[0337] In some aspects, the present disclosure provides a method of modulating mutant AKT1. In some embodiments, the method of modulating mutant AKT1 comprises, administering to a subject in need thereof a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III- C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), or a pharmaceutically acceptable composition thereof. In some embodiments, the mutant AKT1 is AKT1 E17K. In some embodiments, the administering to the subject in need thereof comprises a compound or salt as provided in Table 1. In some embodiments, the administering to the subject in need thereof comprises a pharmaceutical composition comprising the compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), and a pharmaceutically acceptable excipient. In some - 131 -WSGR Docket No.61402-716.601 embodiments, the administering to the subject in need thereof comprises a pharmaceutical composition comprising a compound or salt as provided in Table 1, and a pharmaceutically acceptable excipient.

[0338] In some aspects, the present disclosure provides a method of inhibiting mutant AKT1. In some embodiments, the method of inhibiting mutant AKT1 comprises, administering to a subject in need thereof a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III- C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), or a pharmaceutically acceptable composition thereof. In some embodiments, the mutant AKT1 is AKT1 E17K. In some embodiments, the administering to the subject in need thereof comprises a compound or salt as provided in Table 1. In some embodiments, the administering to the subject in need thereof comprises a pharmaceutical composition comprising the compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), and a pharmaceutically acceptable excipient. In some embodiments, the administering to the subject in need thereof comprises a pharmaceutical composition comprising a compound or salt as provided in Table 1, and a pharmaceutically acceptable excipient.

[0339] In some aspects, the present disclosure provides a method of modulating activity of a mutant AKT1 over wild-type AKT2. In some embodiments, the method of modulating activity of a mutant AKT1 over wild-type AKT2 comprises, administering to a subject in need thereof a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III- F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), or a pharmaceutically acceptable composition thereof. In some embodiments, the mutant AKT1 is AKT1 E17K. In some embodiments, the administering to the subject in need thereof comprises a compound or salt as provided in Table 1. In some embodiments, the administering to the subject in need thereof comprises a pharmaceutical composition comprising the compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), and a pharmaceutically acceptable excipient. In some embodiments, the administering to the subject in need thereof comprises a pharmaceutical composition comprising a compound or salt as provided in Table 1, and a pharmaceutically acceptable excipient. In some embodiments, the activity of mutant AKT1 is modulated by at least 1-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 25-fold, at least 50-fold, at least 75-fold, or at least 100-fold, over wild-type AKT2. In some embodiments, the activity of mutant AKT1 is modulated by about 1-fold, about 2-fold, about 3-fold, about 4- fold, about 5-fold, about 10-fold, about 20-fold, about 25-fold, about 50-fold, about 75-fold, or about 100-fold over wild-type AKT2. In some embodiments, the activity of mutant AKT1 is - 132 -WSGR Docket No.61402-716.601 modulated by 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 25-fold, 50-fold, 75-fold, or 100-fold over wild-type AKT2.

[0340] In some aspects, the present disclosure provides a method of inhibiting activity of a mutant AKT1 over wild-type AKT2. In some embodiments, the method of inhibiting activity of a mutant AKT1 over wild-type AKT2 comprises, administering to a subject in need thereof a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III- F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), or a pharmaceutically acceptable composition thereof. In some embodiments, the mutant AKT1 is AKT1 E17K. In some embodiments, the administering to the subject in need thereof comprises a compound or salt as provided in Table 1. In some embodiments, the administering to the subject in need thereof comprises a pharmaceutical composition comprising the compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), and a pharmaceutically acceptable excipient. In some embodiments, the administering to the subject in need thereof comprises a pharmaceutical composition comprising a compound or salt as provided in Table 1, and a pharmaceutically acceptable excipient. In some embodiments, the activity of mutant AKT1 is inhibited by at least 1-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 25-fold, at least 50-fold, at least 75-fold, or at least 100-fold, over wild-type AKT2. In some embodiments, the activity of mutant AKT1 is inhibited by about 1-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 10-fold, about 20-fold, about 25-fold, about 50-fold, about 75-fold, or about 100-fold over wild-type AKT2. In some embodiments, the activity of mutant AKT1 is inhibited by 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 25-fold, 50-fold, 75-fold, or 100-fold over wild-type AKT2.

[0341] In some aspects, the present disclosure provides a method of treating cancer. In some embodiments, the method of treating cancer in a subject in need thereof comprises, administering to a subject in need thereof a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), or a pharmaceutically acceptable composition thereof. In some embodiments, the cancer is selected from breast cancer, colorectal cancer, and meningioma. In some embodiments, the administrating of a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), or pharmaceutically acceptable composition thereof modulates activity of a mutant AKT1. In some embodiments, the mutant AKT1 is AKT1 E17K. In some embodiments, the administering to the subject in need thereof comprises a compound or salt as provided in Table 1. In some embodiments, the administering to the subject in need thereof comprises a pharmaceutical - 133 -WSGR Docket No.61402-716.601 composition comprising the compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D), and a pharmaceutically acceptable excipient. In some embodiments, the administering to the subject in need thereof comprises a pharmaceutical composition comprising a compound or salt as provided in Table 1, and a pharmaceutically acceptable excipient. AKT1 Protein

[0342] In some aspects, the present disclosure provides an AKT1 protein covalently bound to a compound, wherein the compound is covalently bound to a cysteine residue of the AKT1 protein. In some embodiments, the compound is a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV- C), or (IV-D), or a pharmaceutically acceptable composition thereof. In some embodiments, the compound is a compound or salt as provided in Table 1, or a pharmaceutically acceptable composition thereof.

[0343] In some embodiments, the AKT1 protein is selected from a wild-type AKT1 protein and a mutated AKT1 protein. In some embodiments, the AKT1 protein is a mutated AKT1 protein. In some embodiments, the mutated AKT1 protein comprises a mutation selected from a E17K mutation, a E40K mutation, and a E49K mutation. In some embodiments, the mutated AKT1 protein comprises a E17K mutation. In some embodiments, the mutated AKT1 protein comprises a E40K mutation. In some embodiments, the mutated AKT1 protein comprises a E49K mutation.

[0344] In some embodiments, the compound is in contact a cysteine residue of the AKT1 protein as described herein. In some embodiments, the contact is between the cysteine reside of the AKT1 protein and the compound is a covalent bond. In some embodiments, the cysteine reside is selected from C296 and C310. In some embodiments, the cysteine residue is C296. In some embodiments, the cysteine residue is C310.

[0345] In some embodiments, the covalent bond between the compound and the cysteine residue is an irreversible covalent bond. In some embodiments, the irreversible covalent bond is a single bond. In some embodiments, the irreversible covalent bond is a single bond between a carbon atom on the compound and the sulfur atom on the sidechain of the cysteine residue.

[0346] In some embodiments, the covalent bond between the compound and the cysteine residue is an irreversible covalent bond, wherein the cysteine residue is selected from C296 and C310. In some embodiments, the covalent bond between the compound and the cysteine residue is an irreversible single covalent bond, wherein the cysteine residue is selected from C296 and C310. In some embodiments, the covalent bond between the compound and the cysteine residue is an - 134 -WSGR Docket No.61402-716.601 irreversible covalent bond, wherein the cysteine residue is C296. In some embodiments, the covalent bond between the compound and the cysteine residue is an irreversible covalent single bond, wherein the cysteine residue is C296. In some embodiments, the covalent bond between the compound and the cysteine residue is an irreversible covalent bond, wherein the cysteine residue is C310. In some embodiments, the covalent bond between the compound and the cysteine residue is an irreversible covalent single bond, wherein the cysteine residue is C310.

[0347] In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein comprises a carbon-sulfur interaction. In some embodiments, the carbon-sulfur interaction is a carbon-sulfur single bond.

[0348] In some embodiments, the AKT1 protein is covalently bound with the compound, wherein the compound is bound at only one residue of the AKT1 protein. In some embodiments, the AKT1 protein is covalently bond with the compound via one covalent bond. In some embodiments, the AKT1 protein is covalently bound with the compound, wherein the compound is bound at one cysteine residue. In some embodiments, the AKT1 protein has a single covalent bond between a cysteine residue and the compound. In some embodiments, the AKT1 protein has a single covalent bond between C296 and the compound. In some embodiments, the AKT1 protein has a single covalent bond between C310 and the compound.

[0349] In some embodiments, the compound has reduced engagement at other cysteine residues when covalently bound at a cysteine residue selected from C296 and C310. In some embodiments, the compound is in contact with one cysteine residue selected from C296 and C310, and has reduced engagement at the remaining cysteine residues. In some embodiments, the compound is in contact with C296, and has reduced engagement at C310. In some embodiments, the compound is in contact with C310, and has reduced engagement at C296.

[0350] In some embodiments, the AKT1 protein has a single cysteine residue covalently bound with the compound. In some embodiments, the AKT1 protein has a single cysteine residue covalently bound with the compound, wherein the single cysteine residue is selected from C296 and C310. In some embodiments, the AKT1 protein has a single cysteine residue covalently bound with the compound, wherein the single cysteine residue is C296. In some embodiments, the AKT1 protein has a single cysteine residue covalently bound with the compound, wherein the single cysteine residue is C310.

[0351] In some embodiments, the AKT1 protein is in vivo. In some embodiments, the AKT1 protein is in vitro. In some embodiments, the AKT1 protein is ex vivo. In some embodiments, the AKT1 protein is an in vivo engineered protein.

[0352] In some embodiments, the AKT1 protein is an in vivo engineered AKT1 protein, wherein the in vivo engineered AKT1 protein is generated by contacting the AKT1 protein in vivo with - 135 -WSGR Docket No.61402-716.601 the compound. In some embodiments, the AKT1 protein is a mammalian in vivo engineered AKT1 protein, wherein the in vivo engineered AKT1 protein is generated by contacting the AKT1 protein in vivo with the compound. In some embodiments, the AKT1 protein is a human in vivo engineered AKT1 protein, wherein the in vivo engineered AKT1 protein is generated by contacting the AKT1 protein in vivo with the compound.

[0353] In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is between a carbon atom and a sulfur atom. In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is between a carbon atom of the compound and a sulfur atom of the cysteine residue. In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is between a carbon atom of the compound and a sulfur atom of the cysteine residue selected from C296 and C310. In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is between a carbon atom of the compound and a sulfur atom of the C296 cysteine residue. In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is between a carbon atom of the compound and a sulfur atom of the C310 cysteine residue.

[0354] In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is a carbon-sulfur single bond. In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is a carbon-sulfur single bond between the compound and the cysteine residue. In some embodiments, the carbon-sulfur single bond is between the compound and the cysteine residue, wherein the cysteine residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond is between the compound and the C296 cysteine residue. In some embodiments, the carbon-sulfur single bond is between the compound and the C310 cysteine residue.

[0355] In some embodiments, the compound comprises a cysteine susceptible electrophile. In some embodiments, the cysteine susceptible electrophile is selected from: an alkene, an alkyne, an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide, and an epoxide group. In some embodiments, the cysteine susceptible electrophile is selected from: an alkene, an alkyne, an acrylate group, and an acrylamide group. In some embodiments, the cysteine susceptible electrophile is selected from an alkene and an alkyne. In some embodiments, the cysteine susceptible electrophile is an alkene. In some embodiments, the cysteine susceptible electrophile is selected from an alkyne. In some embodiments, the cysteine susceptible electrophile is selected from an acrylate group and an acrylamide group. In some embodiments, the cysteine susceptible electrophile is an acrylamide group. In some embodiments, the compound comprises an alkene, an alkyne, an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an - 136 -WSGR Docket No.61402-716.601 ynamide, and an epoxide group. In some embodiments, the compound comprises an alkene, an alkyne, an acrylate group, an acrylamide group, a vinylsulfone group, and a vinylsulfonamide group. In some embodiments, the compound comprises an alkene, an alkyne, an acrylate group and an acrylamide group. In some embodiments, the compound comprises an acrylamide group. In some embodiments, the compound comprises an alkene. In some embodiments, the compound comprises an alkyne.

[0356] In some embodiments, the irreversible covalent bond is between the cysteine susceptible electrophile and the cysteine residue. In some embodiments, the irreversible covalent bond is between the cysteine susceptible electrophile and the cysteine residue selected from C296 and C310. In some embodiments, the irreversible covalent bond is between the cysteine susceptible electrophile and the C296 cysteine residue. In some embodiments, the irreversible covalent bond is between the cysteine susceptible electrophile and the C310 cysteine residue.

[0357] In some embodiments, the carbon-sulfur bond is an irreversible bond that results from an irreversible reaction. In some embodiments, the carbon-sulfur bond is an irreversible bond that results from an irreversible reaction between the compound and a cysteine residue. In some embodiments, the carbon-sulfur bond is an irreversible bond that results from an irreversible reaction between the compound and a cysteine residue selected from C296 and C310. In some embodiments, the carbon-sulfur bond is an irreversible bond that results from an irreversible reaction between the compound and the C296 cysteine residue. In some embodiments, the carbon-sulfur bond is an irreversible bond that results from an irreversible reaction between the compound and the C310 cysteine residue.

[0358] In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and a cysteine susceptible electrophile on the compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the cysteine susceptible electrophile on the compound, wherein the cysteine residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C296 and a cysteine susceptible electrophile on the compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C310 and a cysteine susceptible electrophile on the compound.

[0359] In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the acrylate group on the compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the acrylate group on the - 137 -WSGR Docket No.61402-716.601 compound, wherein the cysteine residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C296 and the acrylate group on the compound. In some embodiments, the carbon- sulfur single bond results from an irreversible reaction between the thiol functional group of C310 and the acrylate group on the compound.

[0360] In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the acrylamide group on the compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the acrylamide group on the compound, wherein the cysteine residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C296 and the acrylamide group on the compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C310 and the acrylamide group on the compound.

[0361] In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the vinyl group on the compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the vinyl group on the compound, wherein the cysteine residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C296 and the vinyl group on the compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C310 and the vinyl group on the compound.

[0362] In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the alkene group on the compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the alkene group on the compound, wherein the cysteine residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C296 and the alkene group on the compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C310 and the alkene group on the compound.

[0363] In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the alkyne group on the compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction - 138 -WSGR Docket No.61402-716.601 between the thiol functional group of a cysteine residue and the alkyne group on the compound, wherein the cysteine residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C296 and the alkyne group on the compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C310 and the alkyne group on the compound.

[0364] In some embodiments, the compound is a compound or salt as disclosed herein. In some embodiments, the compound is selected from a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV- C), or (IV-D). In some embodiments, the compound is selected from a compound or salt in Table 1. Method of Modifying AKT1 proteins

[0365] In some aspects the present disclosure provides a method of modifying an AKT1 protein as disclosed herein. In some embodiments, the method of covalently modifying an AKT1 protein, comprises contacting the AKT1 protein with an compound, wherein the compound comprises an irreversible electrophilic moiety thereby forming an irreversible covalent AKT1 adduct. In some embodiments, the contacting is in vitro or in vivo. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the AKT1 protein is wild type AKT1 or a mutated AKT1. In some embodiments, the mutated AKT1 is E17K AKT1. In some embodiments, the wild type AKT1 protein is wild type. In some embodiments, the AKT1 protein is E17K AKT1. In some embodiments, the compound is an AKT1 inhibitor. In some embodiments, the irreversible covalent moiety on the AKT1 inhibitor is a cysteine susceptible electrophile. In some embodiments, the irreversible covalent AKT1 adduct is formed between the irreversible covalent moiety and a cysteine reside of the AKT1 protein. In some embodiments, the irreversible covalent AKT1 adduct is formed between the cysteine susceptible electrophile and the cysteine residue of the AKT1 protein. In some embodiments, irreversible covalent AKT1 adduct is formed between the irreversible covalent moiety and a cysteine residue of the AKT1 protein selected from C296 and C310. In some embodiments, irreversible covalent AKT1 adduct is formed between the cysteine susceptible electrophile and a cysteine residue of the AKT1 protein selected from C296 and C310. In some embodiments, irreversible covalent AKT1 adduct is formed between the cysteine susceptible electrophile and the C296 cysteine residue of the AKT1 protein. In some embodiments, irreversible covalent AKT1 adduct is formed between the cysteine susceptible electrophile and the C310 cysteine residue of the AKT1 protein. In some embodiments, the cysteine susceptible - 139 -WSGR Docket No.61402-716.601 electrophile is selected from: an alkene, an alkyne, an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide group, and an epoxide group. In some embodiments, the cysteine susceptible electrophile is selected from: an alkene, an alkyne, an acrylate group, and an acrylamide group. In some embodiments, the cysteine susceptible electrophile is selected from an alkene and an alkyne. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group and an acrylamide group. In some embodiments, the cysteine susceptible electrophile is an acrylamide group. In some embodiments, the cysteine susceptible electrophile is an alkene. In some embodiments, the cysteine susceptible electrophile is an alkyne.

[0366] In some aspects, the compound is a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D). In some embodiments, the AKT1 inhibitor is a compound or salt of Formula (I), (II), (II- A), (III), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-E), (IV), (IV-A), (IV-B), (IV-C), or (IV-D).

[0367] EXAMPLES

[0368] 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.

[0369] 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 similar methods 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.

[0370] Example 1: 3-phenyl-2-[(1S)-1-{[1-(prop-2-enoyl)piperidin-4-yl]amino}-2,3-dihydro- 1H-inden-5-yl]imidazo[1,2-b]pyridazine-6-carboxamide (Compound 1) - 140 -WSGR Docket No.61402-716.601

[0371] Synthetic Route:

[0372] Step 1: Synthesis of 3-phenyl-2-[(1S)-1-{[1-(prop-2-enoyl)piperidin-4-yl]amino}-2,3- dihydro-1H-inden-5-yl]imidazo[1,2-b]pyridazine-6-carboxamide (Compound 1)

[0373] A solution of 2-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-3-phenylimidazo[1,2- b]pyridazine-6-carboxamide (Intermediate 1-1) (100 mg, 0.271 mmol) and 1-(prop-2- enoyl)piperidin-4-one (49.76 mg, 0.325 mmol) in DCE (4 mL) was stirred for 2 h at 40 ℃. Then NaBH3CN (68.04 mg, 1.084 mmol) was added and the obtained suspension was stirred at 40℃ for 2 h. The mixture was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+ 0.05% ammonium bicarbonate). The obtained material was further purified by Prep-HPLC on a XSelect CSH Fluoro Phenyl column using a gradient of acetonitrile in water (+ 0.05% TFA) to afford 3-phenyl-2-[(1S)-1-{[1-(prop-2-enoyl)piperidin-4- yl]amino}-2,3-dihydro-1H-inden-5-yl]imidazo[1,2-b]pyridazine-6-carboxamide (Compound 1) (22.4 mg, 15.72% yield) as a yellow solid. MS (ESI) calcd. for C30H30N6O2: 506.24 m / z, found: 507.25 [M+H]+.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.22 - 8.33 (m, 1H), 7.72 - 7.79 (m, 1H), 7.58 - 7.68 (m, 3H), 7.42 - 7.57 (m, 5H), 6.75 - 6.90 (m, 1H), 6.08 - 6.20 (m, 1H), 5.65 - 5.75 (m, 1H), 4.85 - 4.99 (m, 1H), 4.45 - 4.59 (m, 1H), 4.10 - 4.25 (m, 1H), 3.45 - 3.58 (m, 1H), 3.01 - 3.20 (m, 2H), 2.81 - 2.92 (m, 1H), 2.65 - 2.78 (m, 1H), 2.45 - 2.58 (m, 1H), 2.05 - 2.25 (m, 3H), 1.39 - 1.55 (m, 2H).

[0374] Intermediate 1-1: (S)-2-(1-amino-2,3-dihydro-1H-inden-5-yl)-3-phenylimidazo[1,2- - 141 -WSGR Docket No.61402-716.601 b]pyridazine-6-carboxamide

[0375] Synthetic Route:

[0376] Step 1: Synthesis of tert-butyl N-[(1S)-5-ethenyl-2,3-dihydro-1H-inden-1-yl]carbamate

[0377] To a solution of tert-butyl N-[(1S)-5-bromo-2,3-dihydro-1H-inden-1-yl]carbamate (29 g, 92.887 mmol, 1 equiv) in THF (200 mL) and H2O (50 mL) was added 2-ethenyl-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (18.60 g, 120.753 mmol, 1.3 equiv), Pd(dtbpf)Cl2 (6.05 g, 9.289 mmol, 0.1 equiv) and K3PO4 (59.15 g, 278.661 mmol, 3 equiv). The resulting mixture was maintained under nitrogen and stirred at rt overnight. The reaction was quenched with H2O (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-10% EtOAc / petroleum ether) to afford tert-butyl N-[(1S)-5- ethenyl-2,3-dihydro-1H-inden-1-yl]carbamate (24 g, 99.63%) as a light yellow solid. MS (ESI) calcd. for C16H21NO2: 259.16 m / z, found: 258.05 [M-H]-.

[0378] Step 2: Synthesis of tert-butyl N-[(1S)-5-(2-bromoacetyl)-2,3-dihydro-1H-inden-1- yl]carbamate

[0379] To a solution of tert-butyl N-[(1S)-5-ethenyl-2,3-dihydro-1H-inden-1-yl]carbamate (10 g, 38.558 mmol, 1 equiv) in DMSO (80 mL) was added NBS (7.55 g, 42.414 mmol, 1.10 equiv), IBX (21.59 g, 77.116 mmol, 2 equiv). The resulting mixture was stirred at rt for 1 h. The - 142 -WSGR Docket No.61402-716.601 reaction was quenched with H2O (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to afford tert-butyl N-[(1S)-5-(2-bromoacetyl)-2,3-dihydro-1H-inden-1-yl]carbamate (15 g, crude) as a pink solid. MS (ESI) calcd. for C16H20BrNO3: 353.06 m / z, found: 352.00 [M-H]-.

[0380] Step 3: Synthesis of ethyl 2-[(1S)-1-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden- 5-yl]imidazo[1,2-b]pyridazine-6-carboxylate

[0381] To a solution of tert-butyl N-[(1S)-5-(2-bromoacetyl)-2,3-dihydro-1H-inden-1- yl]carbamate (15 g, 42.344 mmol, 1.00 equiv) in EtOH (300 mL) was added ethyl 6- aminopyridazine-3-carboxylate (7.08 g, 42.344 mmol, 1.00 equiv) and NaHCO3 (14.23 g, 169.376 mmol, 4 equiv). The resulting mixture was stirred at 80°C for 3 h. The solvent was removed by distillation under vacuum. The residue obtained was purified by silica gel chromatography (0-10% EtOAc / petroleum ether) to afford ethyl 2-[(1S)-1-[(tert- butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5-yl]imidazo[1,2-b]pyridazine-6-carboxylate (5.6 g, 31.30%) as a yellow solid. MS (ESI) calcd. for C23H26N4O4: 422.20 m / z, found: 423.15 [M+H]+.

[0382] Step 4: Synthesis of 2-[(1S)-1-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5- yl]imidazo[1,2-b]pyridazine-6-carboxylic acid

[0383] To a solution of ethyl 2-[(1S)-1-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5- yl]imidazo[1,2-b]pyridazine-6-carboxylate (4.6 g, 10.888 mmol, 1 equiv) in THF (80 mL) and H2O (24 mL) was added LiOH (2M in H2O, 10.89 mL, 21.776 mmol, 2 equiv). The resulting mixture was stirred at rt for 1 h. The mixture was acidified to pH 5 with HCl / H2O (2N). The resulting mixture was extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to afford 2-[(1S)-1-[(tert- butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5-yl]imidazo[1,2-b]pyridazine-6-carboxylic acid (4.1 g, 95.47%) as a yellow solid. MS (ESI) calcd. for C21H22N4O4: 394.16 m / z, found: 395.15 [M+H]+.

[0384] Step 5: Synthesis of tert-butyl N-[(1S)-5-{6-carbamoylimidazo[1,2-b]pyridazin-2-yl}- 2,3-dihydro-1H-inden-1-yl]carbamate

[0385] To a solution of 2-[(1S)-1-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5- yl]imidazo[1,2-b]pyridazine-6-carboxylic acid (5 g, 12.676 mmol, 1 equiv) in DMF (80 mL) was added DIEA (4915.19 mg, 38.028 mmol, 3 equiv), HATU (7230.07 mg, 19.014 mmol, 1.5 equiv), NH4Cl (2712.26 mg, 50.704 mmol, 4 equiv). The resulting mixture was stirred at rt for 1 h. The resulting mixture was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+ 0.05% ammonium bicarbonate) to afford tert- butyl N-[(1S)-5-{6-carbamoylimidazo[1,2-b]pyridazin-2-yl}-2,3-dihydro-1H-inden-1- - 143 -WSGR Docket No.61402-716.601 yl]carbamate (4.5 g, 90.23%) as a yellow solid. MS (ESI) calcd. for C21H23N5O3: 393.18 m / z, found: 394.15 [M+H]+.

[0386] Step 6: Synthesis of tert-butyl N-[(1S)-5-{6-carbamoyl-3-iodoimidazo[1,2-b]pyri...

Claims

WSGR Docket No.61402-716.601 CLAIMS WHAT IS CLAIMED IS:

1. A compound represented by the structure of Formula (I):or a pharmaceutically acceptable salt thereof wherein: X is selected from O, C(R5A)2, S, and N(R5B); Y1is selected from N and C(R1D); Y2is selected from N and C(R1D); wherein one of Y1or Y2is N and the other of Y1or Y2is C(R1D); R1A, R1B, R1C, and R1Dare each independently selected at each occurrence from (i), (ii), and (iii): (i) hyd(ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -S(O)2N(R11)2, -NO2, =O, =S, =N(R11), and -CN; and (iii) 3- to 10-membered heterocycle and C3-10 carbocycle, 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, -C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one 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, -N(R11)C(O)OR11, - OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -S(O)R11, -S(O)2R11, - N(R11)S(O)2R11, -S(O)2N(R11)2, -NO2, =O, =S, =N(R11), and -CN; - 327 -WSGR Docket No.61402-716.601 R2is selected from halogen, -OR12, -SR12, -N(R12)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, - SR12, -N(R12)2, -NO2, and -CN; L is represented by -L1-L2-L3-L4-, wherein L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -O-, -N(R13)-, -S-, -S(O)-, -S(O)2-, -S(O)(NR13)-, -N(R13)C(O)-, -N(R13)C(O)O-, -N(R13)S(O)2-, -N(R13)S(O)2N(R13)-, -S(O)(NR13)N(R13)-, -N(R13)N(R13)-, - N(R13)C(O)N(R13)-, and -N(R13)C(O)N(R13)N(R13)-; (b) C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, each of which is optionally substituted with one or more substituents independently selected halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, - OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, -S(O)R13, - S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =N(R13), -NO2, and -CN; and (c) C3-10 carbocyclene and 3- to 10-membered heterocyclene, 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, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, - N(R13)C(O)N(R13)2, -S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =N(R13), -NO2, and -CN; and C1-6 alkyl 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, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, - OC(O)N(R13)2, -N(R13)C(O)N(R13)2, -S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, - S(O)2N(R13)2, =O, =S, =N(R13), -NO2, and -CN; wherein L2, L3, and L4are each optionally absent; wherein no more than two of L1, L2, L3, and L4are selected from (a) and the two selected are not adjacent; R3is a cysteine susceptible electrophile; each R4is independently selected at each occurrence from halogen, -OR14, -SR14, -N(R14)2, - NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -NO2, and -CN; each R5Ais independently selected at each occurrence from hydrogen, halogen, -OR15, -SR15, - N(R15)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -NO2, and - CN; - 328 -WSGR Docket No.61402-716.601 R5Bis selected from hydrogen and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR16, -SR16, -N(R16)2, -NO2, and -CN; R11, R12, R13, R14, R15, and R16are each independently selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; m is selected from 1 and 2; n is selected from 0, 1, 2, and 3; and o is selected from 0, 1, 2, 3, 4, 5, and 6.

2. The compound or salt of claim 1, wherein Y1is C(R1D) and Y2is N.

3. The compound or salt of claim 1 or claim 2, wherein Formula (I) is represented by the structure of Formula (II):

4. The compound or salt of any one of claims 1 to 3, wherein the cysteine susceptible electrophile of R3is selected from: -C(O)R16, -S(O)2R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), -N(R17)S(O)2R16, - S(O)2N(R16)(R17), and -CN; and C1-6 alkyl substituted with one or more substituents independently selected from - C(O)R16, -S(O)2R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), -N(R17)S(O)2R16, - S(O)2N(R16)(R17), and -CN; R16is independently selected at each occurrence from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected - 329 -WSGR Docket No.61402-716.601 from: halogen, -OR18, -SR18, -N(R18)2, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, - N(R18)C(O)R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -N(R18)C(O)N(R18)2, - N(R18)C(O)OR18, -OC(O)N(R18)2, -S(O)R18, -S(O)2R18, -NO2, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; R17is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle; and R18selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl,-O-C1-6 alkyl, -O- C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, and -CN.

5. The compound or salt of claim 4, wherein R3is selected from -C(O)R16, - N(R17)C(O)(R16), -C(O)N(R16)(R17), -NO2, and -CN; and C1-6 alkyl substituted with one or more substituents independently selected from -C(O)R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), -NO2 and -CN.

6. The compound or salt of claim 5, wherein R3is selected from -C(O)R16, - N(R17)C(O)(R16), and -C(O)N(R16)(R17).

7. The compound or salt of claim 6, wherein R3is -C(O)R16.

8. The compound or salt of claim 7, wherein R16is independently selected at each occurrence from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR18, -N(R18)2, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -N(R18)C(O)R18, -NO2 - 330 -WSGR Docket No.61402-716.601 and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, and -O-C1-6 haloalkyl.

9. The compound or salt of claim 8, wherein R16is independently selected at each occurrence from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR18, -N(R18)2, -C(O)N(R18)2; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

10. The compound or salt of claim 9, wherein R16is independently selected at each occurrence from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR18, -N(R18)2, and -C(O)N(R18)2.

11. The compound or salt of any one of claims 4-10, wherein R3is selected from12. The compound or salt of any one of claims 1-11, wherein m is 1.

13. The compound or salt of any one of claims 1-12, wherein n is 0.

14. The compound or salt of any one of claims 1-13, wherein R1Cis selected from hydrogen, halogen, -OR11, -N(R11)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

15. The compound or salt of claim 14, wherein R1Cis hydrogen or methoxy.

16. The compound or salt of any one of claims 1-15, wherein R1Dis selected from hydrogen, halogen, -OR11, -N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -NO2, and -CN.

17. The compound or salt of claim 16, wherein R1Dis selected from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl.

18. The compound or salt of claim 17, wherein R1Dis hydrogen.

19. The compound or salt of any one of claims 1-18, wherein R1Bis selected from (i), (ii), and (iii): - 331 -WSGR Docket No.61402-716.601 (i) hydrogen, 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, -N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, - NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, - C(O)N(R11)2, -N(R11)C(O)R11, -C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, =O, =S, =N(R11), and -CN; and (iii) 3- to 10-membered heterocycle and C3-10 carbocycle, 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, -NO2, =O, =S, =N(R11), and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one 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, -NO2, =O, =S, =N(R11), and - CN.

20. The compound or salt of claim 19, wherein R1Bis selected from hydrogen, 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, -NO2, and -CN.

21. The compound or salt of claim 20, wherein R1Bis selected from hydrogen,,22. The compound or salt of claim 19, wherein R1Bis selected from 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen,OC(O)R11, =O, -NO2, and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

23. The compound or salt of claim 22, wherein R1Bis 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen,WSGR Docket No.61402-716.601 OC(O)R11, =O, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR1C(O)OR11, -OC(O)R24. The compound or salt of claim 23, wherein R1Bis.

25. The compound or salt of any one of claims 1-24, R1Bis selected from hydrogen, methoxy,, fluoro,26. The compound or salt of any one of claims 1-25, wherein R1Ais selected from (i), (ii), and (iii): (i) hydrogen, halogen, -OR11, -N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, - OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -(iii)3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen,C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, C(O)OR1N(R11)C(O)N(R11)2, -NO2, =O, =N(R11), and -CN.

27. The compound or salt of claim 26, wherein R1Ais C3-10 carbocycle optionally substituted with one or more substituents independently selected from: halogen,OC(O)R11, =O, -NO2, and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - - 333 -WSGR Docket No.61402-716.601 C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

28. The compound or salt of claim 27, wherein R1Ais C3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen,OC(O)R11, =O, -NO2, and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

29. The compound or salt of claim 28, wherein R1Ais selected from cyclopropyl and phenyl, each of which is optionally substituted with one or more substituents independently selected from: halogen,OC(O)R11, -NO2, and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

31. The compound or salt of claim 26, wherein R1Ais 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, OC1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN. - 334 -WSGR Docket No.61402-716.601 32. The compound or salt of claim 31, wherein R1Ais 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, OC1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN. . The compound or salt of claim 32, wherein R1Ais selected from.

35. The compound or salt of any one of claims 1-34, wherein L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -O-, -N(R13)-, -N(R13)C(O)-, -N(R13)C(O)O-, -N(R13)N(R13)-, - N(R13)C(O)N(R13)-, and -N(R13)C(O)N(R13)N(R13)-; (b) C1-6alkylene, C2-6alkenylene, C2-6alkynylene, each of which is optionally substituted with one or more substituents independently selected halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, - N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, =O, =N(R13), -NO2, and -CN; and (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, - OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, =O, =N(R13), -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, - N(R13)C(O)N(R13)2, =O, =N(R13), -NO2, and -CN; - 335 -WSGR Docket No.61402-716.601 wherein L2, L3, and L4are each optionally absent; and wherein no more than two of L1, L2, L3, and L4are selected from (a) and the two selected are not adjacent.

36. The compound or salt of claim 35, wherein L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -O-, -N(R13)-, -N(R13)C(O)-, -C(O)OR13, and -OC(O)R13-; (b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, each of which is optionally substituted with one or more substituents independently selected halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, =O, -NO2, and -CN; and (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, - OC(O)R13; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)N(R13)2, - N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, =O, -NO2, and -CN.

37. The compound or salt of any one of claims 1-36, wherein L4is absent.

38. The compound or salt of any one of claims 1-37, wherein L3is 3- to 6-membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

39. The compound or salt of claim 38, wherein L3is piperidinylene, optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, - C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

40. The compound or salt of claim 39, wherein L3is selected from.

41. The compound or salt of any one of claims 1-37, wherein L3is absent.

42. The compound or salt of any one of claims 1-41, wherein L2is selected C1-6 alkylene optionally substituted with one or more substituents independently selected halogen, -OR13, - N(R13)2, =O, -NO2, and -CN. - 336 -WSGR Docket No.61402-716.601 43. The compound or salt of claim 42, wherein L2is methylene.

44. The compound or salt of any one of claims 1-41, wherein L2is selected from C3-10carbocyclene and 3- to 10-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, - C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, - N(R13)C(O)N(R13)2, =O, =N(R13), -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

45. The compound or salt of claim 44, wherein L2is 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

46. The compound or salt of claim 45, wherein L2is selected from piperidinylene, piperazinylene, pyrrolidinylene, and azetidinylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, - C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

47. The compound or salt of claim 46, wherein L2is selected from, , ,.

48. The compound or salt of any one of claims 1-47, wherein L1is selected from -O-, - N(R13)-, -N(R13)C(O)-, -N(R13)C(O)O-, -N(R13)N(R13)-, -N(R13)C(O)N(R13)-, and - N(R13)C(O)N(R13)N(R13)-.

49. The compound or salt of claim 48, wherein L1is selected from -N(R13)- and - N(R13)C(O)-.

50. The compound or salt of claim 49, wherein L1is selected fromand -N(H)-.

51. The compound or salt of any one of claims 1-47, wherein L1is selected from C1-6 alkylene optionally substituted with one or more substituents independently selected halogen, - OR13, -N(R13)2, =O, -NO2, and -CN. - 337 -WSGR Docket No.61402-716.601 52. The compound or salt of claim 51, wherein L1is methylene.

54. The compound or salt of any one of claims 1-53, wherein X is O.

55. The compound or salt of any one of claims 1-54, wherein o is selected from 0 and 1.

56. The compound or salt of claim 55, wherein o is 0.

57. The compound or salt of claim 55, wherein o is 1.

58. The compound or salt of claim 57, wherein R4is independently selected at each occurrence from halogen, -OR14, -N(R14)2, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -NO2, and -CN.

59. The compound or salt of claim 58, wherein R4is independently selected at each occurrence from halogen, C1-6 alkyl, and C1-6 haloalkyl.

60. The compound of salt of claim 1, wherein Y1is N and Y2is C(R1D).

61. The compound or salt of claim 1 or 60, wherein Formula (I) is represented by the structure of Formula (III):or a pharmaceutically acceptable salt thereof wherein: X is selected from O, C(R5A)2, S, and N(R5B); - 338 -WSGR Docket No.61402-716.601 R1A, R1B, R1C, and R1Dare each independently selected at each occurrence from (i), (ii), and (iii): (i) hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -(ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -(iii) 3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, - N(OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -S(O)R11, -S(O)2R11, -S(O)2N(R11)2, -NO2, =O, =S, =N(R11), and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one 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, -N(R11)C(O)OR11, - OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -S(O)R11, -S(O)2R11, - N(R11)S(O)2R11, -S(O)2N(R11)2, -NO2, =O, =S, =N(R11), and -CN; R2is selected from halogen, -OR12, -SR12, -N(R12)2, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, - SR12, -N(R12)2, -NO2, and -CN; L is represented by -L1-L2-L3-L4-, wherein L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -O-, -N(R13)-, -S-, -S(O)-, -S(O)2-, -S(O)(NR13)-, -N(R13)C(O)-, -N(R13)C(O)O-, -N(R13)S(O)2-, -N(R13)S(O)2N(R13)-, -S(O)(NR13)N(R13)-, -N(R13)N(R13)-, - N(R13)C(O)N(R13)-, and -N(R13)C(O)N(R13)N(R13)-; (b) C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, each of which is optionally substituted with one or more substituents independently selected halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, - OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, -S(O)R13, - S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =N(R13), -NO2, and -CN; and (c) C3-10 carbocyclene and 3- to 10-membered heterocyclene, each of which is - 339 -WSGR Docket No.61402-716.601 optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C1-6 alkyl 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, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, - OC(O)N(R13)2, -N(R13)C(O)N(R13)2, -S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, - S(O)2N(R13)2, =O, =S, =N(R13), -NO2, and -CN; wherein L2, L3, and L4are each optionally absent; wherein no more than two of L1, L2, L3, and L4are selected from (a) and the two selected are not adjacent; R3is a cysteine susceptible electrophile; each R4is independently selected at each occurrence from halogen, -OR14, -SR14, -N(R14)2, - NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -NO2, and -CN; each R5Ais independently selected at each occurrence from hydrogen, halogen, -OR15, -SR15, - N(R15)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -NO2, and - CN; R5Bis selected from hydrogen and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR16, -SR16, -N(R16)2, -NO2, and -CN; R11, R12, R13, R14, R15, and R16are each independently selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -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, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; m is selected from 1 and 2; - 340 -WSGR Docket No.61402-716.601 n is selected from 0, 1, 2, and 3; and o is selected from 0, 1, 2, 3, 4, 5, and 6.

62. The compound or salt of any one of claims 1, 3, or 61, wherein the cysteine susceptible electrophile is selected from a haloacetamide, a haloalkyl ketone, a halo amidine, a halo benzylphosphonate, an acyloxyalkyl ketone, a sulfonyl oxirane, an epoxide, a diazoalkyl ketone, a halotriazine, an acrylamide, a cyano acrylamide, a vinyl sulfone, a vinyl sulfonamide, an acrylate, a fumarate, a carbonyl acrylate, a maleimide, a ketoamide, a nitrile, an alkene, an alkyne, a keto heterocycle, an ynamide, a squaric acid group, a squaric ester group, and a squaramide ester group.

63. The compound or salt of any one of claims 1, 3, or 61, wherein the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide, an alkene, an alkyne, an epoxide group, a squaric acid group, a squaric ester group, and a squaramide ester group.

64. The compound or salt of claim 63, wherein the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, a vinylsulfone group, a vinylsulfonamide group, an alkene, an alkyne, a squaric acid group, a squaric ester group, and a squaramide ester group.

65. The compound or salt of claim 64, wherein the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, an alkene, an alkyne, a squaric acid group, a squaric ester group, and a squaramide ester group.

66. The compound or salt of claim 65, wherein the cysteine susceptible electrophile is selected from a squaric acid group, a squaric ester group, and a squaramide ester group.

67. The compound or salt of claim 66, wherein the cysteine susceptible electrophile is a squaric ester group.

68. The compound of salt of claim 67, wherein the cysteine susceptible electrophile is.

69. The compound or salt of any one of claims 1, 3, or 65, wherein the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, an alkene, and an alkyne. - 341 -WSGR Docket No.61402-716.601 70. The compound or salt of any one of claims 1, 3, or 62, wherein the cysteine susceptible electrophile is selected from an alpha-beta unsaturated carbonyl, an alpha-beta unsaturated sulfone, an alpha-beta unsaturated amide, and an alpha-beta unsaturated sulfonamide.

71. The compound or salt of claim 70, wherein the cysteine susceptible electrophile is selected from an alpha-beta unsaturated carbonyl and an alpha-beta unsaturated amide.

72. The compound or salt of claim 71, wherein the cysteine susceptible electrophile is an alpha-beta unsaturated carbonyl.

73. The compound or salt any one of claims 1, 3, or 62, wherein the cysteine susceptible electrophile of R3is selected from: -C(O)R16, -S(O)2R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), -N(R17)S(O)2R16, - S(O)2N(R16)(R17), and -CN; and C1-6 alkyl substituted with one or more substituents independently selected from - C(O)R16, -S(O)2R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), -N(R17)S(O)2R16, - S(O)2N(R16)(R17), and -CN; R16is independently selected at each occurrence from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR18, -SR18, -N(R18)2, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, - N(R18)C(O)R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -N(R18)C(O)N(R18)2, - N(R18)C(O)OR18, -OC(O)N(R18)2, -S(O)R18, -S(O)2R18, -NO2, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; R17is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle; and R18selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents - 342 -WSGR Docket No.61402-716.601 independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl,-O-C1-6 alkyl, -O- C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN.

74. The compound or salt of any one of claims 61-73, wherein m is 1.

75. The compound or salt of any one of claims 61-74 wherein n is selected from 1 and 2; and R2is selected from OR12, -SR12, -N(R12)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

76. The compound or salt of any one of claims 61-74, wherein n is 0.

77. The compound or salt any one of claims 61-76, wherein R1Cis selected from hydrogen, halogen, -OR11, -N(R11)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

78. The compound or salt of claim 77, wherein R1Cis selected from hydrogen, halogen, and methoxy.

79. The compound or salt of any one of claims 74 and 76-78, wherein the structure of Formula (I) is represented by the structure of Formula (III-B) :or a pharmaceutically acceptable salt thereof.

80. The compound or salt of any one of claims 61-79, wherein R1Dis selected from (i), (ii), and (iii): (i) hydrogen, halogen, -OR11, -N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, - OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -(iii)3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: - 343 -WSGR Docket No.61402-716.601 halogen,NO2, =O, =N(R11), and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen,C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, - N(R11)C(O)N(R11)2, -NO2, =O, =N(R11), and -CN.

81. The compound or salt of claim 80, wherein R1Dis selected from hydrogen, halogen, - OR11, -N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -NO2, and -CN.

82. The compound or salt of claim 81, wherein R1Dis selected from hydrogen, halogen, and OR11; wherein R11is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl.

83. The compound or salt of claim 82, wherein R1Dis selected from hydrogen and -OCH3.

84. The compound or salt of claim 80, wherein R1Dis selected from C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen,OC(O)R11, =O, -NO2, and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

85. The compound or salt of claim 84, wherein R1Dis selected from C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, OC1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN. - 344 -WSGR Docket No.61402-716.601 86. The compound or salt of claim 85, wherein R1Dis selected from cyclopropyl and pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, OC1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

87. The compound or salt of claim 86, wherein R1Dis selected from:, , and.

88. The compound or salt of any one of claims 61-74 or 76-87, wherein the structure of Formula (I) or (II) is represented by the structure of Formula (III-C):or a pharmaceutically acceptable salt thereof.

89. The compound or salt of any one of claims 61-88, wherein L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -O-, -N(R13)-, -N(R13)C(O)-, -N(R13)C(O)O-, -N(R13)N(R13)-, - N(R13)C(O)N(R13)-, and -N(R13)C(O)N(R13)N(R13)-; (b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, each of which is optionally substituted with one or more substituents independently selected halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, - N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, =O, =N(R13), -NO2, and -CN; and (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, - - 345 -WSGR Docket No.61402-716.601 OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, =O, =N(R13), -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, - N(R13)C(O)N(R13)2, =O, =N(R13), -NO2, and -CN; wherein L2, L3, and L4are each optionally absent; and wherein no more than two of L1, L2, L3, and L4are selected from (a) and the two selected are not adjacent.

90. The compound or salt of claim 89, wherein L1, L2, L3, and L4are each independently selected from (a), (b), and (c): (a) -O-, -N(R13)-, -N(R13)C(O)-, -C(O)OR13, and -OC(O)R13-; (b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, each of which is optionally substituted with one or more substituents independently selected halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, =O, -NO2, and -CN; and (c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, - OC(O)R13; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)N(R13)2, - N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, =O, -NO2, and -CN.

91. The compound or salt of any one of claims 61-90, wherein L4is absent.

92. The compound or salt of any one of claims 61-91, wherein L3is absent.

93. The compound or salt of any one of claims 61-91, wherein L3is selected from 3- to 6- membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

94. The compound or salt of claim 93, wherein L3is selected from pyrimidinylene optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

95. The compound or salt of claim 94, wherein L3is. - 346 -WSGR Docket No.61402-716.601 96. The compound or salt of any one of claims 61-95, wherein L2is selected from C3-10 carbocyclene and 3- to 10-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, - C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, - N(R13)C(O)N(R13)2, =O, =N(R13), -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

97. The compound or salt of claim 96, wherein L2is 3- to 6-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

98. The compound or salt of claim 97, wherein L2is azetidinylene, piperidinylene, and pyrrolidinylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

99. The compound or salt of claim 98, wherein L2is selected from piperidinylene and pyrrolidinylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

100. The compound or salt of any one of claims 61-99, wherein L1is selected from C1-6 alkylene optionally substituted with one or more substituents independently selected halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, =O, -NO2, and -CN.

101. The compound or salt of claim 100, wherein L1is methylene.

102. The compound or salt of any one of claims 61-99, wherein L1is selected from -N(R13)- and -N(R13)C(O)-.

103. The compound or salt of claim 102, wherein L1is -N(R13)- ; and R13is selected at each occurrence from hydrogen C1-6 alkyl, and C1-6 haloalkyl.

104. The compound or salt of claim 103, wherein L1is -N(H)-. - 347 -WSGR Docket No.61402-716.601 105. The compound or salt of any one of claims 61-90, wherein L is selected from:.

106. The compound or salt of any one of claims 61-105, wherein X is O.

107. The compound or salt of any one of claims 61-105, wherein X is N(H).

108. The compound or salt of any one of claims 61-105, wherein X is C(R5A)2.

109. The compound or salt of claim 108, wherein each R5Ais independently selected at each occurrence from hydrogen, halogen, -OR15, -N(R15)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR15, -N(R15)2, -NO2, and -CN.

110. The compound or salt of claim 109, wherein each R5Ais independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl.

111. The compound or salt of claim 110, wherein X is C(H)2.

112. The compound or salt of any one of claims 61-74, 76-105, and 108-111, wherein the structure of Formula (I), (II), or (III) is represented by the structure of Formula (III-D):or a pharmaceutically acceptable salt thereof; whereinoptionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. - 348 -WSGR Docket No.61402-716.601 113. The compound or salt of any one of claims 61-112, wherein o is selected from 0, 1, 2, and 3.

114. The compound or salt of claim 113, wherein o is 0.

115. The compound or salt of claim 113, wherein o is selected from 1, 2, and 3.

116. The compound or salt of claim 115, wherein o is 1.

117. The compound or salt of claim 115 or 116, wherein R4is independently selected at each occurrence from halogen, -OR14, -N(R14)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -NO2, and -CN.

118. The compound or salt of claim 117, wherein R4is independently selected at each occurrence from halogen, C1-6 alkyl, and C1-6 haloalkyl.

119. The compound or salt of claim 118, wherein R4is independently selected at each occurrence from halogen and methyl.

120. The compound or salt of any one of claims 61-74, 76-106, or 113-114, wherein the structure of Formula (I) or (II) is represented by the structure of Formula (III-E):or a pharmaceutically acceptable salt thereof; whereinoptionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -C(O)N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

121. The compound or salt of any one of claims 61-120, wherein R1Bis selected from (i), (ii), and (iii): (i) hydrogen, halogen, -OR11, -N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, - OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, - - 349 -WSGR Docket No.61402-716.601 C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, - OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -NO2, =O, =N(R11), and -CN; and (iii) 3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen,NO2, =O, =N(R11), and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen,C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, - N(R11)C(O)N(R11)2, -NO2, =O, =N(R11), and -CN.

122. The compound or salt of claim 121, wherein R1Bis selected from (i), (ii), and (iii): (i) hydrogen, halogen, -OR11, -N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, - OC(O)R11, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, - C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, =O, and -CN; and (iii) 3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen,C(O)OR11, -OC(O)R11, -NO2, =O, and -CN.

123. The compound or salt of claim 122, wherein R1Bis selected from hydrogen, halogen, - OR11, -N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, and -CN.

124. The compound or salt of claim 123, wherein R1Bis selected from hydrogen, halogen, - OR11, -N(R11)2, and -C(O)N(R11)2; wherein R11is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from C1-3 alkyl. - 350 -WSGR Docket No.61402-716.601 125. The compound or salt of claim 124, wherein R1Bis selected from hydrogen, fluoro,chloro, -126. The compound or salt of claim 121, wherein R1Bis selected from C1-6 alkyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, =O, and -CN.

127. The compound or salt of claim 126, wherein R1Bis selected from -CHF2, -CH3,128. The compound or salt of claim 121, wherein R1Bis 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, OC1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

129. The compound or salt of claim 128, wherein R1Bis 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, OC1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

130. The compound or salt of claim 129, wherein R1Bis selected from pyrazolyl, triazolyl, and pyridinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen,OC(O)R11, =O, -NO2, and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - - 351 -WSGR Docket No.61402-716.601 C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

131. The compound or salt of claim 130, wherein each R1Bis selected from:, ,132. The compound or salt of any one of claims 61-120, wherein each R1Bis selected from:.

133. The compound or salt of any one of claims 61-132, wherein R1Ais selected from (i), (ii), and (iii): (i) hydrogen, halogen, -OR11, -N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, - OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -NO2, =O, =N(R11), and -CN; and (iii) 3- to 10-membered heterocycle and C3-10 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen,NO2, =O, =N(R11), and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen,C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, - - 352 -WSGR Docket No.61402-716.601 N(R11)C(O)N(R11)2, -NO2, =O, =N(R11), and -CN.

134. The compound or salt of claim 133, wherein R1Ais C3-10carbocycle optionally substituted with one or more substituents independently selected from: halogen, OC1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

135. The compound or salt of claim 134, wherein R1Ais C3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, OC1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

136. The compound or salt of claim 135, wherein R1Ais phenyl, optionally substituted with one or more substituents independently selected from: halogen, OC1-6alkyl, C2-6alkenyl, and C2-6alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

137. The compound or salt of claim 136, wherein R1Ais phenyl, optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, -CN, and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, and -CN. - 353 -WSGR Docket No.61402-716.601138. The compound or salt of claim 137, wherein R1A is selected from:

139. The compound or salt of claim 133, wherein R1Ais 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, OC1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

140. The compound or salt of claim 139, wherein R1Ais 4- to 9-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, OC1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

141. The compound or salt of claim 140, wherein R1Ais 6- to 9-membered fused heterocycle optionally substituted with one or more substituents independently selected from: halogen,OC(O)R11, =O, -NO2, and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

142. The compound or salt of claim 141, wherein. - 354 -WSGR Docket No.61402-716.601 143. The compound or salt of claim 140, wherein R1Ais selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, and thiazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen,OC(O)R11, =O, -NO2, and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, =O, -NO2, and -CN.

144. The compound or salt of claim 143, wherein R1Ais selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, and thiazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, -CN, and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, and -CN.

145. The compound or salt of any one of claims 61-132, wherein R1A is selected from,146. The compound or salt of any one of claims 61-132, wherein R1Ais selected from :. - 355 -WSGR Docket No.61402-716.601 147. The compound or salt of any one of claims 61-146, wherein R3is selected from - C(O)R16, -N(R17)C(O)(R16), -C(O)N(R16)(R17), -NO2, and -CN; and C1-6alkyl substituted with one or more substituents independently selected from -C(O)R16, -N(R17)C(O)(R16), - C(O)N(R16)(R17), -NO2 and -CN.

148. The compound or salt of claim 147, wherein R3is selected from -C(O)R16and -CN.

149. The compound or salt of claim 148, wherein R3is -C(O)R16.

150. The compound or salt of any one of claims 61-149, wherein R16is independently selected at each occurrence from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR18, -N(R18)2, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -N(R18)C(O)R18, - N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, -OC(O)N(R18)2, -NO2, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN.

151. The compound or salt of claim 150, wherein R16is independently selected at each occurrence from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR18, -N(R18)2, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -N(R18)C(O)R18, -NO2 and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6alkyl, and -O-C1-6haloalkyl.

152. The compound or salt of claim 151, wherein R16is independently selected at each occurrence from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR18, -N(R18)2, -C(O)N(R18)2; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

153. The compound or salt of claim 152, wherein R16is independently selected at each occurrence from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, C3-6 carbocycle, and 3- to 6- membered heterocycle. - 356 -WSGR Docket No.61402-716.601 154. The compound or salt of any one of claims 99-146, wherein R3is selected from -CN,155. The compound or salt of any one of claims 1-154, wherein the compound is selected from a compound of Table 1, or a pharmaceutically acceptable salt thereof.

156. A pharmaceutical composition comprising a compound or salt of any of claims 1-155 and a pharmaceutically acceptable excipient.

157. A method of modulating activity of wild-type AKT1 comprising, administering to a subject in need thereof a compound or salt of any of claims 1-155, or a pharmaceutical composition of claim 156.

158. A method of modulating activity of mutant AKT1 comprising, administering to a subject in need thereof a compound or salt of any of claims 1-155, or a pharmaceutical composition of claim 156.

159. A method of selectively modulating activity of wild-type AKT1 over wild-type AKT2 comprising administering to a subject in need thereof a compound or salt of any of any of claims 1-155, or a pharmaceutical composition of claim 156.

160. A method of selectively modulating activity of a mutant AKT1 over wild-type AKT2 comprising administering to a subject in need thereof a compound or salt of any of claims 1-155, or a pharmaceutical composition of claim 156.

161. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a compound or salt of any of any of claims 1-155, or a pharmaceutical composition of claim 156.

162. The method of claim 161, wherein the cancer is selected from breast cancer, colorectal cancer, and meningioma. - 357 -WSGR Docket No.61402-716.601 163. The method of claim 161, wherein the administration modulates activity of a mutant AKT1.

164. The method of any one of claims 160, 162, or 163, wherein the mutant AKT1 is AKT1 E17K.

165. The method of claim 163, wherein the administration modulates activity of wild-type AKT1.

166. An AKT1 protein covalently bound to a compound or salt of any of claims 1-155, or a pharmaceutical composition of claim 156.

167. The AKT1 protein of claim 166, wherein the AKT1 protein comprises a E17K mutation, a E40K mutation, or a E49K mutation.

168. The AKT1 protein of any one of claims 166-167, wherein the cysteine residue is selected from C296 and C310.

169. The AKT1 protein of claim 168, wherein the cysteine residue is C296.

170. The AKT1 protein of any one of claims 166-169, wherein the AKT1 protein is in vivo.

171. The AKT1 protein of claim 170, wherein the AKT1 protein is an in vivo engineered AKT1 protein, wherein the in vivo engineered AKT1 protein is generated by contacting the AKT1 protein in vivo with a compound or salt of any of claims 1-155, or a pharmaceutical composition of claim 156.

172. The AKT1 protein of claim 171, wherein the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

173. The AKT1 protein of any one of claims 166 to 172, wherein the covalent bond between the compound and the cysteine residue is an irreversible covalent bond.

174. The AKT1 protein of claim 173, wherein the irreversible covalent bond in the in vivo AKT1 protein is a carbon-sulfur single bond.

175. The AKT1 protein of claim 174, wherein the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C296 and a cysteine susceptible electrophile on the compound, wherein the cysteine susceptible electrophile is selected from: an - 358 -WSGR Docket No.61402-716.601 alkene, an alkyne, an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide, and an epoxide group.

176. The AKT1 protein of claim 175, wherein the cysteine susceptible electrophile is selected from: an alkene, an alkyne, an acrylate group, and an acrylamide group.

177. A method of covalently modifying an AKT1 protein, comprising contacting the AKT1 protein with a compound or salt of any of claims 1-155, or a pharmaceutical composition of claim 156 thereby forming a covalent AKT1 adduct.

178. The method of claim 177, wherein the contacting is in vitro.

179. The method of claim 177, wherein the contacting is in vivo. - 359 -

Images