Cysteine covalent modifiers of AKT1 and uses thereof

Abstract

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

Description

CYSTEINE COVALENT MODIFIERS OF AKT1 AND USES THEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. US 63 / 632,216 filed on April 10, 2024, the entirety of which is incorporated herein by reference.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 structure of Formula (I):or a pharmaceutically acceptable salt thereof wherein:X is selected from O, N(RA), and S;R1and R2are each independently selected from (i), (ii), and (iii):(i) hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -0C(0)N(R11)2, -N(R11)C(O)N(R11)2, - S(O)R11, -S(O)2R11, -N(R11)S(O)2R11, -S(O)2N((R112, -NO2, and -CN;(ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, - N(R11)2, -C(O)R11, -C(0)N(R11)2, -NCR^QOX11, -C(O)OR11, -OC(O)R11, - NCR^C^OR11, -0C(0)N(R11)2, -N(R11)C(O)N(R11)2,-S(O)R11, -S(O)2(R1,1- N(R11)S(O)2R11, -S(O)2N((R112, -NO2, =0, =S, =N(R11), and -CN; and(iii) 3- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N^C^R11, - N(R11)S(0)2R11, -C(O)OR11, -OC(O)R11, -NtR^C^OR11, - 0C(0)N(R11)2, -N(R11)C(0)N(R11)2, -S(O)R11, -S(0)2(R1,1-S(O)2N((R112, -NO2, =0, =S, =N(R11), and -CN;C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, - OR11, -SR11, -N(R11)2, -C(O)R11, -C(0)N((R112, -N^C^R11, - C(O)OR11, -OC(O)R11, -NtR^C^OR11, -0C(0)N(R11)2, - N(R11)C(0)N(R11)2, -S(O)R11, -S(0)2(R1,1-N(R11)S(O)2R11, - S(O)2N(R11)2, -NO2, =0, =S, =N(R11), and -CN; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -N02, -CN, C1-6 alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C1-6 alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -N02, -CN, C1-6 alkyl, and C1-6 haloalkyl; R3is selected from hydrogen, halogen, -OR12, -SR12, -N(R12)2, -N02, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -N02, and -CN;R4is selected from halogen, -OR13, -SR13, -N(R13)2, -N02, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, - SR13, -N(R13)2, -NO2, and -CN;RAis selected from hydrogen, Ci-6 alkyl, and Ci-6 haloalkyl;Ring A is selected from 3- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, - N(R14)C(O)N(R14)2, -S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -NO2, and -CN; andC1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, - C(O)14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, - OC( (R14)C(O)N(R14)2, -S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, - S(O) =S, =N(R14), -N02, and -CN;L is represented bywherein L1, L2, L3, and L4are each independently selected from (a), (b), and (c):(a) -0-, -N(R15)-, -S-, -S(0)-, -S(0)2-, -S(O)(NR15)-, -N(R15)C(0)-, -N(R15)C(0)0-, -N(R15)S(O)2-, -N(R15)S(O)2N(R15)-, -S(O)(NR15)N(R15)-, -N(R15)N(R15)-, - (R15)NC(O)N(R15)-, and -(R15)NC(O)N(R15)N(R15)-;(b) C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, any of which is optionally substituted with one or more substituents independently selected halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, - OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, - S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, =0, =S, =N(R15), -N02, and -CN; and(c) C3-10 carbocyclene and 3- to 10-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(0)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(0)0R15, -0C(0)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, - N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, =0, =S, =N(R15), -N02, and -CN; andC1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, - C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, - OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, - S(O)2N(R15)2, =0, =S, =N(R15), -N02, 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;R5is a cysteine susceptible electrophile;R6is selected from halogen, -OR16A, -SR16A, -N(R16A)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR16A, -SR16A, -N(R16A)2, -NO2, and -CN;R10, R11, R12, R13, R14, R15and R16Aare 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, =0, -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, =0, and -CN; andC3-10 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, =0, and -CN; m is selected from 1 and 2; n is selected from 0, 1, 2, and 3; and p is selected from 0, 1, 2, 3, 4, 5, and 6.

[0004] In another aspect, the present disclosure provides the structure of Formula (I) is represented by the structure of Formula (II):or a pharmaceutically acceptable salt thereof wherein:X is selected from O, N(RA), and S;R1and R2are each independently 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(0)R11,(ii) Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)S(O)2R11, -S(O)2N((R1)12, -NO2, =0, =S, =N(R11), and -CN; and(iii) 3- to 10-membered heterocycle and C3-10 carbocycle, any 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 of which is optionally substituted with one or more substituents independently selected from: halogen, -C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -N02, and -CN;R3is selected from hydrogen, 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, -N02, and -CN;R4is selected from halogen, -OR13, -SR13, -N(R13)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, - SR13, -N(R13)2, -NO2, and -CN;RAis selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl;Ring A is selected from 3- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, - N(R14)C(O)N(R14)2, -S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -NO2, and -CN; andCi-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, - C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, - OC(O)N(R14)2, -N(R14)C(O)N(R14)2, -S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, - S(O)2N(R14)2, =0, =S, =N(R14), -N02, and -CN;L is represented by -iJ-L2-!?-! / -, wherein L1, L2, L3, and L4are each independently selected from (a), (b), and (c):(a) -0-, -N(R15)-, -S-, -S(0)-, -S(0)2-, -S(O)(NR15)-, -N(R15)C(0)-, -N(R15)C(0)0-, -N(R15)S(O)2-, -N(R15)S(O)2N(R15)-, -S(O)(NR15)N(R15)-, -N(R15)N(R15)-, - (R15)NC(O)N(R15)-, and -(R15)NC(O)N(R15)N(R15)-;(b) Ci-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, any of which is optionally substituted with one or more substituents independently selected halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, - OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, - S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, =0, =S, =N(R15), -N02, and -CN; and(c) C3-io carbocyclene and 3- to 10-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(0)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(0)0R15, -0C(0)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, - N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, =0, =S, =N(R15), -N02, and -CN; andCi-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(0)R15, - C(O)N(R15)2, -N(R15)C(O)R15, -C(0)0R15, -0C(0)R15, -N(R15)C(O)OR15, - OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, - S(O)2N(R15)2, =0, =S, =N(R15), -N02, 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;R5is a cysteine susceptible electrophile;R6is selected from halogen, -0R16A, -SR16A, -N(R16A)2, -N02, and -CN; and Ci-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -0R16A, -SR16A, -N(R16A)2, -N02, and -CN;R10, R11, R12, R13, R14, R15and R16Aare each independently selected at each occurrence from: hydrogen;Ci-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-Ci-6 alkyl, -O-Ci-6 haloalkyl, -NH2, -NO2, =0, -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-Ci-6 alkyl, -O- C1-6 haloalkyl, -NH2, -NO2, =0, and -CN; andC3-10 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-Ci-6 alkyl, -O-Ci-6 haloalkyl, -NH2, -NO2, =0, and -CN; m is selected from 1 and 2; n is selected from 0, 1, 2, and 3; and p is selected from 0, 1, 2, 3, 4, 5, and 6.

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

[0006] 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), (Il-a), (Il-b), (III), or (IV), or a pharmaceutical composition comprising a compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), and a pharmaceutically acceptable excipient.

[0007] 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), (Il-a), (Il-b), (III), or (IV), or a pharmaceutical composition comprising a compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), and a pharmaceutically acceptable excipient.

[0008] 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), (Il-a), (Il-b), (III), or (IV), or a pharmaceutical composition comprising a compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), and a pharmaceutically acceptable excipient.

[0009] 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), (Il-a), (Il-b), (III), or (IV), or a pharmaceutical composition comprising a compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), and a pharmaceutically acceptable excipient. In some embodiments, the mutant AKT1 is AKT1 E17K.

[0010] 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), (Il-a), (Il-b), (III), or (IV), or a pharmaceutical composition comprising a compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), 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.

[0011] In another aspect, the present disclosure provides an AKT1 protein covalently bound to a compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), or a pharmaceutical composition comprising a compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), and a pharmaceutically acceptable excipient. In some embodiments, the AKT1 protein comprises a E17K mutation, a E40K mutation, or a E49K mutation. In some embodiments, the cysteine residue is selected from C296 and C310. In some embodiments, the cysteine residue is C296. In some embodiments, the AKT1 protein is in vivo. 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 a compound or pharmaceutical composition as disclosed herein. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein. 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 in the in vivo AKT1 protein is a carbon-sulfur single bond. 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, wherein the cysteine susceptible electrophile is selected from: an alkene, an alkyne, an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinyl sulfonamide 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.

[0012] In another aspect, the present disclosure provides a method of covalently modifying an AKT1 protein, comprising contacting the AKT1 protein with a compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), or a pharmaceutical composition comprising a compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), and a pharmaceutically acceptable excipient, thereby forming a covalent AKT1 adduct. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo.INCORPORATION BY REFERENCE

[0013] 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

[0014] 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:

[0015] FIG. 1 provides a 2-D diagram close-up from the crystal structure of Compound 11 / AKT1 WT co-crystallization complex with Compound 11 depicted by a thicker stick model and the residues of AKT1 WT depicted by a thinner stick model.DETAILED DESCRIPTION OF THE INVENTION

[0016] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0017] Definitions

[0018] 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.

[0019] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0020] "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-C12 alkyl). The alkyl is attached to the remainder of themolecule through a single bond. In certain embodiments, an alkyl comprises one to twelve carbon atoms (i.e., C1-C12 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., Ci-Cs alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., Ci- C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-C5 alkyl). For example, the alkyl group may be attached to the rest of the molecule by a single bond, such as, methyl, ethyl, 1 -propyl (zz-propyl), 1- methylethyl (iso-propyl), 1 -butyl (zz-butyl), 1 -methylpropyl (sec-butyl), 2-methylpropyl (zoobutyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl (zz-pentyl), and the like.

[0021] "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-C12 alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-C6 alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (i.e., C2-C4 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-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like.

[0022] "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-C12 alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-C4 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.

[0023] "Alkylene" refers to a straight 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, 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. The points ofattachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. 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-C10 alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C3-C5 alkylene).

[0024] "Alkenylene" refers to a straight 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. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. 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-C10 alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (i.e., C2-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atom (i.e., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., Cs-Cs alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C3-C5 alkenylene).

[0025] " Alkynylene" refers to a straight 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. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. Alkynylenechain 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-C10 alkynylene). In certain embodiments, an alkynylene comprises two to eight carbon atoms (i.e., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atom (i.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., Cs-Cs alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C3-C5 alkynylene).

[0026] The term “Cx-y” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “C1-6 alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. The term -Cx yalkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example, -C1-6 alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0027] The terms “Cx-y alkenyl” and “Cx.yalkynyl” refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term -Cx.yalkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, - C2-6 alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term -Cx.yalkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkynylene chain. For example, -C2-6 alkynylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0028] The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle include 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Bicyclic carbocycles may be fused, bridged or spiro-ring systems. In some embodiments, the carbocycle is an aryl. In some embodiments, thecarbocycle 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.

[0029] The term “carbocyclene” as used herein refers to a divalent saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. The carbocyclene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. A carbocyclene may be optionally substituted by one or more substituents such as those substituents described herein. Carbocyclene includes divalent 3- to 10-membered monocyclic rings and divalent polycyclic rings (e.g., 6- to 12-membered bicyclic rings). Each ring of a polycyclic carbocyclene may be selected from saturated, unsaturated, and aromatic rings. Polycyclic carbocyclenes may be fused, bridged or spiro-ring systems. Polycyclic carbocyclenes may be fused, bridged or spiro-ring systems. The single bond connecting the carbocyclene to the rest of the molecule and the single bond connecting the carbocyclene to the radical group may be located on the same ring or different rings of a polycyclic carbocyclene. In some embodiments, the carbocycle is an arylene, for example, a phenylene. A “phenylene” as used herein refers to a divalent benzene group. The phenylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. A phenylene may be optionally substituted by one or more substituents such as those substituents described herein.

[0030] "Cycloalkyl" refers to a stable fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, and preferably having from three to twelve carbon atoms (i.e., C3-12 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.

[0031] "Cycloalkenyl" refers to a stable unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused orbridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond (i.e., C3-12 cycloalkenyl). In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms (i.e., C3-10 cycloalkenyl). In other embodiments, a cycloalkenyl comprises five to seven carbon atoms (i.e., C5-7 cycloalkenyl). The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkenyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0032] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic multi cyclic 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) ^-electron system in accordance with the Htickel 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.

[0033] 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 of which is optionally substituted as provided herein.

[0034] The term “heterocycle” as used herein refers to a saturated, unsaturated, non-aromatic or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings and 6- to 12- membered bicyclic rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycle comprises at least 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.

[0035] "Heterocycloalkyl" refers to a stable 3- to 12-membered non-aromatic ring radical that comprises two to twelve carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, Si, P, B, and S atoms. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. The heterocycloalkyl may be selected from monocyclic or bicyclic, and fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4- piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo- thiomorpholinyl. Heterocycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0036] 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 ringor a heteroatom in the heterocyclene ring. A heterocyclene may be optionally substituted by one or more substituents such as those substituents described herein. Heterocyclenes include 3- to 10-membered monocyclic rings and polycyclic rings (e.g., 6- to 12-membered bicyclic rings). Each ring of a polycyclic heterocyclene may be selected from saturated, unsaturated, and aromatic rings. Polycyclic heterocyclenes may be fused, bridged or spiro-ring systems. The single bond connecting the heterocyclene to the rest of the molecule and the single bond connecting the heterocyclene to the radical group may be located on the same ring or different rings of a polycyclic heterocyclene and may be attached to the rest of the molecule or the radical group through any atom of the heterocyclene, valence permitting, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocyclene comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, 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.

[0037] 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 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. 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.

[0038] As used herein, the heteroaryl ring may be selected from monocyclic or polycyclic (bicyclic and fused or bridged) systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Huckel theory. 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.

[0039] An “X-membered heterocycle” refers to the number of endocylic atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.

[0040] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0041] "Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.

[0042] 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, di chloromethyl, bromomethyl, 2,2,2-trifluoroethyl, l-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., tri chloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2- haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, and I). When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected for example, 1 -chloro, 2-fluoroethane.

[0043] The term “adjacent” refers to the connectivity of moi eties where adjacent moi eties are defined as being covalently attached or bonded to another atom. For example, -L1- L2-L3-L4-, L1H H H- / C1-C \2-H and L2are adjacent, L2and L3are adjacent, and L3and L4are adjacent or H H , where C1and C2are adjacent. Adjacent substituents refers to substituents attached to different atoms wherein the two atoms are covalently attached, e.g. for CH2RwlCH2Rw2, where the Rwland Rw2are adjacent substituents.

[0044] 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. 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, 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.

[0045] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazino (=N-NH2), -Rb-0Ra, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)- N(Ra)2,-Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb- N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2),-Rb-S(O)tORa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano(-CN), nitro (-NO2), imino (=N-H), oximo(=N-OH), hydrazine(=N-NH2), -Rb-0Ra, -Rb-OC(O)- Ra, -Rb-OC(O)- ORa, -Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)0Ra, -Rb- C(0)N(Ra)2,-Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); wherein each Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (- CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazine(=N-NH2), -Rb-0Ra, -Rb-0C(0)- Ra, -Rb-0C(0)-0Ra,-Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)0Ra, -Rb-C(0)N(Ra)2, -Rb-0-Rc- C(0)N(Ra)2,-Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(0)tRa(where t is 1 or 2), -Rb-S(O)tRa(wheret is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); and wherein each Rbis independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] The terms "subject," "individual," and "patient" may be used interchangeably and refer to humans, the as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like). In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.

[0050] 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.

[0051] 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 meanproviding a compound of the invention or a prodrug of a compound of the invention to the individual in need.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] Compounds

[0056] In some aspects, the present disclosure provides compounds represented by the structure of Formula (I):or a pharmaceutically acceptable salt thereof wherein:X is selected from O, N(RA), and S;R1and R2are each independently selected from (i), (ii), and (iii):(i) hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -0C(0)N(R11)2, -N(R11)C(O)N(R11)2, - S(O)R11, -S(O)2R11, -N(R11)S(O)2R11, -S(O)2N((R112, -NO2, and -CN;(ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, - N(R11)2, -C(O)R11, -C(0)N(R11)2, -NCR^QOX11, -C(O)OR11, -OC(O)R11, - NCR^C^OR11, -0C(0)N(R11)2, -N(R11)C(O)N(R11)2,-S(O)R11, -S(O)2(R1,1- N(R11)S(O)2R11, -S(O)2N((R112, -NO2, =0, =S, =N(R11), and -CN; and(iii) 3- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, -N^C^R11, - N(R11)S(0)2R11, -C(0)0(R1,1-0C(0)(R1,1-NtR^C^OR11, - 0C(0)N(R11)2, -N(R11)C(0)N(R11)2, -S(O)R11, -S(0)2(R1,1-S(O)2N((R112, -NO2, =0, =S, =N(R11), and -CN;C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, - OR11, -SR11, -N(R11)2, -C(O)R11, -C(0)N((R112, -N^C^R11, - C(O)OR11, -OC(O)R11, -NtR^C^OR11, -0C(0)N(R11)2, - N(R11)C(0)N(R11)2, -S(O)R11, -S(0)2(R1,1-N(R11)S(0)2R11, - S(O)2N(R11)2, -NO2, =0, =S, =N(R11), and -CN; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -N02, -CN, C1-6 alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C1-6 alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle are each optionallysubstituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl;R3is selected from hydrogen, 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;R4is selected from halogen, -OR13, -SR13, -N(R13)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, - SR13, -N(R13)2, -NO2, and -CN;RAis selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl;Ring A is selected from 3- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, - N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, - N(R14)C(O)N(R14)2, -S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -NO2, and -CN; andC1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, - C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, - OC( (R14)C(O)N(R14)2, -S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, - S(O) =S, =N(R14), -NO2, and -CN;L is represented bywherein L1, L2, L3, and L4are each independently selected from (a), (b), and (c):(a) -0-, -N(R15)-, -S-, -S(0)-, -S(0)2-, -S(O)(NR15)-, -N(R15)C(0)-, -N(R15)C(0)0-, -N(R15)S(O)2-, -N(R15)S(O)2N(R15)-, -S(O)(NR15)N(R15)-, -N(R15)N(R15)-, - (R15)NC(O)N(R15)-, and -(R15)NC(O)N(R15)N(R15)-;(b) C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, any of which is optionally substituted with one or more substituents independently selected halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, - OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, - S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, =0, =S, =N(R15), -N02, and -CN; and(c) C3-10 carbocyclene and 3- to 10-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, - N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, =0, =S, =N(R15), -N02, and -CN; andCi-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, - C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, - OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, - S(O)2N(R15)2, =0, =S, =N(R15), -N02, 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;R5is a cysteine susceptible electrophile;R6is selected from halogen, -0R16A, -SR16A, -N(R16A)2, -N02, and -CN; and Ci-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -0R16A, -SR16A, -N(R16A)2, -N02, and -CN;R10, R11, R12, R13, R14, R15and R16Aare each independently selected at each occurrence from: hydrogen;Ci-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-Ci-6 alkyl, -O-Ci-6 haloalkyl, -NH2, -N02, =0, -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-Ci-6 alkyl, -O- C1-6 haloalkyl, -NH2, -N02, =0, and -CN; andC3-10 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-Ci-6 alkyl, -O-Ci-6 haloalkyl, -NH2, -N02, =0, and -CN; m is selected from 1 and 2; n is selected from 0, 1, 2, and 3; and p is selected from 0, 1, 2, 3, 4, 5, and 6.

[0057] In some embodiments, for the compound or salt of Formula (I), R1is selected from (i), (ii), and (iii):(i) hydrogen, halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N(R11)C(0)R11, - C(O)OR11, -OC(O)R11, -NO2, and -CN;(ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N((R112, -NCR^QCOR11, -C(O)OR11, -OC(O)R11, - NO2, =0, and -CN; and(iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N^C^R11, - C(O)OR11, -OC(O)R11, -NO2, =0, and -CN;C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, - NCR^QOX11, -C(O)OR11, -OC(O)R11, -N02, =0, and -CN; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -N02, -CN, Ci-6alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C1-6 alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -N02, -CN, Ci-6alkyl, and Ci-6haloalkyl.

[0058] In some embodiments, for the compound or salt of Formula (I), R1is selected from (i), (ii), and (iii):(i) hydrogen halogen, -OR11, -SR11, -N(R11)2, -NO2, and -CN;(ii) Ci-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -NO2, and -CN; and(iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, and -CN;Ci-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, and -CN; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN, Ci-6alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the Ci-6 alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN, Ci-6alkyl, and Ci-6haloalkyl.

[0059] In some embodiments, for the compound or salt of Formula (I), R1is selected from: hydrogen, halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl; and5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN and C1-6 alkyl, and C1-6 haloalkyl; C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN, Ci-6alkyl, and Ci-6haloalkyl.

[0060] In some embodiments, for the compound or salt of Formula (I), R1is selected from 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, and -CN;Ci-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, and -CN; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, - NO2, -CN, Ci-6 alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the Ci-6 alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN, Ci-6 alkyl, and Ci-6 haloalkyl.

[0061] In some embodiments, for the compound or salt of Formula (I), R1is selected from 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN, Ci-6 alkyl, and Ci-6 haloalkyl; and C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, - SR11, -N(R11)2, -NO2, -CN, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 carbocycle, and 3- to 6- membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycleare each optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

[0062] In some embodiments, for the compound or salt of Formula (I), is selected from 5- to 10- membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from:C3-6 carbocycle, and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl; and C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, - SR11, -N(R11)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

[0063] In some embodiments, for the compound or salt of Formula (I), R1is 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from:C3-6 carbocycle, and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl; and C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, - SR11, -N(R11)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

[0064] In some embodiments, for the compound or salt of Formula (I), R1is 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from:C3-6 carbocycle and 3- to 6-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl; and C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, - SR11, -N(R11)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

[0065] In some embodiments, for the compound or salt of Formula (I), R1is pyrazolyl optionally substituted with one or more substituents independently selected from C3-6 carbocycle and 3- to 6-membered heterocycle each optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6- membered heterocycle, wherein the C3-6 carbocycle, and 3- to 6-membered heterocycle are each 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), R1is selected from

[0067] In some embodiments, the structure of Formula (I) is represented by the structure of Formula (II):or a pharmaceutically acceptable salt thereof wherein:X is selected from O, N(RA), and S;R1and R2are each independently selected from (i), (ii), and (iii):(i) hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -0C(0)N(R11)2, -N(R11)C(O)N(R11)2, - S(O)R11, -S(O)2R11, -N(R11)S(O)2R11, -S(O)2N((R112, -NO2, and -CN;(ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, - N(R11)2, -C(O)R11, -C(0)N(R11)2, -NCR^QOX11, -C(O)OR11, -OC(O)R11, - NCR^C^OR11, -0C(0)N(R11)2, -N(R11)C(O)N(R11)2,-S(O)R11, -S(O)2(R1,1- N(R11)S(O)2R11, -S(O)2N((R112, -NO2, =0, =S, =N(R11), and -CN; and(iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, -NtR^QCOR11, - N(R11)S(0)2R11, -C(0)0(R1,1-0C(0)(R1,1-NtR^C^OR11, - 0C(0)N(R11)2, -N(R11)C(0)N(R11)2, -S(O)R11, -S(0)2(R1,1-S(O)2N((R112, -NO2, =0, =S, =N(R11), and -CN;C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, - OR11, -SR11, -N(R11)2, -C(O)R11, -C(0)N((R112, -NtR^C^R11, - C(O)OR11, -OC(O)R11, -NtR^C^OR11, -0C(0)N(R11)2, - N(R11)C(0)N(R11)2, -S(O)R11, -S(0)2(R1,1-N(R11)S(0)2R11, - S(O)2N(R11)2, -NO2, =0, =S, =N(R11), and -CN; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, and -CN;R3is selected from hydrogen, 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;R4is selected from halogen, -OR13, -SR13, -N(R13)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, - SR13, -N(R13)2, -NO2, and -CN;RAis selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl;Ring A is selected from 3- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, - N(R14)C(O)N(R14)2, -S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -NO2, and -CN; andC1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, - C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, - OC(O)N(R14)2, -N(R14)C(O)N(R14)2, -S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, - S(O)2N(R14)2, =0, =S, =N(R14), -NO2, and -CN;L is represented by -iJ-L2-!?-! / -, wherein L1, L2, L3, and L4are each independently selected from (a), (b), and (c):(a) -0-, -N(R15)-, -S-, -S(0)-, -S(0)2-, -S(O)(NR15)-, -N(R15)C(0)-, -N(R15)C(0)0-, -N(R15)S(O)2-, -N(R15)S(O)2N(R15)-, -S(O)(NR15)N(R15)-, -N(R15)N(R15)-, - (R15)NC(O)N(R15)-, and -(R15)NC(O)N(R15)N(R15)-;(b) C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, any of which is optionally substituted with one or more substituents independently selected halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, - OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, - S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, =0, =S, =N(R15), -N02, and -CN; and(c) C3-10 carbocyclene and 3- to 10-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from:halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, - N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, =0, =S, =N(R15), -N02, and -CN; andCi-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, - C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, - OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, - S(O)2N(R15)2, =0, =S, =N(R15), -N02, 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;R5is a cysteine susceptible electrophile;R6is selected from halogen, -0R16A, -SR16A, -N(R16A)2, -N02, and -CN; and Ci-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -0R16A, -SR16A, -N(R16A)2, -N02, and -CN;R10, R11, R12, R13, R14, R15and R16Aare each independently selected at each occurrence from: hydrogen;Ci-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-Ci-6 alkyl, -O-Ci-6 haloalkyl, -NH2, -N02, =0, -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-Ci-6 alkyl, -O- C1-6 haloalkyl, -NH2, -N02, =0, and -CN; andC3-10 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-Ci-6 alkyl, -O-Ci-6 haloalkyl, -NH2, -N02, =0, and -CN; m is selected from 1 and 2; n is selected from 0, 1, 2, and 3; and p is selected from 0, 1, 2, 3, 4, 5, and 6.

[0068] In some embodiments, for the compound or salt of Formula (I) or (II), 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, analkyne, a keto heterocycle, an ynamide, a squaric acid group, a squaric ester group, and a squaramide ester group.

[0069] In some embodiments, for the compound or salt of Formula (I) or (II), the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinyl sulfonamide group, an ynamide, an alkene, an alkyne, an epoxide group, a squaric acid group, a squaric ester group, and a squaramide ester group. In some embodiments, the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, a vinylsulfone group, a vinyl sulfonamide 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 an acrylate group, an acrylamide group, an alkene, an alkyne, a squaric acid group, a squaric ester group, and a squaramide ester group.

[0070] In some embodiments, for the compound or salt of Formula (I) or (II), 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

[0071] In some embodiments, for the compound or salt of Formula (I) or (II), 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 mal eimide, a ketoamide, a nitrile, an alkene, an alkyne, a keto heterocycle, and an ynamide.

[0072] In some embodiments, for the compound or salt of Formula (I) or (II), 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 mal eimide, 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, -NtR^QOX11, -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)2(R1,1-NtR^StO^R11, -S(O)2N(R11)2, -NO2, and -CN, wherein each instance R11is as defined in Formula (II).

[0073] In some embodiments, for the compound or salt of Formula (I) or (II), the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinyl sulfonamide group, an ynamide, an alkene, an alkyne, and an epoxide group. In some embodiments, the cysteine susceptible electrophile is selected from a vinyl group, a vinylsulfone group, a vinylsulfonamide group, and an ynamide. In some embodiments, the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, an alkene, and an alkyne. In some embodiments, the cystine susceptible electrophile is an acrylate group. In some embodiments, the cystine susceptible electrophile is an acrylamide. In some embodiments, the cystine susceptible electrophile is an alkene. In some embodiments, the cystine susceptible electrophile is alkyne.

[0074] In some embodiments, for the compound or salt of Formula (I) or (II), 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. For example, an alpha-O O beta unsaturated carbonyl may be represented by[n SOmeO embodiments, the alpha-beta unsaturated carbonyl is represented by.

[0075] In some embodiments, for the compound or salt of Formula (I) or (II), the cysteine susceptible electrophile of R5is selected from:-C(O)R16B, -S(O)2R16B, -N(R17)C(O)(R16B), -C(O)N(R16B)(R17), - N(R17)S(O)2R16B, -S(O)2N(R16B)(R17), and -CN; andCi-6 alkyl substituted with one or more substituents independently selected from - C(O)R16B, -S(O)2R16B, -N(R17)C(O)(R16B), -C(O)N(R16B)(R17), -N(R17)S(O)2R16B, - S(O)2N(R16B)(R17), and -CN;R16Bis 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, -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; and C3-6 carbocycle and 3- to 6- membered heterocycle any of which is optionally substituted with halogen, C1-6 alkyl, and C1-6 haloalkyl;R17is independently selected at each occurrence from hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle; andR18selected 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, =0, -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, =0, and -CN; andC3-10 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, =0, and -CN.

[0076] In some embodiments, for the compound or salt of Formula (I) or (II), the cysteine susceptible electrophile of R5is selected from:-C(0)R16B, -S(O)2R16B, -N(R17)C(O)(R16B), -C(O)N(R16B)(R17), - N(R17)S(O)2R16B, -S(O)2N(R16B)(R17), and -CN; andC1-6 alkyl substituted with one or more substituents independently selected from - C(0)R16B, -S(O)2R16B, -N(R17)C(O)(R16B), -C(O)N(R16B)(R17), -N(R17)S(O)2R16B, - S(O)2N(R16B)(R17), and -CN;R16Bis 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, -SR18, -N(R18)2, -NO2, -CN; and C3-6 carbocycle and 3- to 6- membered heterocycle any of which is optionally substituted with halogen, C1-6 alkyl, and C1-6 haloalkyl;R17is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle; andR18selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl.

[0077] In some embodiments, for the compound or salt of Formula (I) or (II), the cysteine susceptible electrophile of R5is selected from:-C(O)R16B, and -N(R17)C(O)(R16B; andC1-6 alkyl substituted with one or more substituents independently selected from - C(O)R16B, and -N(R17)C(O)(R16B);R16Bis independently selected at each occurrence from C2-6 alkenyl and C2-6 alkynyl, any of which is optionally substituted with one or more substituentsindependently selected from halogen, -OR18, -SR18, -N(R18)2, -NO2, -CN; and C3-6 carbocycle and 3- to 6- membered heterocycle any of which is optionally substituted with halogen, C1-6 alkyl, and C1-6 haloalkyl;R17is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; andR18selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl.

[0078] In some embodiments, for the compound or salt of Formula (I) or (II), R5is selected from -C(O)R16B, -S(O)2R16B, -N(R17)C(O)(R16B), -C(O)N(R16B)(R17), -N(R17)S(O)2R16B, and - S(O)2N(R16B)(R17); and wherein R16Bis 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, -SR18, -N(R18)2, -NO2, -CN; and C3-6 carbocycle and 3- to 6- membered heterocycle any of which is optionally substituted with halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0079] In some embodiments, for the compound or salt of Formula (I) or (II), R5is -C(O)R16B; and wherein R16Bis 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; and C3-6 carbocycle and 3- to 6- membered heterocycle any of which is optionally substituted with halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0080] In some embodiments, for the compound or salt of Formula (

[0081] In some embodiments, for the compound or salt of Formula (I) or (II), the cysteine susceptible electrophile of R5is selected from:-C(O)R16B, -S(O)2R16B, -N(R17)C(O)(R16B), -C(O)N(R16B)(R17), -N(R17)S(O)2R16B, -S(O)2N(R16B)(R17), and -CN; andCi-6 alkyl substituted with one or more substituents independently selected from - C(O)R16B, -S(O)2R16B, -N(R17)C(O)(R16B), -C(O)N(R16B)(R17), -N(R17)S(O)2R16B, - S(O)2N(R16B)(R17), and -CN;R16Bis 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, -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; andR17is independently selected at each occurrence from hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle; andR18selected 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, =0, -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, =0, and -CN; andC3-10 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, =0, and -CN.

[0082] In some embodiments, for the compound or salt of Formula (I) or (II), R5is selected from -C(0)R16B, -S(O)2R16B, -N(R17)C(O)(R16B), -C(O)N(R16B)(R17), -N(R17)S(O)2R16B, - S(O)2N(R16B)(R17), and -CN; R16Bis 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(0)R18, -C(O)N(R18)2, -C(0)0R18, -0C(0)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, R5is selected from -C(0)R16B, -S(O)2R16B, -N(R17)C(O)(R16B), -C(O)N(R16B)(R17), -N(R17)S(O)2R16B, -S(O)2N(R16B)(R17), and -CN; R16Bis C2-6 optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(0)R18, -C(O)N(R18)2, - C(0)0R18, -0C(0)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, R5is selected from -C(0)R16B, -N(R17)C(O)(R16B), -C(O)N(R16B)(R17), and - CN; R16Bis C2-6 alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -N(R18)2, -C(0)R18, -C(O)N(R18)2, -C(0)0R18, -0C(0)R18, -NO2, and -CN; and R17is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl.

[0083] In some embodiments, for the compound or salt of Formula (I) or (II), R5is -C(O)R16B; and R16Bis 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, R5is -C(O)R16B; R16Bis 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, R5is -C(O)R16B; and R16Bis 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. In some embodiments, R5is

[0084] In some embodiments, for the compound or salt of Formula (I) or (II), R5is -C(O)R16B; and R16Bis C2-6 alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -N(R18)2, -NO2, and -CN. In some embodiments, R5is -C(O)R16B; and R16Bis C2-6 alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, and -N(R18)2. In some embodiments, R5is -C(O)R16B; and R16Bis C2-6 alkenyl optionally substituted with one or more halogen. In some embodiments, R5is - C(O)R16B; and R16Bis C2-6 alkenyl optionally substituted with one or more fluoro. In some embodiments,

[0085] In some embodiments, for the compound or salt of Formula (I) or (II), R5is -C(O)R16B; and R16Bis 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, R5is -C(O)R16B; and R16Bis 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, and -CN. In some embodiments, R5is -C(O)R16B; and R16Bis C2-6 alkynyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -N(R18)2, -NO2, and - CN. In some embodiments, R5is -C(O)R16B; and R16Bis C2-6 alkynyl optionally substituted with one or more substituents independently selected from halogen, -OR18, and -N(R18)2. In some embodiments, R5is

[0086] In some embodiments, for the compound or salt of Formula (I) or (II), R5is - N(R17)C(O)(R16B); R16Bis 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, R5is -N(R17)C(O)(R16B); R16Bis 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, R5is -N(R17)C(O)(R16B); R16Bis 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.

[0087] In some embodiments, for the compound or salt of Formula (I) or (II), R5is - C(O)N(R16B)(R17); R16Bis 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, R5is -C(O)N(R16B)(R17); R16Bis 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, R5is -C(O)N(R16B)(R17); R16Bis 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.

[0088] In some embodiments, for the compound or salt of Formula (I) or (II), R5is C1-6 alkyl substituted with one or more substituents independently selected from -C(O)R16B, -S(O)2R16B, - N(R17)C(O)(R16B), -C(O)N(R16B)(R17), -N(R17)S(O)2R16B, -S(O)2N(R16B)(R17), and -CN; R16Bis 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, -N02, and -CN; and R17is selected from hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 carbocycle, and 3- to 6- membered heterocycle. In some embodiments, R5is C1-6 alkyl substituted with one or more substituents independently selected from -C(O)R16B, -S(O)2R16B, -N(R17)C(O)(R16B), - C(O)N(R16B)(R17), -N(R17)S(O)2R16B, -S(O)2N(R16B)(R17), and -CN; R16Bis 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, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle. In some embodiments, R5is C1-6 alkyl substituted with one or more substituents independently selected from -C(O)R16B, - N(R17)C(O)(R16B), -C(O)N(R16B)(R17), and -CN; R16Bis 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.

[0089] In some embodiments, for the compound or salt of Formula (I) or (II), R5is C1-6 alkyl substituted with -C(O)R16B; and R16Bis 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, R5is C1-6 alkyl substituted with -C(O)R16B; R16Bis 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, R5is C1-6 alkyl substituted with -C(O)R16B; and R16Bis 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.

[0090] In some embodiments, for the compound or salt of Formula (I) or (II), R5is C1-6 alkyl substituted with -N(R17)C(O)(R16B); R16Bis 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, Ci-6alkyl,and Ci-6 haloalkyl. In some embodiments, R5is -N(R17)C(O)(R16B); R16Bis 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, R5is C1-6 alkyl substituted with -N(R17)C(O)(R16B); R16Bis 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. In some embodiments, R5is

[0091] In some embodiments, for the compound or salt of Formula (I) or (II), R5is C1-6 alkyl substituted with -C(O)N(R16B)(R17); R16Bis 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, Ci-6alkyl, and C1-6 haloalkyl. In some embodiments, R5is C1-6 alkyl substituted with -C(O)N(R16B)(R17); R16Bis 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; and R17is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R5is C1-6 alkyl substituted with - C(O)N(R16B)(R17); R16Bis 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.

[0092] In some embodiments, for the compound or salt of Formula (I) or (II), R5is selected from -C(O)R16B, -N(R17)C(O)(R16B), -C(O)N(R16B)(R17), and -CN; and Ci-6alkyl substituted with one or more substituents independently selected from -C(O)R16B, -N(R17)C(O)(R16B), - C(O)N(R16B)(R17), and -CN. In some embodiments, R5is selected from -C(O)R16B, - N(R17)C(O)(R16B), and -C(O)N(R16B)(R17); and Ci-6 alkyl substituted with one or more substituents independently selected from -C(O)R16B, -N(R17)C(O)(R16B), and -C(O)N(R16B)(R17). In some embodiments, R5is selected from -C(O)R16B, -N(R17)C(O)(R16B), and - C(O)N(R16B)(R17); and Ci-6 alkyl substituted with one or more substituents selected from -C(O)R16Band-N(R17)C(O)(R16B). In some embodiments, R5is selected from -C(O)R16Band - N(R17)C(O)(R16B); and C1-3 alkyl substituted with one or more substituents selected from - C(O)R16Band -N(R17)C(O)(R16B). In some embodiments, R5is selected from -C(O)R16Band C1-3 alkyl substituted with -N(R17)C(O)(R16B); wherein R17is selected from hydrogen, C1-3 alkyl, and C1-3 haloalkyl.

[0093] In some embodiments, for the compound or salt of Formula (I) or (II), R5is selected from -C(O)R16Band -N(R17)C(O)(R16B) and C1-6 alkyl substituted with one or more substituents independently selected from -C(O)R16B, and -N(R17)C(O)(R16B). In some embodiments, wherein R5is selected from -C(O)R16Band -N(R17)C(O)(R16B); and C1-3 alkyl substituted with one or more substituents selected from -C(O)R16Band -N(R17)C(O)(R16B).

[0094] In some embodiments, for the compound or salt of Formula (I) or (II), R5is selected from -C(O)R16B, -S(O)2R16B, -N(R17)C(O)(R16B), -C(O)N(R16B)(R17), -N(R17)S(O)2R16B, - S(O)2N(R16B)(R17), and -CN. In some embodiments, R5is selected from -C(O)R16B, - N(R17)C(O)(R16B), -C(O)N(R16B)(R17), and -CN. In some embodiments, R5is -C(O)R16BIn some embodiments, R5is -N(R17)C(O)(R16B). In some embodiments, R5is -C(O)N(R16B)(R17). In some embodiments, R5is -CN.

[0095] In some embodiments, for the compound or salt of Formula (I), or (II), R5is selected from -C(O)R16B, -N(R17)C(O)(R16B), -C(O)N(R16B)(R17), and -CN. In some embodiments, R5is selected from -C(O)R16Band -N(R17)C(O)(R16B).

[0096] In some embodiments, for the compound or salt of Formula (I) or (II), R5is C1-6 alkyl substituted with one or more substituents independently selected from -C(O)R16B, -S(O)2R16B, - N(R17)C(O)(R16B), -C(O)N(R16B)(R17), -N(R17)S(O)2R16B, -S(O)2N(R16B)(R17), and -CN. In some embodiments, R5is C1-6 alkyl substituted with one or more substituents independently selected from -C(O)R16B, -N(R17)C(O)(R16B), -C(O)N(R16B)(R17), and -CN. In some embodiments, R5is C1-6 alkyl substituted with -C(O)R16B. In some embodiments, R5is C1-6 alkyl substituted with - N(R17)C(O)(R16B). In some embodiments, R5is C1-6 alkyl substituted with -C(O)N(R16B)(R17). In some embodiments, R5is C1-6 alkyl substituted with -CN.

[0097] In some embodiments, for the compound or salt of Formula (I) or (II), R5is selected

[0098] In some embodiments, for the compound or salt of Formula (I) or (II), R5is selected

[0099] In some embodiments, for the compound or salt of Formula (I) or (II), R16Bis 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, R16Bis 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, R16Bis 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, R16Bis C2-4 alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, and -N(R18)2.

[0100] In some embodiments, for the compound or salt of Formula (I) or (II), R16Bis independently selected at each occurrence from C2-4 alkenyl and C2-4 alkynyl, any of which is optionally substituted with one or more halogen. In some embodiments, R16Bis independently selected at each occurrence from C2-4 alkenyl, C2-4 haloalkenyl, and C2-4 alkynyl.

[0101] In some embodiments, for the compound or salt of Formula (I) or (II), R16Bis 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, R16Bis 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, R16Bis 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, R16Bis unsubstituted C2-4 alkenyl.

[0102] In some embodiments, for the compound or salt of Formula (I) or (II), R16Bis 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, -N02, and -CN. In some embodiments, R16Bis C2-6 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, R16Bis 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, R16Bis unsubstituted C2-4 alkenyl.

[0103] In some embodiments, for the compound or salt of Formula (I) or (II), R17is independently selected at each occurrence from hydrogen, Ci-6 alkyl, and Ci-6 haloalkyl. In some embodiments, R17is independently selected at each occurrence from hydrogen and Ci-6 alkyl. In some embodiments, R17is independently selected at each occurrence from hydrogen and Ci-6 haloalkyl. In some embodiments, R17is independently selected at each occurrence from hydrogen. In some embodiments, R17is independently selected at each occurrence from Ci-6 alkyl. In some embodiments, R17is independently selected at each occurrence from Ci-6 haloalkyl.

[0104] In some embodiments, for the compound or salt of Formula (I) or (II), R18is selected at each occurrence from hydrogen and Ci-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-Ci-6 alkyl, -O-Ci-6 haloalkyl, -NH2, -NO2, =0, -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-Ci-6 alkyl, -O-Ci-6 haloalkyl, -NH2, - NO2, =0, 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-Ci-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-Ci-6 alkyl, -NH2, -NO2, and -CN.

[0105] In some embodiments, for the compound or salt of Formula (I) or (II), 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-Ci-6 alkyl, -O-Ci-6 haloalkyl, -NH2, -NO2, =0, 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-Ci-6 alkyl, -NH2, -NO2, and -CN.

[0106] In some embodiments, for the compound or salt of Formula (I) or (II), p is selected from 0, 1, 2, 3, 4, and 5. In some embodiments, p is selected from 1, 2, 3, 4, 5, and 6. In someembodiments, p is selected from 0, 1, 2, 3, and 4. In some embodiments, p is selected from 0, 1, and 2. In some embodiments, p is selected from 0 and 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6.

[0107] In some embodiments, for the compound or salt of Formula (I) or (II), R6is selected from halogen, -OR16A, -SR16A, -N(R16A)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16A, -SR16A, -N(R16A)2, - NO2, and -CN. In some embodiments, R6is selected from halogen, -OR16A, -N(R16A)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16A, -N(R16A)2, -NO2, and -CN. In some embodiments, R6is selected from halogen, -OR16A, and -N(R16A)2; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16A, and -N(R16A)2. In some embodiments, R6is selected from halogen, -OR16A, -N(R16A)2, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R6is selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0108] In some embodiments, for the compound or salt of Formula (I) or (II), R6is halogen. In some embodiments, R6is selected from fluoro, chloro, and bromo. In some embodiments, R6is selected from fluoro and chloro. In some embodiments, R6is fluoro.

[0109] In some embodiments, for the compound or salt of Formula (I) or (II), R6is selected from halogen, -OR16A, -SR16A, -N(R16A)2, -NO2, and -CN. In some embodiments, R6is selected from halogen, -OR16A, -N(R16A)2, -NO2, and -CN. In some embodiments, R6is selected from halogen, -OR16A, and -N(R16A)2.

[0110] In some embodiments, for the compound or salt of Formula (I) or (II), R6is C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR16A, -SR16A, -N(R16A)2, -NO2, and -CN. In some embodiments, R6is C1-6 alkyl or C1-6 haloalkyl.

[0111] In some embodiments, for the compound or salt of Formula (I) or (II), m is 1.

[0112] In some embodiments, the compound of Formula (II) is represented by Formula (Il-a):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, X, L, n, and Ring A, are each as defined as in Formula (II).

[0113] In some embodiments, for the compound or salt of Formula (I) or (II), m is 2.

[0114] In some embodiments, the compound of Formula (II) is represented by Formula (Il-b):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, X, L, n, and Ring A, are each as defined as in Formula (II).

[0115] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), R2is selected from 3- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: hydrogen, halogen, - OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N^C^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, =0, =N(R11), and -CN; Ci-6alkyl, 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(0)N((R112, -NtR^QCOR11, -C(O)OR11, -OC(O)R11, - N(R11)C(0)0R11, -OC(O)N(R11)2, -N(R11)C(0)N(R11)2, -NO2, =0, =N(R11), and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -N02, -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, R2is selected from 3- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: hydrogen, halogen, -OR11, -N(R11)2, -C(0)R11, - C(0)N(R11)2, -NtR^QOX11, -C(O)OR11, -OC(O)R11, -N(R11)C(0)0R11, -0C(0)N(R11)2, - N(R11)C(0)N(R11)2, -NO2, =0, =N(R11), and -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, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, - N(R11)C(0)R11, -C(0)0R11, -0C(0)R11, -N(R11)C(0)0R11, -0C(0)N(R11)2, - N(R11)C(0)N(R11)2, -NO2, =0, =N(R11). In some embodiments, R2is selected from 3- to 10- membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: hydrogen, halogen, -OR11, -N(R11)2, -C(0)R11, - C(0)N(R11)2, -NtR^QOX11, -C(0)0R11, -0C(0)R11, -N(R11)C(0)0R11, -0C(0)N(R11)2, - N(R11)C(0)N(R11)2, -NO2, =0, =N(R11), and -CN; and C3-6 carbocycle and 3- to 6-memberedheterocycle, the C3-6 carbocycle and 3- to 6-membered heterocycle are each 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.

[0116] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), R2is 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, -NCR^C^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, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, - N(R11)2, -C(O)R11, -C(O)N((R1)12, -N^KXOX11, -C(O)OR11, -OC(O)R11, - N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -NO2, =0, =N(R11), and -CN; and(iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N^^C^R11, - C(O)OR11, -OC(O)R11, -NtR^C^OR11, -0C(0)N(R11)2, - N(R11)C(0)N(R11)2, -NO2, =0, =N(R11), and -CN;C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, -N^^C^R11, - C(0)0R11, -0C(0)R11, -NtR^C^OR11, -0C(0)N(R11)2, - N(R11)C(0)N(R11)2, -NO2, =0, =N(R11), and -CN; andC3-6 carbocycle and 3- to 6-membered heterocycle, any 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, -N02, and -CN.

[0117] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), R2is selected from (i), (ii), and (iii):(i) hydrogen, halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N(R11)C(0)R11, - C(O)OR11, -OC(O)R11, -NO2, and -CN;(ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N((R112, -NCR^QCOR11, -C(O)OR11, -OC(O)R11, - NO2, =0, and -CN; and(iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N^C^R11, - C(O)OR11, -OC(O)R11, -NO2, =0, and -CN;C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, - NCR^QOX11, -C(O)OR11, -OC(O)R11, -N02, =0, and -CN; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0118] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), R2is selected from (i), (ii), and (iii):(i) hydrogen, halogen, -OR11, -N(R11)2, -N02, and -CN;(ii) C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -N02, =0, and -CN; and(iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, - OR11, -N(R11)2, -NO2, =0, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, - N02, =0, and -CN.

[0119] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), R2is selected from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl; and 5- to 10-membered heterocycle and C3-10 carbocycle, the 5- to 10-membered heterocycle and C3-10 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R2is selected from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0120] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), R2is selected from hydrogen, halogen, -OR11, -C(O)R11, -N(R11)2, -C(0)N(R11)2, -N(R11)C(0)R11, - C(O)OR11, -OC(O)R11, -N(R11)C(0)0R11, -0C(0)N(R11)2, -N(R11)C(0)N(R11)2, -NO2, and - CN. In some embodiments, R2is selected from hydrogen, halogen, -OR11, -C(O)R11, -N(R11)2, - NO2, and -CN. In some embodiments, R2is selected from hydrogen, halogen, -OR11, -NO2, and -CN. In some embodiments, R2is selected from hydrogen, halogen, and -OR11. In some embodiments, R2is selected from hydrogen and halogen. In some embodiments, R2is hydrogen.

[0121] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), R2is selected from Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -S(O)R11, -S(O)2(R1,1-NCR^SCO^R11, -S(O)2N((R1)12, - NO2, =0, =S, =N(R11), and -CN. In some embodiments, R2is selected from C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any 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(0)R11, -C(O)OR11, -OC(O)R11, -NO2, =0, =S, =N(R11), and -CN. In some embodiments, R2is selected from C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, - OR11, -N(R11)2, -C(O)R11, -NO2, and -CN.

[0122] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), R2is C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -NtR^QCOR11, -C(O)OR11, - OC(O)R11, -NtR^C^OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2,-S(O)R11, -S(O)2(R1,1- N(R11)S(O)2R11, -S(O)2N((R1)12, -NO2, =0, =S, =N(R11), and -CN. In some embodiments, R2is C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -NQV^QCOR11, -C(O)OR11, -OC(O)R11, - NO2, =0, =S, =N(R11), and -CN. In some embodiments, R2is C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, - NO2, and -CN. In some embodiments, R2is C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, - N(R11)C(0)R11, -C(O)OR11, -OC(O)R11, -N02, =0, =S, =N(R11), and -CN. In some embodiments, R2is C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -NO2, and -CN.

[0123] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), R2is C1-3 alkyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -OR11, -N(R11)2, and -CN. In some embodiments, R2is C3-6 alkyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, - OR11, -N(R11)2, and -CN. In some embodiments, R2is selected from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R2is selected from C1-3 alkyl and C1-3 haloalkyl. In some embodiments, R2is selected from C3-6 alkyl and C3-6 haloalkyl. In some embodiments, R2is selected from methyl, ethyl, propyl, and isopropyl.

[0124] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), R2is selected from 5- to 10-membered heterocycle and C3-10 carbocycle, any 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, =0, =N(R11), and -CN; Ci-6alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N(R11)C(0)R11, -C(O)OR11, - OC(O)R11, -N(R11)C(0)0R11, -0C(0)N(R11)2, -N(R11)C(0)N(R11)2, -NO2, =0, =N(R11), and - CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, any 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.

[0125] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), R2is optionally substituted 3- to 10-membered heterocycle, wherein the optional substituents are as defined in Formula (II). In some embodiments, R2is an optionally substituted 3- to 10- membered saturated heterocycle. In some embodiments, R2is an optionally substituted 3- to 10- membered unsaturated heterocycle. In some embodiments, R2is an optionally substituted 3- to 10-membered aromatic heterocycle. In some embodiments, the optionally substituted 3- to 10- membered heterocycle of R2comprises 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 R2comprises 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 R2comprises 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 R2comprises 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 R2comprises at least one oxygen heteroatom. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of R2comprises at least one nitrogen heteroatom. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of R2comprises at least one sulfur heteroatom.

[0126] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), R2is 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 (II). In some embodiments, R2is 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 (II).

[0127] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), R2is 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, -N(R11)C(O)OR11, -OC(O)N(R11)2, - N(R11)C(O)N(R11)2, -NO2, =0, =N(R11), and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, -N^K^R11, -C(0)0R11, -0C(0)R11, - N(R11)C(0)0R11, -0C(0)N(R11)2, -N(R11)C(0)N(R11)2, -NO2, =0, =N(R11), and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, any 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, R2is 3- to 7-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, - OR11, -N(R11)2, -C(0)R11, -C(0)N((R112, -NtR^QOX11, -C(0)0R11, -0C(0)R11, - N(R11)C(0)0R11, -0C(0)N(R11)2, -N(R11)C(0)N(R11)2, -N02, =0, =N(R11), and -CN; Ci-6alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, - N(R11)C(0)R11, -C(0)0R11, -0C(0)R11, -N(R11)C(0)0R11, -0C(0)N(R11)2, - N(R11)C(0)N(R11)2, -NO2, =0, =N(R11), and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, any 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, R2is a 3- to 10-membered heterocycle optionally substituted with: halogen, -OR11, -N(R11)2, -NO2, =0, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -NO2, =0, and -CN. In some embodiments, R2is a 3- to 8-membered heterocycle optionally substituted with: halogen, -OR11, -N(R11)2, -NO2, =0, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -NO2, =0, and -CN.

[0128] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), R2is an optionally substituted C3-10 carbocycle, wherein the optional substituents are as defined in Formula (II). In some embodiments, R2is an optionally substituted C3-10 saturated carbocycle. In some embodiments, R2is an optionally substituted C3-10 unsaturated carbocycle. In some embodiments, R2is an optionally substituted C5-10 aromatic carbocycle. In some embodiments, R2is 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- 10 carbocycle, wherein the optional substituents are as defined in Formula (II). In some embodiments, R2is selected from optionally substituted C3 carbocycle, optionally substituted C4 carbocycle, optionally substituted C5 carbocycle, optionally substituted Ce carbocycle, optionally substituted C7carbocycle, optionally substituted Cs carbocycle, optionally substituted C9 carbocycle, and optionally substituted C10 carbocycle, wherein the optional substituents are as defined in Formula (II).

[0129] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), R2is C3-10 carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N(R11)C(0)R11, -C(O)OR11, - OC(O)R11, -N(R11)C(0)0R11, -0C(0)N(R11)2, -N(R11)C(0)N(R11)2, -NO2, =0, =N(R11), and - CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(0)R11, - C(0)N(R11)2, -NtR^QOX11, -C(0)0R11, -0C(0)R11, -N(R11)C(0)0R11, -0C(0)N(R11)2, - N(R11)C(0)N(R11)2, -NO2, =0, =N(R11), and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, any 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, R2is C3-8 carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, - N(R11)C(0)R11, -C(0)0R11, -0C(0)R11, -N(R11)C(0)0R11, -0C(0)N(R11)2, - N(R11)C(0)N(R11)2, -NO2, =0, =N(R11), and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, -N^K^R11, -C(0)0R11, -0C(0)R11, - N(R11)C(0)0R11, -0C(0)N(R11)2, -N(R11)C(0)N(R11)2, -N02, =0, =N(R11), and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, any 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, R2is a C3-8 carbocycle heterocycle optionally substituted with: halogen, -OR11, -N(R11)2, -NO2, =0, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR11, -N(R11)2, -NO2, =0, and -CN. In some embodiments, R2is C3-6 carbocycle optionally substituted with: halogen, -OR11, -N(R11)2, -NO2, =0, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -NO2, =0, and -CN.

[0130] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), R3is selected from hydrogen, halogen, -OR12, -N(R12)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -NO2, and -CN. In some embodiments, R3is selected from hydrogen, halogen, -OR12, -N(R12)2, - NO2, and -CN. In some embodiments, R3is C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -NO2, and -CN. In some embodiments, R3is C1-3 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -NO2, and -CN. In some embodiments, R3is selected from methyl, ethyl, propyl, and isopropyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -NO2, and -CN. In some embodiments, R3is selected from methyl, ethyl, propyl, and isopropyl. In some embodiments, R3is selected from hydrogen, halogen, -OR12, and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen and -OR12. In some embodiments, R3is selected from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R3is selected from hydrogen and halogen. In some embodiments, R3is hydrogen.

[0131] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), R4is selected from hydrogen, 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, -NO2, and -CN. In some embodiments, R4is selected from hydrogen, halogen, -OR13, -N(R13)2, - NO2, and -CN. In some embodiments, R4is C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -NO2, and -CN. In some embodiments, R4is C1-3 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -NO2, and -CN. In some embodiments, R4is selected from methyl, ethyl, propyl, and isopropyl, each of which is optionally substituted with one ormore substituents independently selected from: halogen, -OR13, -N(R13)2, -NO2, and -CN. In some embodiments, R4is selected from methyl, ethyl, propyl, and isopropyl. In some embodiments, R4is selected from hydrogen, halogen, -OR13, and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen and -OR13. In some embodiments, R4is selected from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R4is selected from hydrogen and halogen. In some embodiments, R4is hydrogen.

[0132] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), R4is selected from halogen, -OR13, -N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R4is selected from -OR13, -N(R13)2, -NO2, and -CN. In some embodiments, R4is selected C1-6 alkyl and C1-6 haloalkyl. In some embodiments, R4is selected from -OR13, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R4is selected from -OR13, C1-3 alkyl, and C1-3 haloalkyl.

[0133] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), n is selected from 1, 2, and 3. In some embodiments, n is selected from 1 and 2. In some embodiments, n is selected from 1 and 3. In some embodiments, n is selected from 2 and 3. In some embodiments, n is 3.

[0134] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), n is selected from 0, 1, and 2. In some embodiments, n is selected from 0 and 1. In some embodiments, n is selected from 0 and 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0135] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), n is selected from 1 and 2; and R4is selected from halogen, -OR13, -N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, n is selected from 1 and 2; and R4is selected from halogen, -OR13, -N(R13)2, -NO2, and -CN. In some embodiments, n is selected from 1 and 2; and R4is selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, n is selected from 1 and 2; and R4is selected from halogen, -OR13, C1-6 alkyl, and C1-6 haloalkyl.

[0136] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), n is 1; and R4is selected from halogen, -OR13, -N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, n is 1; and R4is selected from halogen, -OR13, -N(R13)2, -NO2, and -CN. In some embodiments, n is 1; and R4is selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, n is 1; and R4is selected from halogen, -OR13, C1-6 alkyl, and C1-6 haloalkyl.

[0137] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), n is 2; and R4is selected from halogen, -OR13, -N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, n is 2; and R4is selected from halogen, -OR13, -N(R13)2, -NO2, and -CN. Insome embodiments, n is 2; and R4is selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, n is 2; and R4is selected from halogen, -OR13, C1-6 alkyl, and C1-6 haloalkyl.

[0138] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), X is selected from N(RA), O, and S. In some embodiments, X is selected from N(RA) and O. In some embodiments, X is selected from N(RA) and S. In some embodiments, X is selected from O and S. In some embodiments, X is N(RA). In some embodiments, X is O. In some embodiments, X is S.

[0139] In some embodiments, the structure of Formula (I) is represented by the structure of Formula (III):or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is selected from 3- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: hydrogen, halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -NQV^QCOR11, -C(O)OR11, -OC(O)R11, - N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -NO2, =0, =N(R11), and -CN; Ci-6alkyl, 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, -NtR^QOX11, -C(O)OR11, -OC(O)R11, - N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(0)N(R11)2, -NO2, =0, =N(R11), and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, any 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, R1is selected from 3- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: hydrogen, halogen, -OR11, -N(R11)2, -C(O)R11, - C(0)N(R11)2, -NtR^QOX11, -C(O)OR11, -OC(O)R11, -N(R11)C(0)0R11, -0C(0)N(R11)2, - N(R11)C(0)N(R11)2, -NO2, =0, =N(R11), and -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, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, - N(R11)C(0)R11, -C(O)OR11, -OC(O)R11, -N(R11)C(0)0R11, -0C(0)N(R11)2, -N(R11)C(0)N(R11)2, -NO2, =0, =N(R11). In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), or (Il-b), R1is selected from 3- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: hydrogen, halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, -N(R11)C(0)R11, - C(0)0R11, -0C(0)R11, -NCR^C^OR11, -0C(0)N(R11)2, -N(R11)C(0)N(R11)2, -N02, =0, =N(R11), and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, the C3-6 carbocycle and 3- to 6-membered heterocycle are each 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.

[0141] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), is selected from 3- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, -N^^C^R11, -C(0)0R11, - 0C(0)R11, -NO2, =0, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, and C2-6 haloalkynyl; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0142] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is selected from 5- to 10-membered heterocycle and C5-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, -N^^C^R11, -C(0)0R11, - 0C(0)R11, -NO2, =0, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, and C2-6 haloalkynyl; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0143] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is selected from 5- to 6-membered heterocycle and C5-6 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, -N(R11)C(0)R11, -C(0)0R11, - 0C(0)R11, -NO2, =0, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, and C2-6 haloalkynyl; and C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with, C1-6 alkyl, and C1-6 haloalkyl.

[0144] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is selected from 5- to 6-membered heterocycle and C5-6 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl C2-6 alkynyl, and C2-6 haloalkynyl; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with halogen and C1-6 alkyl.

[0145] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is pyrazolyl optionally substituted with one or more substituents independently selected from halogen and C2-6 alkynyl; and C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with halogen and C1-6 alkyl .In some embodiments, R1is pyrazolyl, optionally substituted with one or more substituents independently selected from halogen and C2-6 alkynyl; and C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with C1-6 alkyl. In some embodiments, R1is pyrazolyl, optionally substituted with one or more substituents independently selected from halogen and C2 alkynyl; and cyclopropyl and piperazinyl, any of which is optionally substituted with C1-6 alkyl.

[0146] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III),

[0147] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is 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 R^C^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, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, --CN; and(iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any 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 of which is optionally substituted with one or more substituents independently selected from: halogen,C(O)OR11, -OC(O)R11, -NCR^QCOOR11, -OC(O)N(R1')2, - N(R11)C(O)N(R11)2, -NO2, =0, =N(R11), and -CN; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -N02, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -N02, and -CN.

[0148] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is selected from (i), (ii), and (iii):(i) hydrogen, halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N(R11)C(0)R11, - C(O)OR11, -OC(O)R11, -NO2, and -CN;(ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, - N(R11)2, -C(O)R11, -C(0)N((R112, -N^KXOX11, -C(O)OR11, -OC(O)R11, - NO2, =0, and -CN; and(iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, -N^^C^R11, - C(0)0R11, -0C(0)R11, -NO2, =0, and -CN;C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, - N^KXOX11, -C(0)0R11, -0C(0)R11, -NO2, =0, and -CN; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0149] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is selected from hydrogen, halogen, -OR11, -C(0)R11, -N(R11)2, -C(0)N(R11)2, - N(R11)C(0)R11, -C(0)0R11, -0C(0)R11, -N(R11)C(0)0R11, -0C(0)N(R11)2, - N(R11)C(0)N(R11)2, -NO2, and -CN. In some embodiments, R1is selected from hydrogen, halogen, -OR11, -C(O)R11, -N(R11)2, -N02, and -CN. In some embodiments, R1is selected from hydrogen, halogen, -OR11, -N02, and -CN. In some embodiments, R1is selected from hydrogen, halogen, and -OR11. In some embodiments, R1is selected from hydrogen and halogen. In some embodiments, R1is hydrogen.

[0150] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is selected from C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionallysubstituted with one or more substituents independently selected from halogen, -OR11, -SR11, - N(R11)2, -C(O)R11, -C(O)N(R11)2, -NCR^QOX11, -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)2(R1,1-N(R11)S(O)2R11, -S(O)2N((R112, - NO2, =0, =S, =N(R11), and -CN. In some embodiments, R1is selected from C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, - N(R11)C(0)R11, -C(O)OR11, -OC(O)R11, -N02, =0, =S, =N(R11), and -CN. In some embodiments, R1is selected from C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, - OR11, -N(R11)2, -C(O)R11, -NO2, and -CN. In some embodiments, R1is selected from C1-3 alkyl, C2-4 alkenyl, and C2-4 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -N02, and -CN.

[0151] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N^C^R11, -C(O)OR11, - OC(O)R11, -NtR^C^OR11, -0C(0)N(R11)2, -N(R11)C(O)N(R11)2,-S(O)R11, -S(0)2(R1,1- N(R11)S(O)2R11, -S(O)2N((R112, -NO2, =0, =S, =N(R11), and -CN. In some embodiments, R1is C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N^K^R11, -C(O)OR11, -OC(O)R11, - NO2, =0, =S, =N(R11), and -CN. In some embodiments, R1is C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(0)R11, - NO2, and -CN. In some embodiments, R1is C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, - N(R11)C(0)R11, -C(0)0R11, -0C(0)R11, -N02, =0, =S, =N(R11), and -CN. In some embodiments, R1is C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(0)R11, -N02, and -CN.

[0152] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is C1-3 alkyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -OR11, -N(R11)2, and -CN. In some embodiments, R1is C3-6 alkyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -OR11, -N(R11)2, and -CN. In some embodiments, R1is selected from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1is selected from C1-3 alkyl and C1-3 haloalkyl. In some embodiments, R1is selected from C3-6 alkyl and C3-6 haloalkyl. In some embodiments, R1is selected from methyl, ethyl, propyl, and isopropyl.

[0153] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is selected from 5- to 10-membered heterocycle and C3-10 carbocycle, any 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, =0, =N(R11), and -CN; Ci-6alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, - N(R11)C(0)R11, -C(O)OR11, -OC(O)R11, -N(R11)C(0)0R11, -OC(O)N(R11)2, - N(R11)C(0)N(R11)2, -NO2, =0, =N(R11), and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -N02, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -N02, and -CN.

[0154] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is optionally substituted 3- to 10-membered heterocycle wherein the optional substituents are as defined in Formula (II). In some embodiments, R1is an optionally substituted 3- to 10- membered saturated heterocycle. In some embodiments, R1is an optionally substituted 3- to 10- membered unsaturated heterocycle. In some embodiments, R1is an optionally substituted 3- to 10-membered aromatic heterocycle. In some embodiments, the optionally substituted 3- to 10- membered heterocycle of R1comprises 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 R1comprises 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 R1comprises 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 R1comprises 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 R1comprises at least one oxygen heteroatom. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of R1comprises at least one nitrogen heteroatom. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of R1comprises at least one sulfur heteroatom.

[0155] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is 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 (II). In some embodiments, R1is 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 (II).

[0156] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is 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, -N(R11)C(O)OR11, -OC(O)N(R11)2, - N(R11)C(O)N(R11)2, -NO2, =0, =N(R11), and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, -N^K^R11, -C(0)0R11, -0C(0)R11, - N(R11)C(0)0R11, -0C(0)N(R11)2, -N(R11)C(0)N(R11)2, -NO2, =0, =N(R11), and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, any 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, R1is 3- to 7-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, - OR11, -N(R11)2, -C(0)R11, -C(0)N((R112, -NtR^QOX11, -C(0)0R11, -0C(0)R11, - N(R11)C(0)0R11, -0C(0)N(R11)2, -N(R11)C(0)N(R11)2, -N02, =0, =N(R11), and -CN; Ci-6alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, - N(R11)C(0)R11, -C(0)0R11, -0C(0)R11, -N(R11)C(0)0R11, -0C(0)N(R11)2, - N(R11)C(0)N(R11)2, -NO2, =0, =N(R11), and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, any 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, R1is a 3- to 10-membered heterocycle optionally substituted with: halogen, -OR11, -N(R11)2, -NO2, =0, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -NO2, =0, and -CN. In some embodiments, R1is a 3- to 8-membered heterocycle optionally substituted with: halogen, -OR11, -N(R11)2, -NO2, =0, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -NO2, =0, and -CN.

[0157] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen,OC(O)R11, -NO2, =0, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, and C2-6 haloalkynyl; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0158] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen,OC(O)R11, -NO2, =0, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, and C2-6 haloalkynyl; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0159] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N(R11)C(0)R11, -C(O)OR11, - OC(O)R11, -NO2, =0, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, and C2-6 haloalkynyl; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with, C1-6 alkyl, and C1-6 haloalkyl.

[0160] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from; halogen, -OR11, -N(R11)2, -NO2, =0, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, and C2- 6 haloalkynyl; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0161] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is pyrazolyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -NO2, =0, -CN, C1-6 alkyl, C1-6 haloalkyl C2-6 alkynyl, and C2-6 haloalkynyl; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with halogen, Ci-6 alkyl, and Ci-6 haloalkyl.

[0162] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is pyrazolyl optionally substituted with one or more substituents independently selected from: halogen, Ci-6 alkyl, Ci-6 haloalkyl C2-6 alkynyl, and C2-6 haloalkynyl; and C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with halogen and Ci-6 alkyl.

[0163] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is pyrazolyl optionally substituted with one or more substituents independently selected from halogen and C2-6 alkynyl; and C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with halogen and Ci-6 alkyl .In some embodiments, R1is pyrazolyl, optionally substituted with one or more substituents independently selected from halogen and C2-6 alkynyl; and C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with Ci-6 alkyl. In some embodiments, R1is pyrazolyl, optionally substituted with one or more substituents independently selected from halogen and C2 alkynyl; and cyclopropyl and piperazinyl, any of which is optionally substituted with C1-6 alkyl.

[0164] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III),

[0165] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is 5- 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, -NO2, =0, -CN, Ci-6alkyl, Ci-6haloalkyl; and C3-6 carbocycle optionally substituted with one or more halogen, Ci-6 alkyl, and Ci-6 haloalkyl. In some embodiments, R1is 5- 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, -NO2, =O, -CN, Ci-6alkyl, Ci-6haloalkyl; and C3-6 carbocycle optionally substituted with one or more halogen, Ci-6 alkyl, and Ci-6 haloalkyl.

[0166] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, =O, -CN, Ci-6 alkyl, Ci-6 haloalkyl; and C3-6 carbocycle optionally substituted with one or more halogen, Ci-6 alkyl, and Ci-6haloalkyl. In some embodiments, R1is pyrazolyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, =0, -CN, C1-6 alkyl, C1-6 haloalkyl; and C3-6 carbocycle optionally substituted with halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1is pyrazolyl optionally substituted with one or more substituents independently selected from halogen, Ci-6 alkyl, Ci-6 haloalkyl, and C3-6 carbocycle optionally substituted with halogen. In some embodiments, R1is selected from, . In some embodiments,R1is selected

[0167] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is pyrazolyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N(R11COR11, -C(O)OR11, -OC(O)R11, - NO2, =0, -CN, C1-6 alkyl, C1-6 haloalkyl; and C3-6 carbocycle optionally substituted with one or more halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1is pyrazolyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -NO2, -CN, C1-6 alkyl, C1-6 haloalkyl and C3-6 carbocycle. In some embodiments, R1is pyrazolyl optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl and C3-6 carbocycle.

[0168] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is an optionally substituted C3-10 carbocycle, wherein the optional substituents are as defined in Formula (II). In some embodiments, R1is an optionally substituted C3-10 saturated carbocycle. In some embodiments, R1is an optionally substituted C3-10 unsaturated carbocycle. In some embodiments, R1is an optionally substituted C5-10 aromatic carbocycle. In some embodiments, R1is 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- 10 carbocycle, wherein the optional substituents are as defined in Formula (II). In some embodiments, R1is selected from optionally substituted C3carbocycle, optionally substituted C4 carbocycle, optionally substituted C5carbocycle, optionally substituted C6carbocycle, optionally substituted C7carbocycle, optionally substituted C8carbocycle, optionally substitutedC9 carbocycle, and optionally substituted Cio carbocycle, wherein the optional substituents are as defined in Formula (II).

[0169] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), R1is 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, =0, =N(R11), and - CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, - C(0)N(R11)2, -NtR^QOX11, -C(O)OR11, -OC(O)R11, -N(R11)C(0)0R11, -0C(0)N(R11)2, - N(R11)C(0)N(R11)2, -NO2, =0, =N(R11), and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -N02, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -N02, and -CN. In some embodiments, R1is C3-8 carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, - N(R11)C(0)R11, -C(O)OR11, -OC(O)R11, -N(R11)C(0)0R11, -0C(0)N(R11)2, - N(R11)C(0)N(R11)2, -NO2, =0, =N(R11), and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, -N^K^R11, -C(0)0R11, -0C(0)R11, - N(R11)C(0)0R11, -0C(0)N(R11)2, -N(R11)C(0)N(R11)2, -N02, =0, =N(R11), and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -N02, -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, R1is a C3-8 carbocycle heterocycle optionally substituted with: halogen, -OR11, -N(R11)2, -N02, =0, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR11, -N(R11)2, -NO2, =0, and -CN. In some embodiments, R1is C3-6 carbocycle optionally substituted with: halogen, -OR11, -N(R11)2, -N02, =0, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -NO2, =0, and -CN.

[0170] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), Ring A is selected from optionally substituted 3- to 10-membered heterocycle and optionally substituted C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -C(0)R14, -C(O)N(R14)2, - N(R14)C(O)R14, -C(0)0R14, -0C(0)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)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, -C(O)R14, -C(O)N(R14)2, - N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, - N(R14)C(O)N(R14)2, =0, =N(R14), -NO2, and -CN. In some embodiments, Ring A is selected from optionally substituted 3- to 10-membered heterocycle and optionally substituted C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -C(0)R14, -C(0)0R14, -N02, and -CN; and Ci-6alkyl optionally substituted with one or more substituents independently selected from: halogen, - OR14, -N(R14)2, -C(O)R14, -C(O)OR14, -NO2, =0, and -CN. In some embodiments, Ring A is selected from optionally substituted 3- to 10-membered heterocycle and optionally substituted C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(0)R14, -C(0)0R14, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

[0171] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), Ring A is selected from optionally substituted 3- to 10-membered heterocycle and optionally substituted C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(0)R14, -C(O)N(R14)2, - N(R14)C(O)R14, -C(0)0R14, -0C(0)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, - N(R14)C(O)N(R14)2, -S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -NO2, and -CN. In some embodiments, Ring A is selected from optionally substituted 3- to 10-membered heterocycle and optionally substituted C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(0)R14, - C(0)0R14, -NO2, and -CN. In some embodiments, Ring A is selected from optionally substituted 3- to 10-membered heterocycle and optionally substituted C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -N02, and -CN.

[0172] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), Ring A is selected from optionally substituted 3- to 10-membered heterocycle and optionally substituted C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, - N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, - N(R14)C(O)N(R14)2, -S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, -S(O)2N(R14)2, =0, =S, =N(R14), - NO2, and -CN. In some embodiments, Ring A is selected from optionally substituted 3- to 10- membered heterocycle and optionally substituted C3-10 carbocycle, any of which is optionallysubstituted with one or more substituents independently selected from Ci-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)OR14, -NO2, and -CN. In some embodiments, Ring A is selected from optionally substituted 3- to 10-membered heterocycle and optionally substituted C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from C1-6 alkyl and C1-6 haloalkyl.

[0173] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), Ring A is optionally substituted 3- to 10-membered heterocycle, wherein the optional substituents are as defined in Formula (II). In some embodiments, Ring A is optionally substituted 3- to 10-membered saturated heterocycle. In some embodiments, Ring A is optionally substituted 3- to 10-membered unsaturated heterocycle. In some embodiments, Ring A is optionally substituted 5- to 10-membered aromatic heterocycle. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of Ring A comprises 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 Ring A comprises 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 Ring A comprises 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 Ring A comprises 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 Ring A comprises at least one oxygen heteroatom. In some embodiments, the optionally substituted 3- to 10- membered heterocycle of Ring A comprises at least one nitrogen heteroatom. In some embodiments, the optionally substituted 3- to 10-membered heterocycle of Ring A comprises at least one sulfur heteroatom.

[0174] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), Ring A is 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 (II). In some embodiments, Ring A is selected from optionally substituted 3-membered heterocycle, optionally substituted 4-membered heterocycle, optionally substituted 5-membered heterocycle, optionally substituted 6-membered heterocycle, optionally substituted7-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 (II).

[0175] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), Ring A is 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, - N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, - N(R14)C(O)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, -C(O)R14, -C(O)N(R14)2, - N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, - N(R14)C(O)N(R14)2, =0, =N(R14), -NO2, and -CN. In some embodiments, Ring A is 5- to 6- membered heterocycle optionally substituted with one or more substituents independently selected 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, =0, -NO2, and -CN.

[0176] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), Ring A is pyridinyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, - OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, -NO2, and -CN; and Ci-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, - N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, =0, =N(R14), -N02, and -CN. In some embodiments, Ring A is pyridinyl optionally substituted with one or more substituents independently selected 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,=0, -NO2, and -CN. In some embodiments, Ring A is

[0177] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), Ring A is an optionally substituted C3-10 carbocycle, wherein the optional substituents are as defined in Formula (II). In some embodiments, Ring A is an optionally substituted C3-10 saturated carbocycle. In some embodiments, Ring A is an optionally substituted C3-10 unsaturated carbocycle. In some embodiments, Ring A is an optionally substituted C5-10 aromatic carbocycle. In some embodiments, Ring A is an optionally substituted C3-10 carbocycle, the optionally substituted C3-10 carbocycle is selected from optionally substituted C3-4carbocycle, 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 (II). In some embodiments, Ring A is selected from optionally substituted C3 carbocycle, optionally substituted C4 carbocycle, optionally substituted C5 carbocycle, optionally substituted Ce carbocycle, optionally substituted C7 carbocycle, optionally substituted Cs carbocycle, optionally substituted C9 carbocycle, and optionally substituted C10 carbocycle, wherein the optional substituents are as defined in Formula (II).

[0178] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), Ring A is C3-10 carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, - OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, -NO2, and -CN; and Ci-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, - N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, =0, =N(R14), -NO2, and -CN. In some embodiments, Ring A C3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -NO2, -CN, and Ci-6 alkyl optionally substituted with one or more substituents independently selected from halogen, - OR14, -N(R14)2, -C(O)R14, -NO2, -CN. In some embodiments, Ring A is C3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, - OR14, -N(R14)2, -C(O)R14, -NO2, -CN, C1-6 alkyl, and Ci-6haloalkyl.

[0179] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), Ring A is C3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, - OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, -NO2, and -CN; and Ci-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, - N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, =0, =N(R14), -NO2, and -CN. In some embodiments, Ring A is C3-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -NO2, -CN, and Ci-6 alkyl optionally substituted with one or more substituents independently selected from halogen, - OR14, -N(R14)2, -C(O)R14, -NO2, -CN. In some embodiments, Ring A is C3-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, - OR14, -N(R14)2, -C(O)R14, -NO2, -CN, Ci-6 alkyl, and Ci-6 haloalkyl. In some embodiments, Ring A is C3-6 carbocycle optionally substituted with one or more substituents independently selectedfrom: hydrogen, halogen, -OR14, -N(R14)2, -C(O)R14, and -CN. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is phenyl optionally substituted with one or more substituents independently selected from F, Cl, Br, I, -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, =0, -NO2, and -CN.

[0180] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), Ring A is phenyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, - OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, -NO2, and -CN; and Ci-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, - N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, =0, =N(R14), -NO2, and -CN. In some embodiments, Ring A is phenyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -NO2, -CN, and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, - OR14, -N(R14)2, -C(O)R14, -NO2, -CN. In some embodiments, Ring A is phenyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2,-C(O)R14, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, Ring A isIn some embodiments, Ring A is

[0181] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III), Ring A is phenyl optionally substituted more substituents independently selected from halogen, - OR14, -N(R14)2, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, Ring A is phenyl optionally substituted with one or more substituents independently selected from halogen, - OR14, and, -N(R14)2. In some embodiments, Ring A is phenyl optionally substituted with one or more substituents independently selected from halogen and -N(R14)2. In some embodiments, Ring A is phenyl optionally substituted with halogen or -NH2. In some embodiments, Ring A is phenyl.

[0182] In some embodiments for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III),Ring A is selected from

[0183] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), or (III),Ring A is selected fromIn some embodiments, Ring A is selected from

[0184] In some embodiments, Formula (I), (II), or (III) is represented by the structure ofFormula (IV):or a pharmaceutically acceptable salt thereof.

[0185] In some embodiments, Formula (I), (II), or (III) is represented by the structure of Formula (IV):or a pharmaceutically acceptable salt thereof, wherein L and R5are each as defined as in Formula (II).

[0186] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L1, L2, L3, and L4are each independently selected from (a), (b), and (c):(a) -O-, -N(R15)-, -S-, -S(O)-, -S(O)2-, -S(O)(NR15)-, -N(R15)C(O)-, -N(R15)C(O)O-, -N(R15)S(O)2-, -N(R15)S(O)2N(R15)-, -S(O)(NR15)N(R15)-, -N(R15)N(R15)-, - (R15)NC(O)N(R15)-, and -(R15)NC(O)N(R15)N(R15)-;(b) Ci-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, any of which is optionally substituted with one or more substituents independently selected halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, - S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -N02, and -CN; and(c) C3-10 carbocyclene and 3- to 10-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, - N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, - N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, =0, =S, =N(R15), -NO2, and -CN; andCi-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, - C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, - OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, - S(O)2N(R15)2, =0, =S, =N(R15), -N02, 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.

[0187] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L1, L2, L3, and L4are each independently selected from (a) and (b):(a) -O-, -N(R15)-, -S-, -S(O)-, -S(O)2-, -S(O)(NR15)-, -N(R15)C(0)-, -N(R15)C(0)0-, -N(R15)S(O)2-, -N(R15)S(O)2N(R15)-, -S(O)(NR15)N(R15)-, -N(R15)N(R15)-, - (R15)NC(O)N(R15)-, and -(R15)NC(O)N(R15)N(R15)-; and(b) Ci-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, any of which is optionally substituted with one or more substituents independently selected halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, - OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, - S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, and -CN.

[0188] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L1, L2, L3, and L4are each independently selected from (a) and (c):(a) -O-, -N(R15)-, -S-, -S(O)-, -S(O)2-, -S(O)(NR15)-, -N(R15)C(O)-, -N(R15)C(O)O-,-N(R15)S(O)2-, -N(R15)S(O)2N(R15)-, -S(O)(NR15)N(R15)-, -N(R15)N(R15)-, - (R15)NC(O)N(R15)-, and -(R15)NC(O)N(R15)N(R15)-;(c) C3-io carbocyclene and 3- to 10-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, =0, =S, =N(R15), -NO2, and -CN; andCi-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, - C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, - OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, - S(O)2N(R15)2, =0, =S, =N(R15), -N02, and -CN.

[0189] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L1, L2, L3, and L4are each independently selected from (b) and (c):(b) Ci-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, any of which is optionally substituted with one or more substituents independently selected halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, - OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, - S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, =0, =S, =N(R15), -N02, and -CN;(c) C3-io carbocyclene and 3- to 10-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, - N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, =0, =S, =N(R15), -NO2, and -CN; andCi-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, - C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, - OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, - S(O)2N(R15)2, =0, =S, =N(R15), -N02, and -CN.

[0190] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L1, L2, L3, and L4are each independently selected from (a), (b), and (c):(a) -O-, -N(R15)-, -N(R15)C(0)-, -N(R15)C(0)0-, -N(R15)N(R15)-, - N(R15)C(O)N(R15)-, and -N(R15)C(O)N(R15)N(R15)-;(b) Ci-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, any of which is optionally substituted with one or more substituents independently selected halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, - N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, =0, =N(R15), -NO2, and -CN; and(c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, =0, =N(R15), -N02, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, - C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, - N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, =0, =N(R15), -N02, 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.

[0191] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L1, L2, L3, and L4are each independently selected from (a), (b), and (c):(a) -0-, -N(R15)-, -N(R15)C(0)-, -C(O)OR15-, and -OC(O)R15-;(b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, any of which is optionally substituted with one or more substituents independently selected halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, =0, -N02, and -CN; and(c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected fronrhalogen, -OR15, -N(R15)2, -C(0)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(0)0R15, -0C(0)R15; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(0)R15, - C(O)N(R15)2, -N(R15)C(O)R15, -C(0)0R15, -0C(0)R15, =0, -N02, and -CN.

[0192] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L1, L2, L3, and L4are each independently selected from (a), (b), and (c):(a) -0-, -N(R15)-, -N(R15)C(0)-, -C(O)OR15-, and -OC(O)R15-;(b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, any of which is optionally substituted with one or more substituents independently selected halogen, -OR15, -N(R15)2, =0, -N02, and -CN; and(c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -N02, and -CN; and C1-6 alkyl optionally substitutedwith one or more substituents independently selected from halogen, -OR15, - N(R15)2, =0, -N02, and -CN.

[0193] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L1, L2, L3, and L4are each independently selected from (a), (b), and (c):(a) -O-, -N(R15)-, and -N(R15)C(O)-,(b) C1-6 alkylene optionally substituted with one or more substituents independently selected halogen, -OR15, -N(R15)2, =0, -N02, and -CN; and(c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -N02, -CN, C1-6 alkyl, and C1-6 haloalkyl.

[0194] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L1, L2, L3, and L4are each independently selected from (a), (b), and (c):(a) -N(R15)-, and -N(R15)C(0)-;(b) C1-6 alkylene and C1-6 haloalkylene; and(c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0195] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), one of L2, L3, and L4is absent. In some embodiments, two of L2, L3, and L4are absent. In some embodiments, each of L2, L3, and L4are absent.

[0196] In some embodiments, for the compound salt of (I), (II), (Il-a), (Il-b), (III), or (IV), L2, L3, and L4are each absent. In some embodiments, L3and L4are each absent. In some embodiments, L2is absent. In some embodiments, L3is absent. In some embodiments, L4is absent.

[0197] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L1, L2, L3, and L4are each independently selected from -O-, -N(R15)-, -S-, -S(O)-, -S(O)2-, -S(O)(NR15)-, -N(R15)C(O)-, -N(R15)C(O)O-, -N(R15)S(O)2-, -N(R15)S(O)2N(R15)-, - S(O)(NR15)N(R15)-, -N(R15)N(R15)-, -(R15)NC(O)N(R15)-, and -(R15)NC(O)N(R15)N(R15)-, wherein L2, L3, and L4are each optionally absent. In some embodiments, L1, L2, L3, and L4are each independently selected from -O-, -N(R15)-, -N(R15)C(O)-, -N(R15)C(O)O-, -N(R15)S(O)2-, - N(R15)S(O)2N(R15)-, -N(R15)N(R15)-, -(R15)NC(O)N(R15)-, and -(R15)NC(O)N(R15)N(R15)-, wherein L2, L3, and L4are each optionally absent. In some embodiments, L1, L2, L3, and L4are each independently selected from -O-, -N(R15)-, -N(R15)C(O)-, -N(R15)C(O)O-, -N(R15)S(O)2-, and -N(R15)S(O)2N(R15)-; wherein L2, L3, and L4are each optionally absent. In someembodiments, L1, L2, L3, and L4are each independently selected from -O-, -N(R15)-, and - N(R15)C(O)-; wherein L2, L3, and L4are each optionally absent.

[0198] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L1, L2, L3, and L4are each independently selected from Ci-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, - N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, - N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, =0, =S, =N(R15), - NO2, and -CN; wherein L2, L3, and L4are each optionally absent. In some embodiments, L1, L2, L3, and L4are each independently selected from C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, - OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -NO2, and -CN; wherein L2, L3, and L4are each optionally absent. In some embodiments, L1, L2, L3, and L4are each independently selected from C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, any of which is optionally substituted with one or more substituents independently selected from halogen, - OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -C(O)OR15, -NO2, and -CN; wherein L2, L3, and L4are each optionally absent.

[0199] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L1, L2, L3, and L4are each independently selected from C3-10 carbocyclene and 3- to 10- membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, - N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, - N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, =0, =S, =N(R15), - NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, - S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, =0, =S, =N(R15), -N02, and -CN; wherein L2, L3, and L4are each optionally absent.

[0200] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L1, L2, L3, and L4are each independently selected from C3-10 carbocyclene and 3- to 10- membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, - N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, - N(R15)C(O)N(R15)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or moresubstituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, - N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, - N(R15)C(O)N(R15)2, -NO2, and -CN; wherein L2, L3, and L4are each optionally absent. In some embodiments, L1, L2, L3, and L4are each independently selected from C3-10 carbocyclene and 3- to 10-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, and -CN; wherein L2, L3, and L4are each optionally absent. In some embodiments, L1, L2, L3, and L4are each independently selected from C3-10 carbocyclene and 3- to 10-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

[0201] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L1, L2, L3, and L4are each independently selected from C3-10 carbocyclene optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, - OC(O)N(R15)2, -N(R15)C(O)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, -C(O)R15, - C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, - N(R15)C(O)N(R15)2, -NO2, and -CN; wherein L2, L3, and L4are each optionally absent. In some embodiments, L1, L2, L3, and L4are each independently selected from C3-10 carbocyclene optionally substituted with one or more substituents independently selected from halogen, - OR15, -N(R15)2, -C(O)R15, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, and -CN; wherein L2, L3, and L4are each optionally absent. In some embodiments, L1, L2, L3, and L4are each independently selected from C3-10 carbocyclene optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl; wherein L2, L3, and L4are each optionally absent.

[0202] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L1, L2, L3, and L4are each independently selected from 3- to 10-membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, - OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, - N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -NO2, and -CN; and Ci-6alkyl optionally substituted with one or more substituents independently selected from halogen, - OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -N02, and -CN; wherein L2, L3, and L4are each optionally absent. In some embodiments, L1, L2, L3, and L4are each independently selected from 3- to 10-membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, and -CN; and Ci-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, and -CN; wherein L2, L3, and L4are each optionally absent. In some embodiments, L1, L2, L3, and L4are each independently selected from 3- to 10- membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, -CN, Ci-6 alkyl, and Ci-6 haloalkyl; wherein L2, L3, and L4are each optionally absent.

[0203] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L1, L2, L3, and L4are each independently selected from -N(R15)-, -N(R15)C(O)-, C1-3 alkylene; and C3-6 carbocyclene optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl; wherein L2, L3, and L4are each optionally absent. In some embodiments, L1, L2, L3, and L4are each independently selected from -N(R15)-, -N(R15)C(O)- ,Ci-3 alkylene, and C3-6 carbocyclene, optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl; wherein L2, L3, and L4are each optionally absent.

[0204] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L1, L2, L3, and L4are each independently selected from -N(R15)-, -N(R15)C(O)-, and C1-3 alkylene; wherein L2, L3, and L4are each optionally absent. In some embodiments, one of L1, L2, L3, or L4is -N(R15)-; wherein L2, L3, and L4are each optionally absent. In some embodiments, one of L1, L2, L3, or L4is -N(R15)C(O)-; wherein L2, L3, and L4are each optionally absent. In some embodiments, one of L1, L2, L3, or L4is C1-3 alkylene; wherein L2, L3, and L4are each optionally absent.

[0205] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), one of L1, L2, L3, or L4is -N(R15)-; wherein L2, L3, and L4are each optionally absent. In some embodiments, one of L1, L2, L3, or L4is -N(R15)C(O)-; wherein L2, L3, and L4are each optionally absent. In some embodiments, one of L1, L2, L3, or L4is C1-3 alkylene; wherein L2, L3, and L4are each optionally absent.

[0206] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L1is independently selected from -N(R15)-, -N(R15)C(O)-, and C1-3 alkylene. In some embodiments, L1is -N(R15)-. In some embodiments, L1is -N(R15)C(O)-. In some embodiments, L1is C1-3 alkylene. In some embodiments, L1is selected from -N(R15)-, -N(R15)C(O)-, and C1-3alkylene; and R15is selected at each occurrence from hydrogen Ci-6 alkyl, and Ci-6 haloalkyl. In some embodiments, L1is selected from -N(H)-, -N(H)C(O)-, and C1-3 alkylene.

[0207] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L1, L2, L3, and L4are each independently selected from C3-10 carbocyclene and 3- to 10- membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, - N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, - N(R15)C(O)N(R15)2, =0, =N(R15), -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl; wherein L2, L3, and L4are each optionally absent. In some embodiments, L1, L2, L3, and L4are each independently selected from 3- to 6-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, - C(O)N(R15)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl; wherein L2, L3, and L4are each optionally absent. In some embodiments, L1, L2, L3, and L4are each independently selected from 5- to 6-membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl; wherein L2, L3, and L4are each optionally absent. In some embodiments, L1, L2, L3, and L4are each independently selected from 5- to 6-membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -NO2, -CN, Ci-6alkyl, and Ci-6haloalkyl; wherein L2, L3, and L4are each optionally absent. In some embodiments, L1, L2, L3, and L4are each independently selected from piperidinylene optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, - NO2, -CN, Ci-6 alkyl, and Ci-6 haloalkyl; wherein L2, L3, and L4are each optionally absent. In some embodiments, L1, L2, L3, and L4are each independently selected from piperidinylene optionally substituted with one or more substituents independently selected from halogen, - OR15, -NO2, -CN, C1-3 alkyl, and C1-3 haloalkyl; wherein L2, L3, and L4are each optionally absent. In some embodiments, L1, L2, L3, and L4are each independently selected from piperidinylene optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; wherein L2, L3, and L4are each optionally absent.

[0208] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L1is selected from C3-10 carbocyclene and 3- to 10-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, - OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, - N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, =0, =N(R15), -NO2, -CN, Ci-6alkyl, and Ci-6 haloalkyl. In some embodiments, L1is 3- to 10-membered heterocyclene, any of whichls optionally substituted with one or more substituents independently selected from halogen, - OR15, -N(R15)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L1is 3- to 6- membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -NO2, -CN, Ci-6 alkyl, and C1-6 haloalkyl. In some embodiments, L1is 3- to 6-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L1is 3- to 6-membered heterocyclene. In some embodiments, L1is 4- to 6-membered heterocyclene.

[0209] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or(IV), L1is selected from

[0210] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L2is selected from C3-10 carbocyclene and 3- to 10-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, - OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, - N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, =0, =N(R15), -NO2, -CN, Ci-6alkyl, and C1-6 haloalkyl.

[0211] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L2is 3- to 6-membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)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, - OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -NO2, -CN, Ci-6alkyl, and Ci-6haloalkyl. In some embodiments, L2is 5- to 6-membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, - NO2, -CN, Ci-6 alkyl, and Ci-6 haloalkyl. In some embodiments, L2is piperidinylene optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -NO2, -CN, Ci-6 alkyl, and Ci-6 haloalkyl. In some embodiments, L2is piperidinylene optionally substituted with one or more substituents independently selected from halogen, -OR15, -NO2, -CN, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, L2is piperidinylene optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, for the compound or salt ofFormula (I), (II), (Il-a), (Il-b), (III), or (IV), L2is selected from-Il

[0212] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L2is selected from piperidinylene, piperazinylene, and azetidinylene, any of which is optionally substituted with one or more substituents independently selected from halogen, - OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -NO2, -CN, Ci-6alkyl, and Ci-6haloalkyl. In some embodiments, L2is selected from piperidinylene, piperazinylene, and azetidinylene, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -NO2, -CN, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, L2is selected from piperidinylene, piperazinylene, and azetidinylene, any of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, L2is selected from

[0213] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L1, L2, L3, and L4are each independently selected from C3-10 carbocyclene optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl; wherein L2, L3, and L4are each optionally absent. In some embodiments, L1, L2, L3, and L4are each independently selected from C3-6 carbocyclene, optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl; wherein L2, L3, and L4are each optionally absent. In some embodiments, L1, L2, L3, and L4are each independently selected from phenylene optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, - NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl; wherein L2, L3, and L4are each optionally absent. In some embodiments, L1, L2, L3, and L4are each independently selected from phenylene optionally substituted with one or more substituents independently selected from halogen, - OR15, -NO2, -CN, C1-3 alkyl, and C1-3 haloalkyl; wherein L2, L3, and L4are each optionally absent. In some embodiments, L1, L2, L3, and L4are each independently selected from phenylene optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; wherein L2, L3, and L4are each optionally absent.

[0214] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), L2is C3-10 carbocyclene optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L2is C3-6 carbocyclene optionally substituted with one or moresubstituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, - NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L2is phenylene optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, L2is phenylene optionally substituted with one or more substituents independently selected from halogen, -OR15, -NO2, -CN, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, L2is phenylene optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, and C1-3 haloalkyl.

[0215] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or

[0216] In some embodiments, for the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or(IV), L is selected from:

[0217] In some aspects, the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), is selected from a compound of Table 1. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.

[0218] Table 1. Selected AKT1 modifiers.

[0219] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0220] 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), (Il-a), (Il-b), (III), or (IV), are intended to include all Z-, E- and tautomeric forms as well.

[0221] “ Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system.When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0222] The compounds or salts for Formula (I), (II), (Il-a), (Il-b), (III), or (IV), 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.

[0223] In certain embodiments, compounds or salts for Formula (I), (II), (Il-a), (Il-b), (III), or (IV), may comprise two or more enantiomers or diatereomers of a compound wherein a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers. Methods of producing substantially pure enantiomers are well known to those of skill in the art. For example, a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill;Lochmuller (1975) J. Chromatogr., 113(3): 283-302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for service basis.

[0224] 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), (Il-a), (Il-b), (III), or (IV), 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:

[0225] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0226] In certain embodiments, the compounds disclosed herein have some or all of theJH 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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,nC,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,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.

[0231] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds of Formula (I), (II), (Il-a), (Il-b), (III), or (IV). 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.

[0232] The methods and compositions of Formula (I), (II), (ILa), (Il-b), (III), or (IV), include the use of amorphous forms as well as crystalline forms (also known as polymorphs). Thecompounds 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.

[0233] Compounds of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), 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.

[0234] In certain embodiments, compounds or salts of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), 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.

[0235] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.

[0236] In certain embodiments, the prodrug may be converted, e.g., enzymatically or chemically, to the parent compound under the conditions within a cell. In certain embodiments, the parent compound comprises an acidic moiety, e.g., resulting from the hydrolysis of the prodrug, which may be charged under the conditions within the cell. In particular embodiments, the prodrug is converted to the parent compound once it has passed through the cell membrane into a cell. In certain embodiments, the parent compound has diminished cell membrane permeability properties relative to the prodrug, such as decreased lipophilicity and increased hydrophilicity.

[0237] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64: 181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above-defined compounds. The compounds may be synthesized using conventional techniques.Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0238] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fie ser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0239] Pharmaceutical Formulations

[0240] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I), (II), (ILa), (Il-b), (III), or (IV), and at least one pharmaceutically acceptable excipient.

[0241] 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. Pharmaceutical compositions can comprise at least one active ingredient (e.g., a compound, salt or conjugate).

[0242] A compound or salt of any one of Formula (I), (II), (ILa), (Il-b), (III), or (IV), 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), (Il-a), (Il-b), (III), or (IV), and one or more pharmaceutically acceptableexcipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, antioxidants, solubilizers, and adjuvants.

[0243] Pharmaceutical compositions may also be prepared from a compound or salt of any one of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), and one or more pharmaceutically acceptable excipients suitable for transdermal, inhalative, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical composition are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999).

[0244] Methods of Treatment

[0245] 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.

[0246] 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.

[0247] 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 ofthe disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0248] 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), (Il-a), (Il-b), (III), or (IV). 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), (Il-a), (II- b), (III), or (IV).

[0249] 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), (Il-a), (Il-b), (III), or (IV), 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), (Il-a), (Il-b), (III), or (IV), and a pharmaceutically acceptable excipient.

[0250] 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), (Il-a), (Il-b), (III), or (IV), 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), (Il-a), (Il-b), (III), or (IV), 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.

[0251] 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), (Il-a), (Il-b), (III), or (IV), 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), (Il-a), (Il-b), (III), or (IV), 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.

[0252] 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 asubject in need thereof a compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), 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), (Il-a), (Il-b), (III), or (IV), 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.

[0253] 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), (Il-a), (Il-b), (III), or (IV), 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), (Il-a), (Il-b), (III), or (IV), 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.

[0254] 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), (Il-a), (Il-b), (III), or (IV), 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), (Il-a), (Il-b), (III), or (IV), 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, about2-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 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.

[0255] 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), (Il-a), (Il-b), (III), or (IV), 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), (Il-a), (Il-b), (III), or (IV), 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.

[0256] 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), (Il-a), (Il-b), (III), or (IV), 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), (Il-a), (Il-b), (III), or (IV), 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 composition comprising the compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV), and a pharmaceutically acceptable excipient. In some embodiments, the administering to thesubject in need thereof comprises a pharmaceutical composition comprising a compound or salt as provided in Table 1, and a pharmaceutically acceptable excipient.

[0257] AKT1 Protein

[0258] 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), (Il-a), (Il-b), (III), or (IV), 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. In some embodiments, the compound is a compound or salt as provided in Table 1, or a pharmaceutically acceptable composition thereof.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] 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 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 cysteineresidue 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.

[0263] 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.

[0264] 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.

[0265] 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.

[0266] 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.

[0267] 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.

[0268] 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 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 humanin vivo engineered AKT1 protein, wherein the in vivo engineered AKT1 protein is generated by contacting the AKT1 protein in vivo with the compound.

[0269] 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.

[0270] 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.

[0271] 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 vinyl sulfonamide 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 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 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.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] 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 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 carbonsulfur single bond results from an irreversible reaction between the thiol functional group of C310 and the acrylate group on the compound.

[0276] 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.

[0277] 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.

[0278] 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.

[0279] 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 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-sulfursingle bond results from an irreversible reaction between the thiol functional group of C310 and the alkyne group on the compound.

[0280] 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 Formula (I), (II), (Il-a), (Il-b), (III), or (IV). In some embodiments, the compound is selected from a compound or salt of Table 1.(a) Method of Modifying AKT1 proteins

[0281] 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 electrophile is selected from: an alkene, an alkyne, an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinyl sulfonamide 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. Insome 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.

[0282] In some aspects, the compound is a compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV). In some embodiments, the AKT1 inhibitor is a compound or salt of Formula (I), (II), (Il-a), (Il-b), (III), or (IV).

[0283] EXAMPLES

[0284] 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.

[0285] 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.

[0286] Example 1 : (R)-l-(4-((6-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5- b] pyridin-3-yl)-2,3-dihydrobenzofuran-3-yl) amino) piperidin-l-yl) prop-2-en-l-one (Compound 1)

[0287] Synthetic Route:Compound 1Intermediate 1-3

[0288] Step 1 : Synthesis of (R)-l-(4-((6-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H- imidazo[4,5-b] pyridin-3-yl)-2,3-dihydrobenzofuran-3-yl) amino) piperidin-l-yl) prop-2-en-l- one (Compound 1).

[0289] A solution of 3-{3-[(3R)-3-amino-2,3-dihydro-l-benzofuran-6-yl]-5-(pyrazol-l-yl) imidazo[4,5-b] pyridin-2-yl} pyridin-2-amine (Intermediate 1-3) (120 mg, 0.292 mmol, 1 equiv) and l-(prop-2-enoyl) piperidin-4-one (44.79 mg, 0.292 mmol, 1 equiv) in DCE (4 mL) and MeOH (1 mL) was stirred for 48h at 50°C. To the mixture was added NaBHsCN (55.12 mg, 0.876 mmol, 3 equiv). The resulting mixture was stirred for 24 h at 50°C. The reaction was quenched with water (5mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (3x30 ml) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a gradient of MeOH in DCM. The product was further purified by by Prep-HPLC on a XSelect CSH OBD Column using a gradient of acetonitrile in water (+ 0.1% FA) to afford l-(4-{[(3R)-6-[2-(2-aminopyridin-3-yl)-5- (pyrazol-l-yl) imidazo[4,5-b] pyridin-3-yl]-2,3-dihydro-l-benzofuran-3-yl] amino} piperidin-l- yl) prop-2-en-l-one (Compound 1; formic acid salt) (10.7 mg, 5.95%) as an off- white solid. MS (ESI) cal cd. for C30H29N9O2, 547.24 m / z, found 548.25 [M+H]+. 1H NMR (300 MHz, DMSO- d6) (ppm):5 8.31 - 8.40 (m, 2H), 8.17 (s, 1H), 8.01 - 8.03 (m, 1H), 7.95 - 7.98 (m, 1H), 7.78 -7.84 (m, 1H), 7.48 - 7.50 (m, 1H), 7.28 - 7.32 (m, 1H), 6.94 - 7.02 (m, 1H), 6.87 - 6.91 (m, 1H),6.75 - 6.81 (m, 1H), 6.56 - 6.59 (m, 1H), 6.46 - 6.52 (m, 1H), 6.02 - 6.08 (m, 1H), 5.67 - 5.72(m, 1H), 4.69 - 4.73 (m, 2H), 4.21 - 4.42 (m, 2H), 3.92 - 4.09 (m, 1H), 3.08 - 3.22 (m, 1H), 2.74- 2.98 (m, 2H), 1.79 - 1.97 (m, 2H), 1.05 - 1.35 (m, 2H).

[0290] Synthesis of Intermediates 1-1 to 1-3: tert-butyl (A)-(6-((3-nitro-6-(U / -pyrazol-l- yl)pyridin-2-yl)amino)-2,3-dihydrobenzofuran-3-yl)carbamate (Intermediate 1-1), -tert-butyl (R)- (6-((3-amino-6-(U / -pyrazol-l-yl)pyridin-2-yl)amino)-2,3-dihydrobenzofuran-3-yl)carbamate (Intermediate 1-2), and -(A)-3-(3-(3-amino-2,3-dihydrobenzofuran-6-yl)-5-(U / -pyrazol-l-yl)- 3J / -imidazo[4,5-b]pyri din-2 -yl)pyridin-2-amine (Intermediate 1-3).Intermediate 1-1 Intermediate 1-2 Intermediate 1-3

[0291] Synthetic Route:

[0292] Step 1 : Synthesis of tert-butyl (A’)-(6-((3-nitro-6-( l 7 / -pyrazol- l -yl)pyridin-2-yl)amino)- 2,3-dihydrobenzofuran-3-yl)carbamate (Intermediate 1-1)

[0293] To a mixture of tert-butyl A-[(3 R)-6-bromo-2, 3 -dihydro- 1 -benzofuran-3-yl]carbamate (Intermediate 1-0) (521 mg, 1.658 mmol, 1 equiv), 3-nitro-6-(pyrazol-l-yl)pyridin-2-amine (674 mg, 3.285 mmol, 1.98 equiv) and CS2CO3 (1.14 g, 3.499 mmol, 2.11 equiv) in dioxane (7 mL) were added Pd(OAc)2 (51 mg, 0.227 mmol, 0.14 equiv) and XantPhos (212 mg, 0.366 mmol, 0.22 equiv) in batches at room temperature. The resulting mixture was stirred for 3 h at 100°C under N2. The reaction was quenched with water and extracted with ethyl acetate (3 / 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+ 0.05% TFA) to tert-butyl (A)-(6-((3-nitro-6-(17 / -pyrazol-l-yl)pyridin-2-yl)amino)-2,3-dihydrobenzofuran-3- yl)carbamate (Intermediate 1-1) (253 mg, 34.80 %) as a red solid. MS (ESI) calcd. for C21H22N6O5, 438.17 m / z, found, 439.05 [M+H]+.

[0294] Step 2: Synthesis of tert-butyl (A)-(6-((3-amino-6-(U / -pyrazol-l-yl)pyridin-2-yl)amino)-2.3-dihydrobenzofuran-3-yl)carbamate (Intermediate 1-2)

[0295] To a solution of tert-butyl (A)-(6-((3-nitro-6-(177-pyrazol-l-yl)pyridin-2-yl)amino)-2,3- dihydrobenzofuran-3-yl)carbamate (Intermediate 1-1) (490 mg, 1.118 mmol, 1 equiv) and 62(011)4 (328 mg, 3.659 mmol, 3.27 equiv) in DMF (5 mL) was added 4-(pyridin-4-yl)pyridine (8.7 mg, 0.056 mmol, 0.05 equiv) in batches at 0°C. The resulting mixture was stirred for 2 h at room temperature then quenched with water and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with (0-5% DCM in MeOH) to afford tert-butyl (A)-(6-((3-amino-6- (1 / / -pyrazol - 1 -yl)pyridin-2-yl)amino)-2,3 -dihydrobenzofuran-3 -yl)carbamate (Intermediate 1 -2) (530 mg, quant) as a black solid. MS (ESI) calcd. for C21H24N6O3, 408.19 m / z, found, 409.10 [M+H]+.

[0296] Step 3: Synthesis of tert-butyl (A)-(6-(2-(2-pivalamidopyridin-3-yl)-5-(U7-pyrazol-l-yl)- 3J / -imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrobenzofuran-3-yl)carbamate

[0297] To a solution of tert-butyl (A)-(6-((3-amino-6-(U / -pyrazol-l-yl)pyridin-2-yl)amino)-2,3- dihydrobenzofuran-3-yl)carbamate (Intermediate 1-2) (500 mg, 1.224 mmol, 1 equiv) in AcOH (20 mL) was added cupric acetate (59 mg, 0.325 mmol, 0.27 equiv) and / f-(3 -formyl pyri di n-2- yl)-2,2-dimethylpropanamide (332 mg, 1.610 mmol, 1.32 equiv) in batches at room temperature under air. The resulting mixture was stirred overnight at 65°C under air then concentrated under vacuum. The residue 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 (A)-(6-(2-(2-pivalamidopyridin-3-yl)-5-(U / -pyrazol-l-yl)-3J / -imidazo[4,5-b]pyridin-3-yl)-2,3- dihydrobenzofuran-3-yl)carbamate (330 mg, 45.33 %) as an red / brown solid. MS (ESI) calcd. for C32H34N8O4’ 594.27 m / z, found, 595.15 [M+H]+.

[0298] Step 4: Synthesis of (A)-3-(3-(3-amino-2,3-dihydrobenzofuran-6-yl)-5-(lJ / -pyrazol-l- yl)-3J / -imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 1-3)

[0299] A solution of tert-butyl (A)-(6-(2-(2-pivalamidopyridin-3-yl)-5-(lJ / -pyrazol-l-yl)-3JT- imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrobenzofuran-3-yl)carbamate (308 mg, 0.518 mmol, 1 equiv) in 6N HC1 (0.6 mL) was stirred for 6 h at 100°C. The reaction mixture was diluted with water and the pH of the mixture was adjusted to around 8 with NaHCCL solution then extracted with DCM (3x30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford (A)-3-(3-(3-amino-2.3-dihydrobenzofuran-6-yl)-5-(17 / -pyrazol-l-yl)-3J / -imidazo[4,5-b]pyri din-2 -yl)pyri din-2-amine (Intermediate 1-3) (255 mg, crude) as brown solid. MS (ESI) calcd. for C22H18N8O, 410.16 m / z, found, 411.05 [M+H]+.

[0300] Synthesis of terLbutyl (R)-(6-bromo-2,3-dihydrobenzofuran-3-yl)carbamate(Intermediate 1-0)Intermediate 1-0

[0301] Synthetic Route:Intermediate 1-0

[0302] Step 1 : tert-butyl (R)-(6-bromo-2,3-dihydrobenzofuran-3-yl)carbamate (Intermediate 1-

[0303] To a solution of (R)-6-bromo-2,3-dihydrobenzofuran-3 -amine (1.5 g, 7.007 mmol) and triethylamine (2.13 g, 21.021 mmol) in DCM (25 mL) was added a solution of di-tert-butyl dicarbonate (2.29 g, 10.511 mmol) in DCM (5 mL) dropwise at 0°C. The resulting mixture was stirred for 2h at r.t, then quenched with water (100 mL) and extracted with DCM (3x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (0-20 % ethyl acetate / petroleum ether) to afford tert-butyl (R)-(6-bromo-2,3- dihydrobenzofuran-3-yl)carbamate (Intermediate 1-0) as a light yellow solid (1.8 g, 81.76 % yield). MS (ESI) calcd. for Ci3Hi6BrNO3, 313.03 m / z, found 258.10 [M+H-t-Bu]+.

[0304] Example 2: Synthesis of l-[4-({5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-l-yl)imidazo[4,5- b]pyri din-3 -yl]-2,3 -dihydroindol- 1 -yl }methyl)piperidin- 1 -yl]prop-2-en- 1 -one (Compound 2)

[0305] Synthetic Route:

[0306] Step 1 : Synthesis oftert-butyl 4-({5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-l- yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydroindol-l-yl}methyl)piperidine-l-carboxylate

[0307] To a solution of 3-[3-(2,3-dihydro-lH-indol-5-yl)-5-(pyrazol-l-yl)imidazo[4,5- b]pyridin-2-yl]pyridin-2-amine (Intermediate 2-1) (400 mg, 1.014 mmol, 1 equiv) in MeOH (20 mL) was added tert-butyl 4-formylpiperidine-l -carboxylate (259.54 mg, 1.217 mmol, 1.20 equiv). The resulting mixture was stirred for 12 h at 40°C. NaBHsCN (637.25 mg, 10.140 mmol, 10 equiv) was added and the reaction mixture was stirred at 40°C for 1 hour. The resulting mixture was concentrated under reduced pressure and 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 4-({5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-l-yl)imidazo[4,5- b]pyridin-3-yl]-2,3-dihydroindol-l-yl}methyl)piperidine-l-carboxylate (250 mg, 40.58%) as a yellow solid. MS (ESI) calcd. for C33H37N9O2: 591.3 Im / z, found: 592.30 [M+H]+.

[0308] Step 2: Synthesis of 3-{3-[l-(piperidin-4-ylmethyl)-2,3-dihydroindol-5-yl]-5-(pyrazol-l- yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine

[0309] A solution of tert-butyl 4-({5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-l-yl)imidazo[4,5- b]pyridin-3-yl]-2,3-dihydroindol-l-yl}methyl)piperidine-l-carboxylate (250 mg, 0.422 mmol, 1 equiv) in 4N HC1 in 1,4-dioxane (10 mL) was stirred for Ih at room temperature. The resulting mixture was concentrated under reduced pressure to afford 3-{3-[l-(piperidin-4-ylmethyl)-2,3- dihydroindol-5-yl]-5-(pyrazol- l-yl)imidazo[4,5-b]pyri din-2 -yl}pyridin-2-amine (170 mg, crude) as a yellow solid. MS (ESI) calcd. for C28H29N9: 491.25m / z, found: 492.40 [M+H]+.

[0310] Step 3: Synthesis of l-[4-({5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-l-yl)imidazo[4,5- b]pyri din-3 -yl]-2,3 -dihydroindol- 1 -yl }methyl)piperidin- 1 -yl]prop-2-en- 1 -one (Compound 2)

[0311] To a solution of tert-butyl 4-({5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-l-yl)imidazo[4,5- b]pyridin-3-yl]-2,3-dihydroindol-l-yl}methyl)piperidine-l-carboxylate (170 mg, 0.287 mmol, 1 equiv) in ACN (5 mL) were added triethylamine (290.73 mg, 2.870 mmol, 10 equiv) and acryloyl chloride (18.20 mg, 0.201 mmol, 0.7 equiv) at 0°C. The mixture was stirred at 0°C for 10 min and then at ambient temperature for 1 hour. The resulting mixture was concentrated under reduced pressure and purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+ 0.05% ammonium bicarbonate). The product 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 l-[4-({5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-l- yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydroindol-l-yl}methyl)piperidin-l-yl]prop-2-en-l-one (Compound 2) (32.2 mg, 19.99%) as a yellow solid. MS (ESI) calcd. for C31H31N9O: 545.27 m / z, found: 546.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 (ppm): 8.39 - 8.40 (m, 2H), 8.05 - 8.07 (m, IH), 8.00 - 8.02 (m, IH), 7.91 - 7.92 (m, IH), 7.83 - 7.90 (m, IH), 7.15 - 7.16 (m, IH), 7.06 - 7.09 (m, IH), 6.89 - 6.93 (m, IH), 6.79 - 6.81 (m, IH), 6.55 - 6.58 (m, 2H), 6.08 - 6.13 (m, IH), 5.69 - 5.72 (m, IH), 4.43 - 4.47 (m, IH), 4.06 - 4.08 (m, IH), 3.46 - 3.51 (m, 2H), 3.08 - 3.12 (m, IH), 2.97 - 3.06 (m, 4H), 2.65 - 2.71 (m, 1H),1.95 - 1.97 (m, IH), 1.80 - 1.81 (m, 2H), 1.09 - 1.15 (m, 2H).

[0312] Synthesis of 3-(3-(indolin-5-yl)-5-(U / -pyrazol-l-yl)-3J / -imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine (Intermediate 2-1)Intermediate 2-1

[0313] Intermediate 2-1 was prepared in a manner analogous to Intermediate 1-3 using tertbutyl 5-bromoindoline-l-carboxylate in place of Intermediate 1-0, 2-aminopyridine-3- carbaldehyde in place of A-(3-formylpyridin-2-yl)-2,2-dimethylpropanamide and 4N HC1 in dioxane at room temperature for Ih for the Boc removal. MS (ESI) calcd. for C22H18N8: 394.17m / z, found: 395.05 [M+H]+.

[0314] Examples 3 and 4: Synthesis of (*)-l-(4-((6-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l- yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrobenzo[b]thiophen-3-yl)amino)piperidin-l- yl)prop-2-en-l-one (Compound 3) and (*)-l-(4-((6-(2-(2-aminopyridin-3-yl)-5-(lrt-pyrazol-l- yl)-3JH-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrobenzo[b]thiophen-3-yl)amino)piperidin-l- yl)prop-2-en-l-one (Compound 4)

[0315] Compounds 3 and 4 were prepared in a manner analogous to Example 1 (via Intermediate 1-3) using Intermediate 3-1 in place of Intermediate 1-0 and Tris(dibenzylideneacetone) dipalladium(0) / SPhos in place of Pd(OAc)2 / XantPhos. The enantiomers were separated by Chiral Prep-HPLC on a CHIRALPAK IA column using a mixture of [Hex / DCM (3: 1) (+0.5% 2 M NHs-MeOH)] and ethanol. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer. .

[0316] Compound 3: MS (ESI) calcd. for C30H29N9OS, 563.22 m / z, found 564.30 [M+H]+. 'H NMR (400 MHz, DMSO-t / 6) d 8.50 - 8.24 (m, 2H), 8.02 (dd, J= 4.9, 1.9 Hz, 1H), 7.94 (d, J= 8.6 Hz, 1H), 7.81 (d, J= 1.6 Hz, 1H), 7.42 (d, J= 8.0 Hz, 1H), 7.37 (d, J= 1.9 Hz, 1H), 7.29 (dd, J= 7.6, 1.9 Hz, 1H), 7.17 (dd, J= 8.0, 2.0 Hz, 1H), 6.89 (s, 2H), 6.87 - 6.77 (m, 1H), 6.56 (dd, J= 2.6, 1.7 Hz, 1H), 6.50 - 6.42 (m, 1H), 6.13 - 6.04 (m, 1H), 5.69 - 5.62 (m, 1H), 4.66 (t, .7= 8.1 Hz, 1H), 4.20 (s, 1H), 3.98 (s, 1H), 3.72 - 3.63 (m, 1H), 3.26 - 3.11 (m, 2H), 3.00 - 2.85 (m, 2H), 1.95 (s, 1H), 1.84 (s, 1H), 1.35 - 1.18 (m, 3H).

[0317] Compound 4: MS (ESI) calcd. for C30H29N9OS, 563.22 m / z, found 564.20 [M+H]+. 'H NMR (400 MHz, DMSO-t / 6) d 8.39 - 8.31 (m, 2H), 8.02 (dd, J= 4.9, 1.9 Hz, 1H), 7.94 (d, J= 8.6 Hz, 1H), 7.81 (d, J= 1.7 Hz, 1H), 7.44 - 7.40 (m, 1H), 7.37 (d, J= 1.9 Hz, 1H), 7.29 (dd, J= 7.6, 1.9 Hz, 1H), 7.17 (dd, J= 8.0, 2.0 Hz, 1H), 6.89 (s, 2H), 6.87 - 6.77 (m, 1H), 6.56 (dd, J= 2.6, 1.7 Hz, 1H), 6.46 (dd, J= 7.6, 4.9 Hz, 1H), 6.13 - 6.04 (m, 1H), 5.69 - 5.62 (m, 1H), 4.66(t, .7= 8.1 Hz, 1H), 4.22 (s, 1H), 3.97 (s, 1H), 3.72 - 3.63 (m, 1H), 3.25 - 3.16 (m, 2H), 2.98 -2.86 (m, 2H), 1.95 (s, 1H), 1.84 (s, 1H), 1.29 - 1.21 (m, 3H).

[0318] Intermediate 3-1 : tert-butyl (6-bromo-2,3-dihydrobenzo[b]thiophen-3-yl)carbamate

[0319] Intermediate 3-1 was prepared in a manner analogous to Intermediate 1-0 using 6- bromo-2,3-dihydrobenzo[b]thi ophen-3 -amine in place of (R)-6-bromo-2,3-dihydrobenzofuran- 3-amine and including 0.1 equiv of DMAP. MS (ESI) calcd. for CnHieBrNChS, 329.00 m / z, found 330.10 [M+H]+.

[0320] Example 5: Synthesis of l-[4-({6-[2-(2-aminopyridin-3-yl)-5-(pyrazol-l-yl)imidazo[4,5- b]pyridin-3-yl]-2,3-dihydro-lH-indol-3-yl}amino)piperidin-l-yl]prop-2-en-l-one (Compound 5)Compound 5

[0321] Compound 5 was prepared in a manner analogous to Example 1 using Intermediate 5-1 in place of Intermediate 1-3 and MeOH as the solvent. MS (ESI) calcd. for C30H30N10O, 546.26 m / z, found 547.25 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 8 (ppm): 8.35 - 8.37 (m, 1H), 8.29 - 8.31 (m, 1H), 7.96 - 8.02 (m, 1H), 7.89 - 7.91 (m, 1H), 7.77 - 7.81 (m, 1H), 7.27 - 7.30 (m, 2H), 6.71 - 6.79 (m, 1H), 6.53 - 6.57 (m, 3H), 6.44 - 6.47 (m, 1H), 6.04 - 6.08 (m, 1H), 5.66 - 5.69 (m, 1H), 4.40 - 4.44 (m, 1H), 4.26 - 4.28 (m, 1H), 3.92 - 3.93 (m, 1H), 3.62 - 3.67 (m, 1H), 3.22 - 3.26 (m, 1H), 3.08 - 3.12 (m, 1H), 2.81 - 2.90 (m, 1H), 2.69 - 2.78 (m, 1H), 1.79 - 1.93 (m, 2H), 1.11 - 1.25 (m, 2H).

[0322] Intermediate 5-1 : 6-(2-(2-aminopyridin-3-yl)-5-(177-pyrazol-l-yl)-3Z7-imidazo[4,5- b]pyri din-3 -yl)indolin-3 -amineIntermediate 5-1

[0323] Intermediate 5-1 was prepared in a manner analogous to Intermediate 1-3 using Intermediate 5-0 in place of Intermediate 1-0, Tris(dibenzylideneacetone)dipalladium(0) / RuPhos instead of Pd(OAc)2 / XantPhos, and for the final step (deprotection) the following procedure was used:

[0324] To a solution of tert-butyl N-[(3R)-6-{2-[2-(2,2-dimethylpropanamido)pyridin-3-yl]-5- (pyrazol-l-yl)imidazo[4,5-b]pyridin-3-yl}-l-(4-methylbenzenesulfonyl)-2,3-dihydroindol-3- yl]carbamate (223 mg, 0.298 mmol, 1 equiv) in MeOH (12 mL) was added HC1 (12 mL). After being stirred overnight at 100°C, the solution was concentrated. The residue was stirred in H2SO4 (4 mL) for 1 h at rt. The resulting solution was poured into ice water (5 mL) and basified to pH=9 with NaHCCL a.q. The precipitated solids were collected by filtration and washed with water (3x5 mL) to afford (3R)-6-[2-(2-aminopyridin-3-yl)-5-(pyrazol-l-yl)imidazo[4,5- b]pyridin-3-yl]-2,3-dihydro-lH-indol-3-amine (Intermediate 5-1) (120 mg, 98.35% yield) as a light yellow solid. MS (ESI) calcd. for C22H19N9, 409.17 m / z, found 410.20 [M+H]+.

[0325] Intermediate 5-0: tert-butyl (6-bromo-l-tosylindolin-3-yl)carbamateIntermediate 5-0

[0326] Synthetic Route:

[0327] Step 1 : Synthesis of N-(5-bromo-2-iodophenyl)-4-methylbenzenesulfonamide

[0328] To a stirred solution of 5-bromo-2-iodoaniline (5 g, 16.783 mmol) and Pyridine (3.98 g, 50.349 mmol) in DCM (50 mL) was added TsCl (6.40 g, 33.566 mmol) in portions at 0°C. The mixture was stirred for 16 h at room temperature. Water (500 mL) was added and the resulting mixture was extracted with DCM (3 x 500 mL). The combined organic layers were washed with H2O (500 mL) and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (0~60 %) to afford N-(5-bromo-2-iodophenyl)-4- methylbenzenesulfonamide (6 g, 69.59% yield) as a yellow solid. MS (ESI) calcd. for Ci3HnBrINO2S, 450.87 m / z, found 451.75 [M+H]+.

[0329] Step 2: Synthesis of N-(5-bromo-2-vinylphenyl)-4-methylbenzenesulfonamide

[0330] A mixture of N-(5-bromo-2-iodophenyl)-4-m ethylbenzenesulfonamide (6 g, 13.271 mmol), 2-ethenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (20.44 g, 132.710 mmol), Pd(dppf)C12 (0.97 g, 1.327 mmol) and K2CO3 (5.50 g, 39.813 mmol) in dioxane (60 mL) and H2O (15 mL) was stirred for 16 h at 50°C under N2 atmosphere. The mixture was allowed to cool to room temperature. The reaction was quenched with H2O at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with H2O (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+ 0.05% ammonium bicarbonate) to afford N-(5-bromo-2-vinylphenyl)-4-methylbenzenesulfonamide (3 g, 57.76% yield) as a yellow solid. MS (ESI) calcd. for CisEluBrNCLS, 350.99 m / z, found 352.15 [M+H]+.

[0331] Step 3: Synthesis of 3 -azido-6-bromo-l -tosylindoline

[0332] A solution of N-(5-bromo-2-vinylphenyl)-4-methylbenzenesulfonamide (3.0 g, 8.5 mmol), NaNs (831 mg, 12.8 mmol), Iodine (4.32 mg, 17.0 mmol) and AcOH (0.64 g, 10.646 mmol) in ACN (10 mL) and dioxane (10 mL) was stirred for 3 h at room temperature. The reaction mixture was concentrated under reduced pressure and the resulting residue was purifiedby silica gel column chromatography, eluting with ethyl acetate / petroleum ether (0-100%) to afford 3 -azido-6-bromo-l -tosylindoline (2.4 g, 77.39% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-t / e) 8 (ppm): 7.95 (s, 1H), 7.70 - 7.80 (m, 2H), 7.25 - 7.30 (m, 2H), 7.20 - 7.25 (m, 1 H), 7.10 - 7.18 (m, 1H), 4.72 - 4.80 (m, 1H), 4.00 - 4.10 (m, 1H), 3.90 - 4.00 (m, 1H), 2.41 (s, 3H).

[0333] Step 4: Synthesis of 6-bromo-l-tosylindolin-3 -amine

[0334] A solution of 3 -azido-6-bromo-l -tosylindoline (2.4 g, 6.103 mmol), triphenylphosphine (3.20 g, 12.206 mmol) and triethylamine (1.85 g, 18.309 mmol) in THF (20 mL) and H2O (5 mL) was stirred for 16 h at room temperature. The crude product was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+ 0.05% TFA) to afford 6-bromo-l-tosylindolin-3 -amine (1.5 g, 63.58% yield) as a white solid. MS (ESI) calcd. for Ci5Hi5BrN2O2S, 366.00 m / z, found 350.05 [M-NH2]+.

[0335] Step 5: Synthesis of tert-butyl (6-bromo-l-tosylindolin-3-yl)carbamate (Intermediate 5- 0)

[0336] A solution of 6-bromo-l-tosylindolin-3 -amine (1.4 g, 3.812 mmol), BOC2O (1.66 g, 7.624 mmol) and triethylamine (1.16 g, 11.436 mmol) in DCM (50 mL) was stirred for 16 h at room temperature. The reaction was quenched with H2O at room temperature. The resulting mixture was extracted with DCM (3 x 300 mL). The combined organic layers were washed with H2O (3 x 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl (6-bromo-l-tosylindolin-3-yl)carbamate (Intermediate 5-0) (1.5 g, 71.56% yield) as a yellow solid. MS (ESI) calcd. for C2oH23BrN204S, 466.06 m / z, found 465.00 [M-H]-.

[0337] Example 6: Synthesis of (S)-l-(4-((6-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H- imidazo[4, 5-b]pyri din-3 -yl)-2,3 -dihydrobenzofuran-3 -yl)amino)piperidin- 1 -yl)prop-2-en- 1 -one (Compound 6)

[0338] Compound 6 was prepared in a manner analogous to Example 1 (via Intermediate 1-3 and 1-0) using (S)-6-bromo-2,3 -dihydrobenzofuran-3 -amine in place of (R)-6-bromo-2,3-dihydrobenzofuran-3 -amine. MS (ESI) calcd. for C30H29N9O2, 547.24 m / z, found 548.20 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 8.45 - 8.29 (m, 2H), 8.06 - 7.92 (m, 2H), 7.81 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.28 (d, J= 7.6 Hz, 1H), 7.00 (s, 1H), 6.98 - 6.89 (m, 3H), 6.82 (dd, J= 16.7, 10.5 Hz, 1H), 6.55 (s, 1H), 6.45 (dd, J= 7.7, 4.8 Hz, 1H), 6.08 (dd, J= 16.5, 2.5 Hz, 1H), 5.65 (dd, J= 10.6, 2.5 Hz, 1H), 4.78 - 4.60 (m, 2H), 4.41 - 4.18 (m, 2H), 4.08 - 3.87 (m, 1H), 3.22 - 3.03 (m, 1H), 2.94 - 2.73 (m, 2H), 2.44 - 2.31 (m, 1H), 2.01 - 1.78 (m, 2H), 1.29 - 1.07 (m, 2H).

[0339] Examples 7 and 8: Synthesis of l-((2R,4*)-4-(((R)-6-(2-(2-aminopyridin-3-yl)-5-(1H- pyrazol-l-yl)-3J / -imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrobenzofuran-3-yl)amino)-2- methylpiperidin-l-yl)prop-2-en-l-one (Compound 7) and l-((2R,4*)-4-(((7?)-6-(2-(2- aminopyridin-3-yl)-5-(1H-pyrazol-l-yl)-3J / -imidazo[4,5-b]pyridin-3-yl)-2,3- dihydrobenzofuran-3 -yl)amino)-2-methylpiperidin- 1 -yl)prop-2-en- 1 -one (Compound 8)

[0340] Compounds 7 and 8 were prepared in a manner analogous to Example 1 using Intermediate 7-1 in place of the ketone and DCE / MeOH (1 :1) at 80°C for 6h. The diastereomers were separated by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+ 0.05% ammonium bicarbonate). Compound 7 was further purified by Chiral Prep-HPLC on a CHIRAL Cellulose-SB column using a mixture of [Hex / DCM 3 : 1 (+ 0.1% DEA)] and IPA. Compound 8 was further purified by chiral prep-HPLC on a CHIRALPAK IG-3 column using a mixture of [Hex / DCM (3 : 1) (+ 0.1% DEA)] and IPA. *Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.

[0341] Compound 7: MS (ESI) calcd. for C31H31N9O2, 561.26 m / z, found, 562.15 [M+H]+. 'H NMR (500 MHz, Methanol-^) 8 8.42 (d, J= 2.6 Hz, 1H), 8.28 (d, J= 8.6 Hz, 1H), 8.03 (d, J= 8.6 Hz, 1H), 8.01 (dd, J= 5.0, 1.8 Hz, 1H), 7.76 (d, J= 1.7 Hz, 1H), 7.55 (d, J= 7.9 Hz, 1H), 7.42 (dd, J= 7.6, 1.8 Hz, 1H), 7.01 (d, J= 1.8 Hz, 1H), 6.96 (dd, J= 7.9, 1.9 Hz, 1H), 6.84 - 6.73 (m, 1H), 6.55 - 6.49 (m, 2H), 6.18 (dd, J= 16.9, 10.3 Hz, 1H), 5.78 - 5.71 (m, 1H), 5.03 -4.97 (m, 1H), 4.81 - 4.66 (m, 2H), 4.51 (dd, J = 9.5, 3.6 Hz, 2H), 3.21 (d, J = 11.9 Hz, 1H), 2.12 (s, 1H), 1.95 (s, 1H), 1.58 - 1.41 (m, 1H), 1.37 - 1.22 (m, 5H).

[0342] Compound 8: MS (ESI) calcd. for C31H31N9O2, 561.26 m / z, found, 562.15 [M+H]+. 'H NMR (500 MHz, Methanol-^) 8 8.42 (d, J = 2.6 Hz, 1H), 8.27 (d, J = 8.6 Hz, 1H), 8.05 - 7.98 (m, 2H), 7.76 (d, J= 1.6 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.41 (dd, J= 7.6, 1.8 Hz, 1H), 6.97 (d, J= 1.8 Hz, 1H), 6.94 (dd, J = 1.9, 1.9 Hz, 1H), 6.77 (dd, J= 16.8, 10.6 Hz, 1H), 6.55 - 6.49 (m, 2H), 6.21 (dd, J= 16.7, 2.0 Hz, 1H), 5.74 (dd, J= 10.6, 2.0 Hz, 1H), 4.76 - 4.68 (m, 2H), 4.52 - 4.44 (m, 1H), 4.40 (s, 1H), 3.17 - 3.09 (m, 1H), 2.07 - 1.94 (m, 2H), 1.72 (m, 1H), 1.64 (d, J= 13.7 Hz, 1H), 1.43 (d, J= 6.7 Hz, 3H), 1.31 (s, 2H).

[0343] Intermediate 7-1 : (A)-l-acryloyl-2-methylpiperidin-4-oneIntermediate 7-1

[0344] Synthetic Route:Intermediate 7-1

[0345] Step 1 : Synthesis of (R)-2-methylpiperidin-4-one

[0346] A solution of tert-butyl (R)-2-methyl-4-oxopiperidine-l -carboxylate (1 g, 4.689 mmol) in TFA (5 mL) and DCM (10 mL) was stirred for Ih at room temperature. The reaction mixture was concentrated to afford (R)-2-methylpiperidin-4-one (600 mg, crude) as a yellow oil. MS (ESI) calcd. for C6HnNO, 113.08 m / z. found 114.15 [M+H]+.

[0347] Step 2: Synthesis of (R)-l-acryloyl-2-methylpiperidin-4-one (Intermediate 7-1)

[0348] To a stirred solution of (R)-2-methylpiperidin-4-one (600 mg, crude) and triethylamine (1341.37 mg, 13.257 mmol) in DCM (5 mL) was added acryloyl chloride (479.90 mg, 5.303 mmol) dropwise at 0°C. The resulting mixture was stirred for 2h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (0-50%) to afford (R)- l-acryloyl-2-methylpiperidin-4-one (Intermediate 7-1) (300 mg, 38.31% yield, two steps) as a white solid. MS (ESI) calcd. for C9H13NO2, 167.09 m / z, found 168.15 [M+H]+.

[0349] Example 9: Synthesis of (A)-2-(acrylamidomethyl)-7V-(6-(2-(2-aminopyridin-3-yl)-5-(17 / -pyrazol-l-yl)-3J / -imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrobenzofuran-3-yl)benzamide(Compound 9)

[0351] Step 1 : tert-butyl (R)-(2-((6-(2-(2-aminopyridin-3-yl)-5-(lZ / -pyrazol-l-yl)-3JH- imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrobenzofuran-3-yl)carbamoyl)benzyl)carbamate

[0352] A solution of (A)-3-(3-(3-amino-2,3-dihydrobenzofuran-6-yl)-5-(17 / -pyrazol-l-yl)-3JT- imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 1-3) (92 mg, 0.224 mmol, 1 equiv) and DIEA (115 mg, 0.890 mmol, 3.97 equiv) in DMF (1.2 mL) was treated with 2-(((tert- butoxycarbonyl)amino)methyl)benzoic acid (65 mg, 0.259 mmol, 1.15 equiv) and PyBOP (128 mg, 0.246 mmol, 1.10 equiv) in batches at r.t.The resulting mixture was stirred for 1 h at r.t., diluted with water and extracted with DCM (3x 10 mL). The combined organic layers were washed with water five times and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography,eluting with (0-6 % DCM / MeOH) to afford tert-butyl (A)-(2-((6-(2-(2-aminopyridin-3-yl)-5- ( 1H-pyrazol-l-yl)-3J / -imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrobenzofuran-3- yl)carbamoyl)benzyl)carbamate (108 mg, 74.85 %) as yellow solid. MS (ESI) calcd. for C35H33N9O4, 643.27 m / z, found, 644.15 [M+H]+.

[0353] Step 2: (A)-2-(aminom ethyl)-7V-(6-(2-(2-aminopyri din-3 -yl)-5-( 17 / -pyrazol- l -yl)-3JT- imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrobenzofuran-3-yl)benzamide

[0354] A solution of tert-butyl (R)-(2-((6-(2-(2-aminopyridin-3-yl)-5-( IT / -pyrazol- l -yl)-37 / - imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrobenzofuran-3-yl)carbamoyl)benzyl)carbamate (103 mg, 0.160 mmol, 1 equiv) in [4N HC1 in dioxane] / dioxane (1 :1) (8 mL) was stirred for 1 h at r.t. then concentrated under vacuum to afford (A)-2-(aminomethyl)-7V-(6-(2-(2-aminopyridin-3-yl)- 5-(U / -pyrazol-l-yl)-3J / -imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrobenzofuran-3-yl)benzamide (87 mg, crude). MS (ESI) calcd. for C30H25N9O2, 543.21 m / z, found, 544.40 [M+H]+.

[0355] Step 3: (A)-2-(acrylamidomethyl)-A-(6-(2-(2-aminopyridin-3-yl)-5-(U / -pyrazol-l-yl)- 3Z7-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrobenzofuran-3-yl)benzamide (Example 9)

[0356] To a mixture of (A)-2-(aminomethyl)-7V-(6-(2-(2-aminopyridin-3-yl)-5-(U / -pyrazol-l- yl)-3J / -imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrobenzofuran-3-yl)benzamide (81 mg, 0.149 mmol, 1 equiv) and NaHCCL (60 mg, 0.714 mmol, 4.79 equiv) in H2O (0.4 mL) and THF (1.6 mL) was added acryloyl chloride (13.5 mg, 0.149 mmol, 1.00 equiv) dropwise at 0°C. The resulting mixture was stirred for 5 h at 0°C then diluted with water and extracted with DCM (3x20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by Prep-HPLC on a XBridge Prep OBD C18Column using a gradient of acetonitrile in water (+ 10 mmol / L NH4HCO3) to afford (A)-2-(acrylamidomethyl)-7V-(6-(2-(2-aminopyridin-3-yl)-5-(lrt-pyrazol-l- yl)-3J / -imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrobenzofuran-3-yl)benzamide (Compound 9) (32.7 mg, 36.57 %) as a yellow solid. MS (ESI) calcd. for C33H27N9O3, 597.22 m / z, found, 598.15 [M+H]+. 'H NMR (500 MHz, DMSO-d6) 8 9.22 (d, J= 13 Hz, 1H), 8.52 (t, J= 6.0 Hz, 1H), 8.39 - 8.34 (m, 2H), 8.02 (dd, J= 4.8, 1.8 Hz, 1H), 7.96 (d, J= 8.5 Hz, 1H), 7.82 (d, J= 1.7 Hz, 1H), 7.56 (d, J= 7.9 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.36 - 7.25 (m, 3H), 7.07 (d, J= 1.8 Hz, 1H), 7.00 (dd, J= 7.9, 1.8 Hz, 1H), 6.92 (s, 2H), 6.56 (dd, J= 2.6, 1.7 Hz, 1H), 6.46 (dd, J= 7.6, 4.8 Hz, 1H), 6.32 (dd, J= 17.1, 10.2 Hz, 1H), 6.12 (dd, J= 17.1, 2.1 Hz, 1H), 5.89 - 5.81 (m, 1H), 5.61 (dd, J= 10.2, 2.1 Hz, 1H), 4.91 (t, J= 9.3 Hz, 1H), 4.60 - 4.47 (m, 3H).

[0357] Example 10: Synthesis of (R)-l-(4-((6-(2-phenyl-5-(lH-pyrazol-l-yl)-3H-imidazo[4, 5- b]pyridin-3-yl)-2,3-dihydrobenzofuran-3-yl)amino)piperidin-l-yl)prop-2-en-l-one (Compound 10)Compound 10

[0358] Compound 10 was prepared in a manner analogous to Example 1 using Intermediate 10- 1 in place of Intermediate 1-3 and DCE / MeOH (1 : 1) + 2 equiv triethylamine at 50°C for 2h. MS (ESI) calcd. for C31H29N7O2, 531.24 m / z, found 532.35 [M+H]+. 'HNMR (400 MHz, DMSO- d6) δ 8.40 - 8.33 (m, 2H), 7.95 (d, J= 8.6 Hz, 1H), 7.82 (d, J= 1.6 Hz, 1H), 7.63 - 7.56 (m, 2H), 7.51 - 7.37 (m, 4H), 7.00 (d, J= 1.8 Hz, 1H), 6.94 (dd, J= 7.8, 1.9 Hz, 1H), 6.83 (dd, J= 16.7, 10.5 Hz, 1H), 6.56 (dd, J= 2.6, 1.7 Hz, 1H), 6.09 (dd, J= 16.6, 2.5 Hz, 1H), 5.66 (dd, J= 10.4, 2.5 Hz, 1H), 4.76 - 4.65 (m, 2H), 4.38 - 4.28 (m, 1H), 4.30 - 4.22 (m, 1H), 4.02 - 3.95 (m, 1H), 3.14 (t, J = 12.6 Hz, 1H), 2.93 - 2.78 (m, 2H), 2.48 - 2.43 (m, 1H), 1.93 - 1.76 (m, 2H), 1.24 - 1.19 (m, 2H).

[0359] Intermediate 10-1 : (R)-6-(2-phenyl-5-(l / 7-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)- 2,3 -dihydrobenzofuran-3 -amineIntermediate 10-1

[0360] Synthetic Procedure:Intermediate 1 -1 Intermediate 10-1

[0361] Step 1 : (3R)-6-[2-phenyl-5-(pyrazol-l-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-l- benzofuran-3 -amine (Intermediate 10-1)

[0362] A mixture of Tert-butyl N-[(3R)-6-{[3-nitro-6-(pyrazol-l-yl)pyridin-2-yl]amino}-2,3- dihydro-l-benzofuran-3-yl]carbamate (Intermediate 1-1) (240 mg, 0.547 mmol) and Na2S2O4 (285.90 mg, 1.641 mmol) in MeOH (0.2 mL) and DMSO (1 mL) was treated with benzaldehyde (87.14 mg, 0.821 mmol) in batches at rt. The resulting mixture was stirred for 12 h at 100°C and cooled to room temperature then concentrated under vacuum. The residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+ 0.05% TFA) to afford (3R)-6-[2-phenyl-5-(pyrazol-l-yl)imidazo[4,5-b]pyridin-3-yl]-2,3- dihydro-l-benzofuran-3 -amine (Intermediate 10-1) (130 mg, 60.21%) as a white solid. MS (ESI) mass calcd. for C23H18N6O, 394.00 m / z, found 395.05[M+H]+. *Note that the boc group was removed under the acidic conditions used for purification.

[0363] Example 11 : Synthesis of (R)-l-(4-((6-(2-(2 -fluorophenyl)-5-(lH-pyrazol-l-yl)-3H- imidazo[4, 5-b]pyri din-3 -yl)-2,3 -dihydrobenzofuran-3 -yl)amino)piperidin- 1 -yl)prop-2-en- 1 -one (Compound 11)Compound 11

[0364] Compound 11 was prepared in a manner analogous to Example 1 using Intermediate 11- 1 in place of Intermediate 1-3 and MeOH at 40°C for 2h. MS (ESI) calcd for C31H28FN7O2: 549.23 m / z, found: 550.35 [M+H]+. 1H NMR (300 MHz, DMSO-d6) 5(ppm): 9.31 - 9.37 (m, 1H), 9.09 - 9.15 (m, 1H), 8.36 - 8.48 (m, 2H), 7.96 - 8.07 (m, 1H), 7.82 - 7.88 (m, 1H), 7.71 -7.81 (m, 1H), 7.54 - 7.69 (m, 2H), 7.33 - 7.44 (m, 1H), 7.18 - 7.31 (m, 2H), 7.01 - 7.13 (m, 1H),6.78 - 6.93 (m, 1H), 6.56 - 6.64 (m, 1H), 6.07 - 6.19 (m, 1H), 5.66 - 5.76 (m, 1H), 5.29 - 5.35(m, 1H), 4.77 - 4.85 (m, 2H), 4.46 - 4.57 (m, 1H), 4.17 - 4.23 (m, 1H), 2.96 - 3.22 (m, 1H), 2.56- 2.44 (m, 1H),2.O6 - 2.21 (m, 2H), 1.42 - 1.48 (m, 2H). 19F NMR (282 MHz, DMSO-d6) 5(ppm): -74.23, -112.62. (TFA salt)

[0365] Intermediate 11-1 : (A)-6-(2-(2-fluorophenyl)-5-(lJ / -pyrazol-l-yl)-3J / -imidazo[4,5- b]pyridin-3-yl)-2,3 -dihydrobenzofuran-3 -amineIntermediate 11-1

[0366] Synthetic Route:Intermediate 11-1

[0367] Step 1 : Synthesis of tert-butyl ((3R)-6-(2-(2-fluorophenyl)-5-(lH-pyrazol-l-yl)-l,2- dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrobenzofuran-3-yl)carbamate

[0368] A solution of tert-butyl N-[(3R)-6-{[3-amino-6-(pyrazol-l-yl)pyridin-2-yl]amino}-2,3- dihydro-l-benzofuran-3-yl]carbamate (Intermediate 1-2) (500 mg, 1.224 mmol, 1 equiv) and 2- fluor-benzaldehyde (151.93 mg, 1.224 mmol, 1 equiv) in MeOH (10 mL) and AcOH (10 mL) was stirred at 65°C overnight. The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography on Cl 8 silica gel using a gradient of acetonitrile in water (+ 0.05% ammonium bicarbonate) to afford tert-butyl N-[(3R)-6-[2-(2- fluorophenyl)-5-(pyrazol-l-yl)-lH,2H-imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-l-benzofuran-3- yl]carbamate (300 mg, 47.63%) as a brown yellow solid. MS (ESI) calcd for C28H27FN6O3: 514.21 m / z, found: 515.25 [M+H]+.

[0369] Step 2: Synthesis of tert-butyl (R)-(6-(2-(2-fluorophenyl)-5-(lH-pyrazol-l-yl)-3H- imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrobenzofuran-3-yl)carbamate

[0370] A mixture of tert-butyl N-[(3R)-6-[2-(2-fluorophenyl)-5-(pyrazol-l-yl)-lH,2H- imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-l-benzofuran-3-yl]carbamate (250 mg, 0.486 mmol, 1 equiv) and MnCL (211.19 mg, 2.430 mmol, 5.00 equiv) in CHCI3 (10 mL) was stirred at 80°Covernight. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, the filter cake was washed with CHCh (30 mL) (3x10 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl N-[(3R)-6-[2-(2-fluorophenyl)-5- (pyrazol-l-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-l-benzofuran-3-yl]carbamate (200 mg, 80.31%) as a yellow green solid. MS (ESI) cal cd for C28H25FN6O3: 512.20 m / z, found: 513.15 [M+H]+.

[0371] Step 3: Synthesis of (R)-6-(2-(2-fluorophenyl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5- b]pyridin-3-yl)-2,3-dihydrobenzofuran-3 -amine (Intermediate 11-1)

[0372] A mixture of tert-butyl N-[(3R)-6-[2-(2-fluorophenyl)-5-(pyrazol-l-yl)imidazo[4,5- b]pyridin-3-yl]-2,3-dihydro-l-benzofuran-3-yl]carbamate (180 mg, 0.351 mmol, 1 equiv) in 4N HC1 in 1,4-di oxane (5 mL) was stirred at room temperature overnight. The residue was purified by reverse-phase flash chromatography on Cl 8 silica gel using a gradient of acetonitrile in water (+ 0.05% ammonium bicarbonate) to afford (3R)-6-[2-(2-fluorophenyl)-5-(pyrazol-l- yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-l-benzofuran-3-amine (Intermediate 11-1) (100 mg, 69.04%) as a light yellow solid. MS (ESI) calcd for C23H17FN6O: 412.14 m / z, found: 413.25 [M+H]+.

[0373] Example 12: Synthesis of l-(4-{ [(3R)-6-[2-(2-aminopyridin-3-yl)-5-(3- cyclopropylpyrazol- 1 -yl)imidazo[4, 5-b]pyri din-3 -yl]-2, 3 -dihydro- 1 -benzofuran-3 - yl]amino}piperidin-l-yl)prop-2-en-l-one (Compound 12)Compound 12

[0374] Compound 12 was prepared in a manner analogous to Example 1 (via Intermediate 1-3) using Intermediate 12-1 in place of 3-nitro-6-(pyrazol-l-yl)pyridin-2-amine, 2-aminopyridine-3- carbaldehyde in place of A-(3-formylpyridin-2-yl)-2,2-dimethylpropanamide, [4N HC1 in dioxane] / DCM (1 : 1) at room temperature for 2h for the deprotection, and DCE / MeOH (10: 1) + 5 equiv triethylamine at 50°C for 2h for the final step. MS (ESI) calcd. for C33H33N9O2: 587.68. found: 588.20 [M+H]+.XH NMR (400 MHz, DMSO ) 6(ppm): 8.31 (d, J= 8.8 Hz, 1H), 8.19 (s, 1H), 8.00 (d, J= 1.6 Hz, 1H), 7.86 (d, J= 8.7 Hz,lH), 7.41 - 7.45 (m, 1H), 7.23 - 7.28 (m, 1H), 6.93 - 6.95 (m, 1H), 6.87 - 6.89 (m, 1H), 6.73 - 6.81 (m, 1H), 6.39 - 6.42 (m, 1 H), 6.17 -6.19 (m, 1H), 6.08 - 6.11 (m, 1H), 5.65 (d, J= 8.1 Hz, 1H), 4.61 - 4.71 (m, 2H), 4.21 - 4.33 (m, 2H), 3.91 - 3.98 (m, 1H), 3.05 - 3.12 (m, 1H), 2.75 - 2.84 (m, 2H), 1.95 - 2.01 (m, 1H), 1.79 - 1.82 (m, 2H), 1.11 - 1.25 (m, 2H), 0.91 - 0.95 (m, 2H), 0.67 - 0.71 (m, 2H).

[0375] Intermediate 12-1 : 6-(3 -cyclopropyl- U / -pyrazol-l-yl)-3-nitropyridin-2-amine

[0376] Synthetic Route:Intermediate 12-1

[0377] Step 1 : Synthesis of 6-(3-cyclopropylpyrazol-l-yl)-3-nitropyridin-2-amine (Intermediate 12-1)

[0378] To a stirred solution of 6-chl oro-3 -nitropyridin-2-amine (4 g, 23.047 mmol, 1 equiv) in DMF (40 mL) were added 3 -cyclopropyl- IH-pyrazole (2.49 g, 23.047 mmol, 1 equiv) and K2CO3 (9.56 g, 69.141 mmol, 3 equiv) in portions at 25 °C. The resulting mixture was stirred at 80 °C for 16 h. The mixture was allowed to cool to 25°C. The reaction was quenched by the addition of water (100 mL) at 0 °C. The precipitated solids were collected by filtration and washed with water (10 mL x 3). The resulting solid was dried under infrared light to afford 6-(3- cyclopropylpyrazol-l-yl)-3-nitropyridin-2-amine (Intermediate 12-1) (1.9 g, 33.62%) as a yellow solid. MS (ESI) calcd. for C11H11N5O2: 245.24. found: 246.05 [M+H]+.

[0379] Example 13: Synthesis of (R)-l-(4-((6-(5-(3-cyclopropyl-lH-pyrazol-l-yl)-2-phenyl-3H- imidazo[4, 5-b]pyri din-3 -yl)-2,3 -dihydrobenzofuran-3 -yl)amino)piperidin- 1 -yl)prop-2-en- 1 -one (Compound 13)

[0380] Compound 13 was prepared in a manner analogous to Example 1 using Intermediate 13- 1 in place or Intermediate 1-3 and DCE / MeOH (10:1) + 5 equiv triethylamine at 50°C for 30 min. MS (ESI) calcd. for C34H33N7O2, 571.27 m / z, found 572.20 [M+H]+. 'HNMR (300 MHz, DMSO-d6) 8 (ppm): 8.28 - 8.31 (d, J= 6.3 Hz, 1H), 8.17 - 8.18 (d, J= 2.4 Hz, 1H), 7.83 - 7.86 (d, J= 9 Hz, 1H), 7.54 - 7.57 (m, 2H), 7.42 - 7.47 (m, 4H), 6.75 - 6.94 (m, 3H), 6.24 - 6.25 (d, J = 2.7 Hz, 1H), 6.09 - 6.10 (d, J= 2.4 Hz, 1H), 5.64 - 5.68 (d, J= 10.2 Hz, 1H), 4.67 - 4.69 (m, 2H), 4.31 - 4.33 (m, 2H), 3.95 - 3.97 (m, 2H), 3.09 - 3.15 (m, 1H), 2.75 - 2.85 (m, 2H), 1.80 - 1.95 (m, 3H), 1.15 - 1.20 (m, 2H), 0.93 - 0.96 (m, 2H), 0.73 - 0.76 (m, 2H).

[0381] Intermediate 13-1 : (R)-6-(5-(3-cyclopropyl-U / -pyrazol-l-yl)-2-phenyl-3Z7-imidazo[4,5- b]pyridin-3-yl)-2,3-dihydrobenzofuran-3 -amineIntermediate 13-1

[0382] Intermediate 13-1 was prepared in a manner analogous to Intermediate 10-1 (via Intermediate 1-1) using Intermediate 13-1 in place of 3-nitro-6-(pyrazol-l-yl)pyridin-2-amine. In this case the Boc group required an additional step to remove and a procedure analogous to Step 2 from Example 9 was used. MS (ESI) calcd. for C26H22N6O, 434.19 m / z, found 435.20 [M+H]+.

[0383] Examples 14 and 15: Synthesis of l-((2R,4*)-4-(((R)-6-(2-(2-aminopyridin-3-yl)-5-(3- cyclopropyl-U / -pyrazol-l-yl)-3Z7-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrobenzofuran-3- yl)amino)-2-methylpiperidin-l-yl)prop-2-en-l-one (Compound 14) and l-((2R,4*)-4-(((R)-6-(2- (2-aminopyridin-3-yl)-5-(3-cyclopropyl-U / -pyrazol-l-yl)-3Z7-imidazo[4,5-b]pyridin-3-yl)-2,3- dihydrobenzofuran-3 -yl)amino)-2-methylpiperidin- 1 -yl)prop-2-en- 1 -one (Compound 15)Compound 14 Compound 15

[0384] Compounds 14 and 15 were prepared in a manner analogous to Example 1 (via Intermediate 1-3) using Intermediate 12-1 in place of 3-nitro-6-(pyrazol-l-yl)pyridin-2-amine, 2-aminopyridine-3-carbaldehyde in place of 7V-(3-formylpyridin-2-yl)-2,2- dimethylpropanamide, [4N HC1 in dioxane] / DCM (1 : 1) at room temperature for 2h for the deprotection, Intermediate 7-1 in place of the ketone (final step) and DCE / MeOH (10: 1) + 5 equiv triethylamine for the final step. The diastereomers were separated by Prep HPLC on a XB ridge Prep Shield RP OBD C18 Column using as gradient of acetonitrile in water (+ 10 mM ammonium bicarbonate). * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.

[0385] Compound 14: MS (ESI) calcd. for C34H35N9O2: 601.75. found: 602.40 [M+H]+. 'H NMR (300 MHz, DMSO-d6 ) 5(ppm): 8.31 (d, J= 8.7 Hz, 1H), 8.19 (s, 1H), 7.99 (d, J= 1.8 Hz, 1H), 7.76 (d, J= 8.7 Hz,lH), 7.46 - 7.51 (m, 1H), 7.25 - 7.28 (m, 1H), 6.98 (s, 1H), 6.81 - 6.91 (m, 3H), 6.77 - 6.80 (m, 1 H), 6.31 - 6.41 (m, 1H), 6.26 (d, J= 2.4 Hz, 1H), 6.01 - 6.09 (m,lH), 5.61 - 5.67 (m,lH), 4.27 - 4.81 (m, 5H), 2.99 - 3.05 (m, 1H), 2.62 - 2.75 (m, 1 H), 2.21 - 2.31 (m, 1H), 1.98 - 2.01 (m, 2H), 1.72 - 1.85 (m, 1H), 1.35 - 1.36 (m, 1H), 1.11 - 1.21 (m, 4H), 0.92 - 0.98 (m, 2H), 0.71 - 0.75 (m, 2H).

[0386] Compound 15: MS (ESI) calcd. for C34H35N9O2: 601.75. found: 602.40 [M+H]+. 'H NMR (300 MHz, DMSO-t / 6) 5(ppm): 8.31 (d, J= 8.4 Hz, 1H), 8.25 - 8.30 (m, 1H), 7.99 (d, J= 1.8 Hz, 1H), 7.76 (d, J= 8.7 Hz,lH), 7.36 - 7.41 (m, 1H), 7.22 - 7.27 (m, 1H), 6.95 - 6.99 (m, 1H), 6.11 - 6.92 (m, 3H), 6.41 - 6.47 (m, 1H), 6.26 (d, J= 2.4 Hz,l H), 6.17 - 6.19 (m, 1H), 6.08- 6.11 (m, 1H), 5.59 - 6.61 (m, 1H), 4.60 - 4.70 (m, 2H), 4.29 - 4.40 (m, 2H), 3.88 - 3.92 (m,1H), 3.21 - 3.39 (m, 1H), 3.01 - 3.08 (m, 1H), 2.26 - 3.02 (m, 1H), 1.95 - 2.02 (m, 1H), 1.69 -1.75 (m, 2H), 1.60 - 1.65 (m, 2H), 1.29 - 1.35 (m, 3H), 0.91 - 0.99 (m, 2H), 0.72 - 0.77 (m, 2H).

[0387] Examples 16 and 17: Synthesis of l-((27?,4*)-2-methyl-4-(((R)-6-(2-phenyl-5-(lJ / - pyrazol-l-yl)-3J / -imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrobenzofuran-3-yl)amino)piperidin-l- yl)prop-2-en-l-one (Compound 16) and l-((2R,4*)-2-methyl-4-(((7?)-6-(2-phenyl-5-(17 / -pyrazol-l-yl)-3J / -imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrobenzofuran-3-yl)amino)piperidin-l- yl)prop-2-en-l-one (Compound 17)Compound 16 Compound 17

[0388] Compounds 16 and 17 were prepared in a manner analogous to Example 1 using Intermediate 10-1 in place of Intermediate 1-3, Intermediate 7-1 in place of the ketone and a reaction temperature of 80°C. The reducing agent was added at 0°C. The diastereomers were separated by chiral Prep HPLC on a CHIRAL ART Cellulose-SZ column using a mixture of [Hex (0.5% 2M NHs-MeOH)] and EtOH. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.

[0389] Compound 16: MS (ESI) calcd. for C32H31N7O2, 545.25 m / z, found 546.20 [M+H]+. 'H NMR (400 MHz, DMSO-t / e) d 8.42 - 8.37 (m, 1H), 8.35 (d, J= 2.6 Hz, 1H), 7.96 (d, J= 8.6 Hz, 1H), 7.83 (d, J= 1.7 Hz, 1H), 7.69 (s, 1H), 7.65 - 7.56 (m, 2H), 7.53 - 7.38 (m, 3H), 7.33 - 7.18 (m, 1H), 7.18 - 6.96 (m, 1H), 6.88 - 6.68 (m, 1H), 6.58 (dd, J= 2.6, 1.6 Hz, 1H), 6.24 - 6.05 (m, 1H), 5.79 - 5.59 (m, 1H), 5.41 - 4.67 (m, 2H), 4.20 (s, 1H), 3.99 (s, 1H), 3.27 (s, 1H), 2.93 (q, J = 6.9 Hz, 1H), 2.38 - 1.99 (m, 2H), 1.82 - 1.55 (m, 2H), 1.24 (s, 4H), 1.16 (t, J= 7.3 Hz, 1H)

[0390] Compound 17: MS (ESI) calcd. for C32H31N7O2, 545.25 m / z, found 546.20 [M+H]+. 'H NMR (400 MHz, DMSO-t / e) d 8.42 - 8.31 (m, 2H), 7.95 (d, J= 8.6 Hz, 1H), 7.81 (d, J= 1.7 Hz, 1H), 7.68 - 7.55 (m, 2H), 7.50 - 7.39 (m, 4H), 7.01 (d, J= 1.8 Hz, 1H), 6.94 (dd, J= 7.8, 1.8 Hz, 1H), 6.87 - 6.72 (m, 1H), 6.55 (dd, J= 2.6, 1.6 Hz, 1H), 6.15 - 6.01 (m, 1H), 5.74 - 5.56 (m, 1H), 4.69 (t, J= 2.4 Hz, 2H), 4.51 - 4.26 (m, 2H), 3.24 - 2.88 (m, 2H), 2.82 - 2.65 (m, 1H), 2.05 - 1.96 (m, 1H), 1.86 - 1.72 (m, 1H), 1.46 - 1.22 (m, 1H), 1.22 - 1.08 (m, 4H), 1.08 - 0.96 (m, 1H).

[0391] Examples 18 and 19: Synthesis of l-((2R,4*)-4-(((R)-6-(2-(2-aminopyridin-3-yl)-5-(3- fluoro-U / -pyrazol-l-yl)-3J / -imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrobenzofuran-3-yl)amino)-2- methylpiperidin-l-yl)prop-2-en-l-one (Compound 18) and l-((27?,4*)-4-(((7?)-6-(2-(2- aminopyri din-3 -yl)-5-(3 -fluoro- 1 / / -pyrazol - 1 -yl)-3J / -imidazo[4,5-b]pyri din-3 -yl)-2,3 - dihydrobenzofuran-3 -yl)amino)-2-methylpiperidin- 1 -yl)prop-2-en- 1 -one (Compound 19)Compound 18 Compound 19

[0392] Compounds 18 and 19 were prepared in a manner analogous to Example 1 using Intermediate 18-1 in place of Intermediate 1-3 and Intermediate 7-1 in place of the ketone. The diastereomers were separated by Prep-HPLC on a XB ridge Prep Shield RP OBD Cl 8 Column using a gradient of acetonitrile in water (+ 0.05% ammonium bicarbonate). *Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.

[0393] Compound 18: MS (ESI) calcd. For C31H30FN9O2: 579.25 m / z, found: 580.35 [M+H]+. 'H NMR (500 MHz, DMSO-t / 6) 8 8.36 (d, J= 8.6 Hz, 1H), 8.29 (t, J= 2.8 Hz, 1H), 8.02 (dd, J = 4.8, 1.9 Hz, 1H), 7.77 (d, J= 8.5 Hz, 1H), 7.44 (d, J= 7.8 Hz, 1H), 7.28 (dd, J= 7.6, 1.9 Hz, 1H), 7.00 (d, J= 1.8 Hz, 1H), 6.94 (dd, J= 7.8, 1.8 Hz, 1H), 6.88 (s, 2H), 6.80 (dd, J= 16.7, 10.5 Hz, 1H), 6.45 (dd, J= 7.6, 4.8 Hz, 1H), 6.37 (dd, J= 5.8, 2.8 Hz, 1H), 6.10 - 6.03 (m, 1H), 5.65 (dd, J= 10.5, 2.4 Hz, 1H), 4.90 - 3.90 (m, 5H), 3.16 - 2.65 (m, 2H), 1.83 - 1.75 (m, 1H), 1.79 (s, 1H), 1.40 - 1.03 (m, 5H).

[0394] Compound 19: MS (ESI) calcd. For C31H30FN9O2: 579.25 m / z, found: 580.35 [M+H]+. 'H NMR (500 MHz, DMSO-t / 6) 6 8.36 (d, J= 8.5 Hz, 1H), 8.29 (t, J= 2.8 Hz, 1H), 8.02 (dd, J = 4.8, 1.9 Hz, 1H), 7.77 (d, J= 8.5 Hz, 1H), 7.44 (d, J= 7.9 Hz, 1H), 7.28 (dd, J= 7.6, 1.9 Hz, 1H), 7.00 (d, J= 1.8 Hz, 1H), 6.95 (dd, J= 7.9, 1.9 Hz, 1H), 6.89 (s, 2H), 6.77 (dd, J= 16.6, 10.5 Hz, 1H), 6.46 (dd, J= 7.7, 4.8 Hz, 1H), 6.37 (dd, J= 5.9, 2.7 Hz, 1H), 6.08 (dd, J= 16.7, 2.6 Hz, 1H), 5.64 (dd, J= 10.4, 2.5 Hz, 1H), 4.72 - 4.66 (m, 2H), 4.39 - 4.34 (m, 2H), 3.93 (s, 1H), 3.07 (t, J= 4.5 Hz, 1H), 2.38 (d, J= 8.5 Hz, 1H), 1.81 - 1.58 (m, 4H), 1.38 (d, J= 6.8 Hz, 3H).

[0395] Intermediate 18-1 : (R)-3-(3-(3-amino-2,3-dihydrobenzofuran-6-yl)-5-(3-fluoro-U / - pyrazol-l-yl)-3J / -imidazo[4,5-b]pyridin-2-yl)pyridin-2-amineIntermediate 18-1

[0396] Intermediate 18-1 was prepared in a manner analogous to Inter...

Claims

CLAIMSWHAT 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, N(RA), and S;R1and R2are each independently selected from (i), (ii), and (iii):(i) hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -0C(0)N(R11)2, -N(R11)C(O)N(R11)2, - S(O)R11, -S(O)2R11, -N(R11)S(O)2R11, -S(O)2N((R1)12, -NO2, and -CN;(ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, - N(R11)2, -C(O)R11, -C(0)N((R1)12, -NCR^CCOX11, -C(O)OR11, -OC(O)R11, - NCR^C^OR11, -0C(0)N(R11)2, -N(R11)C(O)N(R11)2,-S(O)R11, -S(O)2(R1,1- N(R11)S(O)2R11, -S(O)2N((R1)12, -NO2, =0, =S, =N(R11), and -CN; and(iii) 3- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N^C^R11, - N(R11)S(0)2R11, -C(O)OR11, -OC(O)R11, -NtR^C^OR11, - 0C(0)N(R11)2, -N(R11)C(0)N(R11)2, -S(O)R11, -S(0)2(R1,1-S(O)2N((R1)12, -NO2, =0, =S, =N(R11), and -CN;C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, - OR11, -SR11, -N(R11)2, -C(O)R11, -C(0)N((R1)12, -N^C^R11, - C(O)OR11, -OC(O)R11, -NtR^C^OR11, -0C(0)N(R11)2, - N(R11)C(0)N(R11)2, -S(O)R11, -S(0)2(R1,1-N(R11)S(0)2R11, - S(O)2N(R11)2, -NO2, =0, =S, =N(R11), and -CN; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -N02, -CN, C1-6 alkyl, C3-6 carbocycle,and 3- to 6-membered heterocycle, wherein the Ci-6 alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl;R3is selected from hydrogen, 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;R4is selected from halogen, -OR13, -SR13, -N(R13)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, - SR13, -N(R13)2, -NO2, and -CN;RAis selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl;Ring A is selected from 3- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, - N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, - N(R14)C(O)N(R14)2, -S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -NO2, and -CN; andC1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, - C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, - OC(O)N(R14)2, -N(R14)C(O)N(R14)2, -S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, - S(O)2N(R14)2, =0, =S, =N(R14), -NO2, and -CN;L is represented by -iJ-L2-!?-! / -, wherein L1, L2, L3, and L4are each independently selected from (a), (b), and (c):(a) -0-, -N(R15)-, -S-, -S(0)-, -S(0)2-, -S(O)(NR15)-, -N(R15)C(0)-, -N(R15)C(0)0-, -N(R15)S(O)2-, -N(R15)S(O)2N(R15)-, -S(O)(NR15)N(R15)-, -N(R15)N(R15)-, - (R15)NC(O)N(R15)-, and -(R15)NC(O)N(R15)N(R15)-;(b) C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, any of which is optionally substituted with one or more substituents independently selected halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, - OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, - S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, =0, =S, =N(R15), -N02, and -CN; and(c) C3-10 carbocyclene and 3- to 10-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from:halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, - N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, =0, =S, =N(R15), -N02, and -CN; andCi-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, - C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, - OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, - S(O)2N(R15)2, =0, =S, =N(R15), -N02, 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;R5is a cysteine susceptible electrophile;R6is selected from halogen, -0R16A, -SR16A, -N(R16A)2, -N02, and -CN; and Ci-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -0R16A, -SR16A, -N(R16A)2, -N02, and -CN;R10, R11, R12, R13, R14, R15and R16Aare each independently selected at each occurrence from: hydrogen;Ci-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-Ci-6 alkyl, -O-Ci-6 haloalkyl, -NH2, -N02, =0, -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-Ci-6 alkyl, -O- C1-6 haloalkyl, -NH2, -N02, =0, and -CN; andC3-10 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-Ci-6 alkyl, -O-Ci-6 haloalkyl, -NH2, -N02, =0, and -CN; m is selected from 1 and 2; n is selected from 0, 1, 2, and 3; and p is selected from 0, 1, 2, 3, 4, 5, and 6.

2. The compound or salt of claim 1, wherein m is 1.

3. The compound or salt of claim 1 or claim 2, wherein R1is selected from (i), (ii), and (iii): (i) hydrogen, halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, -N(R11)C(0)R11, -C(0)0R11, -0C(0)R11, -N02, and -CN;(ii) Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, - N(R11)2, -C(O)R11, -C(0)N((R1)12, -NCR^CCOX11, -C(O)OR11, -OC(O)R11, - NO2, =0, and -CN; and(iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, -NCR^C^R11, - C(0)0R11, -0C(0)R11, -NO2, =0, and -CN;C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, - NCR^QOX11, -C(O)OR11, -OC(O)R11, -N02, =0, and -CN; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -N02, -CN, Ci-6alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C1-6 alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -N02, -CN, Ci-6alkyl, and Ci-6haloalkyl.

4. The compound or salt of claim 3, wherein R1is 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from:C3-6 carbocycle, and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN, Ci-6 alkyl, and Ci-6 haloalkyl; and C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, - SR11, -N(R11)2, -NO2, -CN, Ci-6 alkyl, and Ci-6 haloalkyl.

5. The compound or salt of claim 4, wherein R1is 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from:C3-6 carbocycle and 3- to 6-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN, Ci-6 alkyl, and Ci-6 haloalkyl; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, - SR11, -N(R11)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

6. The compound or salt of claim 5, wherein R1is pyrazolyl optionally substituted with one or more substituents independently selected from C3-6 carbocycle and 3- to 6-membered heterocycle each optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle, and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

7. The compound or salt of claim 6, wherein R1is selected from8. The compound of Formula (I) represented by the structure of Formula (II):or a pharmaceutically acceptable salt thereof wherein:X is selected from O, N(RA), and S;R1and R2are each independently selected from (i), (ii), and (iii):(i) hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -0C(0)N(R11)2, -N(R11)C(O)N(R11)2, - S(O)R11, -S(O)2R11, -N(R11)S(O)2R11, -S(O)2N((R1)12, -NO2, and -CN;(ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any 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, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR1N(R11)OC(O)N(R11)2, -N(R11)C(O)N(R11)2, -S(O)R11, -S(O)2(R1,1-S(O)2N(R11)2, -NO2, =0, =S, =N(R11), and -CN;C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, -C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -N02, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -N02, and -CN;R3is selected from hydrogen, halogen, -OR12, -SR12, -N(R12)2, -N02, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -N02, and -CN;R4is selected from halogen, -OR13, -SR13, -N(R13)2, -N02, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, - SR13, -N(R13)2, -N02, and -CN;RAis selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl;Ring A is selected from 3- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, - N(R14)C(O)N(R14)2, -S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -NO2, and -CN; andC1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, - C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, - OC(O)N(R14)2, -N(R14)C(O)N(R14)2, -S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, - S(O)2N(R14)2, =0, =S, =N(R14), -N02, and -CN;L is represented by -L'-LAIJ-L4-, wherein L1, L2, L3, and L4are each independently selected from (a), (b), and (c):(a) -O-, -N(R15)-, -S-, -S(O)-, -S(O)2-, -S(O)(NR15)-, -N(R15)C(O)-, -N(R15)C(O)O-, -N(R15)S(O)2-, -N(R15)S(O)2N(R15)-, -S(O)(NR15)N(R15)-, -N(R15)N(R15)-, - (R15)NC(O)N(R15)-, and -(R15)NC(O)N(R15)N(R15)-;(b) Ci-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, any of which is optionally substituted with one or more substituents independently selected halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, - OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, - S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, =0, =S, =N(R15), -N02, and -CN; and(c) C3-10 carbocyclene and 3- to 10-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, - N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, =0, =S, =N(R15), -N02, and -CN; andCi-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(0)R15, - C(O)N(R15)2, -N(R15)C(O)R15, -C(0)0R15, -0C(0)R15, -N(R15)C(O)OR15, - OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, - S(O)2N(R15)2, =0, =S, =N(R15), -N02, 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;R5is a cysteine susceptible electrophile;R6is selected from halogen, -0R16A, -SR16A, -N(R16A)2, -N02, and -CN; and Ci-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -0R16A, -SR16A, -N(R16A)2, -N02, and -CN;R10, R11, R12, R13, R14, R15and R16Aare each independently selected at each occurrence from: hydrogen;Ci-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-Ci-6 alkyl, -O-Ci-6 haloalkyl, -NH2, -N02, =0, -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 substituentsindependently selected from: halogen, -OH, Ci-6 alkyl, Ci-6 haloalkyl, -O-Ci-6 alkyl, -O- Ci-6 haloalkyl, -NH2, -NO2, =0, and -CN; andC3-10 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, =0, and -CN; m is selected from 1 and 2; n is selected from 0, 1, 2, and 3; and p is selected from 0, 1, 2, 3, 4, 5, and 6.

9. The compound or salt of claim 1 or claim 8, 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.

10. The compound or salt of claim 1 or claim 8, 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, and an ynamide.

11. The compound or salt of claim 1 or claim 8, 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.

12. The compound or salt of claim 1 or claim 8, 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, and an epoxide group.

13. The compound or salt of claim 11, 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.

14. The compound or salt of claim 12, wherein the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, a vinylsulfone group, a vinylsulfonamide group, an alkene, and an alkyne.

15. The compound or salt of claim 13, 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.

16. The compound or salt of claim 15, wherein the cysteine susceptible electrophile is selected from a squaric acid group, a squaric ester group, and a squaramide ester group.

17. The compound or salt of claim 15, wherein the cysteine susceptible electrophile is a squaric ester group.

18. The compound of salt of claim 17, wherein the cysteine susceptible electrophile is19. The compound or salt of claim 14, wherein the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, an alkene, and an alkyne.

20. The compound or salt of claim 1 or claim 8, wherein the cysteine susceptible electrophile is an alpha-beta unsaturated carbonyl, an alpha-beta unsaturated sulfone, an alpha-beta unsaturated amide, and an alpha-beta unsaturated sulfonamide.

21. The compound or salt of claim 20, wherein the cysteine susceptible electrophile is selected from an alpha-beta unsaturated carbonyl and an alpha-beta unsaturated amide.

22. The compound or salt of claim 21, wherein the cysteine susceptible electrophile is an alpha-beta unsaturated carbonyl.

23. The compound or salt of claim 1 or claim 8, wherein cysteine susceptible electrophile of R5is selected from:-C(O)R16B, -S(O)2R16B, -N(R17)C(O)(R16B), -C(O)N(R16B)(R17), -N(R17)S(O)2R16B, -S(O)2N(R16B)(R17), and -CN; andCi-6 alkyl substituted with one or more substituents independently selected from - C(O)R16B, -S(O)2R16B, -N(R17)C(O)(R16B), -C(O)N(R16B)(R17), -N(R17)S(O)2R16B, - S(O)2N(R16B)(R17), and -CN;R16Bis 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, -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; and C3-6 carbocycle and 3- to 6- membered heterocycle any of which is optionally substituted with halogen, C1-6 alkyl, and C1-6 haloalkyl;R17is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle; andR18selected 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, =0, -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, =0, and -CN; andC3-10 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, -N02, =0, and -CN.

24. The compound or salt of claim 23, wherein R5is selected from -C(0)R16B, -S(O)2R16B, - N(R17)C(O)(R16B), -C(O)N(R16B)(R17), -N(R17)S(O)2R16B, and -S(O)2N(R16B)(R17); and wherein R16Bis 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, -SR18, -N(R18)2, -N02, -CN; and C3-6 carbocycle and 3- to 6- membered heterocycle any of which is optionally substituted with halogen, C1-6 alkyl, and C1-6 haloalkyl.

25. The compound or salt of claim 24, wherein R5is -C(0)R16B; and wherein R16Bis 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; and C3-6 carbocycle and 3- to 6- membered heterocycle any of which is optionally substituted with halogen, C1-6 alkyl, and C1-6 haloalkyl.

26. The compound or salt of claim 25, wherein.

27. The compound or salt of claim 23, wherein cysteine susceptible electrophile of R5is selected from:-C(O)R16B, -S(O)2R16B, -N(R17)C(O)(R16B), -C(O)N(R16B)(R17), - N(R17)S(O)2R16B, -S(O)2N(R16B)(R17), and -CN; andCi-6 alkyl substituted with one or more substituents independently selected from - C(O)R16B, -S(O)2R16B, -N(R17)C(O)(R16B), -C(O)N(R16B)(R17), -N(R17)S(O)2R16B, - S(O)2N(R16B)(R17), and -CN;R16Bis 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, -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; andR17is independently selected at each occurrence from hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle; andR18selected 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, =0, -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, -N02, =0, and -CN; andC3-10 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, -N02, =0, and -CN.

28. The compound or salt of any one of claims 1-27, wherein, n is selected from 1 and 2; and R4is selected from -OR13, -N(R13)2, -N02, -CN, C1-6 alkyl, and C1-6 haloalkyl.

29. The compound or salt of any one of claims 1-27, wherein n is 0.

30. The compound or salt of any one of claims 1-29, wherein p is selected from 0 and 1.

31. The compound or salt of claim 30, wherein p is 0.

32. The compound or salt of claim 30, wherein p is 1.

33. The compound or salt of claim 30 or claim 32, wherein R6is selected from halogen, -OR16A, -SR16A, -N(R16A)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16A, -SR16A, -N(R16A)2, -NO2, and -CN.

34. The compound or salt of claim 33, wherein R6is selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

35. The compound or salt of claim 34, wherein R6is fluoro.

36. The compound or salt of any one of claims 1-35, wherein R3is selected from hydrogen, halogen, -OR12, -N(R12)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -NO2, and -CN.

37. The compound or salt of claim 36, wherein R3is selected from hydrogen, halogen, - OR12, C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen and -OR12.

38. The compound or salt of claim 37, wherein R3is selected from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl.

39. The compound or salt of claim 38, wherein R3is selected from hydrogen and halogen.

40. The compound or salt of claim 39, wherein R3is hydrogen.

41. The compound or salt of any one of claims 1-40, wherein R2is selected from (i), (ii), and(iii):(i) hydrogen, halogen, C(O)OR11, -OC(O)-NO2, and -CN;(ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, --CN; and(iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any 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^C^R11, - C(O)OR11, -OC(O)R11, -NCR^C^OR11, -OC(O)N(R11)2, - N(R11)C(O)N(R11)2, -NO2, =0, =N(R11), and -CN;C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, -N^C^R11, - C(0)0R11, -0C(0)R11, -NCR^C^OR11, -0C(0)N(R11)2, - N(R11)C(0)N(R11)2, -N02, =0, =N(R11), and -CN; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -N02, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -N02, and -CN.

42. The compound or salt of claim 41, wherein R2is selected from (i), (ii), and (iii):(i) hydrogen, halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, -N(R11)C(0)R11, - C(0)0R11, -0C(0)R11, -N02, and -CN;(ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, - N(R11)2, -C(O)R11, -C(0)N((R112, -NCR^CCOX11, -C(O)OR11, -OC(O)R11, - N02, =0, and -CN; and(iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, -N^^C^R11, - C(0)0R11, -0C(0)R11, -N02, =0, and -CN;C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, - N^KXOX11, -C(O)OR11, -OC(O)R11, -N02, =0, and -CN; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

43. The compound or salt of claim 42, wherein R2is selected from (i), (ii), and (iii):(i) hydrogen, halogen, -OR11, -N(R11)2, -N02, and -CN;(ii) C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, =0, and -CN; and(iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -NO2, =0, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -N02, =0, and -CN.

44. The compound or salt of claim 43, wherein R2is selected from: hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl; and5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

45. The compound or salt of claim 44, wherein R2is selected from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl.

46. The compound or salt of claim 45, wherein R2is selected from hydrogen and halogen.

47. The compound or salt of claim 46, wherein R2is hydrogen.

48. The compound or salt of any one of claims 1-47, wherein X is selected from N and S.

49. The compound or salt of any one of claims 1-47, wherein X is O.

50. The compound or salt of any one of claims 1-47 and 49, wherein the structure ofFormula (I) or Formula (II) is represented by the structure of Formula (III):or a pharmaceutically acceptable salt thereof.

51. The compound or salt of any one of claims 1-50, wherein R1is selected from (i), (ii), and(iii):(i) hydrogen, halogen, -OR11, -C(O)R11, -N(R11)2, -C(0)N(R11)2, -N(R11)C(O)R11, - C(O)OR11, -OC(O)R11, -NCR^C^OR11, -0C(0)N(R11)2, -N(R11)C(O)N(R11)2, -NO2, and -CN;(ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, - N(R11)2, -C(O)R11, -C(0)N((R112, -NCR^CCOX11, -C(O)OR11, -OC(O)R11, - N(R11)C(O)OR11, -0C(0)N(R11)2, -N(R11)C(O)N(R11)2, -NO2, =0, =N(R11), and -CN; and(iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, -N^C^R11, - C(0)0R11, -0C(0)R11, -NCR^C^OR11, -0C(0)N(R11)2, - N(R11)C(0)N(R11)2, -NO2, =0, =N(R11), and -CN;C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N^C^R11, - C(O)OR11, -OC(O)R11, -NCR^C^OR11, -0C(0)N(R11)2, - N(R11)C(0)N(R11)2, -NO2, =0, =N(R11), and -CN; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -N02, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -N02, and -CN.

52. The compound or salt of claim 51, wherein R1is selected from (i), (ii), and (iii):(i) hydrogen, halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N(R11)C(0)R11, - C(O)OR11, -OC(O)R11, -NO2, and -CN;(ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, - N(R11)2, -C(O)R11, -C(0)N((R112, -N^KXOX11, -C(O)OR11, -OC(O)R11, - NO2, =0, and -CN; and(iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, -N^^C^R11, - C(O)OR11, -OC(O)R11, -NO2, =0, and -CN;Ci-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(0)N(R11)2, - NCR^QOX11, -C(O)OR11, -OC(O)R11, -NO2, =0, and -CN; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

53. The compound or salt of claim 52, wherein R1is selected from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl.

54. The compound or salt of claim 52, wherein R1is 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen,0C(0)R11, -NO2, =0, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, and C2-6 haloalkynyl; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with halogen, C1-6 alkyl, and C1-6 haloalkyl.

55. The compound or salt of claim 52, wherein R1is 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, - OR11, -N(R11)2, -C(0)R11, -C(0)N((R112, -NCR^CCOX11, -C(0)0(R1,1-0C(0)(R1,1-NO2, =0, - CN, C1-6 alkyl, C1-6 haloalkyl; and C3-6 carbocycle optionally substituted with one or more halogen, C1-6 alkyl, and C1-6 haloalkyl.

56. The compound or salt of claim 54, wherein R1is 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, -N(R11)C(0)R11, -C(0)0R11, - 0C(0)R11, -NO2, =0, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, and C2-6 haloalkynyl; and C3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with, C1-6 alkyl, and C1-6 haloalkyl.

57. The compound or salt of claim 55, wherein R1is 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, - OR11, -N(R11)2, -C(0)R11, -C(0)N(R11)2, -NCR^CCOX11, -C(0)0(R1,1-0C(0)(R1,1-NO2, =0, - CN, C1-6 alkyl, C1-6 haloalkyl; and C3-6 carbocycle optionally substituted with one or more halogen, C1-6 alkyl, and C1-6 haloalkyl.

58. The compound or salt of claim 56, wherein R1is 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from; halogen, -OR11, -N(R11)2, -NO2, =0, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, and C2- 6 haloalkynyl; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with halogen, C1-6 alkyl, and C1-6 haloalkyl.

59. The compound or salt of claim 57, wherein R1is 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, - OR11, -N(R11)2, -NO2, =0, -CN, C1-6 alkyl, C1-6 haloalkyl; and C3-6 carbocycle optionally substituted with one or more halogen, C1-6 alkyl, and C1-6 haloalkyl.

60. The compound or salt of claim 58, wherein R1is pyrazolyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -NO2, =0, -CN, C1-6 alkyl, C1-6 haloalkyl C2-6 alkynyl, and C2-6 haloalkynyl; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with halogen, C1-6 alkyl, and C1-6 haloalkyl.

61. The compound or salt of claim 59, wherein R1is pyrazolyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, =0, -CN, C1-6 alkyl, C1-6 haloalkyl; and C3-6 carbocycle optionally substituted with halogen, C1-6 alkyl, and C1-6 haloalkyl.

62. The compound or salt of claim 60, wherein R1is pyrazolyl optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl C2-6 alkynyl, and C2-6 haloalkynyl; andC3-6 carbocycle and 3- to 6-membered heterocycle, any of which is optionally substituted with halogen and C1-6 alkyl .

63. The compound or salt of claim 61, wherein R1is pyrazolyl optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, and C3- 6 carbocycle optionally substituted with halogen.

64. The compound or salt of claim 62, wherein R1is selected from,65. The compound or salt of claim 63, wherein R1i and66. The compound or salt of any one of claims 1-65, wherein Ring A is selected from 3- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, -NO2, and -CN; andC1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, - C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, =0, =N(R14), -N02, and -CN.

67. The compound or salt of any one of claims 1-66, wherein Ring A is selected from 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, -N02, and -CN; andC1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, - C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, =0, =N(R14), -N02, and -CN.

68. The compound or salt of claim 67, wherein Ring A is 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N02, and -CN; andC1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, - C(O)OR14, -OC(O)R14, =0, -N02, and -CN.

69. The compound or salt of claim 68, wherein Ring A is 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, - OR14, -N(R14)2, -N02, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, =0, -N02, and -CN.

70. The compound or salt of claim 69, wherein Ring A is pyridinyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -N02, and - CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, =0, -N02, and -CN.

71. The compound or salt of claim 70, wherein Ring A is pyridinyl optionally substituted with one or more substituents independently selected from halogen, -N(R14)2, C1-6 alkyl, and C1-6 haloalkyl.

72. The compound or salt of claim 71, wherein Ring A is73. The compound or salt of any one of claims 1-66, wherein Ring A is selected from C3-10 carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, -N02, and -CN; andC1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, - C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, =0, =N(R14), -N02, and -CN.

74. The compound or salt of claim 73, wherein Ring A is C3-10 carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -NO2, and -CN; andC1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, - C(O)OR14, -OC(O)R14, =0, -N02, and -CN.

75. The compound or salt of claim 74, wherein Ring A is phenyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -N02, and -CN;and Ci-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R14)2, =0, -NO2, and -CN.

76. The compound or salt of claim 75, wherein Ring A is phenyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, Ci-6 alkyl, and Ci-6 haloalkyl.

77. The compound or salt of claim 75, wherein Ring A is phenyl optionally substituted with one or more substituents independently selected from halogen, -OR14, Ci-6 alkyl, and Ci-6 haloalkyl.

78. The compound or salt of claim 76, wherein Ring A is selected from80. The compound or salt of any one of claims 1 to 64, wherein Ring A is selected from81. The compound or salt of any one of claims 1 to 64, wherein Ring A is selected from82. The compound or salt of any one of claims 1-72, wherein the structure of Formula (I), Formula (II), or Formula (III) is represented by the structure of Formula (IV):or a pharmaceutically acceptable salt thereof.

83. The compound or salt of any one of claims 1-82, wherein L1, L2, L3, and L4are each independently selected from (a), (b), and (c):(a) -O-, -N(R15)-, -N(R15)C(O)-, -N(R15)C(O)O-, -N(R15)N(R15)-, - N(R15)C(O)N(R15)-, and -N(R15)C(O)N(R15)N(R15)-;(b) Ci-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, any of which is optionally substituted with one or more substituents independently selected halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, - N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, =0, =N(R15), -N02, and -CN; and(c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -N(R15)2, -C(0)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(0)0R15, -0C(0)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, =0, =N(R15), -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, - C(0)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(0)0R15, -0C(0)R15, - N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, =0, =N(R15), -N02, 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.

84. The compound or salt of claim 83, wherein L1, L2, L3, and L4are each independently selected from (a), (b), and (c):(a) -0-, -N(R15)-, -N(R15)C(0)-, -C(O)OR15-, and -OC(O)R15-;(b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, any of which is optionally substituted with one or more substituents independently selected halogen, -OR15,-N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, =0, -N02, and -CN; and(c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -N(R15)2, -C(0)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(0)0R15, -0C(0)R15; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, - C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, =0, -N02, and -CN.

85. The compound or salt of claim 84, wherein L1, L2, L3, and L4are each independently selected from (a), (b), and (c):(a) -0-, -N(R15)-, -N(R15)C(0)-, -C(O)OR15-, and -OC(O)R15-;(b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, any of which is optionally substituted with one or more substituents independently selected halogen, -OR15, -N(R15)2, =0, -N02, and -CN; and(c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -N(R15)2, -N02, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, - OR15, -N(R15)2, =0, -N02, and -CN.

86. The compound or salt of claim 85, wherein L1, L2, L3, and L4are each independently selected from (a), (b), and (c):(a) -0-, -N(R15)-, and -N(R15)C(0)-,(b) C1-6 alkylene optionally substituted with one or more substituents independently selected halogen, -OR15, -N(R15)2, =0, -N02, and -CN; and(c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -N02, -CN, C1-6 alkyl, and C1-6 haloalkyl.

87. The compound or salt of claim 86, wherein L1, L2, L3, and L4are each independently selected from (a), (b), and (c):(a) -N(R15)-, and -N(R15)C(0)-;(b) C1-6 alkylene and C1-6 haloalkylene; and(c) C3-6 carbocyclene and 3- to 6-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, Ci-6 alkyl, and C1-6 haloalkyl.

88. The compound or salt of any one of claims 1-87, wherein L4is absent.

89. The compound or salt of any one of claims 1-88, wherein L3is absent.

90. The compound or salt of any one of claims 1-83, wherein L2is selected from C3-10 carbocyclene and 3- to 10-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, - C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, - N(R15)C(O)N(R15)2, =0, =N(R15), -NO2, -CN, CI-6alkyl, and Ci-6haloalkyl.

91. The compound or salt of claim 90, wherein L2is 3- to 6-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -NO2, -CN, Ci-6alkyl, and Ci-6haloalkyl.

92. The compound or salt of claim 91, wherein L2is 5- to 6-membered heterocyclene optionally substituted with one or more substituents independently selected from halogen, - OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -NO2, -CN, Ci-6alkyl, and Ci-6haloalkyl.

93. The compound or salt of claim 91, wherein L2is piperidinylene, piperazinylene, and azetidinylene, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -NO2, -CN, Ci-6 alkyl, and Ci-6 haloalkyl.

94. The compound or salt of claim 92, wherein L2is piperidinylene optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, - C(O)N(R15)2, -NO2, -CN, Ci-6 alkyl, and Ci-6 haloalkyl.

95. The compound or salt of claim 93, wherein L2is piperidinylene, piperazinylene, and azetidinylene, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -NO2, -CN, C1-3 alkyl, and C1-3 haloalkyl.

96. The compound or salt of claim 94, wherein L2is piperidinylene optionally substituted with one or more substituents independently selected from halogen, -OR15, -NO2, -CN, C1-3 alkyl, and C1-3 haloalkyl.

97. The compound or salt of claim 95, wherein L2is selected from piperidinylene, piperazinylene, and azetidinylene, any of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, and C1-3 haloalkyl.

98. The compound or salt of claim 96, wherein L2is piperidinylene optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, and C1-3 haloalkyl.

99. The compound or salt of claim 97, wherein L2is selected from100. The compound or salt of claim 98, wherein L2is selected from101. The compound or salt of claim 83, wherein L2is C3-6 carbocyclene, optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -NO2, -CN, C1-6 alkyl, and Ci-6haloalkyl.

102. The compound or salt of claim 101, wherein L2is C3-6 carbocyclene optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -NO2, -CN, C1-6 alkyl, and Ci-6haloalkyl.

103. The compound or salt of claim 102, wherein L2is phenylene optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, - C(O)N(R15)2, -NO2, -CN, Ci-6 alkyl, and Ci-6 haloalkyl.

104. The compound or salt of claim 103, wherein L2is phenylene optionally substituted with one or more substituents independently selected from halogen, -OR15, -NO2, -CN, C1-3 alkyl, and C1-3 haloalkyl.

105. The compound or salt of claim 104, wherein L2is phenylene optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, and C1-3 haloalkyl.

106. The compound or salt of claim 105, wherein L2is phenylene.

107. The compound or salt of any one of claims 1-89, wherein L2is absent.

108. The compound or salt of any one of claims 107, wherein L1is selected from C3-10 carbocyclene and 3- to 10-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, - C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, - N(R15)C(O)N(R15)2, =0, =N(R15), -NO2, -CN, CI-6alkyl, and Ci-6haloalkyl.

109. The compound or salt of claim 108, wherein L1is 3- to 10-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -NO2, -CN, Ci-6 alkyl, and Ci-6 haloalkyl.

110. The compound or salt of claim 109, wherein L1is 3- to 6-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -NO2, -CN, Ci-6 alkyl, and Ci-6 haloalkyl.

111. The compound or salt of claim 110, wherein L1is 3- to 6-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, Ci-6 alkyl, and Ci-6 haloalkyl.

112. The compound or salt of claim 111, wherein L1is selected fromand113. The compound or salt of any one of claims 1-106, wherein L1is selected from -N(R15)-, - N(R15)C(O)-, and C1-3 alkylene.

114. The compound or salt of claim 113, wherein L1is selected from -N(R15)-, -N(R15)C(O)-, and C1-3 alkylene; and R15is selected at each occurrence from hydrogen Ci-6 alkyl, and C1-6 haloalkyl.

115. The compound or salt of claim 114, wherein L1is selected from -N(H)-, -N(H)C(O)-, and C1-3 alkylene.

116. The compound or salt of any one of claims 1-115, wherein L is selected from:

117. The compound or salt of any one of claims 1-115, wherein L is selected from:

118. The compound or salt of any one of claims 23-116, wherein R5is selected from - C(O)R16B, -N(R17)C(O)(R16B), -C(O)N(R16B)(R17), and -CN; and Ci-6alkyl substituted with one or more substituents independently selected from -C(O)R16B, -N(R17)C(O)(R16B), - C(O)N(R16B)(R17), and -CN.

119. The compound or salt of claim 118, wherein R5is selected from -C(O)R16B, - N(R17)C(O)(R16B), and-C(O)N(R16B)(R17); and Ci-6 alkyl substituted with one or more substituents independently selected from -C(O)R16B, -N(R17)C(O)(R16B), and -C(O)N(R16B)(R17).

120. The compound or salt of claim 119, wherein R5is selected from -C(O)R16B, - N(R17)C(O)(R16B), and -C(O)N(R16B)(R17); and Ci-6 alkyl substituted with one or more substituents selected from -C(O)R16Band-N(R17)C(O)(R16B).

121. The compound or salt of claim 120, wherein R5is selected from -C(O)R16Band - N(R17)C(O)(R16B); and C1-3 alkyl substituted with one or more substituents selected from - C(O)R16Band -N(R17)C(O)(R16B).

122. The compound or salt of claim 121, wherein R5is selected from -C(O)R16Band C1-3 alkyl substituted with -N(R17)C(O)(R16B); wherein R17is selected from hydrogen, C1-3 alkyl, and C1-3 haloalkyl.

123. The compound or salt of any one of claims 23-122, wherein R16Bis 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.

124. The compound or salt of claim 123, wherein R16Bis 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, -NO2and -CN.

125. The compound or salt of claim 124, wherein R16Bis 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.

126. The compound or salt of claim 125, wherein R16Bis C2-4 alkenyl optionally substituted with one or more substituents independently selected from halogen, -OR18, and -N(R18)2.

127. The compound or salt of claim 126, wherein R16Bis independently selected at each occurrence from C2-4 alkenyl, C2-4 haloalkenyl, and C2-4 alkynyl.

128. The compound or salt of claim 126, wherein R16Bis C2-4 alkenyl.

129. The compound or salt of any one of claims 23-128, wherein R5is selected from130. The compound or salt of any one of claims 23-126 and 128, wherein R5is selected from131. The compound or salt of any one of claims 1-130, wherein the compound is selected from a compound of Table 1, or a pharmaceutically acceptable salt thereof.

132. A pharmaceutical composition comprising a compound or salt of any of claims 1-131 and a pharmaceutically acceptable excipient.

133. 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 1-131, or a pharmaceutical composition of claim 132.

134. A method of modulating activity of mutant AKT1 comprising, administering to a subject in need thereof a compound or salt of any of claims 1-131, or a pharmaceutical composition of claim 132.

135. 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 claims 1-131, or a pharmaceutical composition of claim 132.

136. 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 1-131, or a pharmaceutical composition of claim 132.

137. 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 claims 1-131, or a pharmaceutical composition of claim 132.

138. The method of claim 137, wherein the cancer is selected from breast cancer, colorectal cancer, and meningioma.

139. The method of claim 137, wherein the administration modulates activity of a mutant AKT1.

140. The method of claims 134, 136, or 139, wherein the mutant AKT1 is AKT1 E17K.

141. The method of claim 137, wherein the administration modulates activity of wild-type AKT1.

142. An AKT1 protein covalently bound to a compound or salt of any of claims 1-131, or a pharmaceutical composition of claim 132.

143. The AKT1 protein of claim 142, wherein the AKT1 protein comprises a E17K mutation, a E40K mutation, or a E49K mutation.

144. The AKT1 protein of any one of claims 142-143, wherein the cysteine residue is selected from C296 and C310.

145. The AKT1 protein of claim 144, wherein the cysteine residue is C296.

146. The AKT1 protein of any one of claims 142-145, wherein the AKT1 protein is in vivo.

147. The AKT1 protein of claim 146, 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 a compound or salt of any of claims 1-131, or a pharmaceutical composition of claim 132.

148. The AKT1 protein of claim 147, wherein the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

149. The AKT1 protein of any one of claims 142-148, wherein the covalent bond between the compound and the cysteine residue is an irreversible covalent bond.

150. The AKT1 protein of claim 149, wherein the irreversible covalent bond in the in vivo AKT1 protein is a carbon-sulfur single bond.

151. The AKT1 protein of claim 150, 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 alkene, an alkyne, an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide, and an epoxide group.

152. The AKT1 protein of claim 151, wherein the cysteine susceptible electrophile is selected from: an alkene, an alkyne, an acrylate group, and an acrylamide group.

153. A method of covalently modifying an AKT1 protein, comprising contacting the AKT1 protein with a compound or salt of any of claims 1-131, or a pharmaceutical composition of claim 132 thereby forming a covalent AKT1 adduct.

154. The method of claim 153, wherein the contacting is in vitro.

155. The method of claim 153, wherein the contacting is in vivo.

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