Small molecules to increase NAD levels

Abstract

Provided are compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, or their pharmaceutically acceptable salts for increasing intracellular NAD levels.

Description

SMALL MOLECULES TO INCREASE NAD LEVELSCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 600,547, filed on November 17, 2023. The contents of this application are incorporated herein by reference in its entirety.BACKGROUND

[0002] Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other, nicotinamide. NAD exists in two forms: an oxidized and reduced form, abbreviated as NAD+ and NADH (H for hydrogen), respectively. Some NAD is converted into the coenzyme nicotinamide adenine dinucleotide phosphate (NADP), whose chemistry largely parallels that of NAD, though its predominant role is as a coenzyme in anabolic metabolism. A decline in intracellular NAD is believed to occur in patients as they age and contributes to a wide range of age-related diseases.

[0003] NAD has several essential roles in metabolism. It acts as a coenzyme in redox reactions, as a donor of ADP-ribose moieties in ADP-ribosylation reactions, as a precursor of the second messenger molecule cyclic ADP-ribose. The main role of NAD+ in metabolism is the transfer of electrons from one molecule to another. In addition to these metabolic functions, NAD+ emerges as an adenine nucleotide that can be released from cells spontaneously and by regulated mechanisms, and can therefore have important extracellular roles.

[0004] In recent years, NAD+ has also been recognized as an extracellular signaling molecule involved in cell-to-cell communication. NAD+ is released from neurons in blood vessels, urinary bladder, large intestine, from neurosecretory cells, and from brain synaptosomes, and is proposed to be a novel neurotransmitter that transmits information from nerves to effector cells in smooth muscle organs.Methods to restore or augment NAD levels have applicability across a number of conditions including age-dependent decline in muscle and neuronal function. The rate limiting step in NAD salvage within cells is the enzyme NAMPT. Boosting NAMPT activity with small molecules would therefore be an effective strategy for a wide range of age-related conditions. There is a need in the art for compounds that increase intracellular NAD levels, and the present disclosure satisfies this need. SUMMARY OF THE INVENTION According to one aspect of the present disclosure, described is a compound having a structure of Formula I, or a pharmaceutically acceptable salt thereof:wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;each Cy1is independently selected from the group consisting C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; andeach Rgis independently selected from the group consisting OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. According to another aspect of the present disclosure, described is a compound having a structure of Formula II, or a pharmaceutically acceptable salt thereof:wherein: X1is CH or N;X2is CH2, NH, O, or S; R12, R13, R14, R15, R16, R17, R18, and R19are each independently selected from H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. According to one aspect of the present disclosure, described is a compound having a structure of Formula III, or a pharmaceutically acceptable salt thereof:wherein: R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30and are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl,aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. According to one aspect of the present disclosure, described is a compound having a structure of Formula IV, or a pharmaceutically acceptable salt thereof:wherein: R31, R32, R33, R34, R35, R36, R37, R38, R39, and R40are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; andeach Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. According to one aspect of the present disclosure, described is a compound having a structure of Formula V, or a pharmaceutically acceptable salt thereof:wherein: R41, R42, R43, R44, R45, R46, and R47are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, or R41and R42, together with the nitrogen atom to which they are attached, form a 4-15-membered heterocycloalkyl; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-20 aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. According to one aspect of the present disclosure, described is a compound having a structure of Formula VI, or a pharmaceutically acceptable salt thereof:wherein: R48, R49, R50, R51, R52, R53, and R54are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; or wherein R53and R54taken together form an optionally substituted 5-10 membered heterocycloalkyl or an optionally substituted 5-10 membered heteroaryl; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. According to one aspect of the present disclosure, described is a compound having a structure of Formula VII, or a pharmaceutically acceptable salt thereof:wherein: R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, and R65are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1,NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; or wherein R60and R61taken together form an optionally substituted 5-10 membered heterocycloalkyl or an optionally substituted 5-10 membered heteroaryl; Ar1is selected from the group consisting of C6-10aryl, C6-10aryloxy, and 5-10 membered heteroaryl; X3is selected from the group consisting of CO and SO2; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. According to another aspect of the present disclosure, described is a compound having a structure of Formula VIII, or a pharmaceutically acceptable salt thereof:wherein: R66, R67, R68, R69, and R70are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; or wherein R53and R54taken together form an optionally substituted 5-10 membered heterocycloalkyl or an optionally substituted 5-10 membered heteroaryl; Ar2is selected from the group consisting of C6-10aryl, C6-10aryloxy, and 5-10 membered heteroaryl; X3is selected from the group consisting of C2-6alkenyl, CO, and NH; X4is selected from the group consisting of CO and NH; X5is selected from the group consisting of C2-6alkenyl, CO, and NH; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independentlyselected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they areattached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; p is 0 or 1; q is 0 or 1; r is 0 or 1; and s is 0 or 1. According to yet another aspect of the present disclosure, described is a compound having a structure of Formula IX, or a pharmaceutically acceptable salt thereof:wherein: R71, R72, R73, R74, R75, R76, R77, R78, R79, R80, R81, R82, R83, and R84are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4- 10 membered heterocycloalkyl)-C1-4alkylene, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; or wherein R53and R54taken together form an optionally substituted 5-10 membered heterocycloalkyl or an optionally substituted 5-10 membered heteroaryl; X7is selected from the group consisting of CR85R86, CO, SO2, and N, wherein R85and R86form a three-membered ring with the carbon atom to which they are attached; X8is selected from the group consisting of CH and N; X9is selected from the group consisting of CH and N; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independentlyselected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they areattached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. According to one aspect of the present disclosure, provided are methods for increasing nicotinamide adenine dinucleotide (NAD) levels in a mammal, and / or for increasing nicotinamide phosphoribosyltransferase (NAMPT) activity within the mammal, the method comprising administering to the mammal an effective amount of any one of the compounds described herein. Both the foregoing summary and the following description of the drawings and detailed description are exemplary and explanatory. They are intended to provide further details of the disclosure, but are not to be construed as limiting. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the disclosure.BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIGs. 1A-1E are the NAMPT activator discovery process. FIG. 1A. A GETS A based HTS screen on potential NAMPT binders using a Chemdiv 100k compound library. FIG. 1B. Top hits from initial screen were tested in dose course in OVCAR WT and NAMPT KO cells to measure NAD level. FIG. 1C. Top three hits from B were selected and their analogs were identified from chemical space, total -700 SAR compounds were assayed similar to (B), their EC25s were calculated and grouped into histograms. FIG. 1D. Top three hits are repeated in fine dose course response in OVCAR WT and NAMPT KO cells to measure NAD level. FIG. 1E. Human IPSC cells were cultured in 384 well plate, treated with the top three hits over a dose course for 18h. Cells were then washed and assayed for NAD levels.

[0019] FIG.2 shows a summary of the NAMPT activator structure activity relationship (SAR).

[0020] FIG. 3 shows that ZE76-0087 potently increase NAD in NAMPT independent manner, with Wild Type (WT) cell results shown in FIG. 3 A and NAMPT KO cell results shown in FIG. 3B.

[0021] FIGs. 4A and B show compound efficacy in cellular NAD assay using myotube (FIG. 4A) and NASH (FIG. 4B) patient hepatocytes.

[0022] FIGs. 5A and B show compound efficacy in cellular NAD assay using OVCAR5 WT and NAMPT KO cells and mouse GT1-7 cell line.

[0023] FIGs. 5C and D show representative image of cultured human IPSC neuron (beta-III- tubulin staining, FIG. 5C) and compound efficacy in cellular NAD assay (FIG. 5D).DETAILED DESCRIPTIONI. Overview

[0024] The present invention is directed to the discovery of new compounds that increase intracellular NAD levels, either through an NAMPT-dependent pathway or through an NAMPT- independent pathway.

[0025] A decline in intracellular NAD is believed to occur in patients as they age and contribute to a wide range of age-related diseases. Methods to restore or augment NAD levels would therefore have applicability across a number of conditions including age-dependent decline in muscle and neuronal function. The rate limiting step in NAD salvage within cells is the enzyme NAMPT. Boosting NAMPT activity with small molecules would therefore be an effective strategy for a wide range of age-related conditions. Described herein are molecules that augment NAD levels. The activity of certain molecules is through a NAMPT -dependent pathway, while other molecules described increase NAD levels through NAMPT-independent means.

[0026] Described herein are compounds having the ability to increase NAMPT activity within cells and / or within a mammal, formulations comprising one or more compounds having the ability to increase NAMPT activity within cells and / or within a mammal, methods for making one or more compounds, or formulations comprising the same, having the ability to increase NAMPT activity within cells and / or within a mammal, methods for increasing NAMPT activity within cells and / or within a mammal, and methods for treating mammals (e.g., humans) having a condition responsive to an increase of NAMPT activity.

[0027] Suitable examples of conditions responsive to an increase of NAMPT activity within cells and / or within a mammal include, without limitation, traumatic nerve injuries (e.g., a neuronal crush injury, a traumatic brain injury, chronic traumatic encephalopathy (CTE), or concussion), neuropathies (e.g., a chemotherapeutic-induced sensory neuropathy or diabetic neuropathy), neurodegenerative diseases, disorders, or conditions (e.g., amyotrophic lateral sclerosis, multiple sclerosis, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, Friedreich’s ataxia, Lewy body disease, spinal muscular atrophy, frontotemporal dementia, or cerebellar degeneration), central demyelinating disorders (e.g., multiple sclerosis, adrenoleukodystrophy, adrenomyeloneuropathy, Leber hereditary optic neuropathy, neuromyelitis optica, or acute disseminated encephalomyelitis), peripheral demyelinating disorders (e.g., Charcot-Marie-Tooth disease or Guillain-Barre syndrome), other primarily inflammatoiy neuropathies (e.g., a multifocal motor neuropathy, an anti-MAG neuropathy, or a chronic inflammatory demyelinating polyneuropathy), glaucoma, ischemic injuries, retinal andoptic nerve ischemia, and stroke. Other conditions that can be treated using one or more of the compounds described herein include, without limitation, age-related vision or hearing loss, hepatosteatosis, insulin resistance syndromes and their associated manifestations, obesity, sarcopenia, disorders of inflammation and / or auto-immunity, skin aging, skin cancer development or progression, cardiovascular diseases, heart failure, acute and / or chronic kidney injury, and infertility. In some embodiments, overall lifespan can be prolonged using one or more of the compounds described herein. n. Experimental Results

[0028] As detailed in the Examples below, several exemplary compounds exhibiting high potency and efficacy as small molecule NAMPT activators were identified. A cellular thermal shift (CETSA)-based high throughput screening (HTS) platform was used to identify potential NAMPT binders having a strong NAMPT GETS A signal. Ten initial compounds were identified, as shown in FIG IB: (1) 4019-0025, (2) E207-0877, (3) L036-2269, (4) G395-1397, (4) F738- 0043, (6) G800-0245, (7) G395-1209, (8) L036-2268, (9) K783-0604, and (10) G395-1301.

[0029] The three most potent compounds from this assay, 4019-0025, E207-0877 and L036- 0389, were further analyzed, and the structure of each of these three compounds is shown below and in FIG. 1C:

[0030] All of these compounds were found to increase NAD+ levels in a relevant human target cell (FIG. ID). Through a further compound screen, compounds that that share similar scaffolds to 4019-0065, E207-0877 and L036-0389 were identified, namely ZE76-0003, ZE76-0092, and ZE76-0123. These compounds were found to have <500nM IC25 in cellular efficacy and are metabolically stable.

[0031] A further class of molecule that increases cellular NAD in a NAMPT independent manner was also identified, and a representative lead compound for this class is designated ZE76-0087. The structure of this compound is shown below:

[0032] In the activity assays, the concentration needed to increase intracellular NAD+ by 25% was calculated. The rationale of choosing this threshold is that in general, aging causes a -40% decrease in tissue NAD+ levels. As such, a 25% increase in NAD equals an approximate 50% recovery in NAD+ levels, which is believed likely biologically meaningful. The biological assays confirmed the efficacy of the compounds designated as 4019-0065, E207-0877, L036- 0389, ZE76-0087, ZE76-0003, ZE76-0092, and ZE76-0123 in NAD assays.III. Compounds

[0033] Provided herein are compounds that increase intracellular NAD levels. The compounds described herein increase NAD levels either through an NAMPT-dependent pathway or through an NAMPT-independent pathway.

[0034] In an aspect, the compounds described herein have a structure of Formula I, or a pharmaceutically acceptable salt thereof:wherein:R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, for the compound of Formula (I): (a) R1, R2, R3, R4, R6, R7, and R9are each H; (b) R5is OH; (c) R8is C1-6alkyl; and (d) R10is ORa1or Cy1. In some embodiments,R8is C1alkyl. In some embodiments, R10is a 5 membered heteroaryl. In some embodiments,R10isIn some embodiments, R10is OCH3. The compound of Formula (I) may have one of the following structures:In an aspect, the compounds described herein have a structure of Formula II, or a pharmaceutically acceptable salt thereof:wherein: X1is CH or N; X2is CH2, NH, O, or S; R12, R13, R14, R15, R16, R17, R18, and R19are each independently selected from H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1,C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, for the compound of Formula (II): (a) X1is N or CH; (b) X2is O or NH; (c) R12is C1alkyl; (d) R13, R14, R15, R16, R18, and R19are each H; and (e) R17is C1alkyl or C1haloalkyl. In some embodiments, for the compound of Formula (II): (a) X1is N; (b) X2is O; (c) R12is C1alkyl; (d) R13, R14, R15, R16, R18, and R19are each H; and (e) R17is C1alkyl. In some embodiments, for the compound of Formula (II): (a) X1is CH; (b) X2is NH; (c) R12is C1alkyl; (d) R13, R14, R15, R16, R18, and R19are each H; and (e) R17is C1haloalkyl. In some embodiments, R17is CF3.The compound of Formula (II) may have one of the following structures:In an aspect, the compounds described herein have a structure of Formula III, or a pharmaceutically acceptable salt thereof:wherein: R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30and are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1;wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, for the compound of Formula (III): (a) R20is C1-6alkyl; (b) R21, R22, R23, R24, R25, R26, R28, R29are each H; (c) R27is H or C1-6alkyl; (d) R30is a (4-10 membered heterocycloalkyl)-C1-4alkylene optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg. In some embodiments, for the compound of Formula (III): (a) R20is C1alkyl; (b) R21, R22, R23, R24, R25, R26, R28, R29are each H; (c) R27is C1alkyl; (d) R30is a (6 membered heterocycloalkyl)-C3alkylene. In some embodiments, for the compound of Formula (III): (a) R20is C1alkyl; (b) R21, R22, R23, R24, R25, R26, R28, R29are each H; (c) R27is H; (d) R30is a (5 membered heterocycloalkyl)-C1alkylene substituted with 1 substituents independently selected from Rg. In some embodiments, Rgis C4alkyl.The compound of Formula (III) may have one of the following structures:. In an aspect, the compounds described herein have a structure of Formula IV, or a pharmaceutically acceptable salt thereof:wherein: R31, R32, R33, R34, R35, R36, R37, R38, R39, and R40are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; andeach Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, for the compound of Formula (IV): (a) R31is halo; (b) R32, R33, R34, R37, R38, R39are each H; (c) R35and R36are each C1-6alkyl; and (d) R40is (5-10 membered heteroaryl)-C1-4alkylene. In some embodiments, for the compound of Formula (IV): (a) R35and R36are each C1alkyl; and (b) R40is (5 membered heteroaryl)-C1alkylene. In someembodiments, R40 isThe compound of Formula (IV) may have the following structure:.In an aspect, the compounds described herein have a structure of Formula V, or a pharmaceutically acceptable salt thereof:wherein: R41, R42, R43, R44, R45, R46, and R47are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, or R41and R42, together with the nitrogen atom to which they are attached, form a 4-15-membered heterocycloalkyl;wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-20aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, for the compound of Formula (V): (a) R41is C6aryl-C1alkylene; (b) R42is methyl; (c) R43, R44, R45, and R46are each H; and (d) R47is C(O)NRc1Rd1, wherein Rc1is H and Rd1is C6-20aryl. In some embodiments, R47isIn some embodiments, for the compound of Formula (V): (a) R41and R42are each C6aryl-C1alkylene; (b) R43, R44, R45, and R46are each H; and (c) R47is NRc1C(O)Rb1, wherein Rc1is H and Rb1is C1alkyl.

[0049] The compound of Formula (V) may have one of the following structures:

[0050] In an aspect, the compounds described herein have a structure of Formula VI, or a pharmaceutically acceptable salt thereof:wherein: R48, R49, R50, R51, R52, R53, and R54are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; or wherein R53and R54taken together form an optionally substituted 5-10 membered heterocycloalkyl or an optionally substituted 5-10 membered heteroaryl; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1,S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, for the compound of Formula (VI): (a) R48and R49are each methyl; (b) R50, R51, and R52are each H; and (c) R53and R54taken together form an optionally substituted 6-membered heterocycloalkyl ring. In some embodiments, R53and R54taken together form a substituted 6-membered heterocyclic ring having the following structure:. The compound of Formula (VI) may have one of the following structures:

[0053] In an aspect, the compounds described herein have a structure of Formula VII, or a pharmaceutically acceptable salt thereof:wherein: R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, and R65are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; or wherein R60and R61taken together form an optionally substituted 5-10 membered heterocycloalkyl or an optionally substituted 5-10 membered heteroaryl; Ar1is selected from the group consisting of C6-10aryl, C6-10aryloxy, and 5-10 membered heteroaryl; X3is selected from the group consisting of CO and SO2; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independentlyselected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they areattached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments, for the compound of Formula (VII): (a) R55, R56, R57, R58, and R59are each H; (b) R60and R61taken together form an optionally substituted 6-membered heterocycloalkyl ring; (c) R62is methyl; (d) R63is H; (e) R64is branched C4alkyl; and (f)Ar1is optionally substituted aryl. In some embodiments, R60and R61taken together form a 6-membered heterocycloalkyl ring having the following structure:In some embodiments, Ar1is

[0055] The compound of Formula (VII) may have one of the following structures:-91-In an aspect, the compounds described herein have a structure of Formula VIII, or a pharmaceutically acceptable salt thereof:wherein: R66, R67, R68, R69, and R70are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; or wherein R53and R54taken together form an optionallysubstituted 5-10 membered heterocycloalkyl or an optionally substituted 5-10 membered heteroaryl; Ar2is selected from the group consisting of C6-10aryl, C6-10aryloxy, and 5-10 membered heteroaryl; X3is selected from the group consisting of C2-6alkenyl, CO, and NH; X4 is selected from the group consisting of CO and NH; X5is selected from the group consisting of C2-6alkenyl, CO, and NH; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; p is 0 or 1;q is 0 or 1; r is 0 or 1; and s is 0 or 1.

[0057] The compound of Formula (VIII) may have one of the following structures:In an aspect, the compounds described herein have a structure of Formula IX, or a pharmaceutically acceptable salt thereof:wherein: R71, R72, R73, R74, R75, R76, R77, R78, R79, R80, R81, R82, R83, and R84are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; or wherein R53and R54taken together form an optionally substituted 5-10 membered heterocycloalkyl or an optionally substituted 5-10 membered heteroaryl; X7is selected from the group consisting of CR85R86, CO, SO2, and N, wherein R85and R86form a three-membered ring with the carbon atom to which they are attached; X8is selected from the group consisting of CH and N; X9is selected from the group consisting of CH and N; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy.

[0059] The compound of Formula (IX) may have one of the following structures:

[0060] In some embodiments, a salt of any one of the compounds disclosed herein is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

[0061] In some embodiments, acids commonly employed to form pharmaceutically acceptable salts of the compounds disclosed herein include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bi sulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne- 1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenyl acetate, phenylpropionate, phenylbutyrate, citrate, lactate, P -hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0062] In some embodiments, bases commonly employed to form pharmaceutically acceptable salts of the compounds disclosed herein include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributylamine; pyridine; N-methyl, N- ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2- OH-(C1-C6)- alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2- hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like.

[0063] In some embodiments, any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, is substantially isolated.IV. Methods of treatment

[0064] Also provided herein are methods for increasing nicotinamide adenine dinucleotide (NAD) levels in a mammal, and / or for increasing nicotinamide phosphoribosyltransferase (NAMPT) activity within the mammal, the method comprising administering to the mammal an effective amount of a compound described herein.

[0065] In some embodiments, the compound increases NAD levels in a mammal through a NAMPT dependent pathway. In some embodiments, the compound increases NAD levels in a mammal by increasing NAMPT levels in the mammal.

[0066] In some embodiments, the compound increases NAD levels in a mammal through a NAMPT independent pathway.

[0067] In some embodiments, the method results in NAD levels increasing, as compared to the levels present prior to treatment, by about 20% to 150%.

[0068] In some embodiments, the method results in NAMPT activity increasing, as compared to the levels present prior to treatment, by about 20% to 150%.

[0069] In some embodiments, the method for increasing NAMPT activity within a cell includes contacting the cell with one or more compounds provided herein, or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, methods for increasing NAMPT activity within cells can be performed in vivo. For example, one or more compounds provided herein can be administered to a mammal (e.g., a human) to increase NAMPT activity within cells within that mammal.

[0071] In some embodiments, methods for increasing NAMPT activity within cells can be performed in vitro. For example, one or more compounds provided herein can be added to a cell culture containing cells (e.g., human cells) to increase NAMPT activity within those cells. In some embodiments, such intervention can improve the quality of the cell while in culture or subsequently.

[0072] In some embodiments, the methods for increasing NAMPT activity within a mammal include administering one or more compounds provided herein to the mammal. For example, one or more cytokine activities of NAMPT can be increased within a mammal by administering one or more compounds provided herein to the mammal.

[0073] Provided herein are methods for increasing NAD+levels within a cell (e.g., a neuron). Such methods can comprise administering, to a mammal (e.g., a human) containing the cell, a therapeutically effective amount of any one or more of the compounds described herein or a pharmaceutical composition containing same.

[0074] In some embodiments, the mammal is a human. In some embodiments, the mammal has a condition and / or disease characterized by dysregulation of cellular NAD+levels.

[0075] In some embodiments, NAD levels are measured by liquid chromatography coupled to mass spectrometry (LC-MS) or enzymatic assays.

[0076] In some embodiments, NAMPT activity is measured by a multicoupled fluorometric assay.

[0077] Provided are methods for treating (or preventing) a disease, disorder, or condition responsive to an increase in a NAMPT activity (thereby increasing NAD+levels within a cell (e.g., a neuron)). Such methods can comprise administering, to a mammal (e.g., a human) having the disease, disorder, or condition, a therapeutically effective amount of any one or more of the compounds described herein or a pharmaceutical composition comprising same.

[0078] Provided are methods for treating diseases, disorders, and conditions in a mammal by administering one or more compounds provided herein to a mammal in need thereof. In some embodiments, the disease, disorder, or condition being treated can be a disease, disorder, orcondition that is responsive to increasing NAMPT activity within cells and / or within the mammal. Examples of diseases, disorders, and conditions that can be treated with one or more compounds provided herein include, without limitation, traumatic nerve injuries (e.g., a neuronal crush injury, a traumatic brain injury, chronic traumatic encephalopathy (CTE), or concussion), neuropathies (e.g., a chemotherapeutic-induced sensory neuropathy or diabetic neuropathy), neurodegenerative diseases, disorders, or conditions (e.g., amyotrophic lateral sclerosis, multiple sclerosis, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, Friedreich’s ataxia, Lewy body disease, spinal muscular atrophy, frontotemporal dementia, or cerebellar degeneration), central demyelinating disorders (e.g., multiple sclerosis, adreno leukodystrophy, adrenomyeloneuropathy, Leber hereditary optic neuropathy, neuromyelitis optica, or acute disseminated encephalomyelitis), peripheral demyelinating disorders (e.g., Charcot-Marie-Tooth disease or Guillain-Barre syndrome), other primarily inflammatory neuropathies (e.g., a multifocal motor neuropathy, an anti-MAG neuropathy, or a chronic inflammatory demyelinating polyneuropathy), glaucoma, ischemic injuries, retinal and optic nerve ischemia, and stroke. Additional examples of diseases, disorders, and conditions that can be treated with one or more compounds provided herein include, without limitation, conditions pre-disposing to age-related vision or hearing loss, hepatosteatosis (e.g., NAFLD or NASH), insulin resistance syndromes and their associated manifestations (e.g., diabetic neuropathy, diabetic nephropathy, and diabetic retinopathy), obesity, sarcopenia and other acquired or genetic diseases of muscle weakness (e.g., inherited muscular dystrophies), disorders of inflammation and / or auto-immunity (e.g., systemic lupus erythematosus, rheumatoid arthritis, and related conditions), skin aging, skin cancer (e.g., basal cell carcinoma) development or progression, cardiovascular diseases (e.g., heart failure, atherosclerotic vascular disease, or related complications), acute or chronic kidney injuries (e.g., acute or chronic kidney injury initiated by genetic pre-disposition or environmental exposure), and infertility (e.g., female infertility or male infertility). In some embodiments, overall lifespan can be prolonged using one or more of the compounds described herein. In some embodiments, skin cancer (e.g., basal cell carcinoma) can be prevented using one or more of the compounds described herein.

[0079] In some embodiments: (a) the traumatic nerve injury is selected from the group consisting of a neuronal crush injury, a traumatic brain injury, chronic traumatic encephalopathy (CTE), and concussion; b) the neuropathy is selected from the group consisting of a chemotherapeutic-induced sensory neuropathy and diabetic neuropathy; (c) the neurodegenerative diseases, disorders, or conditions is selected from the group consisting of amyotrophic lateral sclerosis, multiple sclerosis, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, Friedreich’s ataxia, Lewy body disease, spinal muscular atrophy, frontotemporal dementia, and cerebellar degeneration; (d) the central demyelinating disorders is selected from the group consisting of multiple sclerosis, adrenoleukodystrophy, adrenomyeloneuropathy, Leber hereditary optic neuropathy, neuromyelitis optica, and acute disseminated encephalomyelitis; (e) the peripheral demyelinating disorder is selected from the group consisting of Charcot-Marie-Tooth disease and Guillain-Barre syndrome; and (f) the primarily inflammatory neuropathy is selected from the group consisting of a multifocal motor neuropathy, an anti-MAG neuropathy, and a chronic inflammatory demyelinating polyneuropathy.

[0080] In some embodiments, one or more compounds provided herein can be used as described herein (e.g., to increase NAMPT activity within cells and / or within a mammal and / or to treat a disease, disorder, or condition as described herein) as the sole active ingredient(s). For example, a composition containing a compound described herein, can lack any other active ingredients that increase NAMPT activity within cells and / or a mammal. In some embodiments, a composition containing a compound set forth in Formula (I), or a pharmaceutically acceptable salt thereof, can lack any other active ingredients that are effective to treat a disease, disorder, or condition as described herein.V. Methods of making the therapeutic compounds

[0081] Compounds as set forth in any one of the Formulae disclosed herein, including salts thereof, can be prepared using organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. A person skilled in the art knows how to select and implement appropriate synthetic protocols and appreciates that a broad repertoire of syntheticorganic reactions is available to be potentially employed in synthesizing compounds provided herein. Suitable synthetic methods of starting materials, intermediates, and products can be identified by reference to the literature, including reference sources such as: Advances in Heterocyclic Chemistry, Vols. 1-107 (Elsevier, 1963-2012); Journal of Heterocyclic Chemistry Vols.1-49 (J. Heterocyclic Chemistry, 1964-2012); Carreira et al., (Ed.) Science of Synthesis, Vols.1-48 (2001-2010) and Knowledge Updates KU2010 / 1-4; 2011 / 1-4; 2012 / 1-2 (Thieme, 2001-2012); Katritzky et al., (Ed.) Comprehensive Organic Functional Group Transformations, (Pergamon Press, 1996); Katritzky et al., (Ed.) Comprehensive Organic Functional Group Transformations II (Elsevier, 2ndEdition, 2004); Katritzky et al., (Ed.) Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984); Katritzky et al., Comprehensive Heterocyclic Chemistry II, (Pergamon Press, 1996); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6thEd. (Wiley, 2007); Trost et al. (Ed.) Comprehensive Organic Synthesis (Pergamon Press, 1991). The reactions for preparing the compounds provided herein can be carried out in suitable solvents that can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures that can range from the solvent’s freezing temperature to the solvent’s boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan. Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in P. G. M. Wuts and T. W. Greene, Protective Groups in Organic Synthesis, 4thEd., Wiley & Sons, Inc., New York (2006). VI. Pharmaceutical compositions and formulations

[0084] Provided herein are pharmaceutical compositions comprising an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. The pharmaceutical composition also can comprise any one of the additional therapeutic agents and / or therapeutic molecules described herein. The carrier(s) are “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.

[0085] Pharmaceutically acceptable carriers, adjuvants, and vehicles that can be used in the pharmaceutical compositions provided herein include, without limitation, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0086] The compositions or dosage forms can contain any one or more of the compounds or therapeutic agents described herein in the range of 0.005 percent to 100 percent with the balance made up from the suitable pharmaceutically acceptable carriers or excipients. The contemplated compositions can contain from about 0.001 percent to about 100 percent (e.g., from about 0.1 percent to about 95 percent, from about 75 percent to about 85 percent, or from about 20 percent to about 80 percent) of any one or more of the compounds or therapeutic agents provided herein, wherein the balance can be made up of any pharmaceutically acceptable carrier or excipient described herein, or any combination of these carriers or excipients.VII. Routes of administration and dosage forms

[0087] The therapeutic compounds and / or pharmaceutical compositions provided herein (e.g., a composition containing one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof) can include those suitable for any acceptable route of administration.Acceptable routes of administration include, without limitation, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracistemal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, vaginal, intravitreal, subretinal or other intraocular routes of administrations.

[0088] Compositions and formulations described herein can conveniently be presented in a unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and can be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed. 2000). Such preparative methods include, without limitation, the step of bringing into association with the molecule to be administered ingredients such as a carrier that constitutes one or more accessory ingredients. In general, the compositions can be prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0089] In some embodiments, any one or more of the compounds or therapeutic agents described herein can be administered orally. Compositions described herein that are suitable for oral administration can be presented as discrete units such as capsules, sachets, granules, or tablets each containing a predetermined amount (e.g., effective amount) of the active ingredient(s); a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus. Soft gelatin capsules can be useful for containing such suspensions, which can beneficially increase the rate of compound absorption. In the case of tablets for oral use, carriers that are commonly used include, without limitation, lactose, sucrose, glucose, mannitol, silicic acid, andstarches. Other acceptable excipients can include, without limitation, (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as carb oxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (1) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For oral administration in a capsule form, useful diluents include, without limitation, lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient(s) can be combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents can be added. Compositions suitable for oral administration include, without limitation, lozenges comprising ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient(s) in an inert basis such as gelatin and glycerin, or sucrose and acacia.

[0090] Compositions suitable for parenteral administration include, without limitation, aqueous and non-aqueous sterile injection solutions or infusion solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous sterile suspensions that may include suspending agents and thickening agents. The formulations can be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injections, saline (e.g., 0.9% saline solution), or 5% dextrose solution, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets. The injection solutions can be in the form of, for example, a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. A sterile injectable preparation also can be a sterile injectable solution or suspension in a non-toxicparenterally- acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer’s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils can be used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used including, without limitation, synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives can be used to prepare injectables. In some embodiments, natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxy ethylated versions, can be used to prepare injectables. These oil solutions or suspensions also can contain a long-chain alcohol diluent or dispersant.

[0091] In some embodiments, a therapeutic compound and / or pharmaceutical composition provided herein can be administered in the form of suppository for rectal administration. These compositions can be prepared by mixing a compound described herein (e.g., any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof) with a suitable nonirritating excipient that is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active component(s). Such materials include, without limitation, cocoa butter, beeswax, and polyethylene glycols.

[0092] In some embodiments, a therapeutic compound and / or pharmaceutical composition provided herein can be administered by nasal aerosol or inhalation. Such compositions can be prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bio availability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. See, for example, U.S. Patent No. 6,803,031. Additional formulations and methods for intranasal administration are found in Ilium, L., J. Pharm.Pharmacol., 56:3-17 (2004); and Ilium, L., Eur. J. Pharm. Sci., 11:1 -18 (2000).

[0093] In some embodiments, a therapeutic compounds and / or pharmaceutical composition provided herein can be prepared as a topical composition and used in the form of an aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, soap, or other formscommonly employed in the art of topical administration and / or cosmetic and skin care formulation. The topical compositions can be in an emulsion form. Topical administration of a therapeutic compounds and / or pharmaceutical composition provided herein can be useful when the desired treatment involves areas or organs readily accessible by topical application. In some embodiments, a topical composition can include a combination of any one or more of the compounds or therapeutic agents described herein (e.g., a compound set forth in any one of Formulae disclosed herein, or a pharmaceutically acceptable salt thereof), and one or more additional ingredients, carriers, excipients, or diluents including, without limitation, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, coloring agents / pigments, emollients (moisturizers), emulsifiers, film-forming / holding agents, fragrances, leave-on exfoliants, prescription drugs, preservatives, scrub agents, silicones, skin-identical / repairing agents, slip agents, sunscreen actives, surfactants / detergent cleansing agents, penetration enhancers, and thickeners.

[0094] In some embodiments, one or more compounds or therapeutic agent described herein (e.g., any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof) can be incorporated into a composition for coating an implantable medical device such as a prosthesis, artificial valve, vascular graft, stent, or catheter. Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in U.S. Patent Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings can be biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, or mixture thereof. In some embodiments, the coating can optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

[0095] In some embodiments, provided herein is an implantable drug release device impregnated with or containing one or more compounds or therapeutic agents described herein (e.g., any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof) such that the compound(s) or therapeutic agent(s) are released from the device and are therapeutically active.VIII. Dosages and regimens

[0096] A composition (e.g., pharmaceutical compositions provided herein) containing a compound provided herein, or a pharmaceutically acceptable salt thereof, can include that compound in an effective amount (e.g., a therapeutically effective amount).

[0097] Effective doses can vary, depending on the diseases being treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents, and the judgment of the treating physician.

[0098] In some embodiments, an effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, can range, for example, from about 0.1 mg to about 1000 mg. In some embodiments, the effective amount can be from about 0.5 mg to about 500 mg of a compound disclosed herein, or any amount in between these two values, for example, one of about 0.5 mg, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg. The effective amount can be an amount sufficient to alleviate or reduce one or more of the symptoms associated with a disease, disorder, or condition being treated as described herein.

[0099] In some embodiments, an effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, can range, for example, from about 0.001 mg / kg to about 500 mg / kg (e.g., from about 0.001 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 150 mg / kg; from about 0.01 mg / kg to about 100 mg / kg; from about 0.01 mg / kg to about 50 mg / kg; from about 0.01 mg / kg to about 10 mg / kg; from about 0.01 mg / kg to about 5 mg / kg; from about 0.01 mg / kg to about 1 mg / kg; from about 0.01 mg / kg to about 0.5 mg / kg; from about 0.01 mg / kg to about 0.1 mg / kg; from about 0.1 mg / kg to about 200 mg / kg; from about 0.1 mg / kg to about 150 mg / kg; from about 0. 1 mg / kg to about 100 mg / kg; from about 0.1 mg / kg to about 50 mg / kg; from about 0. 1 mg / kg to about 10 mg / kg; from about 0.1 mg / kg to about 5 mg / kg; from about 0.1 mg / kg to about 2 mg / kg; from about 0.1 mg / kg to about 1 mg / kg; from about 0.1 mg / kg to about 0.5 mg / kg, or from about 0.5 mg / kg to about 500 mg / kg).

[0100] In some embodiments, an effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, can be about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, or about 5 mg / kg.

[0101] The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses, e.g., once daily, twice daily, thrice daily) or on anon-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weekly, once every two weeks, or once a month). In some embodiments, the dosages can be administered every 4 hours, 6 hours, 8 hours, 12 hours, or 24 hours.IX. Kits

[0102] Provided herein are pharmaceutical kits useful, for example, to activate NAMPT within cells within a mammal (e.g., a human). In some embodiments, provided are pharmaceutical kits useful, for example, to treat diseases, disorders, and conditions referred to herein. Such pharmaceutical kits can include one or more containers containing a pharmaceutical composition that includes a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, such kits can further include, if desired, one or more of various conventional pharmaceutical kit components such as containers with one or more pharmaceutically acceptable carriers. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components also can be included in a kit provided herein.X. Combination therapies

[0103] In some embodiments, one or more compounds provided herein, or a pharmaceutically acceptable salt thereof, can be combined with one or more therapeutic molecules. Examples of therapeutic molecules that can be used in combination with one or more compounds provided herein, or a pharmaceutically acceptable salt thereof, include, without limitation, nicotinamide riboside, nicotinamide mononucleotide, NAD precursor molecules, inhibitors of NAD degradation (e.g., CD38 inhibitors), and inhibitors of NAD consumption (e.g., PARP inhibitors).One or more compounds provided herein, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic molecules can be administered in any order or simultaneously. If simultaneously administered, they can be provided in a single, unified, form or in multiple forms (e.g., either as a single pill or as two separate pills). One of the items can be given in multiple doses, or both can be given as multiple doses. If not simultaneous, the timing between the multiple doses can vary from more than zero weeks to less than four weeks. XI. Definitions The term “about” as used herein has its original meaning of approximately and is to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In general, the term “about” refers to the usual error range for the respective value readily known to the skilled person in this technical field. If the degree of approximation is not otherwise clear from the context, “about” means either within plus or minus 10% of the provided value, or rounded to the nearest significant figure, in all cases inclusive of the provided value. Where ranges are provided, they are inclusive of the boundary values. At various places in this disclosure, substituents of compounds provided herein are disclosed in groups or in ranges. It is specifically intended that these groups and ranges include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6alkyl” is specifically intended to individually disclose methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, and C6alkyl. At various places in this disclosure various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term “a pyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring. It is further appreciated that certain features described herein, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features described herein which are, for brevity,described in the context of a single embodiment, also can be provided separately or in any suitable subcombination. As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution can be at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency. The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a saturated monovalent hydrocarbon radical, having, in some embodiments, one to eight (e.g., C1-C8alkyl), or one to six (e.g., C1-C6alkyl), or one to three (e.g., C1-C3alkyl) carbon atoms, respectively. The term “alkyl” encompasses straight and branched-chain hydrocarbon groups. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), n- propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isopentyl, tert-pentyl, n-pentyl, isohexyl, n-hexyl, n-heptyl, 4-isopropylheptane, n-octyl, and the like. In some embodiments, the alkyl groups are C1-C4alkyl groups (e.g., methyl, ethyl, isopropyl, or t-butyl). In some embodiments, the alkyl groups are C1-C3alkyl groups (e.g., methyl, ethyl, n-propyl, or isopropyl). The term “alkenyl”, as used herein, refers to a straight or branched monovalent hydrocarbon radical having, in some embodiments, two to eight carbon atoms (e.g., C2-C8alkenyl), or two to six carbon atoms (e.g., C2-C6alkenyl), or two to three carbon atoms (e.g., C2- C3alkenyl), and having at least one carbon-carbon double bond. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, isobutenyl, butadienyl and the like. The term “alkylene” refers to a straight or branched, saturated, hydrocarbon radical having, in some embodiments, one to six (e.g., C1-C6alkylene), one to four (e.g., C1-C4alkylene), or one to three (e.g., C1-C3alkylene), or one to two (e.g., C1-C2alkylene) carbon atoms, and linking at least two other groups, i.e., a divalent hydrocarbon radical. When two moieties are linked to the alkylene they can be linked to the same carbon atom (i.e., geminal), or different carbon atoms of the alkylene group. For instance, a straight chain alkylene can be the bivalent radical of -(CH2)n-,where n is 1, 2, 3, 4, 5 or 6 (i.e., a C1-C6alkylene). Representativealkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, secbutylene, pentylene, hexylene and the like. In some embodiments, the alkylene groups are C1-C2alkylene groups (e.g., methylene, or ethylene). As used herein, the term “haloalkyl”, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+1 halogen atoms that may be the same or different, where “s” is the number of carbon atoms in the alkyl group. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, “alkynyl” refers to an alkyl group having one or more triple carbon- carbon bonds. Example alkynyl groups include, without limitation, ethynyl, propyn-l-yl, propyn- 2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, the term “alkoxy” refers to an alkyl group, as defined herein, that is attached to the remainder of the molecule via an oxygen atom (e.g., -O-C1-C12alkyl, -O-C1-C8alkyl, -O-C1-C6alkyl, or -O-C1-C3alkyl). Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and the like. In some embodiments, the alkoxy groups are C1-C3alkoxy groups (e.g., methoxy, ethoxy, n-propoxy, or iso-propoxy). As used herein, “haloalkoxy” refers to a group of formula -O-haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCFs. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “amino” refers to a group of formula -NH2. As used herein, the term “alkyl amino” refers to a group of formula -NH(alkyl). In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include, without limitation, N-methylamino, N-ethylamino, N- propylamino (e.g., N-(propyl)amino and N-isopropylamino), N-butylamino (e.g., N- (butyl)amino and N-(- butyl)amino). and the like.

[0119] As used herein, the term “di(alkyl)amino” refers to a group of formula - N(alkyl)2. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0120] As used herein, the term “alkoxy carbonyl” refers to a group of formula -C(O)O-alkyl. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkoxycarbonyl groups include, without limitation, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl (e.g., n-propoxycarbonyl and isopropoxycarbonyl), butoxycarbonyl (e.g., n- butoxycarbonyl and n-butoxycarbonyl). and the like. As used herein, the term “alkyl carbonyl” refers to a group of formula -C(O)-alkyl. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylcarbonyl groups include, without limitation, methylcarbonyl, ethylcarbonyl, propylcarbonyl (e.g., n-propylcarbonyl and isopropylcarbonyl), butylcarbonyl (e.g., n- butylcarbonyl and n-butylcarbonyl). and the like.

[0121] As used herein, the term “alkylcarbonylamino” refers to a group of formula -NHC(O)- alkyl. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0122] As used herein, the term “alkyl sulfonylamino” refers to a group of formula -NHS(O)2- alkyl. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0123] As used herein, the term “aminosulfonyl” refers to a group of formula -S(O)2NH2.

[0124] As used herein, the term “alkylaminosulfonyl” refers to a group of formula - S(O)2NH(alkyl). In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0125] As used herein, the term “di(alkyl)aminosulfonyl” refers to a group of formula - S(O)2N(alkyl)2. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0126] As used herein, the term “aminosulfonylamino” refers to a group of formula - NHS(O)2NH2.

[0127] As used herein, the term “alkylaminosulfonylamino” refers to a group of formula - NHS(O)2NH(alkyl). In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0128] As used herein, the term “di(alkyl)aminosulfonylamino” refers to a group of formula - NHS(O)2N(alkyl)2. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0129] As used herein, the term “aminocarbonylamino”, employed alone or in combination with other terms, refers to a group of formula -NHC(O)NH2. As used herein, the term “alkylaminocarbonylamino” refers to a group of formula -NHC(O)NH(alkyl). In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0130] As used herein, the term “di(alkyl)aminocarbonylamino” refers to a group of formula - NHC(O)N(alkyl)2. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0131] As used herein, the term “carbamyl” to a group of formula -C(O)NH2.

[0132] As used herein, the term “alkylcarbamyl” refers to a group of formula -C(O)-NH(alkyl).In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.[0.133] As used herein, the term “di(alkyl)carbamyl” refers to a group of formula - C(O)N(alkyl)2. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0134] As used herein, the term “thio” refers to a group of formula -SH.

[0135] As used herein, the term “alkylthio” refers to a group of formula -S-alkyl. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0136] As used herein, the term “alkylsulfinyl” refers to a group of formula -S(O)-alkyl. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0137] As used herein, the term “alkylsulfonyl” refers to a group of formula -S(O)2-alkyl. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0138] As used herein, the term “carbonyl”, employed alone or in combination with other terms, refers to a -C(=O)- group, which may also be written as C(O).

[0139] As used herein, the term “carboxy” refers to a -C(O)OH group. In some embodiments, the “carboxy” group also refers to a bioisostere replacement group selected from the group consisting of:

[0140] and the like, where R refers to a hydrogen, (Ci-Cs) alkyl, or Ce aryl.

[0141] As used herein, the term “cyano-Ci-s alkyl” refers to a group of formula -(C1-3 alkylene)-CN.

[0142] As used herein, the term “HO-C1-3 alkyl” refers to a group of formula -(C1-3 alkylene)- OH.

[0143] As used herein, “halo” or “halogen” means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" and “haloalkoxy” refer to alkylgroups and alkoxy groups, respectively, as defined herein, that are substituted with one or more halogen(s) (e.g., 1-3 halogen(s)). For example, the term "C1-C4haloalkyl" is meant to include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. As another example, the term “C1-C3haloalkoxy” is meant to include trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, and the like. The term "aryl" refers to an aromatic ring system containing one ring, or two or three rings fused together, and having, in some embodiments, six to fourteen (i.e., C6-C14aryl), or six to ten (i.e., C6-C10aryl), or six (i.e., C6aryl) carbon atoms. Non-limiting examples of aryl groups include phenyl, naphthyl and anthracenyl. In some embodiments, aryl groups are phenyl. The term "cycloalkyl" refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system having, in some embodiments, 3 to 14 carbon atoms (e.g., C3-C14cycloalkyl), or 3 to 10 carbon atoms (e.g., C3-C10cycloalkyl), or 3 to 8 carbon atoms (e.g., C3-C8cycloalkyl), or 3 to 6 carbon atoms (e.g., C3-C6cycloalkyl) or 3 to 4 carbon atoms (e.g., C3-C4cycloalkyl). Cycloalkyl groups can be saturated or characterized by one or more points of unsaturation (i.e., carbon- carbon double and / or triple bonds), provided that the points of unsaturation do not result in an aromatic system. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cyclooctyl, cyclooctenyl, cyclooctadienyl and the like. The rings of bicyclic and polycyclic cycloalkyl groups can be fused, bridged, or spirocyclic. Non-limiting examples of bicyclic, spirocyclic and polycyclic cycloalkyl groups include bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, adamantyl, indanyl, spiro[5.5]undecane, spiro[2.2]pentane, spiro[2.2]pentadiene, spiro[2.3]hexane, spiro[2.5]octane, spiro[2.2]pentadiene, and the like. In some embodiments, the cycloalkyl groups of the present disclosure are monocyclic C3- C6cycloalkyl moieties (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In some embodiments, the cycloalkyl groups of the present disclosure are monocyclic C3-C4cycloalkyl moieties (e.g., cyclopropyl, or cyclobutyl). The term "heteroaryl" refers to monocyclic or fused bicyclic aromatic groups (or rings) having, in some embodiments, from 5 to 14 (i.e., 5- to 14-membered heteroaryl), or from 5 to 10(i.e., 5- to 10-membered heteroaryl), or from 5 to 6 (i.e., 5- to 6-membered heteroaryl) members (i.e., ring vertices), and containing from one to five, one to four, one to three, one to two or one heteroatom independently selected from nitrogen (N), oxygen (O), and sulfur (S). A heteroaryl group can be attached to the remainder of the molecule through a carbon atom or a heteroatom of the heteroaryl group, when chemically permissible. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, purinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl and the like. In some embodiments, the heteroaryl groups of the present disclosure are monocyclic 5- to 6-membered heteroaryl moieties having 1-3 heteroatoms independently selected from N, O, and S (e.g., pyridinyl, pyrimidinyl, pyridazinyl, triazolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, or thiazolyl). In some embodiments, the heteroaryl groups of the present disclosure are monocyclic 5- to 6-membered heteroaryl moieties having 1-2 ring nitrogen atoms (e.g., pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, or pyrazolyl). The term "heterocycloalkyl" refers to a non-aromatic monocyclic, bicyclic or polycyclic cycloalkyl ring having, in some embodiments, 3 to 14 members (e.g., 3- to 14-membered heterocycle), or 3 to 10 members (e.g., 3- to 10-membered heterocycle), or 3 to 8 members (e.g., 3- to 8-membered heterocycle), or 3 to 6 members (e.g., 3- to 6-membered heterocycle), or 5 to 6 members (e.g., 5- to 6-membered heterocycle), and having from one to five, one to four, one to three, one to two or one heteroatom or heteroatom groups independently selected from nitrogen (N), oxygen (O), sulfur (S), sulfoxide (S(O)), and sulfone (S(O)2). Heterocycloalkyl groups are saturated or characterized by one or more points of unsaturation (e.g., one or more carbon-carbon double bonds, carbon-carbon triple bonds, carbon-nitrogen double bonds, and / or nitrogen- nitrogen double bonds), provided that the points of unsaturation do not result in an aromatic system. The rings of bicyclic and polycyclic heterocycloalkyl groups can be fused, bridged, or spirocyclic. Non-limiting examples of heterocycloalkyl groups include aziridine, oxirane, thiirane, pyrrolidine, imidazolidine, pyrazolidine, dioxolane, phthalimide, piperidine, 1,4- dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, 3,4,5,6-tetrahydropyridazine, tetrahydropyran, pyran, decahydroisoquinoline, 3-pyrroline, thiopyran, tetrahydrofuran, tetrahydrothiophene, tetrahydro-1, l-dioxido-2H-thiopyran, quinuclidine, 1,4-oxazepane, 2-azabicyclo[4.1.0]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, 2- azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, 3- oxa-6-azabicyclo[3.1.1 ]heptane, 2,5-diazabicyclo[2.2.1 ]heptane, 2-thia-6-azaspiro[3.3 ]heptane 2,2-dioxide, 2,6-diazaspiro[3.3]heptane, 2-azaspiro[3.3 ]heptane, l-oxaspiro[3.3]heptane, 5- azaspiro[2.4]heptane, 6-azaspiro[3.4]octane, 6-azaspiro[2.5]octane, 4-oxa-7-azaspiro[2.5]octane, 3-oxa-8-azabicyclo[3.2.1]octane, and the like. A heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon atom, or a ring heteroatom, when chemically permissible. In some embodiments, the heterocycloalkyl groups of the present disclosure are monocyclic 4- to 8- membered heterocycloalkyl moieties having one or two heteroatom or heteroatom groups independently selected from N, 0, S and S(O)2(e.g., azetidine, piperidine, piperazine, morpholine, pyrrolidine, imidazolidine, pyrazolidine, tetrahydrofuran, tetrahydropyran, 1,4-oxazepane, 6-oxa-3-azabicyclo[3.1.1 jheptane, 3-oxa-6- azabicyclo[3.1.1 jheptane, 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide, and the like).

[0148] As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be anN-oxide. In some embodiments, the heteroaiyl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a fivemembered or sixmembered heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected fromN, 0, and S. Exemplary five-membered ring heteroaryls include, without limitation, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1 ,2,3- triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1 ,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4- oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A sixmemberedheteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected fromN, O, and S. Exemplary six-membered ring hetero aryls include, without limitation, pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl. Ring-forming carbon atoms of a heteroaryl group can be optionally substituted by 1 or 2 independently selected oxo or sulfide groups (e.g., C(O) or C(S)). As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, 7-, 8-, 9-, or 10- membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles. Example heterocycloalkyl groups include, without limitation, pyrrolidin- 2-one, l,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). The heterocycloalkyl group can be attached through a ringforming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.

[0149] At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring can be attached at any position of the ring, whereas a pyridin-3-yl ring is attached at the 3 - position.

[0150] As used herein, the term “oxo” refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to a carbon (e.g., C=O), or attached to a heteroatom forming a sulfoxide or sulfone group. The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted.Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0151] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds provided herein that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Any appropriate method can be used to prepare optically active forms from, for example, optically inactive starting materials. For example, techniques such as resolution of racemic mixtures or stereoselective synthesis can be used to prepare optically active forms of a compound provided herein. Many geometric isomers of olefins, C=N double bonds, N=N double bonds, and the like also can be present in a compound described herein, and all such stable isomers are contemplated herein. Cis and trans geometric isomers of the compounds provided herein are described and can be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, a compound provided herein has the In some embodiments, a compound provided herein has theconfiguration.

[0152] Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers that are isomeric protonation states having the same empirical formula and total charge. Example prototropictautomers include, without limitation, ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4- triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or stoically locked into one form by appropriate substitution. For example, in aqueous solution, pyrazoles can exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0153] As readily understood by one skilled in the art, a wide variety of functional groups and other structures can exhibit tautomerism, and all tautomers of compounds as described herein are within the scope provided herein.

[0154] As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal (e.g., a human). In some embodiments, an in vitro cell can be a cell in cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal (e.g., a human).[0155) As used herein, the term “contacting” refers to the bringing together of indicated moieties or items in an in vitro system, an ex vivo system, or an in vivo system. For example, “contacting” a cell with a compound provided herein includes the act of administering that compound to a mammal (e.g., a human) containing that cell as well as, for example, introducing that compound into a cell culture containing that cell.

[0156] As used herein, the term “mammal” includes, without limitation, mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, elephants, deer, nonhuman primates (e.g., monkeys and apes), house pets, and humans.

[0157] As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, mammal, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician.

[0158] As used herein, the term “treating” or “treatment” refers to (a) inhibiting a disease, disorder, or condition, for example, inhibiting a disease, disorder, or condition in a mammal (e.g., human) that is experiencing or displaying the pathology or symptomatology of the disease, disorder, or condition (e.g., arresting further development of the pathology and / or symptomatology), or (b) ameliorating the disease, disorder, or condition, for example, ameliorating a disease, disorder, or condition in a mammal (e.g., a human) that is experiencing or displaying the pathology or symptomatology of the disease, disorder, or condition (e.g., reversing the pathology and / or symptomatology).

[0159] As used herein, the term “preventing” or “prevention” of a disease, disorder, or condition refers to decreasing the risk of occurrence of the disease, disorder, or condition in a mammal or group of mammals (e.g., a mammal or group of mammals predisposed to or susceptible to the disease, disorder, or condition). In some embodiments, preventing a disease, disorder, or condition refers to decreasing the possibility of acquiring the disease, disorder, or condition and / or its associated symptoms. In some embodiments, preventing a disease, disorder, or condition refers to completely or almost completely stopping the disease, disorder, or condition from occurring.

[0160] As referred to herein, "pharmaceutically acceptable salt" is meant to include salts of the compounds according to this disclosure that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount ofthe desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N’ -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S.M., et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure may contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0161] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.

[0162] The use of the terms “a” and “an” and “the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed tocover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.

[0163] Various embodiments are described hereinafter. It should be noted that the specific embodiments are not intended as an exhaustive description or as a limitation to the broader aspects discussed herein. One aspect described in conjunction with a particular embodiment is not necessarily limited to that embodiment and can be practiced with any other embodiment(s).

[0164] The present invention, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.EXAMPLES

[0165] Example 1. Identification of Compounds

[0166] Given the clear biological significance of increasing NAMPT activity, the purpose of this experiment was to identify an orally active, small molecule NAMPT activator. A cellular thermal shift (CETSA)-based high throughput screening (HTS) platform was developed. This platform allows for the identification of novel ligand binders to a protein of interest.

[0167] The platform was used to screen potential NAMPT binders from a pool of 100K compounds ChemDIV diversity library (FIG. 1A). FIG. 1A shows a graph of the initial NAMPT GETS A screen to identify compounds having a strong NAMPT GETS A signal.

[0168] It was reasoned that a subset of molecules that bound to NAMPT might be capable of increasing NAMPT activity and raise cellular NAD+ levels. To identify such molecules, the top 360 hits were selected from the CETSA-based binder screen and the activity of the compounds in cells was examined.

[0169] The activity of these compounds was directly tested using a cell-based NAD+ assay that was adapted to a high throughput 384 well format. As a test for specificity, by CRISPR-based gene editing, a series of NAMPT KO cells were generated, to use as a counter screen. Specifically, true NAMPT activators should be unable to raise NAD+ levels in NAMPT KO cells.

[0170] FIG 1B identifies the 10 most potent compounds identified in the NAD+ cellular assay: (1) 4019-0025, (2) E207-0877, (3) L036-2269, (4) G395-1397, (4) F738-0043, (6) G800-0245, (7) G395-1209, (8) L036-2268, (9) K783-0604, and (10) G395-1301.The assays were then repeated to ensure their rigor and reproducibility.

[0171] The three most potent compounds (4019-0025, E207-0877 and L036-0389) were also resynthesized with structural confirmation and retested, generating consistent results in the assays mentioned above (FIG 1C). The structure of each of these three compounds is shown below and in FIG. 1C:

[0172] Finally, these three compounds were validated in human iPSC-derived neurons, where the compounds demonstrated their capacity to increase NAD+ levels in a relevant human target cell (FIG. ID).

[0173] This example demonstrates the successful identification of ten compounds having significant activity in a cell-based NAD+ assay. Further, three compounds were identified as having significant potency in the assay, namely 4019-0025, E207-0877 and L036-0389.

[0174] Example 2: Synthesis of a compound of Formula (V) (UP-B142)

[0175] Scheme 1. Overall synthesis of UP-B142

[0176] Preparation of tert-butyl ((lr,4r)-4-((benzylamino)methyl)cyclohexyl)carbamate (2)To a solution of tert-butyl ((1r,4r)-4-(aminomethyl)cyclohexyl)carbamate 1 ( 1.00 g, 4.38 mmol) and benzaldehyde (465 mg, 4.38 mmol) in MeOH (25 mL) was added NaBH(OAc)3(1.86 g, 8.76 mmol) and two drops of HOAc below 0ºC. The reaction mixture was stirred for 2h at room temperature, then separated with EtOAc (30 mL*3) and NaHCO3solution (30 mL), the organic phase concentrated under vacuum to give crude product tert-butyl ((1r,4r)-4- ((benzylamino)methyl)cyclohexyl)carbamate 2 (1 g, 72% yield) as a yellow solid. LCMS (ESI) calculated for C19H30N2O2[M + H]+m / z 319.23, found 319.20. Preparation of tert-butyl ((1r,4r)-4-(((N-benzyl-4-nitrophenyl)sulfonamido)methyl) cyclohexyl)carbamate (4)To a solution of tert-butyl ((1r,4r)-4-((benzylamino)methyl)cyclohexyl)carbamate 2 (1.00 g, 3.14 mmol) and DIEA (810 mg, 6.28 mmol) in ACN (25 mL) was added 4- nitrobenzenesulfonyl chloride 3 (835 mg, 3.77 mmol) below 0ºC, stirred for 2h at room temperature, then separated with EtOAc (30 mL*3) and brine (30 mL), the organic phase concentrated under vacuum, The residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 98 : 2) to give tert-butyl ((1r,4r)-4-(((N-benzyl-4- nitrophenyl)sulfonamido)methyl)cyclohexyl)carbamate 4 (1 g, 61% yield) as a yellow solid. LCMS (ESI) calculated for C25H33N3O6S [M + Na]+m / z 526.21, found 526.15. Preparation of N-(((1r,4r)-4-aminocyclohexyl)methyl)-N-benzyl-4- nitrobenzenesulfonamide (5)To a solution of tert-butyl ((1r,4r)-4-(((N-benzyl-4- nitrophenyl)sulfonamido)methyl)cyclohexyl)carbamate 4 (1.00 g, 1.99 mmol) in DCM (10 mL) was added TFA (5 mL), stirred for 2h at room temperature. the mixture was concentrated under vacuum then dissolved with MeOH (10 mL), added TEA (1 mL), concentrated again to give crude product N-(((1r,4r)-4-aminocyclohexyl)methyl)-N-benzyl-4-nitrobenzenesulfonamide 5 (700 mg, 87% yield) as a yellow solid. LCMS (ESI) calculated for C20H25N3O4S [M + H]+m / z 404.50, found 404.10. Preparation of N-benzyl-N-(((1r,4r)-4-(dimethylamino)cyclohexyl)methyl)-4- nitrobenzenesulfonamide (6)To a solution of tert-butyl ((1r,4r)-4-(((N-benzyl-4- nitrophenyl)sulfonamido)methyl)cyclohexyl)carbamate 5 (700 mg, 1.74 mmol) and paraformaldehyde (261 mg, 8.70 mmol) in MeOH (15 mL) was added NaBH3CN (328 mg, 5.22 mmol) and two drops of HOAc below 0ºC. The reaction mixture was stirred for 2h at 50ºC, concentrated under vacuum then the residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 98 : 2) to give N-benzyl-N-(((1r,4r)-4- (dimethylamino)cyclohexyl)methyl)-4-nitrobenzenesulfonamide 6 (500 mg, 67% yield) as a yellow solid.LCMS (ESI) calculated for C22H29N3O4S [M + H]+m / z 432.19, found 432.15. Preparation of 4-amino-N-benzyl-N-(((1r,4r)-4-(dimethylamino)cyclohexyl)methyl) benzenesulfonamide (7)To a solution of N-benzyl-N-(((1r,4r)-4-(dimethylamino)cyclohexyl)methyl)-4- nitrobenzenesulfonamide 6 (500 mg, 1.16 mmol) in MeOH (15 mL) was added Pd / C (100 mg), stirred for 2h at 50ºC under H2atmosphere, then cooled to room temperature, filtered and the filtrate was concentrated under vacuum to give crude product 4-amino-N-benzyl-N-(((1r,4r)-4- (dimethylamino)cyclohexyl)methyl)benzenesulfonamide 7 (400 mg, 86% yield) as a yellow solid. LCMS (ESI) calculated for C22H31N3O2S [M + H]+m / z 402.57, found 402.15. Preparation of N-benzyl-N-(((1r,4r)-4-(dimethylamino)cyclohexyl)methyl)-4-(3- ethylureido)benzenesulfonamide (UP-B142)To a solution of Triphosgene (178 mg, 0.60 mmol) and DIEA (129 mg, 1.00 mmol) in DCM (10 mL) was added 4-amino-N-benzyl-N-(((1r,4r)-4- (dimethylamino)cyclohexyl)methyl)benzenesulfonamide 7 (200 mg, 0.50 mmol) in DCM (8 mL) dropwise, stirred for 1h at room temperature, then ethylamine (1 mL, 1M in MeOH, 1.00 mmol)was added, stirred for 1h at room temperature. Separated the reaction with DCM and brine, the organic phase concentrated and purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 91 : 9) to give N-benzyl-N-(((1r,4r)-4-(dimethylamino)cyclohexyl)methyl)-4-(3- ethylureido)benzenesulfonamide UP-B142 (55 mg, 23% yield) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.98 (s, 1 H), 7.68 (d, J = 8.8 Hz, 2 H), 7.59 (d, J = 8.8 Hz, 2 H), 7.37-7.22 (m, 5 H), 6.31 (t, J = 5.6 Hz, 1 H), 4.21 (s, 2 H), 3.16-3.07 (m, 2 H), 2.82 (d, J = 7.2 Hz, 2 H), 2.16 (s, 7 H), 1.67 (d, J = 10.8 Hz, 2 H), 1.54 (d, J = 12.0 Hz, 2 H), 1.15 (s, 1 H), 1.06 (t, J = 7.2 Hz, 3 H), 0.90-0.78 (m, 2 H), 0.74-0.58 (m, 2 H). LCMS (ESI) calculated for C25H36N4O3S [M + H]+m / z 473.25, found 473.20. Example 3: Activity analysis of high potency compounds The purpose of this example was to further analyze the three compounds with the highest potency from Example 1 (4019-0065, E207-0877 and L036-0389). The three compounds having the highest potency from Example 1 (4019-0065, E207- 0877 and L036-0389) were selected for potential structure–activity relationship analysis (SAR) based on potency and potential chemical scalability. By searching ChemDIV’s 1.6 million compound collection, >600 compounds were identified that shared similar scaffolds to 4019-0065, E207-0877 and L036-0389. These compounds were then tested in a dose response in WT and NAMPT KO cells to determine their SAR (FIG.1E). The SAR analysis comprised culturing human IPSC cells in a 384 well plate, and treating the cells with 4019-0065, E207-0877 or L036-0389 over a dose course for 18h. Cells were then washed and assayed for NAD levels. Since activators not inhibitors were being tested, it is difficult to calculate the absolute EC50. As such, the concentration needed to increase intracellular NAD+ by 25% was calculated. The rationale of choosing this arbitrary cut off is that in general, aging causes a ~40% decrease in tissue NAD+ levels. As such, a 25% increase in NAD equals an approximate 50% recovery in NAD+ levels, which is believed likely biologically meaningful. All three classes of molecules (4019, E207, and L036) showed clear SAR patterns, with distinct activity cliffs (FIG.1E).

[0200] Further SAR studies were executed around these 3 classes of compounds (4019, E207 and L036). More than >100 novel compounds have been synthesized and tested, and three lead- like compounds surrounding these classes have been generated. These compounds have <500nM IC25 in cellular efficacy and are metabolically stable (FIG. 2). The three lead compounds were designated ZE76-0003, ZE76-0092, and ZE76-0123, and the structure of the compounds is shown below:

[0201] During the discovery process, another class of molecule that potently increases cellular NAD in a NAMPT independent manner was also identified. A representative lead compound for this class is designated ZE76-0087, and the structure of this compound is shown below:This compound dose-dependently increases cellular NAD in both WT cells and NAMPT KO cells (FIG. 3).Example 4: Compound Efficacy The purpose of this example was to evaluate the efficacy of compounds identified in Examples 1 and 2 in cellular NAD assay using muscle Myotube and NASH patient hepatocytes. As detailed in FIG.4A, compounds designated as 4019-0065, E207-0877, L036-0389, and ZE76-0087 were evaluated for efficacy in muscle myotube at different concentrations (10 µM, 3.3 µM, 1.1 µM, and 0.4 µM). FIG.4B shows the results of compounds designated as ZE76-0003, ZE76-0092, ZE76-0123, and ZE76-0087 in a cellular NAD assay using NASH patient hepatocytes. 2,000 cells / well were added to a 384 well plate and, at the same time, test compounds dissolved in media were added at the desired concentration to each well. Treated cells were incubated overnight in a CO2incubator. Cells were washed 6 times with PBS with 1 mM CaCl2and 1 mM MgCl2. In the last wash, 10 µL of PBS with 1 mM CaCl2and 1 mM MgCl2was left in each well.10µL 0.4% dodecyltrimethylammonium bromide (DTAB) in phosphate buffer pH 8.0 was immediately added and the plate was shaken at 1000 rpm for 5 min.60 µL of reaction mix (Table 1) was added and fluorescence was immediately monitored at Ex / Em 530 / 585. A linear increase was achieved with 8 cycles every 92 seconds, 10 number of flashes / well / cycle. The reaction mix was prepared following Table 1 below, respecting the amount and order in which each component is added:[0207| The assays confirm the efficacy of the compounds designated as 4019-0065, E207-0877, L036-0389, ZE76-0087, ZE76-0003, ZE76-0092, and ZE76-0123 in NAD assays.

[0208] Example 5: Ability to Increase Cellular NAD

[0209] The compounds described herein were assessed for their ability to increase cellular NAD in OVCAR-5 and GT1-7 cells (FIG. 5A-5B). The assay was carried out similarly to the assay described in Example 4. The results are summarized in Table 2 below:-155-***

[0210] FIGs. 5C and D further show representative image of cultured human IPSC neuron (beta- III-tubulin staining) and compound UP-B142 efficacy in a cellular NAD assay.

[0211] While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the technology in its broader aspects as defined in the following claims.

[0212] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of’ excludes any element not specified.

[0213] The present disclosure is not to be limited in terms of the particular embodiments described in this application. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and compositions within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds, or compositions, which can of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0214] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0215] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member.

[0216] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

[0217] Other embodiments are set forth in the following claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1,wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4- 10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy.

2. The compound of claim 1, wherein: (a) R1, R2, R3, R4, R6, R7, and R9are each H; (b) R5is OH; (c) R8is C1-6alkyl; and (d) R10is ORa1or Cy1.

3. The compound of claim 1 or 2, wherein R8is C1alkyl.

4. The compound of any one of claims 1-3, wherein R10is a 5 membered heteroaryl.

5. The compound of any one of claims 1-4, wherein R10is.

6. The compound of any one of claims 1-3, wherein R10is OCH3.

7. The compound of any one of claims 1-6, wherein the compound of Formula (I) is.

8. A compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: X1is CH or N; X2is CH2, NH, O, or S; R12, R13, R14, R15, R16, R17, R18, and R19are each independently selected from H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1;wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4- 10 membered heterocycloalkyl)-C1-4alkylene, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy.

9. The compound of claim 8, wherein:(a) X1is N or CH; (b) X2is O or NH; (c) R12is C1alkyl; (d) R13, R14, R15, R16, R18, and R19are each H; and (e) R17is C1alkyl or C1haloalkyl.

10. The compound of claim 8 or 9, wherein: (a) X1is N; (b) X2is O; (c) R12is C1alkyl; (d) R13, R14, R15, R16, R18, and R19are each H; and (e) R17is C1alkyl.

11. The compound of claim 8 or 9, wherein: (a) X1is CH; (b) X2is NH; (c) R12is C1alkyl; (d) R13, R14, R15, R16, R18, and R19are each H; and (e) R17is C1haloalkyl.

12. The compound of claim 8, 9, or 11, wherein R17is CF3.

13. The compound of any one of claims 8-12, wherein the compound of Formula (II) is.

14. A compound of Formula (III):or a pharmaceutically acceptable salt thereof, wherein: R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30and are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting of Cy1, CN, NO2, ORa1,C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4- 10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 memberedheterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy.

15. The compound of claim 14, wherein: (a) R20is C1-6alkyl; (b) R21, R22, R23, R24, R25, R26, R28, R29are each H; (c) R27is H or C1-6alkyl;(d) R30is a (4-10 membered heterocycloalkyl)-C1-4alkylene optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg.

16. The compound of claim 14 or 15, wherein: (a) R20is C1alkyl; (b) R21, R22, R23, R24, R25, R26, R28, R29are each H; (c) R27is C1alkyl; (d) R30is a (6 membered heterocycloalkyl)-C3alkylene.

17. The compound of claim 14 or 15, wherein: (a) R20is C1alkyl; (b) R21, R22, R23, R24, R25, R26, R28, R29are each H; (c) R27is H; (d) R30is a (5 membered heterocycloalkyl)-C1alkylene substituted with 1 substituents independently selected from Rg.

18. The compound of 14, 15, or 17, wherein Rgis C4alkyl.

19. The compound of any one of claims 14-18, wherein the compound is20. A compound of Formula (IV):or a pharmaceutically acceptable salt thereof, wherein: R31, R32, R33, R34, R35, R36, R37, R38, R39, and R40are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4- 10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy,cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy.

21. The compound of claim 20, wherein: (a) R31is halo; (b) R32, R33, R34, R37, R38, R39are each H; (c) R35and R36are each C1-6alkyl; and (d) R40is (5-10 membered heteroaryl)-C1-4alkylene.

22. The compound of claim 20 or 21, wherein (a) R35and R36are each C1alkyl; and (b) R40is (5 membered heteroaryl)-C1alkylene.

23. The compound of any one of claims 20-22, wherein R40is.

24. The compound of any one of claims 20-23, wherein the compound is.

25. A compound of Formula (V):or a pharmaceutically acceptable salt thereof, wherein: R41, R42, R43, R44, R45, R46, and R47are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)- C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, or R41and R42, together with the nitrogen atom to which they are attached, form a 4-15- membered heterocycloalkyl; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11isindependently selected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-20aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4- 10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy.

26. The compound of claim 25, wherein: (a) R41is C6aryl-C1alkylene; (b) R42is methyl;(c) R43, R44, R45, and R46are each H; and (d) R47is C(O)NRc1Rd1, wherein Rc1is H and Rd1is C6-20aryl.

27. The compound of claim 25 or 26, wherein R47is28. The compound of any one of claims 25-27, wherein the compound is:.

29. The compound of claim 25, wherein: (a) R41and R42are each C6aryl-C1alkylene; (b) R43, R44, R45, and R46are each H; and (c) R47is NRc1C(O)Rb1, wherein Rc1is H and Rb1is C1alkyl.

30. The compound of claim 25 or 29, wherein the compound is:

31. A compound of Formula (VI):or a pharmaceutically acceptable salt thereof, wherein R48, R49, R50, R51, R52, R53, and R54are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)- C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; or wherein R53and R54taken together form an optionally substituted 5-10 membered heterocycloalkyl or an optionally substituted 5-10 membered heteroaryl; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4- 10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl- C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy.

32. The compound of claim 31, wherein: (a) R48and R49are each methyl; (b) R50, R51, and R52are each H; and (c) R53and R54taken together form an optionally substituted 6-membered heterocycloalkyl ring.

33. The compound of claim 31 or 32, wherein R53and R54taken together form a substituted 6- membered heterocyclic ring having the following structure:.

34. The compound of any one of claims 31-33, wherein the compound is.

35. A compound of Formula (VII):or a pharmaceutically acceptable salt thereof, wherein R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, and R65are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; or wherein R60and R61taken together form an optionally substituted 5-10 membered heterocycloalkyl or an optionally substituted 5-10 membered heteroaryl; Ar1is selected from the group consisting of C6-10aryl, C6-10aryloxy, and 5-10 membered heteroaryl; X3is selected from the group consisting of CO and SO2; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1,S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4- 10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy.

36. The compound of claim 35, wherein: (a) R55, R56, R57, R58, and R59are each H; (b) R60and R61taken together form an optionally substituted 6-membered heterocycloalkyl ring; (c) R62is methyl; (d) R63is H; (e) R64is branched C4alkyl; and (f) Ar1is optionally substituted aryl.

37. The compound of claim 35 or 36, wherein R60and R61taken together form a 6-membered heterocycloalkyl ring having the following structure:.

38. The compound of any one of claims 35-37, wherein Ar1is39. The compound of any one of claims 35-38, wherein the compound is:.

40. A compound of Formula VIII:or a pharmaceutically acceptable salt thereof, wherein: R66, R67, R68, R69, and R70are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; or wherein R53and R54taken together form an optionally substituted 5-10 membered heterocycloalkyl or an optionally substituted 5-10 membered heteroaryl; Ar2is selected from the group consisting of C6-10aryl, C6-10aryloxy, and 5-10 membered heteroaryl; X4is selected from the group consisting of C2-6alkenyl, CO, and NH; X5is selected from the group consisting of CO and NH; X6is selected from the group consisting of C2-6alkenyl, CO, and NH; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independentlyselected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino,aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; p is 0 or 1; q is 0 or 1; r is 0 or 1; and s is 0 or 1.

41. A compound of Formula IX:or a pharmaceutically acceptable salt thereof, wherein: R71, R72, R73, R74, R75, R76, R77, R78, R79, R80, R81, R82, R83, and R84are each independently selected from the group consisting of H, OH, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C2-6haloalkenyl, C2-6haloalkynyl, CN, NO2, Cy1, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4- 10 membered heterocycloalkyl)-C1-4alkylene, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1,NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, C(NRe1)NRclRd1, C(NRe1)NRc1ORa1, NRc1C(O)NRc1Rd1, NRc1C(S)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; or wherein R53and R54taken together form an optionally substituted 5-10 membered heterocycloalkyl or an optionally substituted 5-10 membered heteroaryl; X7is selected from the group consisting of CR85R86, CO, SO2, and N, wherein R85and R86form a three-membered ring with the carbon atom to which they are attached; X8is selected from the group consisting of CH and N; X9is selected from the group consisting of CH and N; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11, and wherein each R11is independently selected from the group consisting of Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1is independently selected from the group consisting of C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and wherein each RCy1is independently selected from the group consisting of halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; and wherein each R12is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra1, Rb1, Rc1, and Rd1is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene, and wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, and (4-10 membered heterocycloalkyl)-C1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1and Rd1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Re1is selected from H, ORa1, NRc1Rd1, and C1-4haloalkyl; and each Rgis independently selected from the group consisting of OH, NO2, CN, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, cyano-C1-3alkylene, HO-C1-3alkylene, C6-10aryl, C6-10aryloxy, C3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4alkylene, C3-10cycloalkyl-C1-4alkylene, (5-10 membered heteroaryl)-C1-4alkylene, (4-10 membered heterocycloalkyl)-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkenylcarbonyl, C1-6alkynylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkyl amino sulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylamino sulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino, and wherein any C1-6alkyl, C1-6alkoxy, C6-10aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rgis optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, NO2, CN, halo, C1-6alkyl, C1-4haloalkyl, C1-6alkoxy, and C1-6haloalkoxy.

42. A compound for increasing nicotinamide adenine dinucleotide (NAD) levels in a mammal, wherein the compound comprises 4019-0065, E207-0877, L036-0389, ZE76-0087, ZE76-0003, ZE76-0092, or ZE76-0123.

43. A method for increasing nicotinamide adenine dinucleotide (NAD) levels in a mammal, and / or for increasing nicotinamide phosphoribosyltransferase (NAMPT) activity within the mammal, the method comprising administering to the mammal an effective amount of the compound of any one of claims 1-42.

44. The method of claim 43, wherein the compound increases NAD levels in a mammal through a NAMPT dependent pathway.

45. The method of claim 43 or 44, wherein the compound increases NAD levels in a mammal by increasing NAMPT levels in the mammal.

46. The method of any one of claims 43-45, wherein the method results in NAD levels increasing, as compared to the levels present prior to treatment, by about 20% to 150%.

47. The method of any one of claims 43-45, wherein the method results in NAMPT activity increasing, as compared to the levels present prior to treatment, by about 20% to 400%.

48. The method of any one of claims 43-47, wherein the increase in NAD levels and / or increase in NAMPT activity is measured using any pharmaceutically acceptable technique.

49. The method of any one of claims 43-48, wherein NAD levels are measured by liquid chromatography coupled to mass spectrometry (LC–MS) or enzymatic assays.

50. The method of any one of claims 43-49, wherein NAMPT activity is measured by a multicoupled fluorometric assay.

51. The method of any one of claims 43-50, wherein the mammal is a human.

52. The method of any one of claims 43-51, wherein the mammal has a condition and / or disease characterized by dysregulation of cellular NAD+levels.

53. The method of any one of claims 43-52, wherein the method treats, and / or ameliorates symptoms of, a disease or condition selected from the group consisting of cardiovascular disease, heart failure, obesity, insulin resistance syndromes and their associated manifestations, a neurodegenerative disease or condition, inflammation, an inflammation disorder, auto-immunity, chronological aging, skin aging, pellagra, a metabolic disorder, progeroid phenotypes, traumatic nerve injuries, neuropathies, neurodegenerative diseases, disorders, or conditions, central demyelinating disorders, peripheral demyelinating disorders, primarily inflammatory neuropathies, glaucoma, ischemic injuries, retinal and optic nerve ischemia, stroke, infertility, acute and / or chronic kidney injury, age-related vision or hearing loss, hepatosteatosis, skin cancer development or progression, and sarcopenia.

54. The method of claim 53 wherein:(a) the traumatic nerve injury is selected from the group consisting of a neuronal crush injury, a traumatic brain injury, chronic traumatic encephalopathy (CTE), and concussion;(b) the neuropathy is selected from the group consisting of a chemotherapeutic- induced sensory neuropathy and diabetic neuropathy;(c) the neurodegenerative diseases, disorders, or conditions is selected from the group consisting of amyotrophic lateral sclerosis, multiple sclerosis, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, Friedreich’s ataxia, Lewy body disease, spinal muscular atrophy, frontotemporal dementia, and cerebellar degeneration;(d) the central demyelinating disorders is selected from the group consisting of multiple sclerosis, adrenoleukodystrophy, adrenomyeloneuropathy, Leber hereditary optic neuropathy, neuromyelitis optica, and acute disseminated encephalomyelitis;(e) the peripheral demyelinating disorder is selected from the group consisting of Charcot-Marie-Tooth disease and Guillain-Barre syndrome; and(f) the primarily inflammatory neuropathy is selected from the group consisting of amultifocal motor neuropathy, an anti-MAG neuropathy, and a chronic inflammatory demyelinating polyneuropathy.

Images