Compositions and methods for treating metabolic disorders

Abstract

This disclosure generally relates compounds that can also be used for the treatment, prevention, diagnosis and / or management of various metabolic disorders.

Description

263722000840 COMPOSITIONS AND METHODS FOR TREATING METABOLIC DISORDERS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of U.S. Provisional Patent Application No.63 / 694,708, filed September 13, 2024, the disclosure of which is hereby incorporated herein by reference in its entirety. FIELD

[0002] This disclosure generally relates compounds that can also be used for the treatment, prevention, diagnosis and / or management of various metabolic disorders. BACKGROUND

[0003] About 24% of the US population is affected by the metabolic syndrome, a constellation of associated disorders that includes obesity, obesity related disorders, type 2 diabetes, fatty liver, hypertension, cardiovascular disease, and high cholesterol. The amount of people affected by the metabolic syndrome increases significantly every year, and each of the associated conditions often requires individual treatment / medication, imposing a dramatic burden on the health care system. Thus, there remains an unmet need to develop safe medication to combat the epidemic of metabolic disorders. BRIEF SUMMARY

[0004] In some aspects, provided is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: R1is halo, H, alkyl, alkenyl, haloalkyl, or CN; and, wherein each of the foregoing is unsubstituted orMOFO-3609483101263722000840 substituted with one or more Rx; wherein each Rxis independently C1-8alkyl, C1-8alkoxy, phenyl, haloC1-8alkyl, halo, OH, NO2, C(O)Rx1, or CN; wherein the C1-8alkoxy of Rxis optionally substituted with cyclopropyl; the phenyl of Rxis unsubstituted or substituted with C1-8alkyl or halo; Rx1is phenyl substituted with halo, C1-8alkyl, or unsubstituted 5 to 6-membered heteroaryl.

[0005] In some aspects, provided is a compound of Formula (II) or (III):or a pharmaceutically acceptable salt thereof, wherein: R1is halo, H, alkyl, alkenyl, haloalkyl, or CN; p is 0-5; R4aand R4bis H, alkyl, alkoxy, or halo; R3is independently optionally substituted alkoxy, alkyl, alkenyl, halo, haloalkyl, - NO2, or CN; or when at least two R3are present, two adjacent R3combine to form a ring that optionally contains one or more heteroatoms, wherein the ring formed is optionally substituted.

[0006] In some aspects, provided is a compound of Formula (IV):or a pharmaceutically acceptable salt thereof, wherein: R1is halo, H, alkyl, alkenyl, haloalkyl, or CN; w is 0-5; R10is independently optionally substituted alkyl, haloalkyl, alkoxy, phenyl, halo, NO2, SO2NH2, SO2NHC1-8alkyl, SO2N(C1-8alkyl)(C1-8alkyl), SOC1-8alkyl, SO2C1-8alkyl, or CN; and R11is haloalkyl, alkyl, CONH2, CONHC1-8alkyl, CON(C1-8alkyl)(C1-8alkyl), or H.MOFO-3609483102263722000840

[0007] In some aspects, provided herein is a compound of Formula (A-I):or a pharmaceutically acceptable salt thereof, wherein: R1is H or F; R4ais H, F, C2-8alkyl, or C1-8alkoxy; R4bis H, F, C2-8alkyl, or C1-8alkoxy; ring A is phenyl or 6-membered heteroaryl; each R3is independently F, C2-7alkyl, SO2C1-8alkyl, SOC1-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, SO2NH2, SO2NHC1-8alkyl, or SO2N(C1-8alkyl)(C1-8alkyl); and n is 0, 1, 2, 3, or 4.

[0008] In some aspects, provided herein is a compound of Formula (A-I-a) having the structure:or a pharmaceutically acceptable salt thereof, wherein: R1is H or F; each R4ais independently H, F, C1-8alkyl, or C1-8alkoxy; each R4bis independently H, F, C2-8alkyl, or C1-8alkoxy; ring A is phenyl or 6-membered heteroaryl; each R3is independently F, C2-7alkyl, SO2C1-8alkyl, SOC1-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, SO2NH2, SO2NHC1-8alkyl, or SO2N(C1-8alkyl)(C1-8alkyl); and n is 0, 1, 2, 3, or 4.

[0009] In some aspects, provided herein is a compound of Formula (A-I’):MOFO-3609483103263722000840or a pharmaceutically acceptable salt thereof, wherein: R1is H or F; R4ais H, F, C1-8alkyl, or C1-8alkoxy; R4bis H, F, C2-8alkyl, or C1-8alkoxy; ring A is phenyl or 5 or 6-membered heteroaryl; each R3is independently Cl, F, Br, C2-7alkyl, SO2C1-8alkyl, SOC1-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, SO2NH2, SO2NHC1-8alkyl, SO2N(C1-8alkyl)(C1-8alkyl), NO2, phenyl, OSO2C1-8alkyl, CONHC1-8alkyl, SC1-8alkyl, or N(C1-8alkyl)(C1-8alkyl); and n is 0, 1, 2, 3, or 4.

[0010] In some aspects, provided herein is a compound of Formula (A-I-a’):or a pharmaceutically acceptable salt thereof, wherein: R1is H or F; each R4ais independently H, F, C1-8alkyl, or C1-8alkoxy; each R4bis independently H, F, C2-8alkyl, or C1-8alkoxy; ring A is phenyl or 5 or 6-membered heteroaryl; each R3is independently Cl, F, Br, C2-7alkyl, SO2C1-8alkyl, SOC1-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, SO2NH2, SO2NHC1-8alkyl, SO2N(C1-8alkyl)(C1-8alkyl), NO2, phenyl, OSO2C1-8alkyl, CONHC1-8alkyl, SC1-8alkyl, or N(C1-8alkyl)(C1-8alkyl); and n is 0, 1, 2, 3, or 4.

[0011] In some aspects, provided herein is a compound of Formula (A-II):MOFO-3609483104263722000840or a pharmaceutically acceptable salt thereof, wherein: R1is H or F; ring B is pyridine, pyrazine, pyrimidine, or pyridazine; each R3is independently F, C3-7alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, NO2, SO2NH2, SO2NHC1-8alkyl, or SO2N(C1-8alkyl)(C1-8alkyl); and n is 0, 1, 2, 3, or 4.

[0012] In some aspects, provided herein is a compound of Formula (A-II’) having the structure:or a pharmaceutically acceptable salt thereof, wherein: R1is H or F; ring B is pyridine, pyrazine, pyrimidine, or pyridazine; and wherein when ring B is pyridine; each R3is independently F, C1-7alkyl, SO2C1-8alkyl, SOC1-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, NO2, SO2NH2, SO2NHC1-8alkyl, SO2N(C1-8alkyl)(C1-8alkyl), NH2, NHC1-8alkyl, N(C1-8alkyl)(C1-8alkyl), phenyl, 3 to 8- membered heterocycle, Cl, Br, OH, S(C1-8alkyl), or COOH; provided that if ring B is 4-pyridine or 2,4 pyrimidine then the 5-position must be hydrogen; and n is 0, 1, 2, 3, or 4.

[0013] In some aspects, provided herein is a compound of Formula (A-III):or a pharmaceutically acceptable salt thereof,MOFO-3609483105263722000840 wherein: R1is H or F; ring C is furan, thiophene, benzothiophene, or benzofuran; where ring C is optionally fused with another ring; each R3is independently F, C2-8alkyl, SO2C1-8alkyl, SOC1-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, NO2, SO2NH2, SO2NHC1-8alkyl, or SO2N(C1-8alkyl)(C1-8alkyl); and n is 0, 1, 2, 3, or 4

[0014] In some aspects, provided herein is a compound of Formula (A-IV):or a pharmaceutically acceptable salt thereof, wherein: ring A is phenyl or 5 or 6-membered heteroaryl; R1is halo, H, alkyl, alkenyl, haloalkyl, or CN; w is 0-5; R10is independently optionally substituted alkyl, haloalkyl, alkoxy, phenyl, halo, NO2, SO2NH2, SO2NHC1-8alkyl, SO2N(C1-8alkyl)(C1-8alkyl), or CN; wherein the alkyl of R10is optionally substituted with halo, -NO2, -CN, -ORa, -SRa, -NRaRb, - NRaC(O)Rb, -NRaC(O)ORb, -OC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, - NRaS(O)Rb, -NRaS(O)2Rb, C1-8alkyl, haloC1-8alkyl, C2-8alkenyl, or C2-8alkynyl, each of Raand Rbis independently H or C1-6alkyl; and R11is haloalkyl, alkyl, CONH2, CONHC1-8alkyl, CON(C1-8alkyl)(C1-8alkyl), or H.

[0015] In some aspects, provided herein is a compound selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

[0016] In some aspects, provided herein is a pharmaceutical composition comprising a compound of Formula (A-I), (A-I-a), (A-II), (A-IV), (A-I’), (A-I-a’), (A-II’), (A-III), (I), (I- B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II), (II-B), (III), or (IV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.MOFO-3609483106263722000840

[0017] In some embodiments, provided herein is a method of activating H+leak across the inner mitochondrial membrane in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of the compound of Formula (A-I), (A-I-a), (A-II), (A-IV), (A-I’), (A-I-a’), (A-II’), (A-III), (I), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I- H), (I-I), (I-J), (II), (II-B), (III), or (IV), as well as the compound of Table 1, or a therapeutically effective amount of the pharmaceutical composition comprising any of the compounds of Formula (A-I), (A-I-a), (A-II), (A-IV), (A-I’), (A-I-a’), (A-II’), (A-III), (I), (I- B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II), (II-B), (III), or (IV), as well as the compound of Table 1, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

[0018] In some embodiments, provided herein is a method of activating H+leak via AAC (including AAC1-4) in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of the compound of Formula (A-I), (A-I-a), (A-II), (A-IV), (A-I’), (A-I-a’), (A-II’), (A-III), (I), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II), (II-B), (III), or (IV), as well as the compound of Table 1, or a therapeutically effective amount of the pharmaceutical composition comprising any of the compounds of Formula (A- I), (A-I-a), (A-II), (A-IV), (A-I’), (A-I-a’), (A-II’), (A-III), (I), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II), (II-B), (III), or (IV), as well as the compound of Table 1, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

[0019] In some embodiments, provided herein is a method of activating H+leak via UCP1 in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of the compound of Formula (A-I), (A-I-a), (A-II), (A-IV), (A-I’), (A-I-a’), (A-II’), (A-III), (I), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II), (II-B), (III), or (IV), as well as the compound of Table 1, or a therapeutically effective amount of the pharmaceutical composition comprising any of the compounds of Formula (A-I), (A-I-a), (A- II), (A-IV), (A-I’), (A-I-a’), (A-II’), (A-III), (I), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II), (II-B), (III), or (IV), as well as the compound of Table 1, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

[0020] In some embodiments, provided herein is a method of selectively generating H+leak across the inner mitochondrial membrane without generating H+leak across the plasma membrane in a subject in need thereof, comprising administering to said subject aMOFO-3609483107263722000840 therapeutically effective amount of the compound of Formula (A-I), (A-I-a), (A-II), (A-IV), (A-I’), (A-I-a’), (A-II’), (A-III), (I), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II), (II-B), (III), or (IV), as well as the compound of Table 1, or a therapeutically effective amount of the pharmaceutical composition comprising any of the compounds of Formula (A- I), (A-I-a), (A-II), (A-IV), (A-I’), (A-I-a’), (A-II’), (A-III), (I), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II), (II-B), (III), or (IV), as well as the compound of Table 1, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

[0021] In some embodiments, provided herein is an in vitro method of selectively generating H+leak across the inner mitochondrial membrane without generating H+leak across the plasma membrane in a cell, comprising administering to said cell a therapeutically effective amount of the compound of Formula (A-I), (A-I-a), (A-II), (A-IV), (A-I’), (A-I-a’), (A-II’), (A-III), (I), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II), (II-B), (III), or (IV), as well as the compound of Table 1, or a therapeutically effective amount of the pharmaceutical composition comprising any of the compounds of Formula (A-I), (A-I-a), (A- II), (A-IV), (A-I’), (A-I-a’), (A-II’), (A-III), (I), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II), (II-B), (III), or (IV), as well as the compound of Table 1, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

[0022] In some embodiments, provided herein is a method of increasing rate of cell respiration in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of the compound of Formula (A-I), (A-I-a), (A-II), (A-IV), (A-I’), (A-I-a’), (A-II’), (A-III), (I), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II), (II-B), (III), or (IV), as well as the compound of Table 1, or a therapeutically effective amount of the pharmaceutical composition comprising any of the compounds of Formula (A- I), (A-I-a), (A-II), (A-IV), (A-I’), (A-I-a’), (A-II’), (A-III), (I), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II), (II-B), (III), or (IV), as well as the compound of Table 1, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

[0023] In some embodiments, provided herein is an in vitro method of increasing rate of cell respiration in a cell, comprising administering to said cell a therapeutically effective amount of the compound of Formula (A-I), (A-I-a), (A-II), (A-IV), (A-I’), (A-I-a’), (A-II’), (A-III), (I), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II), (II-B), (III), or (IV), asMOFO-3609483108263722000840 well as the compound of Table 1, or a therapeutically effective amount of the pharmaceutical composition comprising any of the compounds of Formula (A-I), (A-I-a), (A-II), (A-IV), (A- I’), (A-I-a’), (A-II’), (A-III), (I), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II), (II-B), (III), or (IV), as well as the compound of Table 1, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

[0024] In some embodiments, provided herein is a method of increasing metabolic rate in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of the compound of Formula (A-I), (A-I-a), (A-II), (A-IV), (A-I’), (A-I-a’), (A-II’), (A-III), (I), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II), (II-B), (III), or (IV), as well as the compound of Table 1, or a therapeutically effective amount of the pharmaceutical composition comprising any of the compounds of Formula (A-I), (A-I-a), (A-II), (A-IV), (A- I’), (A-I-a’), (A-II’), (A-III), (I), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II), (II-B), (III), or (IV), as well as the compound of Table 1, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

[0025] In some embodiments, provided herein is a method of treating, preventing, or managing a disease, disorder or condition in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of the compound of Formula (A-I), (A-I-a), (A-II), (A-IV), (A-I’), (A-I-a’), (A-II’), (A-III), (I), (I-B), (I-C), (I-D), (I-E), (I- F), (I-G), (I-H), (I-I), (I-J), (II), (II-B), (III), or (IV), as well as the compound of Table 1, or a therapeutically effective amount of the pharmaceutical composition comprising any of the compounds of Formula (A-I), (A-I-a), (A-II), (A-IV), (A-I’), (A-I-a’), (A-II’), (A-III), (I), (I- B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II), (II-B), (III), or (IV), as well as the compound of Table 1, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient. In some embodiments of the foregoing, the disease, disorder or condition is obesity, type 2 diabetes, fatty liver disease (including, for example, NAFLD and NASH), heart failure with preserved ejection fraction (HFpEF) and polycystic ovary syndrome. In certain embodiments, the disease, disorder or condition is a neurodegenerative disease, disorder or condition. In one embodiment, the disease, disorder or condition is Alzheimer disease, Huntington's disease, Multiple Sclerosis, Traumatic Brain Injury (TBI), Duchenne Muscular Dystrophy, Parkinson's disease, stroke, or epilepsy. In some variations, the metabolic disorder is type 2 diabetes. In some variations, the metabolicMOFO-3609483109263722000840 disorder is fatty liver disease. In some variations, the metabolic disorder is polycystic ovary syndrome. DETAILED DESCRIPTION

[0026] The following description sets forth exemplary compositions, methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0027] Mitochondria convert the chemical energy of nutrients into ATP and heat. Mitochondrial ATP and heat are generated from the same energy source—voltage (∆Ψ) across the inner mitochondrial membrane (IMM) generated by the electron transport chain. For ATP production, ATP synthase passes H+down ∆Ψ and uses the released energy to generate ATP from ADP and inorganic phosphate. In contrast, heat is generated by so-called uncoupling proteins (UCPs) that pass H+down ∆Ψ without ATP production, instead letting energy dissipate as heat. H+current mediated by UCPs across the IMM is often referred to as mitochondrial H+leak. It reduces coupling of H+flows via the electron transport chain and ATP synthase, reducing the efficiency of mitochondrial ATP production and resulting in a phenomenon known as mitochondrial uncoupling. H+leak also decreases reactive oxygen species (ROS) production, protecting mitochondrial integrity (Skulachev; Korshunov, S. S. et al., FEES lett 416, 15-18 (1997)). H+leak via UCPs is activated by free long-chain fatty acids (FA) (Wojtczak, L. & Schonfeld, P., Biochim Biophys Acta 1183, 41-57 (1993)).

[0028] Uncoupling protein 1 (UCP1) is responsible for mitochondrial H+leak and heat production (thermogenesis) in the specialized thermogenic tissue brown fat (Fedorenko A et al., Cell 151, 400-13 (2012); Nicholls D.G. & Rial E., J Bioenerg Biomembr 31, 399-406 (1999)). UCP1 belongs to a family of mitochondrial solute carriers (SLC25). In other tissues, mitochondrial H+leak is primarily mediated by the mitochondrial ADP / ATP carrier (AAC) another SLC25 family member (Andreyev A., et al., Eur J Biochem 182, 585-92 (1989); Bertholet A.M., et al., Nature 571, 515-520 (2019)). AAC is a major transport protein of the IMM that exchanges mitochondrial ATP for cytosolic ADP and controls cellular ATP production. However, AAC also mediates H+leak and plays a role of UCP. The AAC-mediated H+leak requires free fatty acidsMOFO-36094831010263722000840 and resembles the H+leak via UCP1. The ADP / ATP exchange via AAC negatively regulates the H+leak but does not induce complete inhibition (Bertholet A.M., et al., Nature 571, 515-520 (2019)). This suggests that the H+leak and mitochondrial uncoupling could be dynamically controlled by cellular ATP demand and the rate of ADP / ATP exchange. By mediating two distinct transport modes, ADP / ATP exchange and H+leak, AAC intimately connects coupled (ATP production) and uncoupled (thermogenesis) energy conversion in mitochondria.

[0029] In addition to UCP1 and AAC, it was suggested that all other members of the SLC25 superfamily (the family currently has 53 members) of mitochondrial solute carriers can contribute to H+leak (Roussel, D., et al., J Bioenerg Biomembr 34, 165-176 (2002)), most notably the close UCP1 homologs UCP2 and UCP3 (Echtay, K. S., et al., Proc Natl Acad Sci US A 98, 1416-1421, (2001); Jaburek, M. et al. J Biol Chem 274, 26003-26007 (1999); Krauss, S., et al., Nat Rev Mal Cell Biol 6, 248-261 (2005)), aspartate-glutamate carrier (Samartsev, V. N. et al. Biochim Biophys Acta-Bioenergetics 1319, 251-257 (1997)), dicarboxylate carrier (Wieckowski, M. R. & Wojtczak, L., Biochem Biophys Res Commun 232, 414-417 (1997)), and phosphate carrier (Zackova, M., et al., Int J Biochem Cell Biol 32, 499-508 (2000); Engstova, H. et al., J Biol Chem 276, 4683-4691 (2001)). H+leak may also occur through the lipid phase without protein involvement (Gutknecht, J., J Membr Biol 106, 83-93 (1988)). Thus, under certain conditions and in the presence of certain activators, SLC25 family members other than UCP1 and AAC can mediate mitochondrial H+leak and its physiological effects.

[0030] Members of the mitochondrial carrier family, solute carrier family 25 (SLC25), mediate the transport of amino acids, carboxylic acids, fatty acids, cofactors, inorganic ions, and nucleotides across the mitochondrial inner membrane and are crucial for many cellular processes. They transport solutes across the impermeable inner membrane of mitochondria for important cellular processes, such as oxidative phosphorylation of fats and sugars, amino acid catabolism and interconversion, synthesis of iron sulfur clusters and heme, macromolecular synthesis, and heat production. Nucleotide transporters include the mitochondrial ADP / ATP carrier (AAC) which imports ADP into the mitochondrial matrix, where it can be converted to ATP by ATP synthase, and exports the newly synthesized ATP to the cytosol, where it fuels the metabolic energy-requiring processes that are vital for cell survival (Ruprecht J. J., et al.MOFO-36094831011263722000840 Trends in Biochemical Sciences 45, 244–258 (2020). There are four human AAC isoforms, AAC1(SLC25A4), AAC2 (SLC25A5), AAC3 (SLC25A6) and AAC4 (SLC25A31), each having a unique tissue-specific expression pattern and biological function. AAC1 is mainly expressed in muscle and brain tissue, AAC2 is preferentially expressed in proliferating tissue, AAC3 has a ubiquitous pattern of expression, and AAC4 is localized exclusively to the testis (Clemencon B., et al. Mol. Aspects Med.34, 485–493 (2013)).

[0031] Mitochondrial ATP-Mg / Pi carriers carry out the electroneutral antiport of ATP-Mg (but also ATP, ADP, and AMP) and Pi. The human isoforms include APC1(SLC25A24), APC2 (SLC25A23), APC3 (SLC25A25) and APC4 (SLC25A41). Inorganic ion transporters include the mitochondrial phosphate carrier PIC (SLC25A3) and the uncoupling protein UCP1 (SLC25A7). The aspartate / glutamate carriers AGC1 (SCL25A12) and AGC2 (SLC25A13) are examples of amino acid transporters. Other physiologically important family members include the thiamine pyrophosphate transporter TPC (SLC25A19), the carnitine / acylcarnitine carrier CAC (SLC25A20), the mitochondrial oxoglutarate carrier OGC (SLC25A11), and the tricarboxylate or citrate carrier CIC (SLC25A1).

[0032] Mitochondrial H+leak and thermogenesis represent valuable therapeutic targets for treating metabolic diseases. Activation of mitochondrial H+leak has been shown to increase body energy expenditure and induce weight loss in humans, and more recently, to reverse insulin resistance, type II diabetes, and fatty liver in rodent and primate models (Tainter ML, et al., JAMA 101, 1472-1475 (1933); Perry RJ, et al., Science 347, 1253-6 (2015); Perry RJ et al., Sci Transl Med 11, 10.1126 / scitranslmed.aay0284 (2019)). In addition, activation of mitochondrial H+leak has been shown to reduce oxidative stress and increase lifespan in rodents (Caldeira CC et al., Aging Cell 7, 552-60 (2008)). Thus, pharmacological activation of mitochondrial H+leak can be highly beneficial in various metabolic and age-related conditions (Geisler JG et al., Alzheimers Dement 13, 582-591 (2017)). Compounds capable of increasing H+leak and mitochondrial thermogenesis through activating AAC, UCP1 or other proteins of SLC25 family of mitochondrial solute carriers are needed to realize a therapeutic effect of these targets. CompoundsMOFO-36094831012263722000840

[0033] In some aspects, provided is a compound of Formula (A-I):or a pharmaceutically acceptable salt thereof, wherein: R1is H or F; R4ais H, F, C2-8alkyl, or C1-8alkoxy; R4bis H, F, C2-8alkyl, or C1-8alkoxy; ring A is phenyl or 6-membered heteroaryl; each R3is independently F, C2-7alkyl, SO2C1-8alkyl, SOC1-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, SO2NH2, SO2NHC1-8alkyl, or SO2N(C1-8alkyl)(C1-8alkyl); and n is 0, 1, 2, 3, or 4.

[0034] In some embodiments of Formula (A-I), the compound is not (E)-3-(4- isopropoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)acrylamide, (E)-3-(4- pentoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)acrylamide, (E)-3-(3- methoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)acrylamide, (E)-3-(2- fluorophenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)acrylamide, (E)-3-(4- methoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)acrylamide, (E)-3-(3-fluoro, 4-methoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)acrylamide, (E)-3-(3,4,5 trimethoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)acrylamide, (E)-3-(3,4, dimethoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)acrylamide, or (E)-3- (phenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)acrylamide.

[0035] In some embodiments, R1is F. In some embodiments, R1is H.

[0036] In some embodiments, R4ais H. In some embodiments, R4ais F. In some embodiments, R4ais C2-8alkyl. In some embodiments, R4ais C1-8alkoxy. In some embodiments, R4bis H.

[0037] In some embodiments, R4bis F. In some embodiments, R4bis C2-8alkyl. In some embodiments, R4bis C1-8alkoxy.MOFO-36094831013263722000840

[0038] In some embodiments, ring A is phenyl. In some embodiments, ring A is 6- membered heteroaryl. In some embodiments, ring A is pyridyl.

[0039] In some embodiments, R3is F. In some embodiments, R3is C2-7alkyl. In some embodiments, R3is SO2C1-8alkyl. In some embodiments, R3is SOC1-8alkyl. In some embodiments, R3is C1-8alkoxy. In some embodiments, R3is fluoroC1-8alkyl. In some embodiments, R3is CN. In some embodiments, R3is C2-8alkenyl. In some embodiments, R3is SO2NH2. In some embodiments, R3is SO2NHC1-8alkyl. In some embodiments, R3is SO2N(C1-8alkyl)(C1-8alkyl).

[0040] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0041] In some embodiments, a compound of Formula (A-I) comprises a moiety of

[0042] In some aspects, provided is a compound of Formula (A-I-a):or a pharmaceutically acceptable salt thereof, wherein: R1is H or F; each R4ais independently H, F, C1-8alkyl, or C1-8alkoxy; each R4bis independently H, F, C2-8alkyl, or C1-8alkoxy;MOFO-36094831014263722000840 ring A is phenyl or 6-membered heteroaryl; each R3is independently F, C2-7alkyl, SO2C1-8alkyl, SOC1-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, SO2NH2, SO2NHC1-8alkyl, or SO2N(C1-8alkyl)(C1-8alkyl); and n is 0, 1, 2, 3, or 4;

[0043] In some embodiments, the compound of Formula (A-I-a) is not 3-(4- methoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)propenamide, 3-(4- ethylphenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)propenamide, 3-(3- methoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)propenamide, 3-(4- fluorophenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)propenamide, 3-(3-pyridyl)-N-(5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl)propenamide, 3-(4-pyridyl)-N-(5-(trifluoromethyl)- 1,3,4-thiadiazol-2-yl)propenamide, 3-(2,4-pyrazinyl)-N-(5-(trifluoromethyl)-1,3,4- thiadiazol-2-yl)propenamide, 3-(phenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2- yl)propenamide, 3-(3, 4-dimethoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2- yl)propenamide, 3-(2-ethoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2- yl)propenamide, or 3-(phenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)propenamide.

[0044] In some embodiments, R1is F. In some embodiments, R1is H.

[0045] In some embodiments, R4ais H. In some embodiments, R4ais F. In some embodiments, R4ais C2-8alkyl. In some embodiments, R4ais C1-8alkoxy. In some embodiments, R4bis H.

[0046] In some embodiments, R4bis F. In some embodiments, R4bis C2-8alkyl. In some embodiments, R4bis C1-8alkoxy.

[0047] In some embodiments, ring A is phenyl. In some embodiments, ring A is 6- membered heteroaryl. In some embodiments, ring A is pyridyl.

[0048] In some embodiments, R3is F. In some embodiments, R3is C2-7alkyl. In some embodiments, R3is SO2C1-8alkyl. In some embodiments, R3is SOC1-8alkyl. In some embodiments, R3is C1-8alkoxy. In some embodiments, R3is fluoroC1-8alkyl. In some embodiments, R3is CN. In some embodiments, R3is C2-8alkenyl. In some embodiments, R3is SO2NH2. In some embodiments, R3is SO2NHC1-8alkyl. In some embodiments, R3is SO2N(C1-8alkyl)(C1-8alkyl).MOFO-36094831015263722000840

[0049] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0050] In some aspects, provided is a compound of Formula (A-II):or a pharmaceutically acceptable salt thereof, wherein: R1is H or F; ring B is pyridine, pyrazine, pyrimidine, or pyridazine; each R3is independently F, C3-7alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, NO2, SO2NH2, SO2NHC1-8alkyl, or SO2N(C1-8alkyl)(C1-8alkyl); and n is 0, 1, 2, 3, or 4.

[0051] In some embodiments, the compound of Formula (A-II) is not 2-fluoro-N-(5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl)nicotinamide, 2-methoxy-N-(5-(trifluoromethyl)- 1,3,4-thiadiazol-2-yl)nicotinamide, 2-isopropoxy-6-methoxy-N-(5-(trifluoromethyl)-1,3,4- thiadiazol-2-yl)isonicotinamide, 2-isobutoxy-6-methoxy-N-(5-(trifluoromethyl)-1,3,4- thiadiazol-2-yl)isonicotinamide, 2-methoxy-6-(pentyloxy)-N-(5-(trifluoromethyl)-1,3,4- thiadiazol-2-yl)isonicotinamide, 6-(2,2,2-trifluoroethoxy)-N-(5-(trifluoromethyl)-1,3,4- thiadiazol-2-yl)nicotinamide, N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)nicotinamide, N- (5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)isonicotinamide, or N-(5-(trifluoromethyl)-1,3,4- thiadiazol-2-yl)picolinamide.

[0052] In some embodiments, R1is H. In some embodiments, R1is F.

[0053] In some embodiments, ring B is pyridine. In some embodiments, ring B is pyrazine. In some embodiments, ring B is pyrimidine. In some embodiments, ring B is pyridazine.

[0054] In some embodiments, R3is F. In some embodiments, R3is C3-7alkyl. In some embodiments, R3is C1-8alkoxy. In some embodiments, R3is fluoroC1-8alkyl. In some embodiments, R3is CN. In some embodiments, R3is C2-8alkenyl. In some embodiments,MOFO-36094831016263722000840 R3is NO2. In some embodiments, R3is SO2NH2. In some embodiments, R3is SO2NHC1-8alkyl. In some embodiments, R3is SO2N(C1-8alkyl)(C1-8alkyl).

[0055] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 1, 2, 3, or 4.

[0056] In some aspects, provided is a compound of Formula (A-IV) having the structure:or a pharmaceutically acceptable salt thereof, wherein: ring A is phenyl or 5 or 6-membered heteroaryl; R1is halo, H, alkyl, alkenyl, haloalkyl, or CN; w is 0-5; R10is independently optionally substituted alkyl, haloalkyl, alkoxy, phenyl, halo, NO2, SO2NH2, SO2NHC1-8alkyl, SO2N(C1-8alkyl)(C1-8alkyl), or CN; wherein the alkyl of R10is optionally substituted with halo, -NO2, -CN, -ORa, -SRa, -NRaRb, - NRaC(O)Rb, -NRaC(O)ORb, -OC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, - NRaS(O)Rb, -NRaS(O)2Rb, C1-8alkyl, haloC1-8alkyl, C2-8alkenyl, or C2-8alkynyl, each of Raand Rbis independently H or C1-6alkyl; and R11is haloalkyl, alkyl, CONH2, CONHC1-8alkyl, CON(C1-8alkyl)(C1-8alkyl), or H.

[0057] In some embodiments, ring A is phenyl. In some embodiments, ring A is 5 membered heteroaryl. In some embodiments, ring A is 6-membered heteroaryl.

[0058] In some embodiments, R1is halo. In some embodiments, R1is H. In some embodiments, R1is alkyl. In some embodiments, R1is alkenyl. In some embodiments, R1is haloalkyl. In some embodiments, R1is CN.

[0059] In some embodiments, w is 0. In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4. In some embodiments, w is 5.MOFO-36094831017263722000840

[0060] In some embodiments, R10is unsubstituted alkyl or alkyl substituted with halo, - NO2, -CN, -ORa, -SRa, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -OC(O)Ra, -C(O)Ra, - C(O)ORa, -C(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, C1-8alkyl, haloC1-8alkyl, C2-8alkenyl, or C2-8alkynyl, each of Raand Rbis independently H or C1-6alkyl.

[0061] In some embodiments, R10is haloalkyl. In some embodiments, R10is alkoxy. In some embodiments, R10is phenyl. In some embodiments, R10is halo. In some embodiments, R10is NO2. In some embodiments, R10is SO2NH2. In some embodiments, R10is SO2NHC1-8alkyl. In some embodiments, R10is SO2N(C1-8alkyl)(C1-8alkyl). In some embodiments, R10is CN.

[0062] In some embodiments, R11is haloalkyl. In some embodiments, R11is alkyl. In some embodiments, R11is CONH2. In some embodiments, R11is CONHC1-8alkyl. In some embodiments, R11is CON(C1-8alkyl)(C1-8alkyl). In some embodiments, R11is H.

[0063] In some aspects, provided is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: R1is halo, H, alkyl, alkenyl, haloalkyl, or CN; and, wherein each of the foregoing is optionally substituted.

[0064] In some embodiments, R2is. In some embodiments, R2issome embodiments, R2is. In some embodiments, R2is. In someMOFO-36094831018263722000840 embodiments, R2issome embodiments, R2is. In some embodiments, R2is. In some embodiments, R2 is. In some embodiments, R2issome embodiments, R2issubstituted with one or more Rx.

[0065] In some embodiments, each Rxis independently C1-8alkyl, C1-8alkoxy, phenyl, haloC1-8alkyl, halo, OH, NO2, C(O)Rx1, or CN; wherein the C1-8alkoxy of Rxis optionally substituted with cyclopropyl; the phenyl of Rxis unsubstituted or substituted with C1-8alkyl or halo; Rx1is phenyl substituted with halo, C1-8alkyl, or unsubstituted 5 to 6-membered heteroaryl.

[0066] In some embodiments, Rxis C1-8alkyl. In some embodiments, Rxis C1-8alkoxy. In some embodiments, Rxis phenyl. In some embodiments, Rxis haloC1-8alkyl. In some embodiments, Rxis halo. In some embodiments, Rxis OH. In some embodiments, Rxis NO2. In some embodiments, Rxis C(O)Rx1. In some embodiments, Rxis CN. In some embodiments, the C1-8alkoxy of Rxis optionally substituted with cyclopropyl. In some embodiments, the phenyl of Rxis unsubstituted or substituted with C1-8alkyl or halo. In some embodiments, Rx1is phenyl substituted with halo. In some embodiments, Rx1is C1-8alkyl. In some embodiments, Rx1is unsubstituted 5 to 6-membered heteroaryl.

[0067] In some aspects, provided is a compound of Formula (I-B):or a pharmaceutically acceptable salt thereof, wherein:MOFO-36094831019263722000840 R1is as defined for Formula (I); n is 0-3; and Rbis alkyl, alkoxy, phenyl, or halo; or when at least two Rbare present, two adjacent Rbcombine to form a ring that optionally contains one or more heteroatoms, wherein the ring formed is optionally substituted, optionally, wherein the ring formed is optionally substituted with alkyl.

[0068] In some aspects, provided is a compound of Formula (I-C):or a pharmaceutically acceptable salt thereof, wherein: R1is as defined for Formula (I); n is 0-3; and Rcis alkyl, haloalkyl, or halo.

[0069] In some aspects, provided is a compound of Formula (I-D):or a pharmaceutically acceptable salt thereof, wherein: R1is as defined for Formula (I); n is 0-3; and Rdis alkyl, or halo.

[0070] In some aspects, provided is a compound of Formula (I-E):or a pharmaceutically acceptable salt thereof, wherein: R1is as defined for Formula (I);MOFO-36094831020263722000840 n is 0-2; and Reis alkyl.

[0071] In some aspects, provided is a compound of Formula (I-F):or a pharmaceutically acceptable salt thereof, wherein: R1is as defined for Formula (I); Rfis: alkyl, or phenyl, optionally substituted with alkyl.

[0072] In some aspects, provided is a compound of Formula (I-G):or a pharmaceutically acceptable salt thereof, wherein: R1is as defined for Formula (I); and Rgis: alkyl, phenyl, optionally substituted with halo, or 5-membered heterocyclyl containing at least heteroatom selected from S and O.

[0073] In some variations, the 5-membered heterocyclyl is thiophenyl or furanyl.

[0074] In some aspects, provided is a compound of Formula (I-H):MOFO-36094831021263722000840 or a pharmaceutically acceptable salt thereof, wherein: R1is as defined for Formula (I); Rhis phenyl, optionally substituted with halo.

[0075] In some aspects, provided is a compound of Formula (I-I):or a pharmaceutically acceptable salt thereof, wherein: R1is as defined for Formula (I).

[0076] In some embodiments, the compound is a compound of Formula (I-I’):or a pharmaceutically acceptable salt thereof, wherein R1is as defined for Formula (I); and R3is independently F, C3-7alkyl, SO2C1-8alkyl, SOC1-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, or NO2; and n is 0, 1, 2, 3, or 4.

[0077] In some aspects, provided is a compound of Formula (I-J):or a pharmaceutically acceptable salt thereof, wherein: R1is as defined for Formula (I); q is 0-4; and Rjis alkyl.

[0078] In some aspects, provided is a compound of Formula (II) or (III):MOFO-36094831022263722000840or a pharmaceutically acceptable salt thereof, wherein: R1is halo, H, alkyl, alkenyl, haloalkyl, or CN; p is 0-5; R3is alkoxy, halo, -NO2, or cyano; or when at least two R3are present, two adjacent R3combine to form a ring that optionally contains one or more heteroatoms, wherein the ring formed is optionally substituted, optionally, wherein one or more of the heteroatoms of the ring is O; and each R4aand R4bis H, alkyl, alkoxy, halo, or CN.

[0079] In some embodiments of Formula (II) or (III), R4aand R4bis H, alkyl, alkoxy, or halo; R3is independently optionally substituted alkoxy, alkyl, alkenyl, halo, haloalkyl, -NO2, or CN; or when at least two R3are present, two adjacent R3combine to form a ring that optionally contains one or more heteroatoms, wherein the ring formed is optionally substituted.

[0080] In certain aspects, provided is compound of Formula (II-B):or a pharmaceutically acceptable salt thereof, wherein: R1is halo, H, alkyl, alkenyl, haloalkyl, or CN; R3ais CN, halo, haloalkyl, alkoxy, alkyl, or alkenyl; R3bis H, halo, haloalkyl, alkoxy, alkyl, or alkenyl; each R4aand R4bis H or alkyl.

[0081] In some variations of Formula (II-B), when R3bis H, then R3ais other than halo, OCF2H, CH3, and OCH3.

[0082] In some embodiments of the foregoing, the haloalkyl is CF3.MOFO-36094831023263722000840

[0083] In some aspects, provided is a compound of Formula (IV):or a pharmaceutically acceptable salt thereof, wherein: R1is halo, H, alkyl, alkenyl, haloalkyl, or CN; w is 0-5; R10is alkyl, haloalkyl, alkoxy, phenyl, halo or CN; and R11is haloalkyl, alkyl or H.

[0084] In some embodiments, R10is alkyl, haloalkyl, alkoxy, phenyl, halo, SOC1-8alkyl, SO2C1-8alkyl, or CN.

[0085] In some variations of the foregoing, R10is alkoxy. In other variations, the haloalkyl is fluoroalkyl.

[0086] In some embodiments, R1is halo, alkyl, or CN. In some variations, R1is halo. In certain variations, R1is F. In other variations, R1is alkyl. In certain variations, R1is C1-4 alkyl. In certain variations, R1is methyl. In yet other variations, R1is CN.

[0087] In some embodiments of Formula (IV), R10is independently optionally substituted alkyl, haloalkyl, alkoxy, phenyl, halo, NO2, SO2NH2, SO2NHC1-8alkyl, SO2N(C1-8alkyl)(C1-8alkyl), or CN; and R11is haloalkyl, alkyl, CONH2, CONHC1-8alkyl, CON(C1-8alkyl)(C1-8alkyl), or H.

[0088] In some embodiments of the foregoing, the compound of Formula (A-I), (A-I-a), (A-II), (A-IV), (I), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II), (III), or (IV) is other than Compounds C1-C50 (as set forth in Table 1), or a pharmaceutically acceptable salt thereof, as the case may apply.

[0089] It should be understood that the compounds of the present disclosure also include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted.

[0090] In some variations, the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers,MOFO-36094831024263722000840 are intended unless otherwise indicated. In some variations, compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms.

[0091] In some variations, the tautomeric forms of the compounds described herein result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Examples prototropic tautomers include ketone – enol pairs, amide – imidic acid pairs, lactam – lactim pairs, amide – imidic acid pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 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 sterically locked into one form by appropriate substitution.

[0092] It should be noted that the compounds of the present disclosure also include all of the isotopes of the atoms occurring in the intermediate or final compounds. “Isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium.

[0093] As used herein, in some variations, “alkyl”, by itself or as part of another substituent, refers to a monoradical unbranched or branched saturated hydrocarbon chain. In some embodiments, alkyl has 1 to 20 carbon atoms (i.e., C1-20alkyl), 1 to 8 carbon atoms (i.e., C1-8alkyl), 1 to 6 carbon atoms (i.e., C1-6alkyl), or 1 to 4 carbon atoms (i.e., C1-4alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed; thus, for example, “butyl” can include n-butyl, sec-butyl, isobutyl and t-butyl; “propyl” can include n-propyl and isopropyl.MOFO-36094831025263722000840

[0094] As used herein, in some variations, “alkenyl” refers to an unsaturated hydrocarbon group having at least one site of olefinic unsaturation (e.g., having at least one moiety of the formula C=C). In some embodiments, alkenyl has 2 to 20 carbon atoms (i.e., C2-20alkenyl), 2 to 8 carbon atoms (i.e., C2-8alkenyl), 2 to 6 carbon atoms (i.e., C2-6alkenyl), or 2 to 4 carbon atoms (i.e., C2-4alkenyl).

[0095] In some variations, “alkoxy” refers to the group –OR, where R is alkyl attached through the oxygen bridge. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy.

[0096] In some variations, the term “substituted”, as used herein, means that any one or more hydrogen atoms on the designated atom or group is replaced with a moiety other than hydrogen, provided that the designated atom’s normal valence is not exceeded.

[0097] As used herein, the symbol whether as a bond or displayed perpendicular to a bond indicates the point at which the displayed moiety is attached to the remainder of the molecule.

[0098] In some aspects, provided is a compound selected from a compound of Table 1 below, or a pharmaceutically acceptable salt thereof, including any isomers and tautomers thereof. Table 1. Exemplary CompoundsMOFO-36094831026263722000840MOFO-36094831027263722000840MOFO-36094831028263722000840MOFO-36094831029263722000840MOFO-36094831030263722000840MOFO-36094831031263722000840MOFO-36094831032263722000840MOFO-36094831033263722000840MOFO-36094831034263722000840MOFO-36094831035263722000840MOFO-36094831036263722000840MOFO-36094831037263722000840MOFO-36094831038263722000840MOFO-36094831039263722000840MOFO-36094831040263722000840MOFO-36094831041263722000840MOFO-36094831042263722000840MOFO-36094831043263722000840MOFO-36094831044263722000840MOFO-36094831045263722000840MOFO-36094831046263722000840MOFO-36094831047263722000840MOFO-36094831048263722000840MOFO-36094831049263722000840MOFO-36094831050263722000840MOFO-36094831051263722000840MOFO-36094831052263722000840MOFO-36094831053263722000840MOFO-36094831054263722000840MOFO-36094831055263722000840MOFO-36094831056263722000840MOFO-36094831057263722000840MOFO-36094831058263722000840

[0099] In some aspects, provided is a compound selected from the below, or a pharmaceutically acceptable salt thereof: N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]3-(p-propoxyphenyl)propionamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(4-butoxy-3-methoxyphenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(o-cyanophenyl)acrylamide N-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(p-methoxyphenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-propyl-3-thenamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-propyl-3-isoxazolecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-1-propyl-3-pyrazolecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(p-methoxyphenyl)methacrylamide (E)-2-[(p-propoxyphenyl)methylene]-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]hydrazine N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-4-propoxy-2-thenamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]3-(o-cyanophenyl)propionamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2,3-difluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2,6-difluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-butoxy-2-pyridinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2-cyano-4-methoxyphenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2,4-difluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-6-butoxynicotinamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2-cyano-6-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2-cyano-3-fluorophenyl)acrylamideMOFO-36094831059263722000840 N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(Z)-3-(o-cyanophenyl)-2-fluoroacrylamide (E)-2-[(p-methoxyphenyl)methylene]-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]hydrazine (E)-2-{[p-(2-methoxyethoxy)phenyl]methylene}-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2- yl]hydrazine (E)-4-((2-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)hydrazineylidene)methyl)benzonitrile N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(Z)-3-(o-cyanophenyl)-2-methoxyacrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-2-cyano-3-(o-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(3-fluoro-2-pyridyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-butoxy-2-pyrazinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2,5-difluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(3,5-difluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-6-butoxy-3-pyridazinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-2-butoxy-5-pyrimidinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(4-cyano-2,6- difluorophenyl)methacrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(4-ethoxy-2,6-difluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(5-fluoro-2-pyridyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(5-cyano-2-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(4-cyano-2,6-difluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2-pyrazinyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(5-fluoro-2-pyrimidinyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2,3-difluorophenyl)methacrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-6-cyano-4-fluoro-1-benzothiophene-2- carboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(3-cyano-2-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(3,5-difluoro-2-pyridyl)acrylamide N,N-dimethyl3,5-difluoro-4-[(E)-2-[N-5-(trifluoromethyl)-1,3,4-thiadiazol-2- ylcarbamoyl]ethenyl]benzamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(5-cyano-2-pyridyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-butoxy-2-pyrimidinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2,6-difluoro-4-propylphenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(3-pyridazinyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(4-cyano-2-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(Z)-3-(2,3-difluorophenyl)-2-fluoroacrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-6-cyano-4-fluoro-1-benzofuran-2-carboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-(cyclopropylmethoxy)-2-pyridinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-(cyclopropylmethoxy)-2- pyrimidinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-(2-cyclopropylethoxy)-2-pyridinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-[4-(ethylsulfonyl)-2,6- difluorophenyl]acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(Z)-3-(2,3-difluorophenyl)-3-fluoroacrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-6-(cyclopropylmethoxy)nicotinamideMOFO-36094831060263722000840 N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-6-(2-cyclopropylethoxy)nicotinamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-6-(cyclopropylmethoxy)-3-fluoro-2- pyridinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2,6-difluoro-4-mesylphenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2-fluoro-4-mesylphenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(p-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(m-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(m-cyanophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(p-cyanophenyl)acrylamide; and (E)-2-(2-(2,2,2-trifluoro-1-phenylethylidene)hydrazineyl)-5-(trifluoromethyl)-1,3,4- thiadiazole.

[0100] In some aspects, provided is a compound selected from the below, or a pharmaceutically acceptable salt thereof, including any isomers and tautomers thereof: N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]3-(p-propoxyphenyl)propionamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(4-butoxy-3-methoxyphenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(o-cyanophenyl)acrylamide N-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(p-methoxyphenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-propyl-3-thenamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-propyl-3-isoxazolecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-1-propyl-3-pyrazolecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(p-methoxyphenyl)methacrylamide 2-[(p-propoxyphenyl)methylene]-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]hydrazine N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-4-propoxy-2-thenamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]3-(o-cyanophenyl)propionamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(2,3-difluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(2,6-difluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-butoxy-2-pyridinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(2-cyano-4-methoxyphenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(2,4-difluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-6-butoxynicotinamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(2-cyano-6-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(2-cyano-3-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(o-cyanophenyl)-2-fluoroacrylamide 2-[(p-methoxyphenyl)methylene]-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]hydrazine 2-{[p-(2-methoxyethoxy)phenyl]methylene}-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2- yl]hydrazine 4-((2-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)hydrazineylidene)methyl)benzonitrile N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(o-cyanophenyl)-2-methoxyacrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-2-cyano-3-(o-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(3-fluoro-2-pyridyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-butoxy-2-pyrazinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(2,5-difluorophenyl)acrylamideMOFO-36094831061263722000840 N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(3,5-difluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-6-butoxy-3-pyridazinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-2-butoxy-5-pyrimidinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(4-cyano-2,6-difluorophenyl)methacrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(4-ethoxy-2,6-difluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(5-fluoro-2-pyridyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(5-cyano-2-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(4-cyano-2,6-difluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(2-pyrazinyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(5-fluoro-2-pyrimidinyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(2,3-difluorophenyl)methacrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-6-cyano-4-fluoro-1-benzothiophene-2- carboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(3-cyano-2-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(3,5-difluoro-2-pyridyl)acrylamide N,N-dimethyl3,5-difluoro-4-[2-[N-5-(trifluoromethyl)-1,3,4-thiadiazol-2- ylcarbamoyl]ethenyl]benzamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(5-cyano-2-pyridyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-butoxy-2-pyrimidinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(2,6-difluoro-4-propylphenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(3-pyridazinyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(4-cyano-2-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(2,3-difluorophenyl)-2-fluoroacrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-6-cyano-4-fluoro-1-benzofuran-2-carboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-(cyclopropylmethoxy)-2-pyridinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-(cyclopropylmethoxy)-2- pyrimidinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-(2-cyclopropylethoxy)-2-pyridinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-[4-(ethylsulfonyl)-2,6- difluorophenyl]acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(2,3-difluorophenyl)-3-fluoroacrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-6-(cyclopropylmethoxy)nicotinamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-6-(2-cyclopropylethoxy)nicotinamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-6-(cyclopropylmethoxy)-3-fluoro-2- pyridinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(2,6-difluoro-4-mesylphenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(2-fluoro-4-mesylphenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(p-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(m-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(m-cyanophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(p-cyanophenyl)acrylamide; and 2-(2-(2,2,2-trifluoro-1-phenylethylidene)hydrazineyl)-5-(trifluoromethyl)-1,3,4-thiadiazole.MOFO-36094831062263722000840

[0101] In some embodiments, provided is a compound selected from the group consisting of:MOFO-36094831063263722000840stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Preparation of the Compounds

[0102] The compounds provided herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. In some aspects, the compounds provided herein may be prepared in accordance with the procedures set forth in the Examples below.

[0103] The reactions for preparing compounds provided herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which 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.

[0104] Preparation of 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 T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.MOFO-36094831064263722000840

[0105] Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.,1H or13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0106] The expressions, “ambient temperature,” “room temperature,” and “RT”, as used herein, are understood in the art, and refer generally to a temperature, e.g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 ºC to about 30 ºC.

[0107] Compounds of Formula (I) can be prepared according to numerous preparatory routes known in the literature. Example synthetic methods for preparing compounds of the invention are provided in the Schemes below. Unless noted otherwise, all substituents are as defined herein.

[0108] For example, compounds with the alpha, beta (a,b) unsaturated double bond can be made using Scheme 1 below. Scheme 1: Synthesis of alpha, beta (a,b) unsaturated compounds

[0109] The appropriately substituted ketone can be reacted with a phosphorous ylid ester to form ester (1-2). Alternatively, an ester enolate can be reacted with (1-1) and the subsequent alcohol can be eliminated forming the double bond. The a,b unsaturated ester (1- 2) can then be hydrolyzed under basic conditions to form the acid. The acid can be coupled directly with the aminothiadiazole or converted to the acid chloride which can be reacted with the aminothiadiazole under basic conditions to form (1-3).MOFO-36094831065263722000840 Scheme 2: Synthesis of hydrazone compounds

[0110] With reference to Scheme 2 above, the compounds containing a hydrazone linker (2-3) can be synthesized by taking the corresponding hydrazine (2-1a) and reacting it with a phenyl ketone or aldehyde under acidic or basic conditions. Alternatively, you can start with a primary phenyl hydrazone (2-2b) and use a suitable catalyst (e.g., palladium catalysts) to form the CN bond to generate (2-3). Pharmaceutical Compositions and Formulations of the Compounds

[0111] In certain aspects, provided is a pharmaceutical composition comprising any of the compounds, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient. Such compounds include the compounds of Formula (I), as well as the compounds of Table 1, or pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts

[0112] In some variation, “pharmaceutically acceptable salts”, as used herein, includes derivatives of the active compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. In some variations, “pharmaceutically acceptable salts”, as used herein, includes salts of the active compounds which are prepared with relatively nontoxic bases, depending on the particular substituents found on the compounds described herein. Examples of pharmaceutically acceptable salts include alkali or organic salts of the compounds described herein, including lithium, sodium, potassium, ammonium, and arginine salts.MOFO-36094831066263722000840

[0113] In some variations, the neutral forms of the compounds disclosed herein are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. In some embodiments, the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound.

[0114] In some variations, the compounds and pharmaceutical salts of the present disclosure can be prepared in combination with solvent or water molecules to form solvates and hydrates by routine methods. Formulations

[0115] Formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the compounds disclosed herein into association with an excipient and / or one or more other accessory ingredients, and then, if necessary and / or desirable, dividing, shaping and / or packaging the product into a desired single- or multi-dose unit.

[0116] For the purposes of the present disclosure, the phrase “active ingredient” generally refers to the compound or the pharmaceutical acceptable salt thereof as described herein.

[0117] In some variations, a pharmaceutical composition in accordance with the disclosure may be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. In some embodiments, a “unit dose” is discrete amount of the pharmaceutical composition comprising a predetermined amount of the compounds disclosed herein. In some embodiments, the amount of the active ingredient is generally equal to the dosage of the compound which would be administered to a subject and / or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

[0118] In some variations, relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition in accordance with the disclosure will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. In some embodiments, the composition may comprise between 0.1% andMOFO-36094831067263722000840 100%, e.g., between .5 and 50%, between 1-30%, between 5-80%, at least 80% (w / w) compound.

[0119] In some variations, the compounds of the present disclosure can be formulated using one or more suitable excipients to: (1) increase stability; (2) permit the sustained or delayed release; (3) alter the biodistribution; (4) alter the release profile of the compounds in vivo.

[0120] In some variations, pharmaceutical formulations may comprise a pharmaceutically acceptable excipient, which, as used herein, includes any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as suited to the particular dosage form desired. Except insofar as any conventional excipient medium is incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this disclosure.

[0121] In some embodiments, a pharmaceutically acceptable excipient is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% pure. In some embodiments, an excipient is approved for use in humans and for veterinary use. In some embodiments, an excipient is approved by United States Food and Drug Administration. In some embodiments, an excipient is pharmaceutical grade. In some embodiments, an excipient meets the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and / or the International Pharmacopoeia.

[0122] Pharmaceutically acceptable excipients used in the manufacture of pharmaceutical compositions include, but are not limited to, inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Such excipients may optionally be included in pharmaceutical compositions.

[0123] In some variations, the term “pharmaceutically acceptable”, as used herein, refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems orMOFO-36094831068263722000840 complications commensurate with a reasonable benefit / risk ratio, in accordance with the guidelines of agencies such as the U.S. Food and Drug Administration. A “pharmaceutically acceptable carrier,” as used herein, refers to all components of a pharmaceutical formulation that facilitate the delivery of the composition in vivo. Pharmaceutically acceptable carriers include, but are not limited to, diluents, preservatives, binders, lubricants, disintegrators, swelling agents, fillers, stabilizers, and combinations thereof.

[0124] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to any other animal, e.g., to non-human animals or specifically, e.g., non-human mammals. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions is contemplated include, but are not limited to, humans and / or other primates; mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, dogs, mice, and / or rats; and / or birds, including commercially relevant birds such as poultry, chickens, ducks, geese, and / or turkeys. Methods of Use

[0125] In certain aspects, provided is a method of treating a disease or condition in a subject in need thereof, comprising administering a therapeutically effective amount of any of the compounds, or pharmaceutically acceptable salts thereof, or compositions, including pharmaceutical compositions, described herein. Such compounds include the compounds of Formula (A-I), (A-I-a), (A-II), (A-IV), (I), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II), (III), or (IV), as well as the compounds of Table 1 and in the Examples, or pharmaceutically acceptable salts thereof. In some aspects, provided is a method of treating a disease or condition in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (A-I’), (A-I-a’), (A-II’), (A-III), or (A-IV), or pharmaceutically acceptable salts thereof.

[0126] It is understood that any of the compounds described herein can be used in any of the method of treatment described herein. For example, provided herein is method of treatingMOFO-36094831069263722000840 obesity, overweight, insulin resistance, glucose intolerance, prediabetes, type 2 diabetes, metabolic syndrome; fatty liver disease including NAFLD and NASH, alcoholic fatty liver disease and steatohepatitis, hepatic fibrosis, cirrhosis; dyslipidemia, hyperlipidemia, hypercholesterolemia; coronary artery disease, hypertension, atherosclerosis, thrombosis, peripheral vascular disease, heart failure including HFpEF, HFrEF, and congestive heart failure; obesity-induced asthma and airway dysfunction; HIV-related (HAART-induced) lipodystrophy; polycystic ovary syndrome; Alzheimer disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis, traumatic brain injury, Duchenne muscular dystrophy, stroke, or epilepsy. In some embodiments, the method comprises administering to a subject in need thereof a compound described herein or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, including, for example, compounds of Formula (A- I), (A-I-a), (A-II), (A-IV), (I), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (II), (III), (IV), (A-I’), (A-I-a’), (A-II’), or (A-III), and compounds of Table 1 (e.g. C1-C51 and D1-D66).

[0127] In some aspects, provided is a method of treating a disease or disorder, wherein the method comprises administering to a subject in need thereof a compound of Formula (A- I’) having the structure:or a pharmaceutically acceptable salt thereof, wherein: R1is H or F; R4ais H, F, C1-8alkyl, or C1-8alkoxy; R4bis H, F, C2-8alkyl, or C1-8alkoxy; ring A is phenyl or 5 or 6-membered heteroaryl; each R3is independently Cl, F, Br, C2-7alkyl, SO2C1-8alkyl, SOC1-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, SO2NH2, SO2NHC1-8alkyl, SO2N(C1-8alkyl)(C1-8alkyl), NO2, phenyl, OSO2C1-8alkyl, CONHC1-8alkyl, SC1-8alkyl, or N(C1-8alkyl)(C1- 8alkyl); and n is 0, 1, 2, 3, or 4; and wherein the disease or disorder is not cancer.MOFO-36094831070263722000840

[0128] In some aspects, provided is a method of treating a disease or disorder, wherein the method comprises administering to a subject in need thereof a compound of Formula (A- I-a’) having the structure:or a pharmaceutically acceptable salt thereof, wherein: R1is H or F; each R4ais independently H, F, C1-8alkyl, or C1-8alkoxy; each R4bis independently H, F, C2-8alkyl, or C1-8alkoxy; ring A is phenyl or 5 or 6-membered heteroaryl; each R3is independently Cl, F, Br, C2-7alkyl, SO2C1-8alkyl, SOC1-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, SO2NH2, SO2NHC1-8alkyl, SO2N(C1-8alkyl)(C1-8alkyl), NO2, phenyl, OSO2C1-8alkyl, CONHC1-8alkyl, SC1-8alkyl, or N(C1-8alkyl)(C1-8alkyl); and n is 0, 1, 2, 3, or 4; and wherein the disease or disorder is not cancer.

[0129] In some aspects, provided is a method of treating a disease or disorder, wherein the method comprises administering to a subject in need thereof a compound of Formula (A- II’) having the structure:or a pharmaceutically acceptable salt thereof, wherein: R1is H or F; ring B is pyridine, pyrazine, pyrimidine, or pyridazine; and wherein when ring B is pyridine; each R3is independently F, C1-7alkyl, SO2C1-8alkyl, SOC1-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, NO2, SO2NH2, SO2NHC1-8alkyl, SO2N(C1-MOFO-36094831071263722000840 8alkyl)(C1-8alkyl), NH2, NHC1-8alkyl, N(C1-8alkyl)(C1-8alkyl), phenyl, 3 to 8- membered heterocycle, Cl, Br, OH, S(C1-8alkyl), or COOH; provided that if ring B is 4-pyridine or 2,4 pyrimidine then the 5-position must be hydrogen; and n is 0, 1, 2, 3, or 4.

[0130] In some aspects, provided is a method of treating a disease or disorder, wherein the method comprises administering to a subject in need thereof a compound of Formula (A- III) having the structure:or a pharmaceutically acceptable salt thereof, wherein: R1is H or F; ring C is furan, thiophene, benzothiophene, or benzofuran; where ring C is optionally fused with another ring; each R3is independently F, C2-8alkyl, SO2C1-8alkyl, SOC1-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, NO2, SO2NH2, SO2NHC1-8alkyl, or SO2N(C1-8alkyl)(C1-8alkyl); and n is 0, 1, 2, 3, or 4.

[0131] In some embodiments, each R3is independently F, C2-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, NO2, SO2NH2, SO2NHC1-8alkyl, or SO2N(C1-8alkyl)(C1-8alkyl).

[0132] Formula (A-IV) having the structure:or a pharmaceutically acceptable salt thereof, wherein: ring A is phenyl or 5 or 6-membered heteroaryl; R1is halo, H, alkyl, alkenyl, haloalkyl, or CN; w is 0-5;MOFO-36094831072263722000840 R10is independently optionally substituted alkyl, haloalkyl, alkoxy, phenyl, halo, NO2, SO2NH2, SO2NHC1-8alkyl, SO2N(C1-8alkyl)(C1-8alkyl), or CN; wherein the alkyl of R10is optionally substituted with halo, -NO2, -CN, -ORa, -SRa, -NRaRb, - NRaC(O)Rb, -NRaC(O)ORb, -OC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, - NRaS(O)Rb, -NRaS(O)2Rb, C1-8alkyl, haloC1-8alkyl, C2-8alkenyl, or C2-8alkynyl, each of Raand Rbis independently H or C1-6alkyl; and R11is haloalkyl, alkyl, CONH2, CONHC1-8alkyl, CON(C1-8alkyl)(C1-8alkyl), or H.

[0133] In some aspects, provided is a method of treating a disease or disorder, wherein the method comprises administering to a subject in need thereof a compound is: N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-4-methoxy-2-thenamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-4-methyl-5-phenyl-2-thenamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-methyl-4-phenyl-3-thenamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-1-methyl-5-pyrazolecarboxamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-bromo-2-furamide,N-[5-(trifluoromethyl)-1,3,4- thiadiazol-2-yl]-2,5-dimethyl-3-furamide, N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5- methyl-3-isoxazolecarboxamide, N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-4-bromo-5- ethyl-2-thenamide, N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-methyl-3-thenamide, N- [5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-1-thia-5,6,7,8-tetrahydro-4H-azulene-2- carboxamide, N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-ethyl-1-thia-4,5,6,7- tetrahydro-2-indenecarboxamide, N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-2-methyl-3- furamide, N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-4-chloro-1-methyl-5- pyrazolecarboxamide, N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-1-butyl-5-oxo-3- pyrrolidinecarboxamide, N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-2-thenamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-1-pivaloyl-3-piperidinecarboxamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-1-(2-thenoyl)-4-piperidinecarboxamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-1-(p-fluorobenzoyl)-4-piperidinecarboxamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-1-(2-furoyl)-4-piperidinecarboxamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-1-pivaloyl-4-piperidinecarboxamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-1-(m-fluorobenzoyl)-4-piperidinecarboxamide, N- [5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-oxo-1-(o-tolyl)-3-pyrrolidinecarboxamide, N- [5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl][4-(o-fluorophenyl)-1-piperazinyl]acetamide, N-MOFO-36094831073263722000840 [5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-methyl-2-furamide,N-[5-(trifluoromethyl)- 1,3,4-thiadiazol-2-yl]-3,5-dimethyl-4-isoxazolecarboxamide, N-[5-(trifluoromethyl)-1,3,4- thiadiazol-2-yl]nicotinamide,N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-1-(o- chlorobenzoyl)-4-piperidinecarboxamide, N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-4,5- dimethyl-3-thenamide, N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-ethyl-2-thenamide, N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-chloro-2-thenamide, N-[5-(trifluoromethyl)- 1,3,4-thiadiazol-2-yl]-5-methyl-1-thia-4,5,6,7-tetrahydro-2-indenecarboxamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-1-(p-chlorobenzoyl)-4-piperidinecarboxamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-1-thia-4,5,6,7-tetrahydro-3-indenecarboxamide, N- [5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-1-thia-4,5,6,7-tetrahydro-2-indenecarboxamide, N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-[p-(pentyloxy)phenyl]acrylamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(p-isopropoxyphenyl)acrylamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(o-fluorophenyl)acrylamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(o-nitrophenyl)acrylamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(3,4,5-trimethoxyphenyl)acrylamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2H-1,3-benzodioxol-5-yl)acrylamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(p-nitrophenyl)acrylamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(3,4-dimethoxyphenyl)acrylamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(m-nitrophenyl)acrylamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(p-methoxyphenyl)acrylamide, N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-2-methylcinnamamide, N-[5-(trifluoromethyl)- 1,3,4-thiadiazol-2-yl]-(E)-3-(p-chlorophenyl)acrylamide, N-[5-(trifluoromethyl)-1,3,4- thiadiazol-2-yl]-3-methyl-1-benzofuran-2-carboxamide, or N-[5-(trifluoromethyl)-1,3,4- thiadiazol-2-yl]3-(p-methoxyphenyl)propionamide, or a pharmaceutically acceptable salt thereof.

[0134] In some aspects, methods of using the compounds are provided. In some embodiments, the present disclosure describes methods of treating a metabolic disorder. The method may include administering to a subject in need thereof an effective amount of an agent inducing H+leak across the inner mitochondrial membrane. In some embodiments, the method may include administering to a subject in need thereof an effective amount of an agent inducing H+leak via AAC. In some embodiments, the method may include administering to a subject in need thereof an effective amount of an agent inducing H+leak via UCP1. In some embodiments, the method may include administering to a subject in needMOFO-36094831074263722000840 thereof an effective amount of the compounds or pharmaceutically acceptable salts thereof, as described herein. In some embodiments, the method may include administering to a subject in need thereof an effective amount of the compounds.

[0135] In some embodiments, the present disclosure provides compounds and compositions for modulating, such as activating, H+leak across the inner mitochondrial membrane. In some embodiments, compounds and compositions of the present disclosure activate H+leak without increasing H+current across the plasma membrane. In some embodiments, compounds and compositions of the present disclosure activate H+leak via any protein associated with the IMM. Non-limiting examples of the IMM proteins involved include AAC, UCP1, or other proteins of SLC25 family of mitochondrial solute carriers. In some embodiments, the IMM proteins involved include AAC1(SLC25A4), AAC2 (SLC25A5), AAC3 (SLC25A6), AAC4 (SLC25A31), UCP1 (SLC25A7), UCP2 (SLC25A8), UCP3 (SLC25A9), APC1(SLC25A24), APC2 (SLC25A23), APC3 (SLC25A25), APC4 (SLC25A41), (SLC25A3), AGC1 (SCL25A12), AGC2 (SLC25A13), TPC (SLC25A19), CAC (SLC25A20), OGC (SLC25A11), and CIC (SLC25A1).

[0136] In some embodiments, compounds and compositions of the present disclosure activate H+leak via ADP / ATP carrier (AAC). In some embodiments, compounds and compositions of the present disclosure activate H+leak via AAC1. In some embodiments, compounds and compositions of the present disclosure activate H+leak via AAC2. In some embodiments, compounds and compositions of the present disclosure activate H+leak via AAC3. In some embodiments, compounds and compositions of the present disclosure activate H+leak via AAC4. In some embodiments, compounds and compositions of the present disclosure activate H+leak via any combination of AAC1, AAC2, AAC3 or AAC4. In some embodiments, compounds and compositions of the present disclosure activate H+leak via uncoupling protein 1 (UCP1). In some embodiments, compounds and compositions of the present disclosure activate H+leak via other proteins of SLC25 family of mitochondrial solute carriers. In some embodiments, compounds and compositions of the present disclosure activate H+leak via any combination of AAC1, AAC2, AAC3, AAC4, UCP1 or other proteins of SLC25 family of mitochondrial solute carriers. In some embodiments, the compounds may be used to inhibit H+leak across the inner mitochondrial membrane.MOFO-36094831075263722000840

[0137] In some embodiments, compounds and compositions of the present disclosure selectively generate H+leak across the inner mitochondrial membrane without generating H+current across the plasma membrane. In some embodiments, compounds and compositions of the present disclosure activate H+leak via AAC without increasing H+current across the plasma membrane. In some embodiments, compounds and compositions of the present disclosure activate H+leak via AAC1 without increasing H+current across the plasma membrane. In some embodiments, compounds and compositions of the present disclosure activate H+leak via AAC2 without increasing H+current across the plasma membrane. In some embodiments, compounds and compositions of the present disclosure activate H+leak via AAC3 without increasing H+current across the plasma membrane. In some embodiments, compounds and compositions of the present disclosure activate H+leak via AAC4 without increasing H+current across the plasma membrane. In some embodiments, compounds and compositions of the present disclosure activate H+leak via UCP1 without increasing H+current across the plasma membrane. In some embodiments, compounds and compositions of the present disclosure activate H+leak via other proteins of SLC25 family of mitochondrial solute carriers without increasing H+current across the plasma membrane. In some embodiments, compounds and compositions of the present disclosure activate H+leak via any combination of AAC1, AAC2, AAC3, AAC4, UCP1 or other proteins of SLC25 family of mitochondrial solute carriers without increasing H+current across the plasma membrane. Generally, no H+leak across the plasma membrane means no detectable H+current across the plasma membrane as measured with whole-cell patch-clamp electrophysiology.

[0138] In some embodiments, compounds and compositions of the present disclosure activate H+leak via AAC1(SLC25A4), AAC2 (SLC25A5), AAC3 (SLC25A6), AAC4 (SLC25A31), UCP1 (SLC25A7), UCP2 (SLC25A8), UCP3 (SLC25A9), APC1(SLC25A24), APC2 (SLC25A23), APC3 (SLC25A25), APC4 (SLC25A41), (SLC25A3), AGC1 (SCL25A12), AGC2 (SLC25A13), TPC (SLC25A19), CAC (SLC25A20), OGC (SLC25A11) or CIC (SLC25A1) or any combinations thereof.

[0139] In some embodiments, compounds and compositions of the present disclosure activate H+leak via AAC1(SLC25A4), AAC2 (SLC25A5), AAC3 (SLC25A6), AAC4 (SLC25A31), UCP1 (SLC25A7), UCP2 (SLC25A8), UCP3 (SLC25A9), APC1(SLC25A24), APC2 (SLC25A23), APC3 (SLC25A25), APC4 (SLC25A41), (SLC25A3), AGC1 (SCL25A12), AGC2 (SLC25A13), TPC (SLC25A19), CACMOFO-36094831076263722000840 (SLC25A20), OGC (SLC25A11) or CIC (SLC25A1) or any combinations thereof without increasing H+current across the plasma membrane.

[0140] In some variations, the term “Adenosine diphosphate (ADP) / adenosine triphosphate (ATP) carrier (AAC), adenine nucleotide translocase (ANT) or ADP / ATP translocase (ADT),” as used herein, refers to a transport protein of the inner mitochondrial membrane (IMM) that exchanges mitochondrial ATP for cytosolic ADP and controls cellular ATP production. There are four human AAC isoforms, AAC1-AAC4. AAC1 is also known as ANT-1, or ADT-1. AAC operates by the alternating access mechanism with a single substrate binding site (SBS) intermittently exposed to either cytosolic (c-state) or matrix (m- state) side of the IMM.

[0141] In some variations, the term “AAC-mediated H+current", as used herein, refers to AAC-mediated proton current that requires free fatty acids or other activator and is similar to the H+leak via the thermogenic uncoupling protein 1 (UCP1) of brown fat.

[0142] In some embodiments, compounds and compositions of the present disclosure increase the cell respiration. Cellular respiration involves a set of metabolic processes in the cells of organisms to convert chemical energy from nutrients oxidation into ATP. In some embodiments, compounds and compositions of the present disclosure increase the rate of cell respiration. In some embodiments, compounds and compositions of the present disclosure increase the rate of mitochondrial uncoupled respiration.

[0143] Knowledge of the metabolic pathways and rates of ATP turnover and uncoupled metabolism employed by cells can be useful in developing new therapies to treat various diseases. Metabolic rate and pathway information can also be useful for assessing the health or status of cells. In some embodiments, compounds and compositions of the present disclosure increase the metabolic rate. In some embodiments, compounds and compositions of the present disclosure increase the metabolic rate such as but not limited to increased metabolite turnover, increased heat production (thermogenesis) and increased oxygen consumption.

[0144] In some embodiments, compounds and compositions of the present disclosure are useful for regulating mitochondrial activity, reducing adiposity, treating diseases including diabetes and diabetes-associated complications. In some embodiments, compounds andMOFO-36094831077263722000840 compositions of the present disclosure are used for treating a metabolic disorder. Metabolic disorders affect a wide range of the population with differing severity.

[0145] The compounds and compositions of the present disclosure may be used for treating and / or preventing any of the therapeutic indications described herein. In some embodiments of the foregoing, the disease, disorder or condition is obesity, type 2 diabetes, fatty liver disease (including, for example, NAFLD and NASH), heart failure with preserved ejection fraction (HFpEF) and polycystic ovary syndrome. In certain embodiments, the disease, disorder or condition is a neurodegenerative disease, disorder or condition. In one embodiment, the disease, disorder or condition is Alzheimer disease, Huntington's disease, Multiple Sclerosis, Traumatic Brain Injury (TBI), Duchenne Muscular Dystrophy, Parkinson's disease, stroke, or epilepsy. In some variations, the metabolic disorder is type 2 diabetes. In some variations, the metabolic disorder is fatty liver disease. In some variations, the metabolic disorder is polycystic ovary syndrome. Obesity

[0146] Obesity is defined in general terms as an excess of body fat relative to lean body mass. It is now a world-wide epidemic and is one of the most serious contributors to increased morbidity and mortality. Obesity is prevalent in the United States, affecting more than 61% of the total population (Flegal, et al., Overweight and Obesity in the United States: Prevalence and Trends, 1960-1994. Int J Obes 22:39-47, 1998). Obesity is defined more specifically by the United States Centers for Disease Control and Prevention (CDC) as an excessively high amount of body fat or adipose tissue in relation to lean body mass and overweight is defined as an increased body weight in relation to height, when compared to some standard of acceptable or desirable weight. The CDC alternatively defines overweight as a person with a body mass index (BMI) between 25.0 and 29.9 and obesity is defined as a BMI greater than or equal to 30.0. Obesity is often associated with psychological and medical morbidities, the latter of which includes increased joint problems, vascular diseases such as coronary artery disease, hypertension, stroke, and peripheral vascular disease. Obesity also causes metabolic abnormalities such as insulin resistance and Type II diabetes (non-insulin- dependent diabetes mellitus (NIDDM)), hyperlipidemia, and endothelial dysfunction. These abnormalities predispose the vasculature to injury, cellular proliferation, and lipid oxidation, with resulting atherosclerosis leading to heart attack, stroke, and peripheral vascular diseases.MOFO-36094831078263722000840

[0147] The compositions of the present disclosure are useful for treating obesity and obesity-related disorders. Moreover, the compositions disclosed may also be utilized for treating other obesity-related disorders, including but not limited to, coronary artery disease, hypertension, stroke, peripheral vascular disease, insulin resistance, glucose intolerance, diabetes mellitus, hyperlipidemia, atherosclerosis, cellular proliferation and endothelial dysfunction, diabetic dyslipidemia, HIV-related lipodystrophy, e.g. Highly Active Anti-Retroviral Therapy (HAART)-induced lipodystrophy, and metabolic syndrome, type II diabetes, hyperinsulinemia, diabetic complications including diabetic neuropathy, nephropathy, retinopathy or cataracts, heart failure, hypercholesterolemia, inflammation, thrombosis, congestive heart failure, and any other cardiovascular disease related to obesity or an overweight condition, or obesity induced asthma, airway dysfunction and pulmonary disorders, wherein the method comprises administering a therapeutically effective amount of the compounds of the present disclosure or pharmaceutically acceptable salts thereof.

[0148] The present disclosure also provides a method of treating, controlling, or preventing obesity, or of reducing body weight, or of inhibiting fat accumulation, or of treating, controlling, or preventing the onset of one or more obesity-related disorders or conditions, comprising administering a therapeutically effective amount of the compounds of the present disclosure or pharmaceutically acceptable salts thereof. Type 2 diabetes

[0149] Type 2, or noninsulin-dependent diabetes mellitus (NIDDM) typically develops in adulthood. Type 2 diabetes is associated with resistance of glucose-utilizing tissues like adipose tissue, muscle, and liver, to the actions of insulin. Initially, the pancreatic islet beta cells compensate by secreting excess insulin. Eventual islet failure results in decompensation and chronic hyperglycemia. Conversely, moderate islet insufficiency can precede or coincide with peripheral insulin resistance.

[0150] There are several classes of drugs that are useful for treatment of Type 2 diabetes: 1) alpha-glucosidase inhibitors which block and delay carbohydrate absorption, 2) Bile acid sequestrates that are thought to diminish hepatic gluconeogenesis, 3) basal insulin secretagogues (sulfonylureas), which directly stimulate insulin release, carrying the risk of hypoglycemia; 4) prandial insulin secretagogues (meglitinides), which potentiate glucose- induced insulin secretion, and must be taken before each meal, and also carry risk ofMOFO-36094831079263722000840 hypoglycemia; 5) biguanides, including metformin, which attenuate hepatic gluconeogenesis (which is paradoxically elevated in diabetes); 6) insulin sensitizers, for example the thiazolidinedione derivatives rosiglitazone and pioglitazone, which improve peripheral responsiveness to insulin, but which have side effects like weight gain, edema, and occasional liver toxicity; 7) Dopamine agonists which are thought to reduce hypothalamic dopaminergic tone and insulin resistance; 8) DPP-IV inhibitors which are responsible for the breakdown of DPP-IV, the principle enzyme responsible for GLP-1 degradation; 9) GLP-1 mimetics which are peripherally administered replacements for GLP-1; 10) Amylinomimetics which are peripherally administered replacements of amylin, a neuroendocrine hormone co-secreted with insulin by the β-cells that slows gastric emptying, suppresses post-prandial glucagon secretion, and centrally modulates appetite; 11) basal and bolus insulin injections, which may be necessary in the later stages of Type 2 diabetes when the islets have either failed or lay dormant under chronic hyperstimulation.

[0151] Insulin resistance can also occur without marked hyperglycemia, and is generally associated with atherosclerosis, obesity, hyperlipidemia, and essential hypertension. This cluster of abnormalities constitutes the “metabolic syndrome” or “insulin resistance syndrome.” Insulin resistance is also associated with fatty liver, which can progress to chronic inflammation, nonalcoholic steatohepatitis, fibrosis, and cirrhosis. Cumulatively, insulin resistance syndromes, including but not limited to diabetes, underlies many of the major causes of morbidity and death of people over age 40.

[0152] The present disclosure provides a method of treating, controlling, or preventing Type 2 diabetes, or of treating, controlling, or preventing the onset of Type 2 diabetes, comprising administering a therapeutically effective amount of the compounds of the present disclosure or pharmaceutically acceptable salts thereof. Fatty liver disease

[0153] Fatty liver disease (FLD) is also known as hepatosteatosis. It is a prevalent liver condition that occurs when lipids accumulate in liver cells. The lipid accumulation causes cellular injury and sensitizes the liver to further injuries. The accumulated lipids may also impair hepatic microvascular circulation. It is often associated with insulin resistance, diabetes, or alcoholism.MOFO-36094831080263722000840

[0154] FLD may arise from a number of sources, including excessive alcohol consumption and metabolic disorders, such as those associated with insulin resistance, obesity, and hypertension. Nonalcoholic fatty liver disease (NAFLD) may also result from metabolic disorders such as, e.g., galactosemia, glycogen storage diseases, homocystinuria, and tyrosemia, as well as dietary conditions such as malnutrition, total parenteral nutrition, starvation, and overnutrition. In certain cases, NAFLD is associated with jejunal bypass surgery. Other causes include exposure to certain chemicals such as, e.g., hydrocarbon solvents, and certain medications, such as, e.g., amiodarone, corticosteroids, estrogens (e.g., synthetic estrogens), tamoxifen, maleate, methotrexate, nucleoside analogs, and perhexiline. Acute fatty liver conditions can also arise during pregnancy.

[0155] In some embodiments, the present disclosure provides a method of treating, controlling or preventing variety of forms of FLD, for e.g., nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, alcoholic fatty liver disease, alcoholic steatohepatitis, hepatic fibrosis, cirrhosis as well as related disorders such as hypoadiponectinemia, insulin resistance, or hyperinsulinemia and complications thereof by administering a therapeutically effective amount of the compounds of the present disclosure or pharmaceutically acceptable salts thereof. Polycystic ovary syndrome

[0156] Polycystic ovary syndrome (PCOS) is a common endocrine system disorder affecting women of reproductive age. The disorder is characterized by an imbalance in the sex hormones estrogen and progesterone. Women with PCOS may have enlarged ovaries that contain small collections of fluid—called follicles—located in each ovary as seen during an ultrasound exam. The exact cause of polycystic ovary syndrome is unknown. Early diagnosis and treatment along with weight loss may reduce the risk of long-term complications.

[0157] PCOS is a complex and heterogeneous syndrome associated with a high risk for the development of insulin resistance, type 2 diabetes, obesity, dyslipidemia, and cardiovascular disease. There are three different criteria generally used for the diagnosis of PCOS: androgen excess, irregular menstruation, and polycystic ovary appearance on ultrasound after excluding other causes of hyperandrogenism and anovulation. Because a single etiologic factor is not able to fully account for all of the clinical features in PCOS, the pathogenesis of PCOS is largely unknown. Several genetic and environmental factors may contribute to the development of PCOS; however, the underlying cellular mechanism of theMOFO-36094831081263722000840 induction and progression of PCOS remains to be identified. The present disclosure provides a method of treating, controlling, or preventing PCOS, or of treating, controlling, or preventing the onset of PCOS, comprising administering a therapeutically effective amount of the compounds of the present disclosure or pharmaceutically acceptable salts thereof.

[0158] In certain aspects, provided is a method of modulating H+leak across the inner mitochondrial membrane in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of the compound of Formula (I), as well as the compound of Table 1, or a therapeutically effective amount of the pharmaceutical composition comprising any of the compounds of Formula (I), as well as the compound of Table 1, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, provided is a method of activating H+leak across the inner mitochondrial membrane in a subject in need thereof. In some embodiments, provided is a method of activating H+leak via AAC in a subject in need thereof. In some embodiments, provided is a method of activating H+leak via UCP1 in a subject in need thereof. In some embodiments, provided is a method of selectively generating H+leak across the inner mitochondrial membrane without generating H+leak across the plasma membrane in a subject in need thereof.

[0159] In another aspects, provided is an in vitro method of selectively generating H+leak across the inner mitochondrial membrane without generating H+leak across the plasma membrane in a cell, comprising administering to said subject a therapeutically effective amount of the compound of Formula (I), as well as the compound of Table 1, or a therapeutically effective amount of the pharmaceutical composition comprising any of the compounds of Formula (I), as well as the compound of Table 1, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

[0160] In yet another aspects, provided is a method of increasing rate of cell respiration in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of the compound of Formula (I), as well as the compound of Table 1, or a therapeutically effective amount of the pharmaceutical composition comprising any of the compounds of Formula (I), as well as the compound of Table 1, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.MOFO-36094831082263722000840

[0161] In yet another aspects, provided is an in vitro method of increasing rate of cell respiration in a cell, comprising administering to said subject a therapeutically effective amount of the compound of Formula (I), as well as the compound of Table 1, or a therapeutically effective amount of the pharmaceutical composition comprising any of the compounds of Formula (I), as well as the compound of Table 1, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

[0162] In yet another aspects, provided is a method of increasing metabolic rate in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of the compound of Formula (I), as well as the compound of Table 1, or a therapeutically effective amount of the pharmaceutical composition comprising any of the compounds of Formula (I), as well as the compound of Table 1, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

[0163] In some embodiments, the subject is a human.

[0164] In some aspects of the present disclosure, the terms "treating", as used herein, can include reducing occurrence and / or severity of a disease, disorder or condition in an animal that may be predisposed to the disease, disorder and / or condition but has not yet been diagnosed as having the disease, disorder or condition; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and / or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.

[0165] In some variations, the terms “managing” or “maintaining,” as used herein, can refer to reducing the symptom(s) of a disease, reducing the severity of symptom(s) of the disease, or preventing the symptom(s) of the disease from getting worse.

[0166] In some variations, the term "therapeutic effect" is art-recognized and refers to a local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substance. The term thus means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease, disorder, orMOFO-36094831083263722000840 condition in the enhancement of desirable physical or mental development and conditions in an animal, e.g., a human.

[0167] In some variations, the term “modulation” is art-recognized and refers to up regulation (i.e., activation or stimulation), down regulation (i.e., inhibition or suppression) of a response, or the two in combination or apart. The modulation is generally compared to a baseline or reference that can be internal or external to the treated entity.

[0168] In some variations, the terms “sufficient” and “effective,” as used interchangeably herein, refer to an amount (e.g., mass, volume, dosage, concentration, and / or time period) needed to achieve one or more desired result(s). A “therapeutically effective amount” is at least the minimum concentration required to affect a measurable improvement or prevention of at least one symptom or a particular condition or disorder, to affect a measurable enhancement of life expectancy, or to generally improve patient quality of life. The therapeutically effective amount is thus dependent upon the specific biologically active molecule and the specific condition or disorder to be treated. Therapeutically effective amounts of many active agents, such as antibodies, are known in the art. The therapeutically effective amounts of compounds and compositions described herein, e.g., for treating specific disorders may be determined by techniques that are well within the craft of a skilled artisan, such as a physician.

[0169] In some variations, "inner mitochondrial membrane (IMM)", as used herein, refers to the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space and is highly compartmentalized into numerous cristae to expand its surface area and enhance its ability to produce ATP.

[0170] In some variations, the term "cell plasma membrane", as used herein, refers to a biological membrane that separates the interior of a cell from the outside environment (the extracellular space) which protects the cell from its environment.

[0171] In some variations, "mitochondrial respiration", as used herein, refers to a set of metabolic reactions requiring oxygen to convert the energy stored in macronutrients to ATP within mitochondria.

[0172] In some variations, “metabolic disorder" is a medical condition characterized by problems with an organism's metabolism. Metabolic disorder is a broad range of conditionsMOFO-36094831084263722000840 including, but not limited to, obesity, obesity-related disorders, type 2 diabetes, fatty liver, hypertension, cardiovascular disease, high cholesterol, Tay-Sachs disease, hypothyroidism, galactosemia, dyslipidemia, hypolipidemia, phenylketonuria, CNS disorders, multiple sclerosis, cancer, Huntington's disease, Alzheimer's dementia, Parkinson's disease, ischemia reperfusion injury, and heart failure. Administration

[0173] In certain aspects, the present disclosure encompasses the delivery of the compounds and compositions for any therapeutic, prophylactic, pharmaceutical, diagnostic, or imaging use by any appropriate route taking into consideration likely advances in the sciences of drug delivery.

[0174] The compounds of the present disclosure may be administered by any route which results in a therapeutically effective outcome. These include, but are not limited to enteral, gastroenteral, epidural, oral, transdermal, epidural (peridural), intracerebral (into the cerebrum), intracerebroventricular (into the cerebral ventricles), epicutaneous (application onto the skin), intradermal, (into the skin itself), subcutaneous (under the skin), nasal administration (through the nose), intravenous (into a vein), intraarterial (into an artery), intramuscular (into a muscle), intracardiac (into the heart), intraosseous infusion (into the bone marrow), intrathecal (into the spinal canal), intraperitoneal, (infusion or injection into the peritoneum), intravesical infusion, intravitreal, (through the eye), intracavernous injection, (into the base of the penis), intravaginal administration, intrauterine, extra-amniotic administration, transdermal (diffusion through the intact skin for systemic distribution), transmucosal (diffusion through a mucous membrane), insufflation (snorting), sublingual, sublabial, enema, eye drops (onto the conjunctiva), or in ear drops. In specific embodiments, compositions may be administered in a way which allows them to cross the blood-brain barrier, vascular barrier, or other epithelial barrier.

[0175] In some embodiments, the compounds are administered orally. The oral formulations contain an effective amount of compounds in a pharmaceutical carrier appropriate for administration to an individual in need thereof. DosingMOFO-36094831085263722000840

[0176] The present disclosure provides methods comprising administering compounds as described herein to a subject in need thereof. Compounds as described herein may be administered to a subject using any amount and any route of administration effective for preventing or treating or imaging a disease, disorder, and / or condition (e.g., a disease, disorder, and / or condition relating to working memory deficits). The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular composition, its mode of administration, its mode of activity, and the like.

[0177] Compositions in accordance with the disclosure are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present disclosure may be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective, prophylactically effective, or appropriate imaging dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.

[0178] In some embodiments, compositions in accordance with the present disclosure may be administered at dosage levels sufficient to deliver from about 0.0001 mg / kg to about 100 mg / kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic, diagnostic or prophylactic effect. Dosage Forms

[0179] A pharmaceutical composition described herein can be formulated into a dosage form described herein, such as a topical, intranasal, intratracheal, or injectable (e.g., intravenous, intraocular, intravitreal, intramuscular, intracardiac, intraperitoneal, and subcutaneous). Solid dosage forms may include, for example, tablets, dragees, capsules, pills, and granules. Liquid dosage forms may include, for example, emulsions, microemulsions, solutions, suspensions, syrups, and / or elixirs.MOFO-36094831086263722000840 Combination Therapies

[0180] In some embodiments, the present disclosure provides a method of treating a metabolic disorder described herein, comprising administering a compound of the present disclosure in combination with one or more additional active agents or therapies. Suitable pharmaceutical agents that may be used in combination with the compounds of the present disclosure include compounds useful in the treatment of obesity or diseases associated with the development and progression of obesity and obesity related disorders, such as diabetes, atherosclerosis, hypertension, hyperlipidaemias, dyslipidaemias, and cardiovascular disease.

[0181] The compounds of the present disclosure and the additional active agent(s) may be administered simultaneously, sequentially, or at any order. The compounds of the present disclosure and the additional active agent(s) may be administered at different dosages, with different dosing frequencies, or via different routes, whichever is suitable. Articles of Manufacture

[0182] In certain aspects, the disclosure provides a variety of kits and articles of manufacture for conveniently and / or effectively carrying out methods of the present disclosure. In some embodiments, provided are articles of manufacture which may incorporate compound(s) of the present disclosure. These articles of manufacture contain in a stable formulation available to be immediately delivered to a subject in need thereof, such as a human patient. In some embodiments, the article of manufacture comprises a compound of the present disclosure in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag.

[0183] In other embodiments, kits will comprise sufficient amounts and / or numbers of components to allow a user to perform multiple treatments of a subject(s) and / or to perform multiple experiments. In one embodiment, the present disclosure provides kits for carrying out the methods of the invention, including treating metabolic disorders, comprising a compound of the present disclosure or a combination of compounds of the present disclosure, optionally in combination with any other active agents. The kits may comprise a compound or pharmaceutically acceptable salt thereof as described herein and suitable packaging. The kits may comprise one or more containers comprising any compound described herein. In one aspect, a kit includes a compound of the disclosure or a pharmaceutically acceptable saltMOFO-36094831087263722000840 thereof, and a label and / or instructions for use of the compound in the treatment of a disease or disorder described herein. The kits may comprise a unit dosage form of the compound. EXAMPLES

[0184] The presently disclosed subject matter will be better understood by reference to the following Examples, which are provided as exemplary of the invention, and not by way of limitation. Instruments and Methods

[0185] 1H-NMR spectra were recorded on Bruker Avance III HD 400 MHz or on Bruker Fourier 300 MHz. Chemical shifts are reported as δ values in ppm relative to signals fromresidual non-deuterated solvents used for sample preparation as an internal standard

[0186] LCMS method A: Instrument Aligent 1200 HPLC MSD:6135 single quadrupole MSD. Column:-:XBridge C18, 2.10*50mm, 5um, Column Temp 40oC flowrate 0.8 mL / min Mobile phase A:10mM NH4HCO3, Phase B: ACN. Gradient 0min-3.40 min 5%B 95%A- >95%B 5%A, Static 3.40-3.8595%B 5%A, Gradient 3.85-3.8695%B 5%A->5%B 95%A static 3.86-4.50 min static 5%B 95%A.

[0187] LCMS method B: Instrument Aligent 1260 HPLC MSD:6120 single quadrupole MSD. Column:-:Luna C18, 2.0*50mm, 5um, Column Temp 40oC flowrate 0.8 mL / min Mobile phase A:0.04% aqTFA, Phase B:0.02%TFA ACN. Gradient 0min-3.40 min 5%B95%A->95%B 5%A, Static 3.40-3.8595%B 5%A,Static 0.0-0.45%B 95%A Gradient 0.4-3.005%B 95%A->95%B 5%A static 3.00-4.00 min static 95%B 5%A, Gradient 4.00- 4.0195%B 5%A->5%B 95%A static 4.01-4.50 min static 5%B 95%A.

[0188] LCMS method C: LCMS-Kinetex-20-80-95-7-1-25-UV – NP-QC Instrument Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC. Column:Kinetex uM XB-C182.6 μm (4.6x50mm) column no.00B-4496-E0 column temp 25oC flow rat 1.0 ml / min Mobile phase A:0.1% v / v aqueous formic acid, Mobile Phase B: 0.1% v / vformic acid acetonitrile. Gradient 1-2.080%A 20%B-> 20%A 80%B, Static 2.00- 2.3520%A80%B, Gradient 2.35-2.4520%A 80%B-> 5%A 95%, Static 2.45-4.255%A 95%B, Gradient 4.25-5.005%A 95%B -> 80%A 20%B, Static 5.00-7.0080%A 20%A.

[0189] LCMS method D: LCMS-036-20-80-95-7-1-25-UV-NP: Instrument Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC – Mass SpectrometerMOFO-36094831088263722000840 Column Kinetex® XB-C18 (4.6x50mm), 110A, column no.00B-4496-E0, . Column temperature: 25 °C, Flow 1.0 mL / min. Analysis time: 7 min. Mobile phase A: 0.1% v / v water solution of formic acid. Mobile phase B: 0.1% v / v acetonitrile solution of formic acid. Elution gradient: 0.00 min (80% A, 20% B), 2.00 – 2.35 min (20% A, 80% B), 2.45 – 4.25 min (5% A, 95% B), 5.00 – 7.00 min (80% A, 20% B).

[0190] LCMS method E: LCMS-036-20-80-95-6-1-25-UV-BCM LCMS Instrument Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC – Mass Spectrometer Column Kinetex® XB-C18 (4.6x50mm), 110A, column no.00B-4496-E0. Column temperature: 25 °C, Flow 1.0 mL / min. Analysis time: 7 min. Mobile phase A: 0.1% v / v water solution of formic acid. Mobile phase B: 0.1% v / v acetonitrile solution of formic acid. Elution gradient: 0.00 min (50% A, 50% B), 3.35 – 3.75 min (30% A, 70% B), 3.90 – 4.75 min (5% A, 95% B), 5.00 –6.00 min (50% A, 50% B).

[0191] LCMS method F: Instrument Agilent 1200 HPLC MSD: 6130 quadrupole LC / MS. Column: Durashell C18,3 µm,4.6x50 mm Column Temp: no control (room temp) Flow rate: 1ml / min Mobile phase A: 0.1% TFA in acetonitrile Mobile Phase B: 0.1% TFA in water Gradient 0min-5.75 min 95%B 5%A ->0%B 100%A, static 5.75 min-10 min 0%B 100%A Gradient 10 min-11 min 0%B 100%A->95%B 5%A.

[0192] LCMS method G: Instrument Agilent 1290 UPLCMS with MSD:6135 single quadrupole. Column:-:Zorbax Eclipse Plus C18, 2.10*50mm, 1.8um, Column Temp 40oC flowrate 0.8 mL / min Mobile phase A:0.1% Formic acid in water, Phase B:0.05%Formic acid in ACN. Gradient :0min-0.25 min 5%B; 0.26min-2.50 min 95% B; 2.5min-3.5 min 95% B ;3.6min-4.0min 5%B.

[0193] LCMS method H: Instrument Shimadzu Nexara UPLCMS with MS2020 single quadrupole MSD. Column:-:Phenomenex Kinetex EVO C18, 3.0*50mm, 2.6 um, Column Temp 40oC flowrate 0.8 mL / min Mobile phase A:5mM Ammonium bicarbonate in water, Phase B: ACN. Gradient :0min-0.20 min 5%B; 0.21min-2.50 min 95% B; 2.5min-3.5 min 95% B ;3.6min-4.0min 5%B.

[0194] LCMS method I: LCMS-Kinetex-5-95-95-7-1-25-UV-QC LCMS Instrument Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC – Mass Spectrometer Column Kinetex® XB-C18 (4.6x50mm), 110A, column no.00B-4496-E0. Column temperature: 25 °C, flow rate 1.0 mL / min. Analysis time: 7 min. Mobile phase A:MOFO-36094831089263722000840 0.1% v / v water solution of formic acid. Mobile phase B: 0.1% v / v acetonitrile solution of formic acid. Gradient 0.00 – 5.00 (95%A, 5%B -> 5%A, 95%B), Static 5.00 – 5.75 min (5%A, 95%B), Gradient 5.75 – 6.00 min (5%A, 95%B -> 95% A, 5%B), Static 6.00 –7.00 min (95%A, 5%B).

[0195] LCMS method J: LCMS-Gemini-5-95-95-7-1-25-UV - QC-basic LCMS Instrument Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC – Mass Spectrometer Column Kinetex® XB-C18 (4.6x50mm), 110A, column no.00B-4496- E0. Column temperature: 25 °C, flow rate 1.0 mL / min. Analysis time: 7 min. Mobile phase C: 0.05% water solution of ammonium hydroxide. Mobile phase D: acetonitrile. Gradient 0.00 – 5.00 (95%C, 5%D -> 5%C, 95%D), Static 5.00 – 5.75 min (5%C, 95%D), Gradient 5.75 – 6.00 min (5%C, 95%D -> 95%C, 5%D), Static 6.00 –7.00 min (95%C, 5%D).

[0196] LCMS method K: standard_esi_100_1000 LCMS Instrument Waters ACQUITY UPLC I-Class PLUS System with Waters SQ Detector 2 Column Acquity UPLC BEH C18 1.7 µm (2.1 x 100 mm), column no.186002352. Column temperature: 40 °C, flow rate 0.5 mL / min. Analysis time: 3 min. Mobile phase A: 0.1% v / v water solution of formic acid. Mobile phase B: 0.1% v / v acetonitrile solution of formic acid. Gradient 0.00 – 2.00 (1%B, 99%A -> 100%B, 0%A), Static 2.00 – 3.00 min (100%B, 0%A).

[0197] LCMS method L: 220_254_m_z_100-1000 ALT ig45_3min_standard LCMS Instrument Shimadzu LCMS-2020 Single Quadrupole Liquid Chromatograph Mass Spectrometer Column Acquity UPLC BEH C181.7 µm (2.1 x 100 mm), column no. 186002352. Column temperature: 25 °C, flow rate 0.5 mL / min. Analysis time: 3.5 min. Mobile phase A: 0.1% v / v water solution of formic acid. Mobile phase B: 0.1% v / v acetonitrile solution of formic acid. Static 0.00 – 0.10 min (20%B, 80%A), Gradient -0.10- 2.00 (20%B, 80%A -> 95%B, 5%A), Static 2.00 – 2.70 min (95%B, 5%A), Gradient 2.70- 2.80 min (95%B, 5%A -> 20%B, 80%A), Static 2.80-3.50 min (20%B, 80%A). Synthetic Examples

[0198] Exemplary compounds of the present disclosure may be prepared according to the various schemes described in this example.MOFO-36094831090263722000840 Example 1: Synthesis of Compound D2

[0199] 4-Propoxybenzaldehyde (45 mg; 0,27 mmol; 1 eq.) and molecular sieves were added to the ethanol solution (3 mL) of 2-hydrazino-5-(trifluoromethyl)-1,3,4-thiadiazole (50 mg; 0,27 mmol; 1 eq.). The reaction mixture was heated under reflux overnight. The UPLC- MS analysis confirmed the full conversion and the presence of product in the reaction mixture. The molecular sieves were filtered off and volatiles were removed under vacuum. The crude material was purified by crystallization in ethanol (2 mL). Compound D2 was obtained as a white powder (24.9 mg, 28% Y).

[0200] LC-MS: r.t. = 3.10 min; 99.65% at 254 nm; [M-H]- = 329.15

[0201] 1H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 8.12 (s, 1H), 7.80 – 7.52 (m, 2H), 7.19 – 6.85 (m, 2H), 3.99 (t, J = 6.5 Hz, 2H), 1.75 (q, J = 7.0 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H). Example 2: Synthesis of compound D8

[0202] (2E)-3-(2-cyanophenyl)prop-2-enoic acid (100 mg, 0.57 mmol, 1.0 eq.) and HATU (329 mg, 0.86 mmol, 1.5 eq.) were dissolved in DMF (1 mL) and stirred at 60 °C. DIPEA (0.30 mL, 1.73 mmol, 3.0 eq.) was added and the mixture was stirred for 30 minutes at the same temperature. After that time, 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (110 mg, 0.63 mmol, 1.1 eq.) was added in one portion and the mixture was stirred at 60 °C for 24 h. Then, the volatiles were removed under reduced pressure and the crude material wasMOFO-36094831091263722000840 triturated with MeOH. The powder was dried under reduced pressure until stable mass. Compound D8 was obtained as an off white powder (40 mg, 24% Y).

[0203] LC-MS (method: LCMS-036-20-80-95-7-1-25-UV-NP): r.t. = 2.54 min; 97.80% at 254 nm; [M-H]- = 323.11

[0204] 1H NMR (400 MHz, DMSO-d6) δ 13.75 (s, 1H), 8.05 – 7.94 (m, 3H), 7.85 (t, J = 7.7 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 15.7 Hz, 1H). Example 3: Synthesis of Compound D13

[0205] (2E)-3-(2,3-difluorophenyl)prop-2-enoic acid (8 g.43.4 mmol, 1.0 eq) and 2- amino-5-trifluoromethyl-1,3,4-thiadiazole (7.35 g, 43.4 mmol, 1.1 eq) were dissolved in anhydrous DMF (80 mL), DIPEA (22.8 mL, 130.33 mmol, 3.0 eq) was added, followed by HATU (33 g, 86.9 mmol, 2 eq). The reaction mixture was stirred at 50 °C for 18 h. Then, the mixture was concentrated to dryness and the crude material was triturated with MeOH to afford (2E)-3-(2,3-difluorophenyl)-N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]prop-2- enamide as an off-white solid (5.66 g, 39%Y).

[0206] LCMS (method I): LCMS-Kinetex-5-95-95-7-1-25-UV -QC): r.t.= 4.503 min, 99.71% at 295 nm [M-H]- = 334.0

[0207] 1H NMR (300 MHz, DMSO-d6) δ 13.64 (s, 1H), 7.87 (d, J = 16.1 Hz, 1H), 7.64 – 7.52 (m, 2H), 7.34 (q, J = 7.8, 7.1 Hz, 1H), 7.10 (d, J = 16.0 Hz, 1H). Example 4: Synthesis of Compound D14MOFO-36094831092263722000840

[0208] (2E)-3-(2,6-difluorophenyl)prop-2-enoic acid (0.1 g.0.543 mmol, 1 eq) and 2- amino-5-trifluoromethyl-1,3,4-thiadiazole (0.101 g, 0.597 mmol, 1.1 eq) were dissolved in anhydrous DMF (2.0 mL), DIPEA (0.28 mL, 1.63 mmol, 3.0 eq) was added, followed by HATU (0.412 g, 1.08 mmol, 2 eq). The reaction mixture was stirred at 50 °C for 18 h. Then, the mixture was concentrated to dryness and the crude material was triturated with MeOH to afford (2E)-3-(2,6-difluorophenyl)-N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]prop-2- enamide as an off-white solid (0.088 g, 48%Y).

[0209] LCMS (method I): LCMS-Kinetex-5-95-95-7-1-25-UV-QC): r.t.= 4.430 min, 99.84% at 300 nm [M+H]+= 336.0

[0210] 1H NMR (300 MHz, DMSO-d6) δ 13.63 (s, 1H), 7.80 (d, J = 16.2 Hz, 1H), 7.66 – 7.52 (m, 1H), 7.29 (d, J = 9.0 Hz, 1H), 7.26 – 7.16 (m, 1H). Example 5: Synthesis of Compound D17

[0211] (2E)-3-(2,4-difluorophenyl)prop-2-enoic acid (0.6 g.3.26 mmol, 1 eq) and 2- amino-5-trifluoromethyl-1,3,4-thiadiazole (0.61 g, 3.26 mmol, 1.1 eq) were dissolved in anhydrous DMF (12 mL), DIPEA (1.17 mL, 6.52 mmol, 3.0 eq) was added, followed by HATU (3.72 g, 9.77 mmol, 3 eq). The reaction mixture was stirred at 50 °C for 18 h. Then, the mixture was concentrated to dryness and the crude material was triturated with MeOH to afford (2E)-3-(2,4-difluorophenyl)-N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]prop-2- enamide as an off-white solid (0.275 g, 25% Y).

[0212] LCMS (method I): LCMS-Kinetex-5-95-95-7-1-25-UV-QC): r.t.= 4.410 min, 99.25% at 300 nm [M+H]+= 336.1

[0213] 1H NMR (300 MHz, DMSO-d6) δ 13.58 (s, 1H), 7.91 – 7.79 (m, 2H), 7.44 (ddd, J = 11.6, 9.2, 2.6 Hz, 1H), 7.25 (td, J = 8.6, 2.6 Hz, 1H), 7.03 (d, J = 16.0 Hz, 1H). Example 6: Synthesis of Compound D27MOFO-36094831093263722000840 Step 1

[0214] 3-fluoropyridine-2-carbaldehyde (0.60 g, 4.80 mmol, 1 eq) was dissolved in DCM (12 mL), then methyl (triphenylphosphoranylidene)acetate (2.40 g, 7.19 mmol, 1.5 eq) was added. The reaction was stirred at room temperature for 12 h. After that time, the reaction mixture was concentrated to dryness. Purification by normal phase flash chromatography (0-30% c-hexane / Ethyl acetate) afforded methyl (2E)-3-(3-fluoropyridin-2- yl)prop-2-enoate (0.80 g, 92% Y) as an orange solid.

[0215] LCMS Method K (method: standard_esi_100_1000): r.t. = 1.84 min; 100% at 254 nm; [M+H]+= 182.1.

[0216] 1H NMR (300 MHz, DMSO-d6) δ 8.53 (dt, J = 4.5, 1.6 Hz, 1H), 7.92 – 7.70 (m, 2H), 7.58 (dt, J = 8.6, 4.4 Hz, 1H), 6.94 (d, J = 15.7 Hz, 1H), 3.77 (s, 3H). Step 2

[0217] Methyl (2E)-3-(3-fluoropyridin-2-yl)prop-2-enoate (0.8 g, 4.42 mmol, 1.0 eq) was dissolved in a mixture THF (8.0 mL) and water (1.6 mL), then LiOH monohydrate (0.37 g, 8.83 mmol, 2.0 eq) was added at room temperature. The resulting mixture was stirred at 50 °C for 12 h. The organic solvent was evaporated, and water was added (3 mL). The aqueous layer was acidified to pH 1 with 1M HCl solution. The precipitated solid was collected by filtration washed with water and dried in vacuo to afford (2E)-3-(3- fluoropyridin-2-yl)prop-2-enoic acid (0.30 g, 40% Y) as a brown solid.

[0218] 1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, J = 4.4 Hz, 1H), 7.78 (t, J = 9.6 Hz, 1H), 7.65 – 7.41 (m, 2H), 6.89 (d, J = 15.6 Hz, 1H). Step 3MOFO-36094831094263722000840

[0219] (2E)-3-(3-fluoropyridin-2-yl)prop-2-enoic acid (0.30 g, 1.79 mmol, 1 eq) was dissolved in DMF (6 mL), then 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (0.33 g, 1.97 mmol, 1.1 eq), HATU (1.36 g, 3.59 mmol, 2.0 eq) and DIPEA (0.94 mL, 5.38 mmol, 3.0 eq) were added. The reaction mixture was stirred at 50 °C for 18 h. Then, the mixture was concentrated to dryness and the crude material was triturated with MeOH to afford (2E)-3- (3-fluoropyridin-2-yl)-N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]prop-2-enamide (0.116 g, 20% Y) as a white solid.

[0220] LCMS (method I: LCMS-Kinetex-5-95-95-7-1-25-UV-QC): r.t.= 3.863 min, 99.99% at 310 nm [M+H]+= 319.09

[0221] 1H NMR (300 MHz, DMSO-d6) δ 13.71 (s, 1H), 8.58 (dt, J = 4.6, 1.5 Hz, 1H), 8.00 – 7.83 (m, 2H), 7.61 (dt, J = 8.7, 4.4 Hz, 1H), 7.48 (d, J = 15.5 Hz, 1H). Example 7: Synthesis of Compound D28 Step 1

[0222] To a solution of 5-Chloropyrazine-2-carboxylic acid (0.50 g, 3.15 mmol, 1.0 eq) and 1-butanol (0.58 mL, 6.31 mmol, 2.0 eq) in DMF (10 mL), potassium tert-butoxide (1.01 g, 8.99 mmol, 2.85 eq) was added. The resulting mixture was stirred at 100 °C for 3 h. The reaction was cooled to room temperature and quenched with 1 M HCl solution. The aqueous layer was extracted with ethyl acetate and isopropanol / chloroform (1:10). The organic layers were dried over sodium sulfate anhydrous, filtered and concentrated to afford 5- butoxypyrazine-2-carboxylic acid (0.42 g, 64% Y) as a brownish solid.

[0223] LCMS method K: (method: standard_esi_100_1000): r.t. = 1.83 min; 100% at 254 nm; m / z not visibleMOFO-36094831095263722000840

[0224] 1H NMR (300 MHz, DMSO-d6) δ 8.79 (d, J = 1.3 Hz, 1H), 8.37 (d, J = 1.3 Hz, 1H), 4.39 (t, J = 6.6 Hz, 2H), 1.75 (dq, J = 8.4, 6.6 Hz, 2H), 1.49 – 1.38 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). Step 2

[0225] A mixture of 5-butoxypyrazine-2-carboxylic acid (0.400 g, 2.04 mmol, 1.0 eq), 2-Amino-5-trifluoromethyl-1,3,4-thiadiazole (0.379 g, 2.243 mmol, 1.1 eq), HATU (1.55 g, 4.08 mmol, 2.0 eq) and DIPEA (1.1 mL, 6.12 mmol, 3.0 eq) in DMF (8 mL) was stirred at 50 °C for 12 h. Then, the mixture was concentrated to dryness and the crude material was triturated with MeOH to afford 5-butoxy-N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2- yl]pyrazine-2-carboxamide (0.35 g, 49% Y) as a white solid.

[0226] LCMS (method I: LCMS-Kinetex-5-95-95-7-1-25-UV-QC): r.t.= 4.790 min, 99.66% at 285 nm [M+H]+= 348.1

[0227] 1H NMR (300 MHz, DMSO-d6) δ 8.99 (d, J = 1.3 Hz, 1H), 8.47 (d, J = 1.3 Hz, 1H), 4.45 (t, J = 6.6 Hz, 2H), 1.82 – 1.74 (m, 2H), 1.50 – 1.41 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). Example 8: Synthesis of compound D35 Step 1

[0228] 5-Fluoro-2-formylpyridine (1.0 g, 7.99 mmol, 1.0 eq) was dissolved in anhydrous pyridine (1.90 mL, 23.98 mmol, 3.0 eq). Then, malonic acid (0.83 g, 7.99 mmol, 1.0 eq) was added, followed by piperidine (3 drops). The resulting mixture was stirred at 100oC. After 2 h, the mixture was concentrated under reduced pressure, the aqueous layer was carefully acidified to pH 5 with HCl 1 M solution. The precipitated solid was collected by filtration,MOFO-36094831096263722000840 washed with water and dried to afford (2E)-3-(5-fluoropyridin-2-yl)prop-2-enoic acid hydrochloride (908 mg, 55% Y). as a pale yellow solid.

[0229] LC-MS Method K:(method: standard_esi_100_1000): r.t = 1.6 min, 50% at 254 nm, [M+H]+= 168.1 [M -H]-= 166.1

[0230] 1H NMR (300 MHz, DMSO) δ 8.64 (d, J = 2.7 Hz, 1H), 7.89 – 7.75 (m, 2H), 7.61 (d, J = 15.7 Hz, 1H), 6.76 (d, J = 15.7 Hz, 1H). Step 2

[0231] (2E)-3-(5-fluoropyridin-2-yl)prop-2-enoic acid hydrochloride (0.45 g, 2.17 mmol, 1.0 eq) and 2-Amino-5-trifluoromethyl-1,3,4-thiadiazole (0.366 g, 2.17 mmol, 1.0 eq) were dissolved in anhydrous DMF (9 mL). Then DIPEA (1.51 mL, 8.66 mmol, 4.0 eq) was added followed by HATU (1.65 g, 4.33 mmol, 2.0 eq). The resulting mixture was stirred at 50oC. After 16 h, the mixture was concentrated under reduced pressure obtaining a dark residue, which was triturated with MeOH. The black solid formed was collected by filtration. The solid was suspended in THF and stirred at room temperature for 1 h and filtered through a celite. The filtrate was concentrated providing a residue, which was triturated with MeOH and dried to afford (2E)-3-(5-fluoropyridin-2-yl)-N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]prop-2-enamide (204 mg, Y = 30%) as a white solid.

[0232] LC-MS (method I: LCMS-Kinetex-5-95-95-7-1-25-UV-QC): r.t = 3.877 min, 99.9% at 305 nm [M -H]- = 317.0

[0233] 1H NMR (300 MHz, DMSO) δ 13.61 (s, 1H), 8.71 (d, J = 1.8 Hz, 1H), 7.95 – 7.80 (m, 3H), 7.32 (d, J = 15.4 Hz, 1H). Example 9: Synthesis of Compound D37 Step 1MOFO-36094831097263722000840

[0234] A mixture of 3,5-Difluoro-4-formylbenzonitrile (1.0 g, 5.98 mmol, 1.0 eq) and tert-Butyl 2-(triphenylphosphoranylidene)acetate (2.43 g, 5,98 mmol, 1.0 eq) in THF (20 mL) was stirred at 80 °C for 18 h. Upon cooling down to room temperature, water was added, and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate anhydrous, filtered and concentrated. Purification by normal phase flash chromatography (0-40% c-hexane / Ethyl acetate) afforded tert-butyl (2E)-3-(4-cyano-2,6-difluorophenyl)prop-2-enoate (0.59 g, 36% Y) as a yellowish solid.

[0235] 1H NMR (300 MHz, DMSO-d6) δ 7.93 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 16.4 Hz, 1H), 6.64 (d, J = 16.4 Hz, 1H), 1.50 (s, 9H). Step 2

[0236] To a solution of tert-butyl (2E)-3-(4-cyano-2,6-difluorophenyl)prop-2-enoate (0.59 g, 2.18 mmol, 1.0 eq) in dichloromethane (6 mL), trifluoroacetic acid (1.7 mL, 21.80 mmol, 10.0 eq) was added. The resulting mixture was stirred at room temperature for 18 h. Progress was monitored by TLC. Upon consumption of starting material. The reaction mixture was concentrated to dryness to afford (2E)-3-(4-cyano-2,6-difluorophenyl)prop-2- enoic acid (0.45 g, 94% Y) as a brownish solid.

[0237] 1H NMR (300 MHz, DMSO-d6) δ 12.97 (s, 1H), 7.92 (m, 1H), 7.51 (d, J = 16.4 Hz, 1H), 6.68 (d, J = 16.4 Hz, 1H). Step 3MOFO-36094831098263722000840

[0238] A mixture of (2E)-3-(4-cyano-2,6-difluorophenyl)prop-2-enoic acid (0.45 g, 2.04 mmol, 1.0 eq), 2-Amino-5-trifluoromethyl-1,3,4-thiadiazole (0.38 g, 2.25 mmol, 1.1 eq), HATU (1.55 g, 4.09 mmol, 2.0 eq) and DIPEA (1.83 mL, 10.22 mmol, 5.0 eq) in DMF (8 mL) was stirred at 50 °C for 12 h. Then, the mixture was concentrated to dryness and the crude material was triturated with MeOH to afford (2E)-3-(4-cyano-2,6-difluorophenyl)-N- [5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]prop-2-enamide (0.261 g, 35% Y) as a white solid.

[0239] LCMS (method I: LCMS-Kinetex-5-95-95-7-1-25-UV-QC): r.t.= 4.390 min, 99.10% at 300 nm [M-H]- = 359.01

[0240] 1 H NMR (300 MHz, DMSO-d 6 ) δ 13.74 (s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 16.2 Hz, 1H), 7.30 (d, J = 16.3 Hz, 1H). Example 10: Synthesis of Compound D41 Step 1

[0241] 3,5-Difluoro-4-formylbenzonitrile (1.0 g, 5.98 mmol, 1.0 eq) and Methyl thioglycolate (0.63 mL, 6.58 mmol, 1.1 eq) were dissolved in degassed acetonitrile (30.000 mL, 30.000 vol). Then triethylamine (1.1 mL, 7.78 mmol, 1.3 eq) was added and the reaction mixture was stirred at 85oC. After 16 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by normal phase flash chromatography (0-30% EtOAc / c-hexane) to afford methyl 6-cyano-4-fluoro-1-benzothiophene-2- carboxylate (505.6 mg, 32% Y) as a yellow solid.

[0242] LC-MS Method K:(method: standard_esi_100_1000): r.t = 2 min; 54% at 254 nm; m / z not observedMOFO-36094831099263722000840

[0243] 1H NMR (300 MHz, DMSO) δ 8.63 (d, J = 1.1 Hz, 1H), 8.25 (d, J = 0.8 Hz, 1H), 7.87 (dd, J = 10.0, 1.2 Hz, 1H), 3.93 (s, 3H). Step 2

[0244] Methyl 6-cyano-4-fluoro-1-benzothiophene-2-carboxylate (505 mg, 1.93 mmol, 1.0 eq) was dissolved in a mixture of THF (10 mL) and water (2.5 mL). Then LiOH monohydrate (0.122 g, 2.90 mmol, 1.5 eq) was added and the reaction mixture was stirred at room temperature. After 3 h, the THF was removed under reduced pressure, the aqueous layer was carefully acidified with 1M HCl solution to pH 5. The precipitated solid was collected by filtration, washed with water and dried to afford 6-cyano-4-fluoro-1- benzothiophene-2-carboxylic acid (427 mg, 95% Y).as a pale-yellow solid

[0245] LC-MS Method K: (method: standard_esi_100_1000): r.t = 1.76 min; 30% at 254 nm [M+H]+= -

[0246] 1H NMR (300 MHz, DMSO) δ 8.60 (s, 1H), 8.13 (s, 1H), 7.85 (dd, J = 10.1, 1.2 Hz, 1H). Step 3

[0247] 6-cyano-4-fluoro-1-benzothiophene-2-carboxylic acid (0.43 g, 1.83 mmol, 1.0 eq) and 2-Amino-5-trifluoromethyl-1,3,4-thiadiazole (0.31 g, 1.83 mmol, 1.0 eq) were dissolved in anhydrous DMF (8.5 mL). Then DIPEA (0.96 mL, 5.50 mmol, 3.0 eq) was added followed by HATU (1.39 g, 3.67 mmol, 2 eq). The resulting mixture was stirred at 50oC. After 16, the reaction mixture was concentrated under reduced pressure and the resultingMOFO-360948310100263722000840 residue was triturated with MeOH to afford 6-cyano-4-fluoro-N-[5-(trifluoromethyl)-1,3,4- thiadiazol-2-yl]-1-benzothiophene-2-carboxamide (459 mg, 66% Y) as a pale-yellow solid

[0248] LC-MS (method I): LCMS-Kinetex-5-95-95-7-1-25-UV-QC): r.t = 4.557 min, 97.91 % at 300 nm [M -H]-= 371.0

[0249] 1H NMR (400 MHz, DMSO) δ 8.80 (s, 1H), 8.64 (s, 1H), 7.89 (dd, J = 10.0, 1.2 Hz, 1H) Example 11:Synthesis of Example D47 Step 1

[0250] 2,6-difluoro-4-propylbenzaldehyde (2.15 g, 11.44 mmol, 1.0 eq) was dissolved in anhydrous THF (43 mL). Then, ethyl (triphenylphosphoranylidene) acetate (3.98 g, 11.44 mmol, 1.0 eq) was added and the resulting mixture was stirred at 80oC. After 16 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by normal phase flash chromatography (0-30% EtOAc / c-hexane) to afford ethyl (2E)-3-(2,6- difluoro-4-propylphenyl)prop-2-enoate (2.490 g, 84% Y) as a pale yellow liquid.

[0251] LC-MS Method K: (method: standard_esi_100_1000): r.t = 2.31 min; 38% at 254 nm; [M+H]+= 255.4

[0252] 1H NMR (400 MHz, DMSO) δ 7.57 (d, J = 16.4 Hz, 1H), 7.11 (d, J = 10.5 Hz, 2H), 6.57 (d, J = 16.4 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 2.63 – 2.56 (m, 2H), 1.59 (dt, J = 14.7, 7.4 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H). Step 2MOFO-360948310101263722000840

[0253] Ethyl (2E)-3-(2,6-difluoro-4-propylphenyl)prop-2-enoate (2.49 g, 9.60 mmol, 1.0 eq) was dissolved in a mixture of THF (50 mL) and water (12.5 mL). Then LiOH monohydrate (2.01 g, 47.98 mmol, 5.0 eq) was added and the resulting mixture was stirred at 50oC. After 16 h, the THF was removed under reduced pressure. The resulting aqueous layer was acidified with 1M HCl solution. The precipitate formed was collected by filtration, washed with water and dried to afford (2E)-3-(2,6-difluoro-4-propylphenyl)prop-2-enoic acid (2.17 g, 98% Y) as a white solid.

[0254] LC-MS Method K:(method: standard_esi_100_1000): r.t = 2.01 min, 47% at 254 nm, [M+H]+= 227.2 [M -H]- = 225.3

[0255] 1H NMR (300 MHz, DMSO) δ 12.67 (s, 1H), 7.53 (d, J = 16.4 Hz, 1H), 7.09 (d, J = 10.3 Hz, 2H), 6.52 (d, J = 16.4 Hz, 1H), 2.66 – 2.53 (m, 2H), 1.68 – 1.49 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H). Step 3

[0256] (2E)-3-(2,6-difluoro-4-propylphenyl)prop-2-enoic acid (0.50 g, 2.17 mmol, 1.0 eq) and 2-Amino-5-trifluoromethyl-1,3,4-thiadiazole (0.37 g, 2.17 mmol, 1.0 eq) were dissolved in anhydrous DMF (10 mL). Then DIPEA (1.13 mL, 6.50 mmol, 3.0 eq) was added followed by HATU (1.65 g, 4.33 mmol, 2.0 eq). The resulting mixture was stirred at 50oC. After 16 h, the mixture was concentrated to dryness and the crude material was triturated with MeOH to afford (2E)-3-(2,6-difluoro-4-propylphenyl)-N-[5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl]prop-2-enamide (296 mg, 36% Y) as a white solid.

[0257] LC-MS (method C: LCMS-Kinetex-20-80-95-7-1-25-UV-NP): r.t = 3.363 min, 99.35% at 305 nm [M+H]+= 378.2

[0258] 1H NMR (300 MHz, DMSO) δ 13.58 (s, 1H), 7.77 (d, J = 16.1 Hz, 1H), 7.22 – 7.04 (m, 3H), 2.62 (t, J = 7.6 Hz, 2H), 1.62 (h, J = 7.4 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H). Example 12: Synthesis of Compound D55MOFO-360948310102263722000840 Step 1

[0259] To a solution of 4-Bromo-3,5-difluorobenzenesulfonyl chloride (3.0 g, 10.29 mmol, 1.0 eq) in THF (60 mL) at 0 °C was added dropwise hydrazine monohydrate (2.5 mL, 51.46 mmol, 5.0 eq). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was concentrated to dryness to afford 4-bromo-3,5- difluorobenzene-1-sulfonohydrazide (2.99 g, 99% Y) as a white solid.

[0260] LC-MS Method K: (method: standard_esi_100_1000): r.t = 1.75 min, 100% at 254 nm, m / z not observed

[0261] 1H NMR (300 MHz, DMSO) δ 7.66 – 7.56 (m, 2H). Step 2

[0262] To mixture of 4-bromo-3,5-difluorobenzene-1-sulfonohydrazide (3.0 g, 10.24 mmol, 1.0 eq), Potassium acetate (8.04 g, 81.92 mmol, 8.0 eq) in EtOH (120 mL) was added Iodoethane (7.99 g, 51.20 mmol, 5.0 eq) at room temperature. The reaction mixture was stirred at 90 °C. After 16 h, the reaction mixture was concentrated in vacuo and the residue was purified by normal phase flash chromatography (0-30% EtOAc / c-hexane) to afford 2- bromo-5-(ethanesulfonyl)-1,3-difluorobenzene (1.76 g, 59% Y) as a white solid.

[0263] LC-MS Method K:(method: standard_esi_100_1000): r.t = 1.91 min, 100% at 254 nm, m / z not observed

[0264] 1H NMR (400 MHz, DMSO) δ 7.85 – 7.77 (m, 2H), 3.44 (q, J = 7.3 Hz, 2H), 1.12 (t, J = 7.4 Hz, 3H).MOFO-360948310103263722000840 Step 3

[0265] To a degassed solution of 2-bromo-5-(ethanesulfonyl)-1,3-difluorobenzene (1.76 g, 6.05 mmol, 1.0 eq), 2-Ethoxycarbonylvinylboronic acid pinacol ester (2.05 g, 9.07 mmol, 1.5 eq) in 1,4-Dioxane (35 mL) and water (8.8 mL) were added potassium carbonate (2.51 g, 18.15 mmol, 3.0 eq) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex (0.49 g, 0.60 mmol, 0.1 eq). The resulting mixture was degassed for additional 5 min, and then stirred at 100 °C. After 16 h, the reaction mixture was concentrated to dryness and the resulting residue was purified by normal phase flash chromatography (0-30% EtOAc / c-hexane) to afford ethyl (2E)-3-[4-(ethanesulfonyl)-2,6- difluorophenyl]prop-2-enoate (1.2 g, 64% Y) as a yellow solid.

[0266] LC-MS Method K:(method: standard_esi_100_1000): r.t = 1.95 min, 91% at 254 nm, [M+H]+= 305.2

[0267] 1H NMR (400 MHz, DMSO) δ 7.83 – 7.72 (m, 2H), 7.57 (d, J = 16.4 Hz, 1H), 6.74 (d, J = 16.5 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.46 (q, J = 7.3 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.3 Hz, 3H). Step 4

[0268] To a solution of ethyl (2E)-3-[4-(ethanesulfonyl)-2,6-difluorophenyl]prop-2- enoate (1.2 g, 3.86 mmol, 1.0 eq) in THF (60 mL) and water (12 mL) was added LiOH monohydrate (0.32 g, 7.73 mmol, 2.0 eq). The reaction mixture was stirred at room temperature. After 16 h, the THF was evaporated. The aqueous layer was acidified with 1M HCl solution until pH 2. The resulting precipitate was collected by filtration, washed withMOFO-360948310104263722000840 water and n-pentane, and dried to afford (2E)-3-[4-(ethanesulfonyl)-2,6- difluorophenyl]prop-2-enoic acid (1.08 g, 92% Y) as a yellow solid.

[0269] LC-MS Method K:(method: standard_esi_100_1000): r.t = 1.68 min, 91% at 254 nm, [M-H]- = 275.3

[0270] 1H NMR (400 MHz, DMSO) δ 7.76 (d, J = 7.7 Hz, 2H), 7.53 (d, J = 16.4 Hz, 1H), 6.69 (d, J = 16.4 Hz, 1H), 3.46 (t, J = 7.4 Hz, 2H), 1.13 (t, J = 7.4 Hz, 3H). Step 5

[0271] (2E)-3-[4-(ethanesulfonyl)-2,6-difluorophenyl]prop-2-enoic acid (750 mg, 2.66 mmol, 1.0 eq) and 2-Amino-5-trifluoromethyl-1,3,4-thiadiazole (0.45 g, 2.17 mmol, 1.0 eq) were dissolved in anhydrous DMF (15 mL). Then DIPEA (1.4 mL, 7.98 mmol, 3.0 eq) was added followed by HATU (2.02 g, 5.32 mmol, 2.0 eq). The resulting mixture was stirred at room temperature. After 16 h, the reaction mixture was concentrated under reduced pressure and the resulting residue was triturated with MeOH to afford (2E)-3-[4-(ethanesulfonyl)-2,6- difluorophenyl]-N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]prop-2-enamide as a white solid (445 mg, 39% Y).

[0272] LC-MS (method I: LCMS-Kinetex-5-95-95-7-1-25-UV-QC): r.t = 4.233 min, 99.11% at 295 nm [M -H]- = 426.0

[0273] 1H NMR (300 MHz, DMSO-d 6 ) δ 13.74 (s, 1H), 7.86 – 7.73 (m, 3H), 7.32 (d, J = 16.2 Hz, 1H), 3.47 (q, J = 7.3 Hz, 2H), 1.14 (t, J = 7.3 Hz, 3H). Example 13: Synthesis of Compound D20 Step 1MOFO-360948310105263722000840

[0274] A mixture of 2-bromo-3-fluorobenzonitrile (0.224 g, 1.12 mmol, 1 eq), tetrabutylammonium bromide (0.328 g, 1.02 mmol, 1 eq), NaHCO3(6.2 g, 74.8 mmol), methyl acrylate (0.1 g, 1.02 mmol, 1 eq) and Pd(OAc)2(0.045 g, 0.204mmol, 0.2 eq) in DMF (3 mL) was degassed for 10 min with Argon. The reaction mixture was stirred at 90 °C for 4 h. The reaction was cooled to room temperature and filtered through celite. The filtrate was concentrated to dryness. Purification by normal phase flash chromatography afforded methyl (2E)-3-(2-cyano-6-fluorophenyl)prop-2-enoate (0.198 g, 90% Y).

[0275] LCMS Method K:(method: standard_esi_100_1000): r.t. = 1.89 min; 92% at 254 nm; m / z not visible.

[0276] 1H NMR (300 MHz, Chloroform-d) δ 7.88 (d, J = 16.3 Hz, 1H), 7.59 – 7.40 (m, 3H), 6.91 (d, J = 16.3 Hz, 1H), 3.87 (s, 3H). Step 2

[0277] Methyl (2E)-3-(2-cyano-6-fluorophenyl)prop-2-enoate (0.05 g, 0.581 mmol, 1 eq) was dissolved in a mixture of THF / water (3 mL, 5:1), then LiOH monohydrate (0.049 g, 1.16 mmol, 2 eq) was added in one portion. The reaction mixture was stirred at room temperature for 18 h. The THF was evaporated. Water (3 mL) was added, and the pH was adjusted to 1 with 1M HCl solution. The aqueous layer was extracted with ethyl acetate (3 x 3 mL). The organic layers were dried over sodium sulfate anhydrous, filtered and concentrated under reduced pressure to afford (2E)-3-(2-cyano-6-fluorophenyl)prop-2-enoic acid (0.046 g, 41% Y) as a white solid.

[0278] LCMS Method L. (method: 220_254_m_z_100-1000 ALT ig45_3min_standard): r.t. = 1.68 min; 100% at 254 nm; [M+Na]+= 214.4

[0279] 1H NMR (300 MHz, DMSO-d6) δ 7.84 (dd, J = 7.4, 1.5 Hz, 1H), 7.77 – 7.63 (m, 3H), 6.72 (d, J = 16.2 Hz, 1H). Step 3MOFO-360948310106263722000840

[0280] (2E)-3-(2-cyano-6-fluorophenyl)prop-2-enoic acid (0.05 g, 0.250 mmol, 1.0 eq) and 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (0.05 g, 0.275 mmol, 1.1 eq) were dissolved in anhydrous DMF (1.0 mL), DIPEA (0.13 mL, 0.740 mmol, 3.0 eq) was added, followed by HATU (0.189 g, 0.50 mmol, 2.0 eq). The reaction mixture was stirred at 50 °C for 18 h. Then, the mixture was concentrated to dryness and the crude material was triturated with MeOH to afford (2E)-3-(2-cyano-6-fluorophenyl)-N-[5-(trifluoromethyl)-1,3,4- thiadiazol-2-yl]prop-2-enamide as an off-white solid (0.027 g, 33% Y).

[0281] LC-MS (method I: LCMS-Kinetex-5-95-95-7-1-25-UV-QC): r.t. = 4.147 min; 98.86% at 290 nm; [M-H]-= 341.0

[0282] 1H NMR (300 MHz, DMSO-d6) δ 13.78 (s, 1H), 7.99 – 7.84 (m, 2H), 7.83 – 7.65 (m, 2H), 7.31 (d, J = 16.0 Hz, 1H). Biological Examples Example B1. Cell Respiration Assays

[0283] This example demonstrates that exemplary compounds induce the mitochondrial H+leak. Certain exemplary compounds of the present disclosure were tested for their ability to increase mitochondrial uncoupled respiration (associated with the mitochondrial H+leak) in intact cells.

[0284] Cellular oxygen consumption (respiration) measurements of mouse C2C12 myoblast cells were performed using an Oxygraph-2k (O2K) high-resolution respirometer (Oroboros Instruments). Cell cultures were maintained in DMEM supplemented with 5.6 mM glucose, 4 mM L-Glutamine, 1 mM sodium pyruvate, and 10% FBS. The respiration medium was DMEM supplemented with 5.6 mM glucose, 4 mM L-Glutamine, 1 mM sodium pyruvate, 25 mM HEPES and 0.2% FBS. The experiments were conducted at 37oC at a cell concentration of 1.5 × 106cells per mL and continuously stirred at 750 rpm. After the oxygen consumption rate reached steady-state, the ability of the exemplary compounds to increaseMOFO-360948310107263722000840 the oxygen consumption rate (OCR) was measured (see Table 2). In the table: +: equal to or greater than 10 µM; ++: 1- 10 µM, +++ less than 1 uM. Table 2. EC50for OCR increase and concentrations for 50% OCR increaseMOFO-360948310108263722000840MOFO-360948310109263722000840

[0285] It should generally be understood that the protocols in this example may be used to test any of the compounds of the invention described herein.MOFO-360948310110

Claims

263722000840 CLAIMS What is claimed is:

1. A method, comprising: administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is:wherein: R1is halo, H, alkyl, alkenyl, haloalkyl, or CN; and, wherein each of the foregoing is unsubstituted or substituted with one or more Rx; wherein each Rxis independently C1-8alkyl, C1-8alkoxy, phenyl, haloC1-8alkyl, halo, OH, NO2, C(O)Rx1, or CN; wherein the C1-8alkoxy of Rxis optionally substituted with cyclopropyl; the phenyl of Rxis unsubstituted or substituted with C1-8alkyl or halo; Rx1is phenyl substituted with halo, C1-8alkyl, or unsubstituted 5 to 6-membered heteroaryl; wherein the compound of Formula (II) or (III) is:R1is halo, H, alkyl, alkenyl, haloalkyl, or CN;MOFO-360948310111263722000840 p is 0-5; R4aand R4bis H, alkyl, alkoxy, or halo; R3is independently optionally substituted alkoxy, alkyl, alkenyl, halo, haloalkyl, -NO2, or CN; or when at least two R3are present, two adjacent R3combine to form a ring that optionally contains one or more heteroatoms, wherein the ring formed is optionally substituted; wherein the compound of Formula (IV) is:wherein: R1is halo, H, alkyl, alkenyl, haloalkyl, or CN; w is 0-5; R10is independently optionally substituted alkyl, haloalkyl, alkoxy, phenyl, halo, NO2, SO2NH2, SO2NHC1-8alkyl, SO2N(C1-8alkyl)(C1-8alkyl), or CN; and R11is haloalkyl, alkyl, CONH2, CONHC1-8alkyl, CON(C1-8alkyl)(C1-8alkyl), or H.

2. The method of claim 1, wherein the compound is a compound of Formula (I-B):or a pharmaceutically acceptable salt thereof, wherein: R1is as defined for Formula (I); n is 0-3; and Rbis alkyl, alkoxy, phenyl, or halo; or when at least two Rbare present, two adjacent Rbcombine to form a ring that optionally contains one or more heteroatoms, wherein the ring formed is optionally substituted, optionally, wherein the ring formed is optionally substituted with alkyl.

3. The method of claim 1, wherein the compound is a compound of Formula (I-C):MOFO-360948310112263722000840or a pharmaceutically acceptable salt thereof, wherein: R1is as defined for Formula (I); n is 0-3; and Rcis alkyl, haloalkyl, or halo.

4. The method of claim 1, wherein the compound is a compound of Formula (I-D):or a pharmaceutically acceptable salt thereof, wherein: R1is as defined for Formula (I); n is 0-3; and Rdis alkyl, or halo.

5. The method of claim 1, wherein the compound is a compound of Formula (I-E):or a pharmaceutically acceptable salt thereof, wherein: R1is as defined for Formula (I); n is 0-2; and Reis alkyl.

6. The method of claim 1, wherein the compound is a compound of Formula (I-F):MOFO-360948310113263722000840 or a pharmaceutically acceptable salt thereof, wherein: R1is as defined for Formula (I); Rfis: alkyl, or phenyl, optionally substituted with alkyl.

7. The method of claim 1, wherein the compound is a compound of Formula (I-G):or a pharmaceutically acceptable salt thereof, wherein: R1is as defined for Formula (I); and Rgis: alkyl, phenyl, optionally substituted with halo, or 5-membered heterocycle containing at least heteroatom selected from S and O.

8. The method of claim 1, wherein the compound is a compound of Formula (I-H):or a pharmaceutically acceptable salt thereof, wherein: R1is as defined for Formula (I); Rhis phenyl, optionally substituted with halo.

9. The method of claim 1, wherein the compound is a compound of Formula (I-I’):or a pharmaceutically acceptable salt thereof, wherein: R1is as defined for Formula (I);MOFO-360948310114263722000840 R3is independently F, C3-7alkyl, SO2C1-8alkyl, SOC1-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, or NO2; and n is 0, 1, 2, 3, or 4.

10. The method of claim 1, wherein the compound is a compound of Formula (I-J):or a pharmaceutically acceptable salt thereof, wherein: R1is as defined for Formula (I); q is 0-4; and Rjis alkyl.

11. The method of any one of claims 1 to 10, wherein R1is halo.

12. The method of any one of claims 1 to 11, wherein the compound is a compound from Table 1, or a pharmaceutically acceptable salt thereof.

13. The method of any one of claims 1 to 12, wherein the method activates H+leak across the inner mitochondrial membrane in the subject.

14. The method of any one of claims 1 to 12, wherein the method activates H+leak via AAC in the subject.

15. The method of any one of claims 1 to 12, wherein the method activates H+leak via UCP1 in the subject.

16. The method of any one of claims 1 to 12, wherein the method selectively generates H+leak across the inner mitochondrial membrane without generating H+leak across the plasma membrane in the subject.

17. The method of any one of claims 1 to 12, wherein the method is an in vitro method that selectively generates H+leak across the inner mitochondrial membrane without generating H+leak across the plasma membrane in a cell of the subject.

18. The method of any one of claims 1 to 12, wherein the method increases rate of cell respiration in the subject.MOFO-360948310115263722000840 19. The method of any one of claims 1 to 12, wherein the method is an in vitro method that increases rate of cell respiration in a cell of the subject.

20. The method of any one of claims 1 to 12, wherein the method increases metabolic rate in the subject.

21. The method of any one of claims 1 to 12, wherein the method treats, prevents, or manages a disease, disorder or condition in the subject.

22. The method of claim 21, wherein the disease, disorder or condition is obesity, type 2 diabetes, fatty liver disease, heart failure with preserved ejection fraction (HFpEF), or polycystic ovary syndrome.

23. The method of any one of claims 1 to 12, wherein the disease, disorder or condition is obesity or obesity related disorder.

24. The method of any one of claims 1 to 12, wherein the disease, disorder or condition is type 2 diabetes.

25. The method of any one of claims 1 to 12, wherein the disease, disorder or condition is fatty liver disease.

26. The method of any one of claims 1 to 12, wherein the disease, disorder or condition is polycystic ovary syndrome.

27. The method of any one of claims 1 to 12, wherein the disease, disorder or condition is a neurodegenerative disease, disorder or condition.

28. The method of any one of claims 1 to 12, wherein the disease, disorder or condition is Alzheimer disease, Huntington's disease, Multiple Sclerosis, Traumatic Brain Injury (TBI), Duchenne Muscular Dystrophy, Parkinson's disease, stroke, or epilepsy.

29. A compound of Formula (IV) having the structure:or a pharmaceutically acceptable salt thereof, wherein:MOFO-360948310116263722000840 R1is halo, H, alkyl, alkenyl, haloalkyl, or CN; w is 0-5; R10is independently optionally substituted alkyl, haloalkyl, alkoxy, phenyl, halo, NO2, SO2NH2, SO2NHC1-8alkyl, SO2N(C1-8alkyl)(C1-8alkyl), SOC1-8alkyl, SO2C1-8alkyl, or CN; and R11is haloalkyl, alkyl, CONH2, CONHC1-8alkyl, CON(C1-8alkyl)(C1-8alkyl), or H.

30. A compound of Formula (II-B) having the structure:or a pharmaceutically acceptable salt thereof, wherein: R1is halo, H, alkyl, alkenyl, haloalkyl, or CN; R3ais CN, halo, haloalkyl, alkoxy, alkyl, or alkenyl; R3bis H, halo, haloalkyl, alkoxy, alkyl, or alkenyl; each R4aand R4bis F, alkoxy, H, or alkyl, provided that when R3bis H, then R3ais other than halo, OCF2H, CH3, or OCH3; or when R3ais H, R3bis not alkoxy or chloro.

31. A compound selected from any one of Compounds D1-D66, or a pharmaceutically acceptable salt thereof.

32. A compound selected from a group consisting of: N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]3-(p-propoxyphenyl)propionamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(4-butoxy-3-methoxyphenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(o-cyanophenyl)acrylamide N-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(p-methoxyphenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-propyl-3-thenamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-propyl-3-isoxazolecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-1-propyl-3-pyrazolecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(p-methoxyphenyl)methacrylamide (E)-2-[(p-propoxyphenyl)methylene]-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]hydrazine N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-4-propoxy-2-thenamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]3-(o-cyanophenyl)propionamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2,3-difluorophenyl)acrylamideMOFO-360948310117263722000840 N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2,6-difluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-butoxy-2-pyridinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2-cyano-4-methoxyphenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2,4-difluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-6-butoxynicotinamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2-cyano-6-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2-cyano-3-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(Z)-3-(o-cyanophenyl)-2-fluoroacrylamide (E)-2-[(p-methoxyphenyl)methylene]-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]hydrazine (E)-2-{[p-(2-methoxyethoxy)phenyl]methylene}-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2- yl]hydrazine (E)-4-((2-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)hydrazineylidene)methyl)benzonitrile N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(Z)-3-(o-cyanophenyl)-2-methoxyacrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-2-cyano-3-(o-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(3-fluoro-2-pyridyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-butoxy-2-pyrazinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2,5-difluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(3,5-difluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-6-butoxy-3-pyridazinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-2-butoxy-5-pyrimidinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(4-cyano-2,6- difluorophenyl)methacrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(4-ethoxy-2,6-difluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(5-fluoro-2-pyridyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(5-cyano-2-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(4-cyano-2,6-difluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2-pyrazinyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(5-fluoro-2-pyrimidinyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2,3-difluorophenyl)methacrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-6-cyano-4-fluoro-1-benzothiophene-2- carboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(3-cyano-2-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(3,5-difluoro-2-pyridyl)acrylamide N,N-dimethyl3,5-difluoro-4-[(E)-2-[N-5-(trifluoromethyl)-1,3,4-thiadiazol-2- ylcarbamoyl]ethenyl]benzamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(5-cyano-2-pyridyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-butoxy-2-pyrimidinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2,6-difluoro-4-propylphenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(3-pyridazinyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(4-cyano-2-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(Z)-3-(2,3-difluorophenyl)-2-fluoroacrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-6-cyano-4-fluoro-1-benzofuran-2-carboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-(cyclopropylmethoxy)-2-pyridinecarboxamideMOFO-360948310118263722000840 N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-(cyclopropylmethoxy)-2- pyrimidinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-5-(2-cyclopropylethoxy)-2-pyridinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-[4-(ethylsulfonyl)-2,6- difluorophenyl]acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(Z)-3-(2,3-difluorophenyl)-3-fluoroacrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-6-(cyclopropylmethoxy)nicotinamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-6-(2-cyclopropylethoxy)nicotinamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-6-(cyclopropylmethoxy)-3-fluoro-2- pyridinecarboxamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2,6-difluoro-4-mesylphenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(2-fluoro-4-mesylphenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(p-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(m-fluorophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(m-cyanophenyl)acrylamide N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-(E)-3-(p-cyanophenyl)acrylamide; and (E)-2-(2-(2,2,2-trifluoro-1-phenylethylidene)hydrazineyl)-5-(trifluoromethyl)-1,3,4- thiadiazole; or a pharmaceutically acceptable salt thereof.

33. A compound of Formula (A-I) having the structure:or a pharmaceutically acceptable salt thereof, wherein: R1is H or F; R4ais H, F, C2-8alkyl, or C1-8alkoxy; R4bis H, F, C2-8alkyl, or C1-8alkoxy; ring A is phenyl or 6-membered heteroaryl; each R3is independently F, C2-7alkyl, SO2C1-8alkyl, SOC1-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, SO2NH2, SO2NHC1-8alkyl, or SO2N(C1-8alkyl)(C1-8alkyl); and n is 0, 1, 2, 3, or 4; provided the compound is not (E)-3-(4-isopropoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4- thiadiazol-2-yl)acrylamide, (E)-3-(4-pentoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol- 2-yl)acrylamide, (E)-3-(3-methoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-MOFO-360948310119263722000840 yl)acrylamide, (E)-3-(2-fluorophenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2- yl)acrylamide, (E)-3-(4-methoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2- yl)acrylamide, (E)-3-(3-fluoro, 4-methoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2- yl)acrylamide, (E)-3-(3,4,5 trimethoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2- yl)acrylamide, (E)-3-(3,4, dimethoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2- yl)acrylamide, or (E)-3-(phenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)acrylamide.

34. A compound of Formula (A-I-a) having the structure:or a pharmaceutically acceptable salt thereof, wherein: R1is H or F; each R4ais independently H, F, C1-8alkyl, or C1-8alkoxy; each R4bis independently H, F, C2-8alkyl, or C1-8alkoxy; ring A is phenyl or 6-membered heteroaryl; each R3is independently F, C2-7alkyl, SO2C1-8alkyl, SOC1-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, SO2NH2, SO2NHC1-8alkyl, or SO2N(C1-8alkyl)(C1- 8alkyl); and n is 0, 1, 2, 3, or 4; provided the compound is not 3-(4-methoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4- thiadiazol-2-yl)propenamide, 3-(4-ethylphenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2- yl)propenamide, 3-(3-methoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2- yl)propenamide, 3-(4-fluorophenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2- yl)propenamide, 3-(3-pyridyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)propenamide, 3- (4-pyridyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)propenamide, 3-(2,4-pyrazinyl)-N- (5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)propenamide, 3-(phenyl)-N-(5-(trifluoromethyl)- 1,3,4-thiadiazol-2-yl)propenamide, 3-(3, 4-dimethoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4- thiadiazol-2-yl)propenamide, 3-(2-ethoxyphenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2- yl)propenamide, or 3-(phenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)propenamide.MOFO-360948310120263722000840 35. A method of treating a disease or disorder, wherein the method comprises administering to a subject in need thereof a compound of Formula (A-I’) having the structure:or a pharmaceutically acceptable salt thereof, wherein: R1is H or F; R4ais H, F, C1-8alkyl, or C1-8alkoxy; R4bis H, F, C2-8alkyl, or C1-8alkoxy; ring A is phenyl or 5 or 6-membered heteroaryl; each R3is independently Cl, F, Br, C2-7alkyl, SO2C1-8alkyl, SOC1-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, SO2NH2, SO2NHC1-8alkyl, SO2N(C1-8alkyl)(C1-8alkyl), NO2, phenyl, OSO2C1-8alkyl, CONHC1-8alkyl, SC1-8alkyl, or N(C1-8alkyl)(C1-8alkyl); and n is 0, 1, 2, 3, or 4; and wherein the disease or disorder is not cancer.

36. A method of treating a disease or disorder, wherein the method comprises administering to a subject in need thereof a compound of Formula (A-I-a’) having the structure:or a pharmaceutically acceptable salt thereof, wherein: R1is H or F; each R4ais independently H, F, C1-8alkyl, or C1-8alkoxy; each R4bis independently H, F, C2-8alkyl, or C1-8alkoxy; ring A is phenyl or 5 or 6-membered heteroaryl; each R3is independently Cl, F, Br, C2-7alkyl, SO2C1-8alkyl, SOC1-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, SO2NH2, SO2NHC1-8alkyl, SO2N(C1-8alkyl)(C1-MOFO-360948310121263722000840 8alkyl), NO2, phenyl, OSO2C1-8alkyl, CONHC1-8alkyl, SC1-8alkyl, or N(C1-8alkyl)(C1-8alkyl); and n is 0, 1, 2, 3, or 4; and wherein the disease or disorder is not cancer.

37. A compound of Formula (A-II) having the structure:or a pharmaceutically acceptable salt thereof, wherein: R1is H or F; ring B is pyridine, pyrazine, pyrimidine, or pyridazine; each R3is independently F, C3-7alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, NO2, SO2NH2, SO2NHC1-8alkyl, or SO2N(C1-8alkyl)(C1-8alkyl); and n is 0, 1, 2, 3, or 4; provided the compound is not 2-fluoro-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2- yl)nicotinamide, 2-methoxy-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)nicotinamide, 2- isopropoxy-6-methoxy-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)isonicotinamide, 2- isobutoxy-6-methoxy-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)isonicotinamide, 2- methoxy-6-(pentyloxy)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)isonicotinamide, 6- (2,2,2-trifluoroethoxy)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)nicotinamide, N-(5- (trifluoromethyl)-1,3,4-thiadiazol-2-yl)nicotinamide, N-(5-(trifluoromethyl)-1,3,4-thiadiazol- 2-yl)isonicotinamide, or N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)picolinamide.

38. A method of treating a disease or disorder, wherein the method comprises administering to a subject in need thereof a compound of Formula (A-II’) having the structure:or a pharmaceutically acceptable salt thereof,MOFO-360948310122263722000840 wherein: R1is H or F; ring B is pyridine, pyrazine, pyrimidine, or pyridazine; and wherein when ring B is pyridine; each R3is independently F, C1-7alkyl, SO2C1-8alkyl, SOC1-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, NO2, SO2NH2, SO2NHC1-8alkyl, SO2N(C1-8alkyl)(C1-8alkyl), NH2, NHC1-8alkyl, N(C1-8alkyl)(C1-8alkyl), phenyl, 3 to 8- membered heterocycle, Cl, Br, OH, S(C1-8alkyl), or COOH; provided that if ring B is 4-pyridine or 2,4 pyrimidine then the 5-position must be hydrogen; and n is 0, 1, 2, 3, or 4.

39. A method of treating a disease or disorder, wherein the method comprises administering to a subject in need thereof a compound of Formula (A-III) having the structure:or a pharmaceutically acceptable salt thereof, wherein: R1is H or F; ring C is furan, thiophene, benzothiophene, or benzofuran; where ring C is optionally fused with another ring; each R3is independently F, C2-8alkyl, SO2C1-8alkyl, SOC1-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, NO2, SO2NH2, SO2NHC1-8alkyl, or SO2N(C1-8alkyl)(C1-8alkyl); and n is 0, 1, 2, 3, or 4.

40. The method of claim 39, wherein each R3is independently F, C2-8alkyl, C1-8alkoxy, fluoroC1-8alkyl, CN, C2-8alkenyl, NO2, SO2NH2, SO2NHC1-8alkyl, or SO2N(C1-8alkyl)(C1-8alkyl).

41. A compound of Formula (A-IV) having the structure:MOFO-360948310123263722000840or a pharmaceutically acceptable salt thereof, wherein: ring A is phenyl or 5 or 6-membered heteroaryl; R1is halo, H, alkyl, alkenyl, haloalkyl, or CN; w is 0-5; R10is independently optionally substituted alkyl, haloalkyl, alkoxy, phenyl, halo, NO2, SO2NH2, SO2NHC1-8alkyl, SO2N(C1-8alkyl)(C1-8alkyl), or CN; wherein the alkyl of R10is optionally substituted with halo, -NO2, -CN, -ORa, -SRa, -NRaRb, - NRaC(O)Rb, -NRaC(O)ORb, -OC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, - NRaS(O)Rb, -NRaS(O)2Rb, C1-8 alkyl, haloC1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, each of Raand Rbis independently H or C1-6alkyl;and R11is haloalkyl, alkyl, CONH2, CONHC1-8alkyl, CON(C1-8alkyl)(C1-8alkyl), or H.

42. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R1is F and ring A is phenyl; each R3is independently F, SO2C1-8alkyl, or CN; and n is 0, 1, 2, 3, or 4.

43. The compound of claims 33 or 42, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3.

44. The compound of any one of claims 33 and 42-43, or a pharmaceutically acceptable salt thereof, wherein R4ais H.

45. The compound of any one of claims 33 and 42-44, or a pharmaceutically acceptable salt thereof, wherein R4bis H.

46. The compound of any one of claims 33 and 42-45, or a pharmaceutically acceptableMOFO-36094831012426372200084047. A compound selected from the group consisting of:MOFO-360948310125263722000840MOFO-360948310126263722000840stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

48. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable carrier or excipient.

49. A method of treating a disease or disorder, wherein the method comprises administering to a subject in need thereof a compound of any of one of the preceding claims, or a pharmaceutically acceptable salt thereof; or administering to a subject in need thereof a compound of Table 1, or a pharmaceutically acceptable salt thereof; or administering to a subject in need thereof a pharmaceutical composition of claim 48.

50. The method of claim 49, wherein the disease or disorder is obesity, type 2 diabetes, fatty liver disease, heart failure with preserved ejection fraction (HFpEF), polycystic ovary syndrome, Alzheimer disease, Huntington's disease, Multiple Sclerosis, Traumatic Brain Injury (TBI), Duchenne Muscular Dystrophy, Parkinson's disease, stroke, or epilepsy.

51. The method of claim 49, wherein the method is for treating obesity, overweight, insulin resistance, glucose intolerance, prediabetes, type 2 diabetes, metabolic syndrome; fatty liver disease including NAFLD and NASH, alcoholic fatty liver disease and steatohepatitis, hepatic fibrosis, cirrhosis; dyslipidemia, hyperlipidemia, hypercholesterolemia; coronary artery disease, hypertension, atherosclerosis, thrombosis,MOFO-360948310127263722000840 peripheral vascular disease, heart failure including HFpEF, HFrEF, and congestive heart failure; obesity-induced asthma and airway dysfunction; HIV-related (HAART-induced) lipodystrophy; polycystic ovary syndrome; Alzheimer disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis, traumatic brain injury, Duchenne muscular dystrophy, stroke, or epilepsy.MOFO-360948310128

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