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. Such compounds include compounds of Formula (I): in which the variables are as defined herein.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application Nos. 63 / 563,847, filed March 11, 2024, and 63 / 694,703, filed September 13, 2024, each which is 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): n-n o or a pharmaceutically acceptable salt thereof, wherein: R1 is halo, H, alkyl, alkenyl, haloalkyl, or CN; and R2 is optionally substituted phenyl.

[0005] In some aspects, provided herein is a compound selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

[0006] In some aspects, provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0007] 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 (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.

[0008] In some embodiments, provided herein is a method of activating H+ leak via AAC (including AAC 1-4) 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.

[0009] 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 (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.

[0010] 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 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.

[0011] 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 (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.

[0012] 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 (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.

[0013] 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 (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.

[0014] 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 (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.

[0015] 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 (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 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. DETAILED DESCRIPTION

[0016] 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.

[0017] Mitochondria convert the chemical energy of nutrients into ATP and heat. Mitochondrial ATP and heat are generated from the same energy source—voltage (AT) across the inner mitochondrial membrane (IMM) generated by the electron transport chain. For ATP production, ATP synthase passes H+ down AT 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 AT 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)).

[0018] 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 carries (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 acids 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.

[0019] 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 Chern 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 Chern 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.

[0020] 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. 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)).

[0021] 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 camitine / acylcarnitine carrier CAC (SLC25A20), the mitochondrial oxoglutarate carrier OGC (SLC25A11), and the tricarboxylate or citrate carrier CIC (SLC25A1).

[0022] 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. Compounds

[0023] In some aspects, provided is a compound of Formula (I): n-n o or a pharmaceutically acceptable salt thereof, wherein: R1 is halo, H, alkyl, alkenyl, haloalkyl, or CN; and R2 is optionally substituted phenyl.

[0024] In some variations, R1 is halo. In certain variations, R1 is F. In other variations, R1 is alkyl. In certain variations, R1 is Ci-4 alkyl. In certain variations, R1 is methyl. In yet other variations, R1 is CN. In other variations, R1 is H.

[0025] In some variations, R2 is unsubstituted phenyl. In other variations, R2 is substituted phenyl. In certain variations, a substituted phenyl includes bicyclic moieties that include a phenyl ring.

[0026] In certain aspects, provided is a compound of Formula (I-A): or a pharmaceutically acceptable salt thereof, wherein: R1 is as defined for Formula (I) above; n is 0-5; and R2a at each occurrence is independently: alkyl, alkyenyl phenyl, -ORW, wherein Rw is alkyl, alkylenyl, alkylether, heterocyclyl, or phenyl, -NH(C=O)RX, wherein Rx is alkyl or phenyl, halo, -SRy, wherein Ry is alkyl or alkylether, -NO2, -C(=O)ORZ, wherein Rz is alkyl, or NRvlRv2, wherein each Rvl and Rv2 is independently H, alkyl, or alkylether; or Rvl and Rv2 are taken together with the nitrogen atom to which they are attached to form a heterocyclic moiety; or when at least two R2a are present, two adjacent R2a combine to form a ring that optionally contains one or more heteroatoms, wherein, at each occurrence, each of alkyl, alkenyl, alkylether, heterocyclyl, or phenyl is independently optionally substituted.

[0027] In certain embodiments, R2a is alkyl. In certain variations, R2a is C1-4 alkyl. In some variations, the alkyl is unsubstituted.

[0028] In certain embodiments, R2a is alkoxy (or -ORW. wherein Rw is alkyl). In certain variations, R2a is C1-4 alkoxy (or Rw is Rw is alkyl). In certain variations, R2a is methoxy. In some variations, the alkoxy of R2ais substituted with cycloalkyl. In some variations, the cycloalkyl is a C3-10 cycloalkyl. In one variation, the cycloakyl is cyclopropyl. In some variations, the alkoxy of R2ais substituted with heterocyclyl. In some variations, the heterocyclyl is a 3-10 membered heterocyclyl. In certain variations, the one or more heteroatoms is oxygen or nitrogen. In one variation, the heteroatom is oxygen. In one variation, the heterocyclyl is

[0029] In certain embodiments, R2a is phenyl. In certain variations, the phenyl is unsubstituted.

[0030] In other embodiments, R2a is phenoxy (or -ORW. wherein Rw is phenyl). In some variations, the phenoxy is unsubstituted.

[0031] In other embodiments, R2a is -ORW. In some embodiments, Rw is alkyl substituted with cycloalkyl. In some variations, the cycloalkyl is a C3-10 cycloalkyl. In one variation, the cycloakyl is cyclopropyl.

[0032] In other embodiments, Rw is alkyl substituted with heterocyclyl. In some variations, the heterocyclyl is a 3-10 membered heterocyclyl. In certain variations, the one or more heteroatoms is oxygen or nitrogen. In one variation, the heteroatom is oxygen. In one variation, the heterocyclyl is '    .

[0033] In some embodiments, Rw is deuterated alkyl (e.g., -CD3).

[0034] In other embodiments, Rw is alkylether. In some embodiments, Rw is a polyethylene glycol.

[0035] In other embodiments, Rw is heterocyclyl. In some variations, the heterocyclyl is a 3-10 membered heterocyclyl. In certain variations, the one or more heteroatoms is oxygen or nitrogen. In one variation, the heteroatom is oxygen. In one variation, the heterocyclyl is

[0036] In other embodiments, Rw is phenyl. In some variations, the phenyl is unsubstituted.

[0037] In some embodiments, R2a is -NH(C=O)RX. In some variations, Rx is alkyl. In one variation, the alkyl is unsubstituted. In some variations, Rx is phenyl. In one variation, the phenyl is unsubstituted.

[0038] In some embodiments, R2a is halo. In one variation, the halo is chloro. In another variation, the halo is fluoro.

[0039] In some embodiments, R2a is -SRy. In some variations, Ry is alkyl. In one variation, the alkyl is unsubstituted. In some variations, Ry is alkylether. In one variation, the alkylether is unsubstituted.

[0040] In some embodiments, R2a is -C(=O)ORZ. In some variations, Rz is alkyl. In one variation, the alkyl is unsubstituted.

[0041] In some embodiments, R2a is NRvlRw2. In some variations, each Rvl and Rv2 is independently H, alkyl, or alkylether. In one variation, the alkyl or alkylether is unsubstituted. In other variations, Rvl and Rv2 are taken together with the nitrogen atom to which they are attached to form a heterocyclic moiety. In some variations, the heterocyclic c / moiety is              . In some variations, the heterocyclic moiety is \---- /     . In some variations, the heterocyclic moiety is unsubstituted.

[0042] In other embodiments, at least two R2a are present, and two adjacent R2a combine to form a ring that optionally contains one or more heteroatoms. In some variations, the ring is substituted with phenyl. In other variations, the ring is unsubstituted.

[0043] In some embodiments, R1 is halo, optionally substituted alkyl, or CN. In some variations, R1 is halo. In certain variations, R1 is F. In other variations, R1 is alkyl. In certain variations, R1 is Ci-4 alkyl. In certain variations, R1 is methyl. In yet other variations, R1 is CN.

[0044] In some variations, n is 0. In other variations, n is 1, 2, 3, 4 or 5.

[0045] In certain embodiments, at least two R2a are present, and two adjacent R2a combine to form a ring that optionally contains one or more heteroatoms (or a heterocyclic moiety). In some variations, one or more heteroatoms is an oxygen atom.

[0046] In certain variations, the heterocyclic moiety is a 5-membered heterocyclic moiety. In one variation, the heterocyclic moiety is a dioxole moiety.

[0047] In certain aspects, provided is a compound of Formula (I-B-l): or a pharmaceutically acceptable salt thereof, wherein: R1 is as defined for Formula (I) above; m is 0-4; and R2b at each occurrence is independently alkyl, halo, or phenyl.

[0048] In certain aspects, provided is a compound of Formula (I-B-2): or a pharmaceutically acceptable salt thereof, wherein: R1 is as defined for Formula (I) above; m is 0-4; and R2b at each occurrence is independently alkyl or halo.

[0049] In certain aspects, provided is a compound of Formula (I-B-3): or a pharmaceutically acceptable salt thereof, wherein: R1 is as defined for Formula (I) above; m is 0-4; and R2b at each occurrence is independently alkyl or halo.

[0050] In certain aspects, provided is a compound of Formula (I-B-4): (I-B-4) or a pharmaceutically acceptable salt thereof, wherein: R1 is as defined for Formula (I); m is 0-3; R2b is alkyl or halo; and R2c at each occurrence is independently optionally substituted phenyl or alkyl.

[0051] In some variations, R2c is phenyl.

[0052] In some embodiments, R1 is halo, alkyl, or CN. In some variations, R1 is halo. In certain variations, R1 is F. In other variations, R1 is alkyl. In certain variations, R1 is Ci-4 alkyl. In certain variations, R1 is methyl. In yet other variations, R1 is CN.

[0053] In some variations, m is 0. In other variations, m is other than 0. In certain variations, m is 1-4. In certain variations, m is 1-3. In other variations, m is 1, 2, 3, or 4.

[0054] In some variations, R2b is Ci-4 alkyl. In certain variations, R2b is methyl.

[0055] In certain aspects, provided is a compound of Formula (I-C-l): n-n o or a pharmaceutically acceptable salt thereof, wherein: R1 is halo, alkyl, or CN; and R3 is alkyl, alkenyl, cycloalkyl, heterocyclyl, or alkylether, each of which is optionally substituted.

[0056] In some variations of the foregoing, the compound is not: 4-cyclopentyloxy-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide; 4-methoxy-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide; 4-ethoxy-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide; 4-(pentyloxy)-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide; 4-propoxy-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide; 4-phenylmethoxy-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide; 4-(2-methylpropoxy)-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide; 4-hexoxy-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide; 4-(oxolan-2-ylmethoxy)-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide; 4-[2-oxo-2-[[3-(trifluoromethyl)phenyl]amino]ethoxy]-N-[5-(trifluoromethyl)-l,3,4-thi adi azol -2-y 1 ]b enzami de; 4-(trifluoromethoxy)-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide; 4-(3-methylbutoxy)-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide; 4-cyclobutoxy-N-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide; and 4-cyclopentyloxy-N-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide, or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments of the foregoing, the compound of Formula (I), (I-A), (I-B-1), (I-B-2), (I-B-3), (I-B-4) or (I-C-l) is other than Compounds A1-A3 (as set forth in Table 1), or a pharmaceutically acceptable salt thereof, as the case may apply.

[0058] It should be understood that the compounds of the present disclosure also include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted.

[0059] In some variations, the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. 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.

[0060] 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.

[0061] 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. In some variations, for instance, one or more hydrogen atoms of an alkyl moiety may be deuterated.

[0062] As used herein, in some variations, “alkyl” refers to a monoradical unbranched or branched saturated hydrocarbon chain. In some embodiments, alkyl has 1 to 20 carbon atoms (i.e., Ci-20 alkyl), 1 to 8 carbon atoms (i.e., Ci-s alkyl), 1 to 6 carbon atoms (i.e., Ci-6 alkyl), or 1 to 4 carbon atoms (i.e., Ci-4 alkyl). 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.

[0063] 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., C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl).

[0064] As used herein, in some variations, “heterocyclyl” refers to a cyclic group with one or more ring heteroatoms (e.g., oxygen, nitrogen, or sulfur). In one variation, the ring heteroatom is oxygen. In another variation, the ring heteroatom is nitrogen. It should be understood that heterocyclyl may also be referred to as a “heterocyclic moiety” or a “ring that contains one or more heteroatoms”. In some embodiments, the heterocyclyl is a 3-12 membered heterocyclyl. In some embodiments, the heterocyclyl is a 3-6 membered heterocyclyl.

[0065] 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 hex oxy.

[0066] In some variations, “alkylether” refers to any alkyl group as defined herein, wherein at least one carbon-carbon bond is replaced with a carbon-oxygen bond. The carbonoxygen bond may be on the terminal end (as in an alkoxy group) or the carbon oxygen bond may be internal (i.e., C—O—C). In some variations, alkylethers include at least one carbon oxygen bond, but may include more than one. For example, in one variation, polyethylene glycol (PEG) is included within the meaning of alkylether.

[0067] 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.

[0068] 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.

[0069] 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 Compounds No. Structure LCMS Al N—N   O F JI IN JL F<         H [| I A2 F N_n o H w A3 N-N o F >         H ||    1 A4 jt iXX < -¼       W I J - A5 A5 n       X [ P 7 w,    Ax Ax -4- / r t    ? ‘A.-Z O         i •n A6 44 / . x A J A7 R / F F^Sr's\ H .....'Kyy A8 (ry_yf _ ~ hAJ1 HN ^=N F A9 1A o v A10 nV \ / NH 0= / Ci——Br All F M X''F < VS 0    / s / H \ A12 FxZ FVrS\ H F II V—N / =\ A13 R / F pSrA_H 0     Xa 0 x A14 k z%VF V o V-s V-N / H A >7 S\ 0— A20 f7‘A N= / NH H V / N\ / A21 HN S^N F“7~F F A22 F FV N'^xs 1 P NH O=^............ OA 7 ****o A23 )-0 HN^__ >=0 HN F-^f F A24 u bx+ jCj II o A> IZ 'O iT^z U. K A25 O~ci ci HN F A26 y_ / O-N+ \=O / OHM F-pF F A27 O O "v tY *^3 T             1        ’ 7           J || ' x i            o TJ            w A28 <n>^ N A r H, ° F>C^ F A29 k A 3<F o Y-S F Jh y / A A40 H / =\ vssx /    Q          0 HN c ' if F~f-F F A41 u        ......z       ft----( A42 % ? NH Q=^ H A43 A44 ft1! h Fvs 0H^°\ °\ A45 F~4—f nW NH O== / Cl 0 / A46 E / F F \=O HN tv A47 Ci—^Cl HN y-s _ < X / N / ^F F A48 T T j || Vu V-<n O Q / "“H “n A49 F 0-° 2==° HIM X F n^f A50 )=0 HN H F F A51 A + n~o~ V / )=0 HV F A52 HN .hl / F A53 \ HN N^AF A54 O^o / —0  )==0 HN ^X,F IT 7<f F A55 M y=o HN H F N. A / F A56 0 V-N / H A57 n'n hT V            / 7 o y— A58 H / / F H 0 F-A'N F A59 LL \,^- ur\ J zi in A60 0 p— H Qa F F" / 1^0 V_-L .N p-x F A61 A / -< A62 I I x U Bl F ,N~N O । H Method B LCMS (ESI+): Rt = 2.66 min, m / z 331.9 (M+H) + B2 / o / \ C:    < 0 HN + Method C LCMS (ESI+): Rt = 2.91 min, m / z 364.1 (M-H) - B3 \ :\.A —4—f Method C LCMS (ESI+): Rt = 3.06 min, m / z 344.1 (M-H) - B3-Enantioner 1 o       t i| H '■ O ' Method C LCMS (ESI+): Rt = 3.06 min, m / z 344.1 (M-H) - B3-Enantiomer 2 w ..... / hn' }==N F-^F F Method C LCMS (ESI+): Rt = 3.07 min, m / z 344.2 (M-H) - B4 Q HN I F y Method D LCMS (ESI+): Rt = 2.67min, m / z 314.1 (M+H) + B5 ( oz / ^\ K_Z” \ O HN .feN S^N F—L= ’ r—t । F Method C LCMS (ESI+): Rt = 3.04min, m / z 344.2 (M-H) - B6 n 2= / / \ Method E LCMS (ESI+): Rt = 2.84 min, m / z 283.9 (M-H) - B7 Ur U_ X~U-z= / / \ Zy>n Ck _z„ Y x Method D LCMS (ESI+): Rt = 3.23 min, m / z 362.1 (M+H) + B8 ,, I 04— J" O V Method D LCMS (ESI+): Rt = 2.88min, m / z 342.1 (M-H) - B9 4i           ° Method E LCMS (ESI+): Rt = 2.1min, m / z 360.1 (M-H) - BIO S > 0' \ ) V. / HN J I F—L c-r- r—f F Method E LCMS (ESI+): Rt = 2.87 min, m / z 346.1 (M-H) - Bll > ~'V0 t:N c' S'-^N F Method E LCMS (ESI+): Rt = 3.34min, m / z 344.18 (M+H) + B12 K + N^S / Method E LCMS (ESI+): Rt = 3.0min, m / z 316.0 (M+H) + B13 h >--N    / =\ 0           \ / ° Method E LCMS (ESI+): Rt = 2.2min, m / z 316.1 (M+H) + B14 O           2 1 \ II {fl—\ V_-T -f) Method E LCMS (ESI+): Rt = 2.4min, m / z 300.1 (M+H) + B15 H __       jj                             j— E I < Z t M / ------- x K >L v \   / \ >cs HH F Y     o x( x F Method A LCMS (ESI+): Rt = 2.3 min, m / z 322.0 (M+H) + B16 hr\ h F P / ”N pXl s F y    O 7—x F Method A LCMS (ESI+): Rt = 2.29 min, m / z 322.0 (M+H) + B17 F—1-—F \ p N= / NH ........., O”a Method A LCMS (ESI+): Rt = 2.42 min, m / z 338.0 (M+H) + B18 N NH oA R + Xy-Br Method A LCMS (ESI+): Rt = 2.46 min, m / z 395.7.0 (M+H) + B19 0 o z \_0 HN H S>. F—t—p Method B LCMS (ESI+): Rt = 2.97 min, m / z 394.0 (M+H) + B20 F       F F if ---NH / =\ N'   / /    \    /   \ N       \---O O    f / --\ Method C LCMS (ESI+): Rt = 4.76 min, m / z 348.07 (M-H) - B21 0 \                                       II       N---N Method E LCMS (ESI+): Rt = 3.30 min, m / z 392.07 (M+H) + B22 .°          N----N         F JI KL x / 'X -x-'X.    o             / /                         / ^F °"^                        J H S / Method C LCMS (ESI+): Rt = 3.85 min, m / z 436.13 (M+H)+ B23-Enantiomer 1 O __        / /       N---N as-s xvx j k / /          J'         Xl^^X < / H s LCMS (ESI+): Rt = 5.393 min, m / z 360.1 (M+H) + B24-Enantiomer 2 o 1 /         N----N fl    t—\ Jf \\ / /   /  \__U         n-^\ \7       X^*7 LCMS (ESI+): Rt = 5.375 min, m / z 360.0 (M+H) + B25 F F> /  ,.   H     / ^\  0 ______ / \ Method C LCMS (ESI+): Rt = 3.82 min, m / z 480.14 (M+H) + B26-Enantiomer 1 \         ___ 0 \__ / 4n--JI F / LCMS (ESI+): Rt = 6.055 min, m / z 362.0 (M+H) + B27-Enantiomer 2 o \___       Jl -- / A A YAJ » f —0                   H \ / '—              7\ / LCMS (ESI+): Rt = 5.876 min, m / z 362.0 (M+H) + B28-Enantiomer 1 / -v / Ma F A-A hn—e ii F / LCMS (ESI+): Rt = 5.901 min, m / z 362.0 (M+H) + B29-Enantiomer 2 / )   J .........r\4 £ / AA  h LCMS (ESI+): Rt = 6.102 min, m / z 362.0 (M+H) + B31 o II           N-----N °—  rvA V / --A A.    /    h’^^sz / ^ / ^'F LCMS (ESI+): Rt = 5.53 min, m / z 345.9 (M+H) + B32 0 II          N----N AvA J A-'-'A__Il            H s / F A'^A^A           / LCMS (ESI+): Rt = 6.126 min, m / z 329.8 (M+H) + B33 F 7 / X.__ D Z>--NH     / =\ Method C LCMS (ESI+): Rt = 3.33 min, m / z 342.09 (M-H)- B34 o     N-—A A A Mm H Method C LCMS (ESI+): Rt = 3.12 min, m / z 326.08 (M-H)- B35-Enantiomer 1 X   A 1 J J        1!''^- / F Method C LCMS (ESI+): Rt = 3.12 min, m / z 326.08 (M-H)- B36-Enantiomer 2 o        ----N       F Method C LCMS (ESI+): Rt = 4.78 min, m / z 341.95 (M-H)- B37 0 II           N----N J \J A           H S         F Method C LCMS (ESI+): Rt = 2.95 min, m / z 326.07 (M-H)- B38 0        -----N       F ^AAAA^ B r Method C LCMS (ESI+): Rt = 3.07 min, m / z 355.87 (M-H)- B39 F     / N V---NH     /    \ \--- /     \---NH Method C LCMS (ESI+): Rt = 2.94 min, m / z 343.14 (M-H)- B40 F f __s                                                    / ------ FZ ||   \                                / / )-----NH ! \ / ------' 0       v---7       \ Method C LCMS (ESI+): Rt = 3.20 min, m / z 359.15 (M+H)+ B41 o II          N----N Method C LCMS (ESI+): Rt = 4.03 min, m / z 357.08 (M-H)- B42 o ____X       / /       N---N / x AA J \\ / \    ----\         H        XL \ / F Method C LCMS (ESI+): Rt = 2.89 min, m / z 341.36 (M-H)- B43 I                                               __N <      o    y_ Xi ! ----F Method C LCMS (ESI+): Rt = 4.65 min, m / z 330.10 (M-H)- B44 I                                              __N X 1IX (j " F ----F Method C LCMS (ESI+): Rt = 3.19 min, m / z 328.26 (M-H)- B45 o / /             N------N           1= . aXjx x_-""X J / /      H      s         F F Method C LCMS (ESI+): Rt = 3.15 min, m / z 356.08 (M-H)- B46 LCMS (ESI+): Rt = 5.83 min, m / z 308.1 (M+H) + Preparation of the Compounds

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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., 'H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0074] 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 °C to about 30 °C.

[0075] Compounds of Formula (I) can be prepared according to numerous preparatory routes known in the literature. Example synthetic methods for preparing some compounds of the invention are provided in Scheme 1 below. Unless noted otherwise, all substituents are as defined herein. Scheme 1: Synthesis of para ether phenyl amides 2) amide coupling 1 -2                 Step 2 1) basic hydrolysis

[0076] The para ether phenyl amides can be synthesized using reactions (including methods and techniques) known in the literature. For example, an appropriately substituted ester phenyl bromide can be reacted with an aryl, alkyl or alkenyl hydroxy group using either metal catalyzed conditions (copper, nickel or palladium) or basic conditions to form compound 1-2. Alternatively, one can take the appropriately substituted phenol 1 - lb and react it with a nucleophile such as an alkyl or alkenyl halide to form compound 1-2. The ester of 1-2 can be converted to the acid using basic conditions and it can then be coupled directly with the appropriately substituted amino thiadiazole using standard amide coupling conditions to form compound 1-3. Alternatively carboxylic acid generated from the hydrolysis can be converted to the acid chloride and then coupled with the appropriately substituted amino thiadiazole under basic conditions. Pharmaceutical Compositions and Formulations of the Compounds

[0077] 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

[0078] 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.

[0079] 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.

[0080] 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

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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% and 100%, e.g., between .5 and 50%, between 1-30%, between 5-80%, at least 80% (w / w) compound.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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 or 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.

[0090] 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

[0091] 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 (I), as well as the compounds of Table 1 and in the Examples, or pharmaceutically acceptable salts thereof.

[0092] 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 need 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.

[0093] 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).

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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 without increasing H+ current across the plasma membrane.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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 and compositions of the present disclosure are used for treating a metabolic disorder. Metabolic disorders affect a wide range of the population with differing severity.

[0103] 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

[0104] 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-insulindependent 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.

[0105] 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.

[0106] 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

[0107] 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.

[0108] 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 of 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 P-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.

[0109] 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.

[0110] 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

[0111] 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.

[0112] 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.

[0113] 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

[0114] 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.

[0115] 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 the 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] In some embodiments, the subject is a human.

[0122] 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.

[0123] 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.

[0124] 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, or condition in the enhancement of desirable physical or mental development and conditions in an animal, e.g., a human.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] In some variations, “metabolic disorder" is a medical condition characterized by problems with an organism's metabolism. Metabolic disorder is a broad range of conditions 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

[0131] 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.

[0132] 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.

[0133] 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. Dosing

[0134] 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.

[0135] 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.

[0136] 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

[0137] 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. Combination Therapies

[0138] 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.

[0139] 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

[0140] 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.

[0141] 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 salt 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

[0142] 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

[0143] 1H-NMR spectra were recorded on Bruker Avance III HD 400 MHz or on Bruker Fourier 300 MHz. Chemical shifts are reported as 5 values in ppm relative to signals from residual non-deuterated solvents used for sample preparation as an internal standard.

[0144] LCMS method A: Instrument Aligent 1200 HPLC MSD:6135 single quadrupole MSD. Column:-:XBridge C18, 2.10*50mm, 5um, Column Temp 40°C flowrate 0.8 mL / min Mobile phase A:lOmM NH4HCO3, Phase B: ACN. Gradient 0min-3.40 min 5%B 95%A->95%B 5%A, Static 3.40-3.85 95%B 5%A, Gradient 3.85-3.86 95%B 5%A->5%B 95%A static 3.86-4.50 min static 5%B 95%A

[0145] LCMS method B: Instrument Aligent 1260 HPLC MSD:6120 single quadrupole MSD. Column:-:Luna C18, 2.0*50mm, 5um, Column Temp 40°C flowrate 0.8 mL / min Mobile phase A:0.04% aqTFA, Phase B:0.02%TFA ACN. Gradient 0min-3.40 min 5%B 95%A->95%B 5%A, Static 3.40-3.85 95%B 5%A,Static 0.0-0.4 5%B 95%A Gradient 0.43.00 5%B 95%A->95%B 5%A static 3.00-4.00 min static 95%B 5%A, Gradient 4.00-4.01 95%B 5%A->5%B 95%A static 4.01-4.50 min static 5%B 95%A

[0146] LCMS method C: LCMS-Kinetex-20-80-95-7-l-25-UV - NP-QC Instrument Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC. Column: Kinetex uM XB-C18 2.6 pm (4.6x50mm) column no. 00B-4496-E0 column temp 25°C flow rat 1.0 ml / min Mobile phase A:0.1% v / v aqueous formic acid, Mobile Phase B: 0.1% v / v formic acid acetonitrile. Gradient 1-2.0 80%A 20%B-> 20%A 80%B, Static 2.00-2.35 20%A 80%B, Gradient 2.35-2.45 20%A 80%B-> 5%A 95%, Static 2.45-4.25 5%A 95%B, Gradient 4.25-5.00 5%A 95%B -> 80%A 20%B, Static 5.00-7.00 80%A 20%A

[0147] 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 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 (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).

[0148] LCMS method E: LCMS-036-20-80-95-6-1-25-UV-BCM 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 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). Synthetic Examples

[0149] Exemplary compounds of the present disclosure may be prepared according to the various schemes described in this example. The compounds herein may be characterized using 1H-NMR. and LCMS using commercially available equipment and methods known to a skilled artisan. Example 1: Synthesis of Compound A3 °        rkcF            o  n-n ii                                          /                                                           ii           ii O         11         h2nx^s 6 q         II JI / —CF3 JI J              DMAP.TEA,              l| I H DCM, 30 C, 1 h 15                                    Compound A3

[0150] To a solution of 6 (67.44 mg, 398.77 pmol, 0.8 eq) in DCM (1 mL) was added TEA (75.66 mg, 747.69 pmol, 104.07 pL, 1.5 eq), DMAP (730.74 pg, 5.98 pmol, 0.012 eq) and 15 (100 mg, 498.46 pmol, 1 eq) at 0 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with H2O (5 mL) and DCM (3x5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude. The crude was purified by prep-HPLC (neutral) (column: Waters Xbridge BEH C18 100 x 30mm x 10 pm; mobile phase: [H2O (lOmM NH4HCO3)-ACN]; gradient:23%-53% B over 8.0 min) to give Compound A3 (40.5 mg, yield 24.38%) as white solid.

[0151] 'H NMR: 400 MHz DMSO 6 =13.58 (br s, 1H), 7.84 (dd, J = 2.4, 8.8 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 3.87 (s, 6H)

[0152] 19FNMR: 400 MHz DMSO 5 = -58.2

[0153] LCMS (ESI+): Rt = 2.528 min, m / z 334.0 (M+H) + Example 2: Synthesis of Compound Bl

[0154] To a solution of 9 (150 mg, 832.61 pmol, 1 eq) in DCM (1 mL) was added SOCI2 (1.64 g, 13.77 mmol, 1 mL, 16.54 eq) at 20 °C under N2. Then the reaction mixture was stirred at 50 °C for 2 h. LCMS showed starting material was consumed and desired Mass was detected. The reaction mixture was concentrated under reduced pressure to give 10 (160 mg, crude) as yellow oil. 10 Compound B1

[0155] To a solution of 6 (136.25 mg, 805.63 pmol, 1 eq) in DCM (4 mL) was added DMAP (1.18 mg, 9.67 pmol, 0.012 eq), TEA (122.28 mg, 1.21 mmol, 168.20 pL, 1.5 eq) and 10 (160 mg, 805.63 pmol, 1 eq) at 0 °C under N2. Then the reaction mixture was stirred at 30 °C for 1 h. LCMS showed starting material was consumed and desired Mass was detected. The reaction mixture was diluted with water (15 mL) and extracted with dichloromethane (5 mL x 3). The combined organic phase was washed with brine (15 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm x 3 pm; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 40%-80% B over 8.0 min) to give Compound Bl (99.03 mg, yield 37.10%) as light-yellow solid.

[0156] 'H NMR: 400 MHz DMSO 6 = 13.52 (brs, 1H), 7.36 (d, J= 8.4 Hz, 1H), 6.92 (d, J= 8.0 Hz, 1H), 6.13 (s, 2H), 2.31 (s, 3H)

[0157] 19F NMR: 400 MHz DMSO 5 = -58.2

[0158] LCMS (ESI+): Rt = 2.663 min, m / z 331.9 (M+H) + Example 3: Synthesis of Compound B8

[0159] 4-(Cyclopropylmethoxy)benzoic acid (0.1 g, 0.52 mmol, 1.0 eq.) and HATU (0.297 g, 0.78 mmol, 1.5 eq.) were dissolved in DMF (1 mL) and stirred at 50 °C. DIPEA (0.27 mL, 1.561 mmol, 3.0 eq.) was added and the mixture was stirred for 30 minutes at the same temperature. Then, 2-amino-5-trifluoromethyl-l,3,4-thiadiazole (0.097 g, 0.572 mmol, 1.1 eq.) was added in one portion and the mixture was stirred at 50 °C for 24 h. Then, the volatiles were removed under reduced pressure and the crude material was triturated with MeOH. The powder was dried under reduced pressure until stable mass. Compound B8 was isolated as a white solid (56 mg, 31%Y).

[0160] LC-MS: r.t. = 2.87 min; 99.63% at 254 nm; [M-H]' = 346.14

[0161] 'HNMR (300 MHz, DMSO-d6) 5 13.54 (s, 1H), 8.15 (d, J= 8.9 Hz, 2H), 7.11 (d, J= 8.9 Hz, 2H), 3.95 (d, J= 7.1 Hz, 2H), 1.25 (ddt, J= 10.0, 7.4, 3.5 Hz, 1H), 0.65 - 0.56 (m, 2H), 0.40 - 0.32 (m, 2H). Example 4: Synthesis of Compound A4

[0162] 4-Isobutoxybenzoic acid (0.1 g, 0.515 mmol, 1.0 eq.) and HATU (0.294 g, 0.772 mmol, 1.5 eq) were dissolved in DMF (1.5 mL) and stirred at 50 °C. DIPEA (0.27 mL, 1.545 mmol, 3.0 eq.) was added and the mixture was stirred for 30 minutes at the same temperature. Then, 2-amino-5-trifluoromethyl-l,3,4-thiadiazole (0.096 g, 0.566 mmol, 1.1 eq) was added in one portion and the mixture was stirred at 50 °C for 24 h. Then, the volatiles were removed under reduced pressure and the crude material was triturated with MeOH. The powder was dried under reduced pressure until stable mass was achieved. Compound A4 was isolated as an off-white solid (56 mg, 31% Y).

[0163] LC-MS: r.t. = 3.34 min; 99.80% at 254 nm; [M-H]' = 344.18

[0164] 1HNMR(300MHz, Chloroform-d) 8 12.23 (s, 1H), 8.28-8.21 (m, 2H), 4.10 (t, J = 6.5 Hz, 2H), 1.85 (dq, . / =8.5, 6.5 Hz, 2H), 1.59 (t, J= 6.5 Hz, 1H), 1.55 - 1.48 (m, 1H), 1.03 (t, J =7.4 Hz, 3H). Example 5: Synthesis of Compound B9

[0165] 4-(2-Ethoxyethoxy )benzoic acid (0.1 g, 0.48 mmol, 1.0 eq.) and HATU (0.294 g, 0.77 mmol, 1.5 eq) were dissolved in DMF (1.5 mL) and stirred at 50 °C. DIPEA (0.25 mL, 1.43 mmol, 3.0 eq.) was added and the mixture was stirred for 30 minutes at the same temperature. Then, 2-amino-5-trifluoromethyl-l,3,4-thiadiazole (0.089 g, 0.52 mmol, 1.1 eq.) was added in one portion and the mixture was stirred at 50 °C for 24 h. Then, the volatiles were removed under reduced pressure and the crude material was triturated with MeOH. The precipitate was purified via preparative TLC (SiO2, 1000 micron, eluting with DCM:MeOH 100:0 —> 99:1, run 3 times). Compound B9 was isolated as a white solid (0.038 g, 21% Y).

[0166] LC-MS: r.t. = 2.10 min; 96.63% at 254 nm; [M-H]' = 360.13

[0167] 'HNMR (300 MHz, DMSO-d6) 5 13.55 (s, 1H), 8.15 (d, J= 8.9 Hz, 2H), 7.11 (d, J= 8.9 Hz, 2H), 4.21 (dd, J= 5.3, 3.8 Hz, 2H), 3.73 (dd, J= 5.3, 3.8 Hz, 2H), 3.51 (q, J = 7.0 Hz, 2H), 1.14 (t, J= 7.0 Hz, 3H). Example 6: Synthesis of Compound Bl 0

[0168] 4-(2-Methoxy-ethoxy)-benzoic acid (0.1 g, 0.50 mmol, 1.0 eq.) and 2-amino-5-trifluoromethyl-l,3,4-thiadiazole (0.087 g, 0.499 mmol, 1.0 eq.) were dissolved in anhydrous DMF (5.0 mL). DIPEA (0.264 ml, 1.50 mmol, 3.0 eq.) was added, followed by the addition of HATU (0.235 g, 0.60 mmol, 1.2 eq.). The reaction mixture was stirred overnight at room temperature. Then, the volatiles were removed under reduced pressure and the crude material was triturated with MeOH to afford compound B10 as an off-white solid (49 mg, 28% Y).

[0169] LC-MS: r.t. = 2.87 min; 99.63% at 254 nm; [M-H]' = 346.14

[0170] 'HNMR (300 MHz, Chloroform-d) 5 12.23 (s, 1H), 8.29-8.21 (m, 2H), 7.107.02 (m, 2H), 4.10 (t, J = 6.5 Hz, 2H), 1.85 (dq, J= 8.5, 6.5 Hz, 2H), 1.59 - 1.48 (m, 2H), 1.03 (t, J =7.4 Hz, 3H). Example 7: Synthesis of Compound Bl 1

[0171] 4-w-Butoxybenzoic acid (0.1 g, 0.50 mmol, 1.0 eq.) and 2-amino-5- trifluoromethyl-l,3,4-thiadiazole (0.088 g, 0.50 mmol, 1.0 eq.) were dissolved in anhydrous DMF (5.0 mL DIPEA (0.27 ml, 1.51 mmol, 3.0 eq.) was added, followed by the addition of HATU (0.237 g, 0.605 mmol, 1.2 eq). The reaction mixture was stirred overnight at room temperature. Then, the volatiles were removed under reduced pressure and the crude material was triturated with MeOH to produce compound Bl 1 as an off-white solid (0.104 g, 60%Y).

[0172] LC-MS: r.t. = 3.34 min; 99.80% at 254 nm; [M-H]' = 344.18

[0173] 'HNMR (300 MHz, Chloroform-d) 5 12.23 (s, 1H), 8.28-8.21 (m, 2H), 4.10 (t, J = 6.5 Hz, 2H), 1.85 (dq, J= 8.5, 6.5 Hz, 2H), 1.59 (t, J= 6.5 Hz, 1H), 1.55 - 1.48 (m, 1H), 1.03 (t, J =7.4 Hz, 3H). Example 8: Synthesis of Compound Bl2

[0174] 2,3-Dihydro-l-benzofuran-6-carboxylic acid (0.20 g, 1.22 mmol, 1.0 eq.) and (0.70 g, 1.83 mmol, 1.5 eq.) of HATU were dissolved in DMF (2.0 mL) and stirred at 60 °C. 0.6 mL (3.0 eq., 3.66 mmol) of DIPEA was added and the mixture was stirred for 30 minutes at the same temperature. After that time, 2-amino-5-trifluoromethyl-l,3,4-thiadiazole (0.23 g, 1.34 mmol, 1.1 eq.) was added in one portion and the mixture was stirred at 60 °C for 18 h. The reaction mixture was diluted with EtOAc and sequentially washed with brine, water and brine again. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The product was purified by trituration using MeOH with a small amount of ACN to give Compound B12 (25 mg, 5% Y).

[0175] LC-MS: r.t. = 3.00 min; 97.15% at 254 nm; [M-H]'= 314.08

[0176] ^NMR (300 MHz, DMSO-de) 6 13.62 (s, 1H), 7.68 (dd, 7.7, 1.6 Hz, 1H), 7.53 (d, J= 1.6 Hz, 1H), 7.48 - 7.41 (m, 1H), 4.63 (t, J= 8.8 Hz, 2H), 3.29 (s, 2H). Example 9: Synthesis of Compound A9

[0177] 4-Propoxybenzoic acid (5.0 g, 32.8 mmol, 1.0 eq.) and HATU (15.0 g, 39.5 mmol, 1.2 eq.) were dissolved in ACN (50 mL) and stirred at 60 °C. Then, DIPEA (8.6 mL, 49.3 mmol, 1.5 eq.) was added and the mixture was stirred for 30 minutes at the same temperature. Then, 2-amino-5- trifluoromethyl-l,3,4-thiadiazole (5.6 g, 32.8 mmol, 1.0 eq.) was added in one portion and the mixture was stirred at 60 °C for 24 h. The reaction mixture was cooled to 10 °C and the precipitated product was filtered off and washed twice with 10 mL of cold (0 °C) ACN. The beige solid was dried and suspended in 20 mL of MeOH, collected by filtration and washed twice with 10 mL of MeOH to give the pure Compound A9 (5.3 g, Y = 53%).

[0178] LCMS: r.t.= 3.38 min, 99.58% at 254 nm [M-H]'= 330.12

[0179] 'HNMR (300 MHz, DMSO-t / 6) 8 8.15 (d, J= 8.9 Hz, 2H), 7.10 (d, J= 8.9 Hz, 2H), 4.05 (t, J= 6.5 Hz, 2H), 1.76 (q, J= 7.0 Hz, 2H), 0.99 (t, J= 7.4 Hz, 3H). Examplel 0: Synthesis of Compound B44

[0180] 3-Butylbenzoic acid (0.2 g. 1.122 mmol, leq) and 2-amino-5-trifluoromethyl- 1,3,4-thiadiazole (0.208 g, 1.23 mmol, 1.1 eq.) were dissolved in anhydrous DMF (2.0 mL), DIPEA (0.57 mL, 3.36 mmol, 3.0 eq.) was added, followed by the addition of HATU (0.46 g, 1.215 mmol, 2 eq). The reaction mixture was stirred overnight at 50 °C. Then, the volatiles were removed under reduced pressure and the crude material was purified by FCC (using SiO2, elution with n-hexane / EA 0-50%) to produce compound B44 as an off-white solid (0.021 g, 7.3% Y).

[0181] LCMS (method: LCMS-Kinetex-20-80-95-7-l-25-UV-NP): r.t.= 3.193 min, 96.30% at 205 nm [M-H]'= 328.26

[0182] ^NMR (300 MHz, DMSO-t / 6) 8 13.71 (s, 1H), 8.03 (s, 1H), 7.96 (d, J = 7.4 Hz, 1H), 7.55 - 7.46 (m, 2H), 2.69 (t, J= 7.7 Hz, 2H), 1.62 (t, J= 7.6 Hz, 2H), 1.38-1.31 (m, 2H), 0.92 (t, 7=7.3 Hz, 3H). Example 11: Synthesis of Compound B34 Step 1 O

[0183] To a suspension of sodium hydride (0.125 g, 2.096 mmol, 2eq) in THF (4 mL) was added methyl 4-[(diethoxyphosphoryl)methyl]benzoate (0.09 g, 1.57 mmol, 1.5 eq) at 0 °C and the mixture was stirred for 30 minutes. To the reaction mixture was added a solution of propionaldehyde (0.3 g , 1.57 mmol, 1 eq) in THF, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane / ethyl acetate 5:1) to produce Methyl 4-[(lE)-but-l-en-l-yl]benzoate as a white solid. (0.046 g, 38%Y)

[0184] LCMS (method: standard_esi_100_1000): r.t. = 2.17 min; 100% at 254 nm; [M+H]+= 191.3

[0185] 'HNMR (300 MHz, Chloroform-tZ) 5 8.03 - 7.94 (m, 2H), 7.48 - 7.38 (m, 2H), 6.51 - 6.35 (m, 2H), 3.93 (s, 3H), 2.29 (qdd, J= 7.4, 3.5, 1.4 Hz, 2H), 1.13 (t, J= 7.4 Hz, 3H). Step 2 O -Y on

[0186] Methyl 4-[(lE)-but-l-en-l-yl]benzoate (0.046 g, 0.220 mmol, 1 eq) was dissolved in mixed THF / water 5:1 (8 mL), then LiOH*H2O (0.019 g, 0.44 mmol, 2 eq) was added in one portion at room temperature. The reaction mixture was stirred overnight at room temperature. Organic solvent was evaporated 2 mL of water was added. The aqueous layer was acidified to pH 1 and extracted with ethyl acetate 3 times (2 mL). Organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure affording 4-[(lE)-but-l-en-l-yl]benzoic acid as a white solid. (0.026 g, 67%Y).

[0187] LCMS (method: standard_esi_100_1000): r.t. = 1.94 min; 100% at 254 nm; [MH] = 175.0

[0188] 1H NMR (300 MHz, DMSO-t / 6) 8 12.84 (s, 1H), 7.98 - 7.80 (m, 2H), 7.61 - 7.39 (m, 2H), 6.63 - 6.38 (m, 2H), 2.24 (qd, J= 7.4, 5.0 Hz, 2H), 1.07 (t, J= 7.5 Hz, 3H). Step 3 o . Ji (--, < N' "N .      . Ji J H

[0189] 4-[(lE)-but-l-en-l-yl]benzoic acid (0.026 g, 0.146 mmol, 1.0 eq.) and 2-amino-5-trifluoromethyl-l,3,4-thiadiazole (0.027 g, 0.160 mmol, 1.1 eq.) were dissolved in anhydrous DMF (1.0 mL), DIPEA (0.08 mL, 0.438 mmol, 3.0 eq.) was added, followed by the addition of HATU (0.110 g, 0.292 mmol, 2.0 eq). The reaction mixture was stirred overnight at 50 °C. Then, the volatiles were removed under reduced pressure and the crude material was purified by FCC (using SiO2, elution with n-hexane / EA 0-40%) to produce compound B34 as a beige solid (0.027 g, 8% Y).

[0190] LC-MS (method: LCMS-Kinetex-20-80-95-7-l-25-UV-NP): r.t. = 3.117 min; 98.67% at 300 nm; [M-H]' = 326.08

[0191] XHNMR (300 MHz, DMSO-t / 6) 6 13.67 (s, 1H), 8.18 - 8.06 (m, 2H), 7.68 - 7.54 (m, 2H), 6.65 - 6.47 (m, 2H), 2.30 - 2.21 (m, 2H), 1.08 (t, J= 7.4 Hz, 3H). Example 12: Synthesis of Compound B33 CL O A -C . J H X-X'’   ’X^'x*’

[0192] 4-(3-Methylbutyl)benzoic acid (0.100 g, 0.520 mmol, 1.0 eq.) and 2-amino-5-trifluoromethyl-l,3,4-thiadiazole (0.096 g, 0.572 mmol, 1.1 eq.) were dissolved in anhydrous DMF (2.0 mL), DIPEA (0.272 mL, 1.560 mmol, 3.0 eq.) was added, followed by the addition of HATU (0.395 g, 1.04 mmol, 2.0 eq). The reaction mixture was stirred overnight at 50 °C. Then, the volatiles were removed under reduced pressure and the crude material was triturated with MeOH to produce compound B33 as a beige solid (0.023 g, 13% Y).

[0193] LC-MS (method: LCMS-Kinetex-20-80-95-7-l-25-UV-NP): r.t. = 3.330 min; 98.60% at 275 nm; [M-H]' = 342.09.

[0194] 1HNMR(300MHz, DMSO-t / 6) 6 13.65 (s, 1H), 8.18 - 8.01 (m, 2H), 7.42 (d, J = 8.1 Hz, 2H), 2.75 - 2.65 (m, 2H), 1.52 (td, J = 14.3, 13.4, 6.2 Hz, 3H), 0.92 (d, J = 6.1 Hz, 6H) Biological Examples Example Bl. Cell Respiration Assays

[0195] 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.

[0196] 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 37° C at a cell concentration of 1.5 x 10° cells per mL and continuously stirred at 750 rpm. After the oxygen consumption rate reached steady-state, the ability of the exemplary compounds to increase the oxygen consumption rate (OCR) was measured (see Table 2). In the table: +: equal to or greater than 10 pM; ++: 1-10 pM, +++ less than 1 uM. Table 2. ECso for OCR increase and concentrations for 50% OCR increase Compound No. Compound Cone. Required for 50% increase in OCR Response (pM) Al + A2 ++ A3 + Bl ++ A4 ++ A5 ++ A6 + A8 ++ A9 ++ All + A12 ++ A14 + A18 +++ A19 ++ A20 + A22 ++ A28 + A34 ++ A3 6 ++ A3 8 + A3 9 ++ A40 + A42 + A43 ++ A45 +++ A48 ++ A49 ++ A50 ++ A52 + A55 ++ A61 + A62 +++ B3-Enantiomer 1 ++ B3-Enantiomer 2 ++ B8 ++ B9 + BIO +++ Bll ++ B12 ++ B13 +++ B14 +++ B15 ++ B16 +++ B17 ++ B18 +++ B19 +++ B20 ++ B21 + B22 + B23-Enantiomer 1 + B24-Enantiomer 2 + B25 + B26-Enantiomer 1 + B27-Enantiomer 2 + B28-Enantiomer 1 + B29-Enantiomer 2 + B31 + B32 ++ B33 +++ B34 +++ B3 5-Enantiomer 1 ++ B36-Enantiomer 2 ++ B37 +++ B38 ++ B39 + B40 + B41 + B42 + B43 ++ B44 +++ B45 ++ B46

[0197] 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.

Claims

1. A method, comprising: administering to a subject in need thereof a therapeuticallyeffective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof,wherein the compound of Formula (I) is:n-n oR2(I),wherein:R1 is halo, H, alkyl, alkenyl, haloalkyl, or CN; and R2 is optionally substituted phenyl.

2. The method of claim 1, wherein the compound is a compound of Formula (I-A):Fn-n o Ann(I-A),wherein:R1 is as defined for Formula (I);n is 0-5; andR2a at each occurrence is independently:alkyl, alkyenyl phenyl,-ORW, wherein Rw is alkyl, alkylenyl, alkylether, heterocyclyl, or phenyl, -NH(C=O)RX, wherein Rx is alkyl or phenyl,halo,-SRy, wherein Ry is alkyl or alkylether,-NO2,-C(=O)ORZ, wherein Rz is alkyl, orNRvlRw2, wherein each Rvl and Rv2 is independently H, alkyl, or alkylether; or Rvl and Rv2 are taken together with the nitrogen atom to which they are attached to form a heterocyclic moiety;or when at least two R2a are present, two adjacent R2a combine to form a ring that optionally contains one or more heteroatoms,wherein, at each occurrence, each of alkyl, alkenyl, alkylether, heterocyclyl, or phenyl is independently optionally substituted.

3. The method of claim 1, wherein the compound is a compound of Formula (I-B-1) or (I-B-2), (I-B-3):wherein:R1 is as defined for Formula (I);m is 0-4; andR2b at each occurrence is independently alkyl, halo or optionally substituted phenyl.

4. The method of claim 1, wherein the compound is a compound of Formula (I-B-4):wherein:R1 is as defined for Formula (I);m is 0-3;R2b at each occurrence is independently alkyl or halo, and R2c is phenyl.

5. The method of claim 3 or 4, wherein R2b is Ci-4 alkyl.

6. The method of any one of claims 1 to 5, wherein R1 is halo.

7. The method of any one of claims 1 to 6, wherein R1 is fluoro.

8. The method of any one of claims 1 to 7, wherein the method activates H+ leak acrossthe inner mitochondrial membrane in the subject.

9. The method of any one of claims 1 to 7, wherein the method activates H+ leak via AAC in the subject.

10. The method of any one of claims 1 to 7, wherein the method activates H+ leak via UCP1 in the subject.

11. The method of any one of claims 1 to 7, wherein the method selectively generates H+ leak across the inner mitochondrial membrane without generating H+ leak across the plasma membrane in the subject.

12. The method of any one of claims 1 to 7, 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.

13. The method of any one of claims 1 to 7, wherein the method increases rate of cell respiration in the subject.

14. The method of any one of claims 1 to 7, wherein the method is an in vitro method that increases rate of cell respiration in a cell of the subject.

15. The method of any one of claims 1 to 7, wherein the method increases metabolic rate in the subject.

16. The method of any one of claims 1 to 7, wherein the method treats, prevents, or manages a disease, disorder or condition in the subject.

17. The method of claim 16, 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.

18. The method of claim 16, wherein the disease, disorder or condition is obesity or obesity related disorder.

19. The method of claim 16, wherein the disease, disorder or condition is type 2 diabetes.

20. The method of claim 16, wherein the disease, disorder or condition is fatty liverdisease.

21. The method of claim 16, wherein the disease, disorder or condition is polycystic ovary syndrome.

22. The method of claim 16, wherein the disease, disorder or condition is a neurodegenerative disease, disorder or condition.

23. The method of claim 16, 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.

24. A compound of Formula (I-B-l):or a pharmaceutically acceptable salt thereof, wherein:R1 is halo, alkyl, or CN;m is 1-4; andR2b at each occurrence is independently alkyl, halo or optionally substituted phenyl.

25. A compound of Formula (I-C-l):n-n o H Ya R3 °" (l-c-l),or a pharmaceutically acceptable salt thereof, wherein:R1 is halo, alkyl, or CN; andR3 is alkyl, alkenyl, cycloalkyl, heterocyclyl, or alkylether, wherein each of the foregoing is optionally substituted,provided that that compound is not:4-cyclopentyloxy-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide;4-methoxy-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide;4-ethoxy-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide;4-(pentyloxy)-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide;4-propoxy-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide;4-phenylmethoxy-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide;4-(2-methylpropoxy)-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide;4-hexoxy-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide;4-(oxolan-2-ylmethoxy)-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide;4-[2-oxo-2-[[3-(trifluoromethyl)phenyl]amino]ethoxy]-N-[5-(trifluoromethyl)-l,3,4-thi adi azol -2-y 1 ]b enzami de;4-(trifluoromethoxy)-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide;4-(3-methylbutoxy)-N-[5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide;4-cyclobutoxy-N-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide; and 4-cyclopentyloxy-N-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]benzamide,or a pharmaceutically acceptable salt thereof.

26. A compound selected from any one of Compounds B1-B46, or a pharmaceutically acceptable salt thereof.

27. A pharmaceutical composition comprising a compound of any one of claims 24 to 26, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.